Personalized Nutrition

NUTRIGENOMICS
AND THE FUTURE OF NUTRITION
PROCEEDINGS OF A WORKSHOP
Leslie Pray, Rapporteur
Food Forum
Food and Nutrition Board
Health and Medicine Division
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Nutrigenomics and the future of nutrition: Proceedings of a workshop. Washington,
DC: The National Academies Press. doi: https://doi.org/10.17226/25147.
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PLANNING COMMITTEE FOR A WORKSHOP ON
NUTRIGENOMICS AND THE FUTURE OF NUTRITION1
PATSY M. BRANNON, Professor, Division of Nutritional Sciences,

Cornell University, Ithaca, New York
NAOMI K. FUKAGAWA, Director, Beltsville Human Nutrition Research
Center, Agricultural Research Service, U.S. Department of Agriculture,
Beltsville, Maryland
WENDY L. JOHNSON, Vice President of Nutrition, Health, and Wellness,
Nestlé Corporate Affairs, Arlington, Virginia
SARAH ROLLER, Partner, Kelley Drye & Warren, LLP, Washington, DC
1 The National Academies of Sciences, Engineering, and Medicine’s planning committees
are solely responsible for organizing workshops, identifying topics, and choosing speakers.
Responsibility for the published Proceedings of a Workshop rests with the workshop rap
porteur and the institution.
v
FOOD FORUM (DECEMBER 2017)1
SYLVIA ROWE (Chair), SR Strategy, LLC, Washington, DC

ARTI ARORA, The Coca-Cola Company, Atlanta, Georgia
FRANCIS (FRANK) BUSTA, University of Minnesota, St. Paul
PAUL M. COATES, Office of Dietary Supplements, National Institutes of
Health, Bethesda, Maryland
JOY DUBOST, Unilever Research and Development, Englewood Cliffs,
New Jersey
NAOMI K. FUKAGAWA, Agricultural Research Service, U.S. Department
of Agriculture, Beltsville, Maryland
DAVID GOLDMAN, Food Safety and Inspection Service, U.S. Department
of Agriculture, Washington, DC
DANIEL A. GOLDSTEIN, Monsanto, St. Louis, Missouri
DANIELLE GREENBERG, PepsiCo, Purchase, New York
SONYA A. GRIER, American University, Washington, DC
JEAN HALLORAN, Consumers Union, Yonkers, New York
JACKIE HAVEN, Center for Nutrition Policy and Promotion,
U.S. Department of Agriculture, Alexandria, Virginia
KATE J. HOUSTON, Cargill, Inc., Washington, DC
LEE-ANN JAYKUS, North Carolina State University, Raleigh
HELEN H. JENSEN, Iowa State University, Ames
RENÉE S. JOHNSON, Library of Congress, Washington, DC
WENDY L. JOHNSON, Nestlé Corporate Affairs, Arlington, Virginia
CHRISTINA KHOO, Ocean Spray Cranberries, Inc., Lakeville,
Massachusetts
LORE KOLBERG, Tate & Lyle, Hoffman Estates, Illinois
VIVICA I. KRAAK, Virginia Tech, Blacksburg
SUSAN M. KREBS-SMITH, Division of Cancer Control and Population
Sciences, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland
CATHERINE KWIK-URIBE, Mars, Inc., Germantown, Maryland
CHRISTOPHER JOHN LYNCH, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health, Bethesda,
Maryland
SUSAN T. MAYNE, U.S. Food and Drug Administration, College Park,
Maryland
KAREN McINTYRE, Health Canada, Ottawa, Ontario, Canada
S. SUZANNE NIELSEN, Purdue University, West Lafayette, Indiana
1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables
do not issue, review, or approve individual documents. The responsibility for the published
Proceedings of a Workshop rests with the workshop rapporteur and the institution.
vii
ERIK D. OLSON, Natural Resources Defense Council, Washington, DC
ROBERT C. POST, Chobani, LLC, New York, New York
KRISTIN REIMERS, ConAgra Foods, Omaha, Nebraska
CLAUDIA RIEDT, Dr Pepper Snapple Group, Plano, Texas
SARAH ROLLER, Kelley Drye & Warren, LLP, Washington, DC
SHARON A. ROSS, Division of Cancer Prevention, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland
PAMELA STARKE-REED, Agricultural Research Service, U.S. Department
of Agriculture, Beltsville, Maryland
MAHA TAHIRI, General Mills, Inc., Minneapolis, Minnesota
REGINA L. TAN, Office of Food Safety, Food and Nutrition Service,
U.S. Department of Agriculture
Health and Medicine Division Staff

HEATHER DEL VALLE COOK, Director
ROMY NATHAN, Program Officer
ANNA BURY, Research Associate
CYPRESS LYNX, Senior Program Assistant
ANN L. YAKTINE, Director, Food and Nutrition Board
viii
Reviewers
T
his Proceedings of a Workshop was reviewed in draft form by indi
viduals chosen for their diverse perspectives and technical expertise.
The purpose of this independent review is to provide candid and
critical comments that will assist the National Academies of Sciences,
Engineering, and Medicine in making each published proceedings as sound
as possible and to ensure that it meets the institutional standards for qual
ity, objectivity, evidence, and responsiveness to the charge. The review
comments and draft manuscript remain confidential to protect the integrity
of the process.
We thank the following individuals for their review of this proceedings:
JOHANNA DWYER, Tufts University, Boston, Massachusetts

NAOMI K. FUKAGAWA, Beltsville Human Nutrition Research
Center, Agricultural Research Service, U.S. Department of
Agriculture, Beltsville, Maryland
DAVID GOLDMAN, Food Safety and Inspection Service, U.S.
Department of Agriculture, Washington, DC
Although the reviewers listed above provided many constructive com

ments and suggestions, they were not asked to endorse the content of the
proceedings nor did they see the final draft before its release. The review
of this proceedings was overseen by HUGH H. TILSON, University of
North Carolina. He was responsible for making certain that an indepen
dent examination of this proceedings was carried out in accordance with
standards of the National Academies and that all review comments were
carefully considered. Responsibility for the final content rests entirely with
the rapporteur and the National Academies.
ix
Contents
1 INTRODUCTION 1
Setting the Stage: Introduction and Overview, 2
Organization of This Proceedings, 10
2 NUTRIGENOMICS AND CHRONIC DISEASE ENDPOINTS 11

Genotypes and Disease Risk: What Is Currently Known About
Nutrition and Epigenetics?, 11
Mitochondrial Genetics and Disease Risk: Exploring Current
Evidence, 17
3 PERSONALIZED NUTRITION IN THE REAL WORLD 29

Exploring Personal, Dense, Dynamic Data Clouds and the
Future of Personalized Medicine, 29
Sickle Cell Disease: An Arginine Deficiency Syndrome with
Distinctive Nutritional Requirements, 34
Personalized Nutrition in the Real World: Where Do We
Stand?, 44
Is Genetic Testing for Personalized Nutrition Ready for Prime
Time?, 49
Discussion, 56
4 NUTRIGENOMICS APPLICATIONS: DIETARY GUIDANCE

AND FOOD PRODUCT DEVELOPMENT 61
Nutrient Requirements as Complex Traits: What Consumers
Need to Know, 61
xi
xii CONTENTS
Gene-Guided Nutrition Interventions, 71
Discussion, 77
5 NUTRIGENOMICS: REGULATORY, ETHICAL, AND
SCIENCE POLICY CONSIDERATIONS 85
Scientific Basis of Genetically Personalized Nutrition:
Ethical Implications of Methodological Limitations, 85
Vetting Personalized and Genomically Guided Nutrition:
Issues and Strategies, 93
Potential Regulatory Policy Considerations Presented by
Nutrigenomics in the Commercial Context, 97
Discussion, 103
6 RETHINKING THE RELATIONSHIP BETWEEN DIET
AND HEALTH: CAN NUTRIGENOMICS HELP? 107
The Usefulness of the Precision Medicine Paradigm in
Nutrition, 108
Behavioral Aspects of Nutrigenomics, 110
Why the Focus on Genetics in This Era of Data Integration?, 111
The Relevance of Nutrigenomics to Low-Income Populations, 112
Trust—and Distrust—in Nutrigenomics, 114
The Relevance of Agriculture to Nutrigenomics, 115
REFERENCES 117
APPENDIXES
A WORKSHOP AGENDA 127
B ACRONYMS AND ABBREVIATIONS 131
C SPEAKER AND FACILITATOR BIOGRAPHIES 135
Introduction
O
n December 5, 2017, the Food Forum of the National Academies
of Sciences, Engineering, and Medicine hosted a public workshop
titled Nutrigenomics and the Future of Nutrition in Washington,
DC, to review current knowledge in the field of nutrigenomics as it relates
to nutrition. Workshop participants explored the influence of genetic and
epigenetic expression on nutritional status and the potential impact of per
sonalized nutrition on health maintenance and chronic disease prevention
(see Box 1-1 for the workshop’s complete Statement of Task).1
In her welcoming remarks, Food Forum chair Sylvia Rowe, SR Strategy,
LLC, described how the Food Forum, through public workshops such as
this, convenes scientists, administrators, and policy makers from academia,
government, industry, and the public sector to discuss problems and issues
related to food, food safety, and regulation and to identify possible ap
proaches for addressing these problems and issues. She emphasized that
while the forum compiles information, develops options, brings interested
parties together, and provides a rapid way to identify areas of concordance
among workshop participants, it does not make recommendations, nor
does it offer specific advice. She noted that, in addition to diverse and ex
1 The role of the workshop planning committee was limited to planning the workshop, and
this Proceedings of a Workshop was prepared by the rapporteur as a factual account of what
occurred at the workshop. Statements, recommendations, and opinions expressed are those
of individual presenters and participants and are not necessarily endorsed or verified by the
National Academies of Sciences, Engineering, and Medicine. They should not be construed as
reflecting any group consensus.
2 NUTRIGENOMICS AND THE FUTURE OF NUTRITION
BOX 1-1
Statement of Task
An ad hoc committee will plan and conduct a 1-day public workshop that will
review current knowledge in the field of nutrigenomics as it relates to nutrition.
The workshop will explore the influence of genetic and epigenetic expression on
nutritional status, including the potential impact of personalized nutrition on health
maintenance and chronic disease prevention. The workshop will also investigate
the clinical implications of nutrigenomics, key public health and regulatory policy
considerations presented in the context of emerging nutrigenomics applications
to personalized nutrition, and the challenges to globalization of public health
guidance that may be informed by nutrigenomic research.
The committee will define the specific topics to be addressed, develop the
agenda, and select and invite speakers and other participants. After the workshop,
proceedings of a workshop in brief and full proceedings of the presentations
and discussions at the workshop will be prepared by a designated rapporteur in
accordance with institutional guidelines.
pert presentations, the agenda for the workshop included built-in time for
discussion.
This Proceedings of a Workshop is a factual summary of the presen
tations and discussions that took place during the workshop. It is not
intended to serve as a comprehensive overview of the subject, nor are the
citations herein intended to serve as a comprehensive set of references for
any topic. Additionally and importantly, the information presented here re
flects the knowledge and opinions of individual workshop participants and
should not be construed as reflecting consensus on the part of the workshop
planning committee; the Food Forum; or the National Academies.
SETTING THE STAGE: INTRODUCTION AND OVERVIEW

Following Rowe’s welcoming remarks, Patsy Brannon, Division of
Nutritional Sciences, Cornell University, set the stage for the workshop
by discussing the central role of a risk assessment framework in current,
population-based dietary guidance and the challenges of transitioning to
personalized nutrition guidance. Her presentation is summarized here, with
highlights provided in Box 1-2.
INTRODUCTION 3
BOX 1-2
Highlights from Patsy Brannon in Her
Introductory Presentation
• A risk assessment approach is central to current population-based dietary

guidance. Dietary reference intakes (DRIs) are based on a distribution of nutri-
ent intake, and it is impossible for any given individual to ascertain where in
the distribution that individual falls.
• Therefore, it has been impossible to provide specific nutrition recommenda-
tions for individuals. “That’s at the heart of the change of what nutrigenomics
opens up as a possibility,” Brannon said.
• The variety of ways in which different authoritative bodies have defined
nutrigenomics reflects the complexity of the interrelationships among genetics,
epigenetics, nutrient–gene interactions, and individual variations in nutritional
kinetics and dynamics.
• Added to this complexity is the very important role of consumer and food
behavior. Taste, not health, is often the primary force driving food choices.
• Because of these complexities, instead of thinking about population-based and
personalized dietary guidance as an either-or situation, the two approaches
will likely need to be integrated.
An Overview of Population-Based Dietary Guidance:
The Centrality of the Risk Assessment Framework
Brannon began by discussing the risk assessment framework, which she

said underlies many, though not necessarily all, current population-based
dietary guidance. She explained that the first step in risk assessment is to
identify, based on a review and synthesis of evidence in the literature, what
is known in the field of risk assessment as the “hazard identification,”
which, in the context of nutrition, is a health outcome. The second step,
she continued, is to characterize the dose-response relationship between the
exposure, which in this case is a nutrient or diet, and the health outcome.
“These two steps are central to why we use a population-based approach,”
she said. She then discussed each step in detail.
Step 1: Synthesizing the Evidence

In addressing the process of synthesizing the evidence, Brannon cited
two sources: (1) food-based dietary guidance from the European Food
Safety Authority (EFSA) and also, to some extent, from the U.S. Dietary
Guidelines for Americans, particularly the Nutrition Evidence Library; and
(2) nutrient requirements, including the dietary reference intakes (DRIs),
particularly the traditional DRI model (that is, before chronic disease end
points were proposed).
EFSA’s population approach, as reflected in its Scientific Opinion on
Establishing Food-Based Dietary Guidelines (EFSA, 2010), focused explic
itly on dietary patterns, which Brannon noted is comparable to the focus of
the U.S. Dietary Guidelines for Americans (HHS/USDA, 2015), emphasiz
ing “desirable food and nutrient intakes.” But, she added, EFSA’s focus also
was on diet and disease relationships of relevance to a specific population.
She explained that the EFSA (2010) panel used a stepwise approach in
reviewing the evidence and identifying diet–health relationships, country-
specific diet-related health problems (in contrast to the U.S. focus on na
tionwide health problems and their public health significance), nutrients of
public health concern, foods relevant for food-based dietary guidelines, and
food consumption patterns. She commented that, other than the focus on
country-specific diet-related health problems, EFSA’s approach was compa
rable to that used to establish the U.S. Dietary Guidelines for Americans.
Brannon then turned to the analytical frameworks used for the synthesis
of evidence in establishing the U.S. Dietary Guidelines for Americans, which,
like the EFSA approach, reflected a population-based approach. She cited the
example of the framework used to evaluate adherence to a dietary pattern
in relation to outcomes for breast, colorectal, prostate, and lung cancers.
Step 2: Characterizing Dose-Response Relationships

Brannon next considered how an understanding of the DRIs is help
ful for understanding why the U.S. population-based approach is different
from what is possible with nutrigenomics. The DRIs, she explained, are
based on a distribution of intake requirements, so that it is impossible to
ascertain where in the distribution a given individual falls (IOM, 2006).2
As shown in Figure 1-1, the DRI values include the estimated average
requirement (EAR) for 50 percent of the population, a recommended dietary
allowance (RDA) for 97.5 percent of the population, and an upper level (UL)
at which adverse effects begin to be seen. The European approach, Brannon
noted, uses comparable values. She added that the proposed chronic disease
DRIs (NASEM, 2017a) are based on acceptable ranges of intakes instead of
singular dietary reference values (see Figure 1-2).
Because of this distribution-based approach, Brannon observed, “we
have been unable to give a specific recommendation for an individual,
and that is at the heart of the change of what nutrigenomics opens up
as a possibility.” This is true, she noted, for both the current model (left
distribution in Figure 1-3) and the proposed expanded model with chronic
2 More about the DRIs can be found at www.nas.edu/dris (accessed April 23, 2018).
INTRODUCTION 5
High
EAR UL
% Healthy Population
At RISK RDA
of Adverse Health Outcome
50%
Low
97.5%
INTAKE
FIGURE 1-1 The distribution of intake requirements (bell-shaped curve) upon
which the dietary reference intakes (DRIs) (estimated average requirements [EARs],
recommended dietary allowances [RDAs], and tolerable upper intake levels [ULs])
are set, with intake on the x-axis and frequency of risk of adverse health outcome
on the y-axis.
SOURCE: Presented by Patsy Brannon on December 5, 2017.
FIGURE 1-2 Two possible distributions of intake ranges (horizontal bars) when
chronic disease risk decreases with increasing intake (left) and when chronic disease
risk increases with increasing intake (right).
NOTE: RDA = recommended dietary allowance; UL = tolerable upper intake level.
SOURCES: Presented by Patsy Brannon on December 5, 2017, from NASEM,
2017a.
FIGURE 1-3 For any given individual (represented by the blue figure) in a popu
lation, it is impossible to know where in either distribution (traditional dietary
reference intake [DRI] distribution on the left, and chronic disease risk distribution
on the right) that individual falls.
SOURCE: Presented by Patsy Brannon on December 5, 2017.
disease endpoints (right distribution in Figure 1-3). She suggested that this
distribution of requirements raises the question of why there is variability
in requirements for a nutrient or in the response to a nutrient or dietary
component related to health promotion or disease prevention.
Nutritional Kinetics, Dynamics, and Requirements

Brannon chose to frame her consideration of the question of variability
in terms of nutritional kinetics, dynamics, and requirements because she
believes it is useful to step back and ask, Why do people actually vary?
She explained that when people consume food, there are both kinetic and
dynamic aspects to the nutrient concentration at the site of action.
Brannon listed several different processes related to kinetics: absorp
tion (e.g., processes related to digestion and bioavailability); distribution
throughout the tissues (e.g., processes related to the volume of circulating
fluids, the volume of the compartments into which they are being distrib
uted, and body composition); metabolism, including metabolic rates; and
excretion, including rates of excretion.
Likewise, Brannon continued, there are several different processes in
volved in dynamics that affect the actions of a nutrient. Among these pro
cesses are dose-response at the site of action (including complexities related
to the differential distribution of nutrients in different compartment pools
and their differential effects), maximal efficacy, and the temporal response
INTRODUCTION 7
as nutrients are consumed. Adverse or beneficial effects, Brannon observed,

also depend on dose-response at the site of action and the target tissue, as
well as on deficiency; toxicity; temporal response; and, for DRIs for chronic
disease, the ranges of dose-response effects. Additionally, she noted, as more
is learned about the inflammatory response, it is clear that the dynamics of
nutrients, as well as some of their kinetics, can also be influenced by the
inflammatory response.
Brannon then cited a number of factors that affect individual variation
in nutritional kinetics and dynamics, including genetics, epigenetics, and
nutrient–gene interactions. She explained that genetics encompasses both
the mitochondrial genome and the nuclear genome, plus interactions be
tween the two, as well as other factors including age, sex, and physiological
state (e.g., growing, pregnancy, lactation, stress, disease). Also relevant are
nutrient–diet interactions, nutrient–environment interactions, and drug–
nutrient interactions. When one considers all of these processes and factors,
Brannon observed, “it becomes quite clear why nutrigenomics can help
us understand what an individual needs as opposed to an average for the
population.”
Definitions of Nutrigenomics
Upon searching for definitions of nutrigenomics, Brannon found that
what she thought nutrigenomics meant agreed largely with how it was
defined, including by such authoritative sources as Nature and medical
dictionaries. However, she noted, although all of the definitions included
nutrients, their impact on health, and the interaction between nutrients
and genetics, they varied in how they characterized those relationships. For
example, some focused on nutrients affecting health, with the effect being
mediated through genetics, whereas what she described as more reflective
definitions pointed out, first, that nutrients and the genome interact with
each other and are mutually influencing and, second, that nutrients and
health influence each other.
Additionally, Brannon found variability in whether a definition in
cluded nutrients, diet, foods, or food components. She sees this variability,
coupled with the mutuality of nutrient–health and nutrient–genome rela
tionships, as reflecting the complexities of nutrigenomics and their impact
on how nutritional and dietary guidance would be provided to a specific
individual. She pointed to Figure 1-4 as making these complexities readily
evident, noting that the dietary and genetic interrelationships depicted in
this figure are multiple and complex, affecting different phenotypes for, in
this example, cardiovascular disease. She suggested that all of these com
plexities will need to be addressed as nutrigenomics begins to be applied to
specific, personalized nutrition.
FIGURE 1-4 Complexities of nutrigenomics, using cardiovascular disease (CVD)
phenotypes as the endpoints.
NOTE: GRS = genetic risk score; NGS = next-generation sequencing; SNP = single
nucleotide polymorphism.
SOURCES: Presented by Patsy Brannon on December 5, 2017, from Corella et al.,
2017. Reprinted by permission from Taylor & Francis Group: Expert Review of
Molecular Diagnostics. D. Corella, O. Coltell, G. Mattingley, J. V. Sorli, and J. M.
Ordovás. Utilizing nutritional genomics to tailor diets for the prevention of cardio
vascular disease: a guide for upcoming studies and implementations. 17(5):495–513,
copyright (2017).
Consumer and Food Behavior

Adding to the complexity illustrated in Figure 1-4, Brannon continued,
is the reality that consumer and food behavior is “very, very difficult to
fully elucidate and understand.” She noted that each consumer is a complex
psychological unit that informs both poor and good food behavior choices.
She stressed that, based on the body of literature on consumers and food
behavior, one issue that will need to be addressed is the reality that health
is not the only driving force in food choices, and likely not even the major
one. She acknowledged that, based on the theory of self-determination,
health can be an important driving force in food choices, and it is known
that as individuals’ health changes, their willingness to think about their
health and the framing of their food choices can also change. However, she
added, she knows many clinical dietitians who wish effecting change in
INTRODUCTION 9
food choices were as simple as telling a patient, “You have this disease and
you need to make this change in your diet.” “The reality is far different and
more difficult to understand and influence,” she stated.
Rather than health, Brannon continued, taste is often the primary force
behind food choices. Even when dining with fellow nutritionists, she may
hear them say, almost with a guilty chuckle, such things as, “Well, I know
I shouldn’t eat this, but I really like the way it tastes.” That is the reality of
how people choose their foods, she asserted, and while nutrigenomics may
change how people frame their choices and influence how they prioritize
health, taste will remain an important factor.
Another issue Brannon believes will need to be addressed is that be
havior change is neither easy nor fully understood. Nor are professionals
necessarily as effective as they would like to be in facilitating behavior
change in their clients and customers.
Finally, Brannon observed, individual consumers face a barrage of con
flicting information about the risks of disease and diet and what to do about
them both, and now they are faced with conflicting information about
nutrigenomics as well. She stressed the importance of remembering that
consumers want simplicity, clarity, and direction. In sum, she said, “As we
move forward in nutrigenomics and the future of nutrition and diet advice,
we are going to need to keep in mind what consumers are going to want.”
Integrating Population-Based and Personalized Dietary Guidance

Brannon next reflected on the many discussions related to nutrigenom
ics that pose guidance as either population-based or personalized for the
individual, observing that the world is not that simple or clear cut. She
argued that population-based and personalized dietary guidance will need
to be integrated.
Brannon commented on the fact that 43 nutrients need to be supplied
in the diet and that these nutrients exist in variable amounts in different
foods. For example, she elaborated, the reason there is more protein in
MyPlate than is actually required in the DRI is that some food groups
rich in protein are rich in micronutrients, such as riboflavin, that are not
abundant in the food supply. Thus, she explained, achieving a personalized
dietary pattern meeting the needs for all of these nutrients would involve
modeling a very complex set of multifactorial, interactive issues while also
considering other bioactive food components. In sum, she said, much will
have to be learned about nutrigenomics and its complexities before it can
be applied as a sole approach.
Nutrigenomics and the Future of Nutrition:
Complexities and Opportunities
In closing, Brannon presented an outline for the remainder of the

workshop. Session 1 would focus on the interrelationships among diet,
genomics, and health or disease prevention. Session 2 would focus on ways
of applying nutrigenomics to diets tailored to individuals. Session 3 would
turn to policy and ethical implications, with a close look at the nature and
strength of the evidence—both what it needs to be and what it is—in terms
of consumer perspective and behavior. Lastly, Session 4 would conclude
with a panel discussion on the opportunities for nutrigenomics and the
future of nutrition.
ORGANIZATION OF THIS PROCEEDINGS

The organization of this Proceedings of a Workshop parallels that of
the workshop (see Appendix A for the workshop agenda). Chapter 2 sum
marizes the first portion of session 1 on Nutrigenomics and Chronic Disease
Endpoints, which included two presentations. Chapter 3 summarizes the
remainder of session 1 on Personalized Nutrition in the Real World. Chap
ter 4 turns to session 2 on Nutrigenomics Applications: Dietary Guidance
and Food Product Development. Chapter 5 describes the presentations of
session 3 on Nutrigenomics: Regulatory, Ethical, and Science Policy Consid
erations. Finally, Chapter 6 summarizes session 4, the panel discussion on
Rethinking the Relationship Between Diet and Health: Can Nutrigenomics
Help?
2
Nutrigenomics and
Chronic Disease Endpoints
I
n session 1, moderated by Naomi Fukagawa, U.S. Department of Agri
culture, speakers discussed the interrelationships among diet, genomics,
and health or disease prevention. This chapter summarizes the first por
tion of the session, which included presentations by José Ordovás, Tufts
University, and Douglas Wallace, Perelman Medical School, University of
Pennsylvania. (The remainder of the session is summarized in Chapter 3.)
Highlights from the presentations of Ordovás and Wallace are provided in
Box 2-1.
GENOTYPES AND DISEASE RISK: WHAT IS CURRENTLY
KNOWN ABOUT NUTRITION AND EPIGENETICS?
The genome contains more than 3 billion base pairs, Ordovás observed,
in contrast to the epigenome’s 30 million CpG dinucleotides1 in various
states of methylation. Although the smaller size of the epigenome may make
it appear easier to work with than the genome, he stated that it in fact poses
a greater challenge. According to Ordovás, this is the case because unlike
single nucleotide polymorphisms (SNPs), which either do or do not exist
across all cells in an organism, the epigenome changes over time and across
organs and cell types. “So we have something much more difficult to deal
1 CpG is a coupling of a cytosine and guanine nucleotide in linear sequence; the cytosines
in CpG dinucleotides can be methylated, unmethylated, or hemimethylated, with methylation

status affecting gene expression.
11
BOX 2-1
Overview of Points Presented by Individual Speakers*
• The root of personalized therapies is newborn screening. Each year in the

United States, for example, more than 1,000 babies are born with congenital
hypothyroidism (CH), a monogenic disease whose treatment requires specific
foods. (Ordovás)
• A less extreme example than CH is what scientists have been learning about
APOA2. Several replicated studies have demonstrated that, under low saturated
fat conditions, APOA2 genotype does not matter. But when consuming a diet
high in saturated fat, which stresses the physiology, individuals with the CC
genotype gain more weight relative to those with either the CT or TT genotype.
(Ordovás)
• In addition to what scientists have learned about the genome in relation to
nutrition, evidence that in humans, nutrition-related epigenetic changes can
influence adult-onset diseases is beginning to emerge. (Ordovás)
• The basic assumptions made by the scientific community in studying disease
need to be reconsidered. Instead of focusing only on nuclear DNA and inheri-
tance, it is important to think about mitochondrial DNA and inheritance as well.
(Wallace)
• Because they are maternally inherited, the different components of the mito-
chondrial “wiring diagram” have co-evolved and have remained tightly coupled
over evolutionary time, making energy production more efficient than it would
otherwise be. (Wallace)
• However, mitochondria are constantly replicating, and as they do so, muta-
tions accumulate, the “wiring” loosens, and energy output decreases. Results
of several studies suggest a central role for mitochondrial mutations and bio-
energetic dysfunction in human disease. (Wallace)
* This list is the rapporteur’s summary of the main points made by individual speakers
(noted in parentheses). The statements have not been endorsed or verified by the National
Academies of Sciences, Engineering, and Medicine, and they are not intended to reflect a
consensus among workshop participants.
with in terms of using the epigenome as part of this task of nutrigenomics,

or nutrigenetics,” he said.
Moreover, Ordovás continued, scientists have studied the genome more
than they have the epigenome. The SNP database2 now contains more than
300 million of what he called “needles in this haystack.” And there has
been enough research in this area, he added, to know that the genome can
2 The SNP database (dbSNP) is a public domain archive of SNP and other small-scale ge
netic variations, not just in humans but in all species. See https://www.ncbi.nlm.nih.gov/snp
(accessed February 20, 2018).
NUTRIGENOMICS AND CHRONIC DISEASE ENDPOINTS 13
indicate what people can eat, as well as what people want to eat. But there
has also been enough research to know the complexity of the road ahead, he
cautioned. Thus, to provide some context for his discussion of the epigenome
in relation to nutrition, he began by speaking briefly of the genome in rela
tion to nutrition.
Nutrition and the Genome

The root of personalized medicine and nutrition, Ordovás said, is
newborn screening, which he considers the simplest example of genomic
screening for specific personalized treatments. In the United States, he re
ported, about 12,000 of the 4.2 million babies born each year are born with
a monogenic disease—a disease that if not detected in time, usually at birth,
can mean death or a life with severe disabilities. One of the most common
such diseases is congenital hypothyroidism (CH), which is detected in more
than 1,000 infants annually in the United States. According to Ordovás,
the approximate cost of screening for CH is $20 million, compared with
$400 million in benefits (i.e., later costs avoided by having diagnosed and
treated the disease).3 “So the benefit [of genetic screening] is obvious—it’s
20 times the cost,” he said. Regardless of the economic costs and benefits,
he added, “what we know is that, based on genotype, individuals need to
receive specific therapies and either can eat or cannot eat certain foods.”
Ordovás acknowledged that CH is an extreme case. As a broader
example of how the genome and health influence one another, he pointed
to past positive selection as a significant driver of nutrition-related genetic
variation. He cited the lactase persistent gene as the classic example of this
phenomenon, with different ethnic groups having more or less prevalence
of the gene depending on past access to dairy products. The same is true
of the fat-related APOE gene, he noted, with respect to its prevalence
among groups with a hunter-gatherer versus agricultural history, as well
as of alcohol-related ADH1B. All three examples, he observed, illustrate
that what individuals from different cultures eat is determined partly by
how their genomes have been responding to selective pressures in their
nutritional environments.
Ordovás went on to explain that past exposure to different nutrition-
related environments has impacted genetic variation in taste and food
preference as well (e.g., Chmurzynska and Mlodzike, 2017). To illustrate
3 Another one of these diseases with an important nutritional implication, Ordovás noted,
is phenylketonuria (PKU), which is detected in about 400 infants born each year in the
United States. The approximate cost of screening per child with PKU detected is $2,500,
and the cost of dietary treatment for 10 years is approximately $8,000. In comparison,
the expected cost of institutionalization over a 30-year period is estimated to be $162,000
(Grosse, 2015).
this point, he described what scientists have been learning about APOA2,
a gene that is expressed primarily in the liver and that produces APOA2, a
protein present in high-density lipoprotein (HDL). He noted that, although
scientists have known about this protein and its abundance in plasma for
some 40 years, only when the genetic work began did they start to see
some of what it actually does. He pointed to one of the initial findings
from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)
nutri-pharmacogenomic study, which enrolled more than 1,000 people.
The researchers found that APOA2 has a common polymorphism in the
promoter region of the gene (APOA2 m265T>C), and individuals who are
homozygous for the C allele, which is the less common of the two alleles,
eat more and weigh more relative to individuals with the TT and TC geno
types (Corella et al., 2007). He described the polymorphism as “an example
of a genetic variant that predisposes you to obesity because it drives you to
eat more of certain foods.”
In later GOLDN and other studies (Correla et al., 2009, 2011; Delgado
et al., 2007; Smith et al., 2012), Ordovás and his team replicated a gene–
diet interaction between the APOA2 polymorphism and saturated fat and
found that under low saturated fat conditions, one’s genotype does not
matter; body mass index (BMI) is the same. It is only when the physiol
ogy, or genome, is stressed by a diet high in saturated fat that individuals
with the CC genotype have higher BMIs, whereas for individuals with
the TT or TC genotype, the amount of saturated fat in the diet does not
matter for their BMI. In the past, Ordovás added, lack of validation, or
replication, has been a problem with gene–environment interaction studies.
The fact that this same pattern has been seen in six independent popula
tions and five ethnicities across the world indicates, he said, that “this is a
polymorphism that may have a significant impact in terms of personalized
recommendations.” However, he again cautioned that this is only one piece
of the complex nutrigenomics puzzle, which he predicted probably will not
be completed any time soon. “But at least we have a better idea of where
the pieces fit together,” he said.
Epigenetics in Nutrition Research

Ordovás reiterated that, compared with genetics, epigenetics is more
difficult to study with respect to its importance in nutrition because it is
what he described as a “moving target,” with different organs, different
tissues, and different cells having different epigenetic patterns. Moreover,
he explained, because the study of epigenetics is restricted primarily to
those cells researchers can access, much of the progress in understanding
epigenetics in relation to nutrition has been made in experimental animal
models. That said, he added, evidence in humans is beginning to emerge.
As an example of this evidence, Ordovás highlighted what is being

learned about the famous Dutch Hunger Winter of 1944–1945 in the
Netherlands, when people had to survive on rations as low as 400–800
calories per day. An estimated 22,000 people died. But those deaths were
not the end of the story, Ordovás noted. He explained that investigators
studied individuals who were still in the fetal state during that time and
found, for example, that their birthweight had been different relative to
those not exposed to the Hunger Winter. Moreover, individuals exposed
to the famine, particularly those exposed during middle and late gestation,
had impaired glucose tolerance even at age 60 years (e.g., de Rooij et al.,
2006a,b; Ravelli et al., 1998). According to Ordovás, researchers have
found other differences as well, such as problems with obesity and neuro
logical disorders among those exposed to the Hunger Winter during fetal
development, and highly significant differences in the epigenetic profiles of
individuals who were and were not born during the Hunger Winter (e.g.,
Tobi et al., 2014).
Ordovás then turned from the Dutch Hunger Winter, a set point in
history, to parts of the world that experience yearly seasonalities, reporting
that investigators have found similar changes in the DNA methylation pat
terns depending on the season of conception. In The Gambia, for example,
there are two seasons—dry and wet. Waterland and colleagues (2010)
found that individuals born during the wet, or harvest, season have differ
ent DNA methylation patterns from those of individuals born during the
dry, or hungry, season. Ordovás remarked that these differences may play
a significant role in survival and disease.
As another example of nutrition-related epigenetic differences, Ordovás
cited whole fruits versus fruit juices. He observed that whole fruits are
typically presented as being rich in fiber and low in energy and containing
intact vitamins and minerals, whereas fruit juices are portrayed as being
deficient in fiber and high in energy because of added sugar, and lacking in
most vitamins and minerals found in whole fruits (although in some cases,
he noted, the lost vitamins and minerals are replenished). But, he asked,
how true are these characterizations? Using data from the Framingham
study, Nicodemus-Johnson and Sinnott (2017) examined the epigenomes of
individuals who consumed whole fruits and those who consumed fruit juices
and found significant differences in the epigenetic signatures associated with
pathways involved in the immune system. More specifically, the whole fruit–
specific epigenetic signature was enriched for adaptive immune system genes
but not innate immune system genes, and for genes involved in telomere
maintenance and other aging-related pathways. In contrast, the juice-specific
epigenetic signature was enriched for both adaptive and immune system
genes, so for genes involved in proinflammatory pathways. Based on these
findings, Ordovás said, “it’s better to eat fruits, thanks to the epigenome.”
The Integration of Genetics and Epigenetics in Nutrition Research

Ordovás observed that methylation, on which he had been focusing
during his presentation to this point, is only a small fraction of the complex
epigenome. That said, he continued, methylation is dependent on two factors
within the context of nutrition: (1) what one eats and (2) what one’s genome
is. Regarding the latter, he explained that any time a gene variant removes
either the C or the G from a CpG site, that site will no longer be methylated.
Conversely, if a variant introduces a new CpG site, methylation will emerge
in a place where it did not exist before. So it is not only the environment,
or diet, that affects methylation, Ordovás stated, but also the genome itself
(Zhi et al., 2013).
To illustrate, Ordovás described how ABCA1, which is involved with
HDL metabolism, is a common genetic variant that sits atop a differentially
methylated 5′ CpG region of the genome. By sitting there, it can not only
change the methylation of that CpG but also affect the methylation of all the
other neighboring CpGs. Ordovás described the results of a meta-analysis
of methylation data from more than 10,000 individuals from different co
horts showing that a change in EPA4 in the diet resulted in either decreased
methylation and increased HDL cholesterol or increased methylation and
decreased HDL, depending on the ABCA1 genotype (Ma et al., 2016).
More specifically, with a 1 percent increase in EPA, individuals with the CC
genotype experienced decreased methylation, increased gene expression, and
increased HDL cholesterol, in contrast to the increased methylation, reduced
gene expression, and lowered HDL cholesterol experienced by individuals
with the GG genotype under the same conditions. (Ordovás noted that de
creased methylation is usually associated with increased gene expression.)
Thus, he said, this is a case in which both genetics and epigenetics need to
be considered. Otherwise, he stated, a general recommendation to increase
one’s EPA levels would have a positive effect in some individuals with respect
to HDL cholesterol but a negative effect in others.
As another example of a nutrition-related gene–epigene interac
tion, Ordovás cited perilipin, a protein that surrounds lipid droplets in
adipocytes. Many studies have shown, he reported, that variation in the
perilipin genes affects obesity risk. His research team found that one of
these genes, PERILIPIN4 (PLIN4), is not in the promoter region of the
gene, as are the other polymorphisms, but in the 3′ region of the gene
(Richardson et al., 2011). It turns out, he explained, that microRNAs
(miRNAs), which are another type of epigenetic phenomenon, can bind
to the 3′ region and decrease expression. This particular polymorphism
is at a site where there normally is no bound miRNA, but when a G is
4 EPA is eicosapentaenoic acid, an omega-3 fatty acid.

replaced with an A, miRNA suddenly binds and decreases the expression

of PLIN4. The question, Ordovás suggested, is whether something can be
done about this. In fact, his team has observed that when individuals with
the less common allele—that is, with bound miRNA at that site—are placed
on a diet rich in omega-3s, their phenotype reverts from that of the less
common allele to that of the more common allele. So again, he said, this is
an example of gene–diet interaction that works through a combination of
genomics and epigenomics. He noted that there are thousands of miRNAs,
many of which scientists know very little about, although they are begin
ning to make progress, especially in terms of understanding miRNAs in
relation to cancer.
The Future
In closing, Ordovás remarked that the microbiome plays a role in
nutrition and that personalized nutrition will require not just combining
genomics and epigenomics but also considering the microbiome, as well as
the metabolome. “I don’t know that we’ll ever get to perfect,” he observed,
meaning perfect personalized nutrition. However, quoting Voltaire,5 who
in turn borrowed from an old Italian proverb, Ordovás said, “perfection is
the enemy of good.” There is enough evidence now, in his opinion, to begin
putting the pieces of the puzzle together and to control some of what he
described as the “snake oil” being sold by some consumer ventures.
MITOCHONDRIAL GENETICS AND DISEASE RISK:
EXPLORING CURRENT EVIDENCE
“Why can’t we understand or cure the common metabolic and degen

erative diseases?” Wallace asked, noting that there is an enormous number
of such diseases, including neurodegenerative and neuropsychiatric dis
orders (e.g., autism, Alzheimer’s disease), heart and muscle diseases (e.g.,
cardiomyopathy, chronic fatigue), visceral diseases (e.g., renal and hepatic
diseases), metabolic diseases (e.g., diabetes, obesity, cardiovascular disease),
cancer, and aging. He suspects that perhaps the problem is not the effort
expended, given the trillions of dollars that have been spent trying to under
stand human disease, but the basic assumptions the scientific community is
making in addressing the problem.
According to Wallace, the first basic assumption upon which Western
medicine is premised is that disease is organ based, an assumption that
goes back to Andreas Vesalius.6 For example, if one has a headache, one is
5 Voltaire was an 18th-century writer, historian, and philosopher.
6 Vesalius was a 16th-century anatomist and physician.
referred to a neurologist because the assumption is that a symptom in the

head means there is something wrong with the head. “I call that the ana
tomical paradigm of disease,” Wallace said. The second basic assumption,
he continued, goes back to Gregor Mendel: if a trait is inherited according
to “the laws of Mendel,” then it is genetic, and if it is not inherited, then
it must be environmental. He remarked that these ideas are the framework
with which all medical students are taught and all basic scientists design
their experiments.
According to Wallace, however, these ideas may not be sufficient. While
it is true that anatomy is encoded by Mendelian genes and that there are
specific disease mutations that gave rise to the newborn screening program,
he observed, this knowledge does not appear to be helping with the com
mon complex diseases. “It is not enough to have an anatomy,” he said.
“One has to be animated.” He mentioned Newton’s work and the fact that
mass does not change unless it is acted upon by energy. “Therefore,” he
asserted, “if we are going to think about being alive, we have to think not
only about anatomy, but also energy.” Furthermore, he argued, one must
think not only about the information for anatomy, but also the informa
tion for energy, and when one begins to think this way, medicine becomes
not just about anatomy but also about energetics. He believes bioenergetic
dysfunction lies at the nexus of the genetic and environmental “causes” of
the common complex diseases.
The Dichotomy Between Anatomy and Energy

Wallace then turned to how the dichotomy between anatomy and
energy arose from the origin of the very cells that make up the human
body, that is, the eukaryotic cells, which in turn arose from the symbiosis
between Archaebacteria and the oxidative Alphaproteobacteria. It was
the Archaebacteria that ultimately gave rise to the nuclear cytosol and the
Alphaproteobacteria that gave rise to the mitochondria.
These different bacteria, Wallace continued, each had—and still
have—their own information storage and retrieval systems. The nucleus
has DNA, which is transcribed into RNA, which in turn is translated in
the cytosolic ribosomes, producing about 20,000 to 25,000 proteins. An
estimated 1,000 to 2,000 of these proteins make up the anatomy of the
mitochondria. But the mitochondria have retained their own DNA as well,
Wallace emphasized. Their DNA is replicated and transcribed in the mito
chondria, and the messenger RNA is translated on mitochondria ribosomes
in a bacteria-like way. Not only is mitochondrial translation initiated by
N-formyl methionine, just as bacterial proteins are, but mitochondria
ribosomes also are sensitive to chloramphenicol and aminoglycosides, just
as bacterial ribosomes are.
Over evolutionary time, Wallace explained, the two originally co-equal

genomes began to specialize, with the nuclear genome specializing in cre
ating the anatomy not only of the cell but also of the mitochondria, and
the mitochondrial genome specializing in energy and developing what he
described as “the wiring diagram for the power plant.” More specifically,
the mitochondrial DNA evolved to code for critical proteins involved in
the energy process called oxidative phosphorylation, including 7 of the
45 respiratory complex I proteins, 1 of the 11 complex III proteins, 3 of
the 13 complex IV proteins, and 2 of the 15 complex V proteins. Wallace
explained that each of these complexes is a system by which the cell takes
the nutrients in the diet and the oxygen that is being breathed and converts
them into potential energy. That energy, he said, “you then use for every
thing that you want to do.”
With respect to how these complexes are involved in oxidative phos
phorylation, Wallace explained that glucose goes through glycolysis to
produce pyruvate, which can then be either reduced to produce lactate
or amino-grouped to produce alanine. Alternatively, the pyruvate can be
transported into the mitochondria through the pyruvate transporter, where
it is converted by pyruvate dehydrogenase to make acetyl coA, driving the
tricarboxylic acid (TCA) cycle. The purpose of the TCA cycle, Wallace
continued, is to strip hydrogens off hydrocarbons and put them on the
carrier nicotinamide adenine dinucleotide (NAD), creating NADH. The
two hydrogens of NADH are then burned by what is called the electron
transport chain, which is made up of complexes I, III, and IV, as well as
coenzyme Q and cytochrome C. As they flow down this chain, the two
electrons (of the two hydrogens) react with oxygen to produce water.
The energy that is released is not just dissipated, Wallace clarified, but
is used to create what is essentially a capacitor. As the electrons flow
through the complexes (I, III, and IV), they pump protons from inside the
mitochondrial matrix, across the mitochondrial inner membrane, and into
the intermembrane space, thereby creating a positive, acid exterior and a
negative, alkaline interior. This membrane potential can be used for many
functions, Wallace added, one of which is to make adenosine triphosphate
(ATP): protons flow through a proton channel in complex V (i.e., ATP
synthase) to condense adenosine diphosphate (ADP) and phosphate and
make ATP. This coupling of oxidation and phosphorylation is oxidative
phosphorylation. The membrane potential can also be used in other ways,
Wallace noted—for example, to regulate a positive cation, such as calcium,
by electrophoresing into the negatively charged mitochondrial matrix.
“So sitting in your chair right now,” Wallace said, there are 100 trillion
cells, each cell with about 1,000 mitochondrial bacteria—about 30 percent
of one’s body weight—and each mitochondrion having a potential across
its membrane of about 0.2 volts. “So the total energetics in your body right
now is the equivalent of a lightning bolt,” he said, “and that is the energy
for everything that you do every day of your life . . . so this flow of energy is
absolutely critical.”
However, like any furnace, Wallace continued, mitochondria also make
smoke—the reactive oxidant species that form when not fully oxidized
electrons bind with oxygen (O2) to produce hydrogen peroxide. If the
hydrogen peroxide is not reduced to water (i.e., by nicotinamide nucleoside
transhydrogenase), then another electron, provided by a transition metal,
will bind with it to produce a hydroxyl radical, a reactive oxygen species
and a potent damaging agent. Wallace noted that some people take vitamin
C, vitamin E, beta carotene, or coenzyme Q (CoQ) to prevent this from
happening.
The mitochondria also have a self-destruct system (i.e., apoptosis).
According to Wallace, there is active debate around what the structure of
this system is, but its job normally is to maintain a closed door. He ex
plained that when the membrane potential becomes low, high-energy phos
phates decline, oxidative stress becomes excessive, or calcium load occurs,
the self-destruct system senses these changes and ultimately pops into an
open channel that short-circuits the membrane potential. As a result, fluids
flow in, the inner membrane swells, and pro-apoptotic proteins flow out
and degrade the cell from the inside out. Without enough energy, this self-
destruct system fails. If bacteria are released into the bloodstream with all
of their bacterial antigens, the result will be inflammation, which is believed
to accompany all the metabolic and degenerative diseases.
In summary, Wallace said, the mitochondria generate most of the body’s
energy; regulate the redox state of the cells; make reactive oxygen species,
which are signaling molecules but at high levels are toxic; regulate calcium;
regulate apoptosis; and generate all the intermediates for regulating the
epigenome (e.g., ATP, acetyl CoA).
Wallace added that different tissues have different energetic demands.
For example, the brain is about 3 percent of body weight but uses about
20 percent of all mitochondrial energy. So a 10 percent reduction in mito
chondrial energy, Wallace said, “is going to give you a very bad headache.”
The headache occurs not because the brain has altered, he clarified, but
because there is a systemic defect, and the brain is specifically affected. The
hierarchy of energetics, he explained, is brain, heart, muscle, renal, endocrine,
and liver, which are the organs affected in all the common, complex diseases.
Mitochondrial Inheritance
The 13 proteins retained by the mitochondria that make up what
Wallace described as the “electron and proton wires of the wiring diagram”
must co-evolve, he argued, because if any one were to become leaky for
protons, it would “short the capacitor.” This is the case, he elaborated,

because the wiring diagram is an integrated circuit, with all of the enzymes
in the system relying on the same substrate, that is, the membrane poten
tial. But how could such co-evolution occur, he asked, since nuclear genes
undergo recombination? Thus, for example, if there were a polymorphism
in complex I but not in complexes III and IV, recombination would be mix
ing and matching coupled and uncoupled variation.
To explain coupling, Wallace described someone who burns the least
number of calories for the maximum amount of ATP as someone who
is very good at taking in calories, burning them, making that membrane
potential, and then converting the membrane potential to ATP. In other
words, this person’s coupling system is tight. Because a calorie is a unit of
heat, Wallace continued, that person also generates less heat. But, he added,
someone who is less efficient at pumping protons out or converting protons
into ATP must burn more calories for the same amount of ATP, plus that
person generates more heat. In other words, this person’s coupling system
is loose. “Your mitochondria is regulating your thermal and your energy
balance based on the coupling efficiency,” Wallace said.
The wiring diagram of the mitochondria is inherited only from women,
Wallace continued, thus ensuring that there will never be recombination.
That is, mitochondrial DNA is transmitted from a mother to all of her chil
dren and from her daughters to the daughters’ children, and so on, while
when a male’s mitochondria enter the egg, they are perceived as foreign and
selectively destroyed.
Mitochondrial Mutations and Heteroplasmy

Wallace went on to explain that mitochondria are constantly replicat
ing inside the cell. They are also constantly being eaten by mycophagy, and
thus are in what he described as a colony in steady state. Nonetheless, as
they replicate, mutations accumulate. Wallace observed that, because mito
chondria have very high mutation rates—one or two orders of magnitude
greater than that of nuclear DNA—they are characterized by a tremendous
amount of genetic variation. Moreover, he added, as mutations accumulate,
they create mixed populations of mutant and normal mitochondria within
single cells. If one of these mixed, so-called heteroplasmic cells were to
divide down the middle, both new cells would have some mutant and some
normal mitochondria, so they would both be heteroplasmic. But a cell could
also divide such that one new cell would contain only normal mitochondria,
the other containing twice as many mutant mitochondria. Thus, Wallace
said, “the tissues in our bodies are a mosaic of different mitochondrial
genotypes, with different tissues having different percentages of mutant and
normal mitochondrial DNAs.” And as the number of mutant mitochondrial
DNAs increases, he noted, energy output declines, eventually falling below

the minimum energy for that organ and reaching what he characterized as
the equivalent of an energetic disease.
Three Types of Mitochondrial Mutations

Wallace next described three categories of mitochondrial mutations.
First are mutations that arise along the maternal lineage and give rise
to maternally inherited diseases. For example, if an individual inherits
a mutation in the ND4 gene at nucleotide position 11778, he or she
will be fine throughout midlife, but then will suddenly go blind in one
eye and then in the other because of what is known as Leber’s heredi
tary optic neuropathy. A mutation in the ND6 gene at 14484 causes the
same Leber’s blindness, and a mutation in ND6 at 14459 causes a more
severe Leber’s blindness when heteroplasmic and generalized dystonia when
homoplamic (i.e., pure mutant). As another example, Wallace cited a muta
tion in the ATPase6 gene at 8993, which causes retinitis pigmentosa at
70 percent mutant, olivopontocerebellar atrophy at 85 percent mutant, and
death as an infant with Leigh’s syndrome at 90 percent mutant.
According to Wallace, there are also several (maternally) inherited
protein synthesis mutations, including a mutation in the tRNA leucine
gene at 3243, which causes diabetes at 20 percent mutant, cardiovascular
disease at 50 percent, and lethality in childhood at 100 percent. A mutation
in the tRNA glutamine gene accounts for about 3–5 percent of late-onset
Alzheimer’s and Parkinson’s disease. And a mutation in the tRNA lysine
gene causes myoclonic epilepsy. Added to these are many kinds of cancer
mutations.
Wallace then described a second class of mitochondrial mutations—
the ancient polymorphisms. For example, one variant in the ND1 gene is
found in three-quarters of sub-Saharan Africans (“macrohaplogroup L”);
another variant (H) is found in half of Europeans; and four variants (A, B,
C, and D) arose in central Asia and then crossed the Bering land bridge,
allowing people to colonize the Americas. “We believe these are markers
for mitochondrial lineages that adapted human energy metabolism to live
in different environments,” Wallace said.
Finally, Wallace explained, as people age, they accumulate somatic
mutations. This, he said, is “the aging clock.”
The Mitochondrial Etiology of Complex Diseases:
An Energetic Approach to Medicine
Wallace reiterated, “Once we begin to think energetically, then all

the common diseases have the same etiology: a bioenergetic defect due to
oxidative phosphorylation.” Nuclear mutations can affect this process,

he noted, as can changes in the epigenome, as well as both ancient adap
tive polymorphisms and recent deleterious mutations. Finally, he added,
the calories and types of nutrients one ingests, or how one exercises and
uses those nutrients, as well as whether one smokes or is exposed to other
toxins, all impinge on energetics.
If energetics is affected, Wallace continued, then mitochondrial DNA
damage accumulates over time, which leads to age-related decline and the
delayed onset and progressive course of all the common diseases. Addi
tionally, he explained, as the furnace is impaired, substrates (glucose,
fatty acids, and cholesterol) build up, and that is what creates metabolic
syndrome. When apoptosis fails, he noted, bacteria are released into the
bloodstream, initiating all of the inflammatory processes that accompany
the complex diseases. And finally, turning to cancer, he characterized it as
“all about adjusting energy based on nutrients and oxygen. In fact, a bio
energetic way of looking at the disease takes us away from the anatomical
approach and into an energetic approach to medicine.”
Studies of Mitochondrial Mutations

Wallace went on to describe results from studies of mitochondrial muta
tions, beginning with work he and his team did in the 1980s on a family in
which the mother had lactic acidosis and growth retardation, and many of
her children had lactic acidosis, growth retardation, progressive dementia,
stroke-like episodes, hypertrophic cardiomyopathy, and cardiac conduction
defects. Additionally, mitochondrial oxidative fibers degenerated in the mus
cle, although the glycolate muscle fibers were fine. All of these individuals
had the same mutation in the tRNA dileucine gene. However, Wallace noted,
different percentages of heteroplasmy in this same mutation can cause dif
ferent phenotypes. Thus, he explained, individuals with greater than about
70 percent of the mutant mitochondria have myopathy, cardiomyopathy,
and stroke-like episodes; individuals with 10–30 percent have autism and
type 1 or type 2 diabetes; and individuals with 100 percent die as infants
from Leigh syndrome.
Wallace and his team wanted to know whether a change in hetero
plasmy in a cell could affect these different phenotypes, so starting with
normal cells, or cells with zero percent heteroplasmy, they made what are
known as cytoplasmic hybrids, or cybrids—cells with the same nucleus but
different percentages of mutant mitochondrial DNA. They characterized
the cybrids physiologically, then performed RNA sequencing and examined
all the transcription factors that were regulated in the different cell lines.
The patterns they observed indicated to Wallace that phenotype (e.g., the
diabetes and autism associated with 10–30 percent heteroplasmy) is in fact
determined by the mitochondrial signaling to the nucleus, which in turn

determines gene expression and phenotype. “So, in fact,” he said, “the
mitochondria is determining what the environmental challenges are and
telling the nucleus how to respond, and that is telling the physician what
he or she will see in the clinic.”
Wallace described another pedigree, which had a mutation in the ND6
gene—one of the complex I genes. A woman had 50 percent mutant mito
chondria in her white blood cells, and she had optic atrophy and cerebellar
ataxia (Malfatti et al., 2007). Her sister had 5 percent mutant mitochondria
in her white blood cells and was perfectly normal, although every one of
the sister’s children was 100 percent mutant and died. Wallace interpreted
this case as an indication of the rapidity of segregation that occurs along the
germline and an explanation for why this class of disease was never under
stood with a Mendelian conceptual framework. This particular mutation,
he noted, changes proline at codon 25 to a leucine (P25L).
Wallace described how he and his team took cultured mouse cells,
mutagenized the mitochondrial DNA, then sequenced all the mutants that
were respiratory deficient. They found an array of different mitochondrial
DNA mutations, one of which was exactly the same mutation as that ob
served in the human phenotype described above. Another was a cytochrome
oxidase mutation that changes valine at codon 421 to alanine (V421A). The
researchers then created pluripotent cytoplasmic hybrids by, first, taking a
cell with mutant mitochondrial DNA, removing its nuclei, and keeping the
cytoplasmic fragment with the mutations and, second, making a female
embryonic stem cell, killing its mitochondria, and then using cell fusion to
substitute the mutant mitochondria (from the cytoplasmic fragment) for the
mitochondria. Next, they put these hybrids into blastocysts and then into
a foster mother to create chimeric females. They then bred the females for
transmission of the dominant agouti locus through the oocytes to pick up
the mutant mitochondrial DNA.
According to Wallace, the researchers found that mice with the P25L
mutation had increased axonal swelling, demyelination, and abnormal
mitochondria. But what he found interesting was that when they looked
biochemically at the synaptosomes of the brains of these mice, they saw
that the problem was not with ATP—the ATP in the mice with and without
the mutation was the same. They observed a 30 percent reduction in respi
ration, but, Wallace noted, if energy demand is increased, respiration will
rise to near normal. Rather than an effect on ATP, he explained, the mice
with the mutation were experiencing reactive oxygen species production
“through the roof.” Wallace characterized this as a “disease of oxidative
stress,” which kills the neurons.
Wallace added that mice with the cytochrome oxidase mutation had
a 50 percent reduction in cytochrome oxidase in all of their tissues. Addi
tionally, they had what he described as the “ragged red fibers” that were
seen in the original human family with abnormal mitochondria, progressive
cardiomyopathy with fibrosis, and type 2 diabetes with aging. So again, he
pointed out, the mice showed the same phenotypes as those seen in humans
with a single-point mutation.
The Effect of Heteroplasmy on Phenotype

Among all of these murine studies, Wallace cited as most interesting that
in which the researchers took two perfectly normal mitochondrial DNAs,
129 and NZB, mixed them together, and then segregated the heteroplasmic
animals with this same nucleus back into homoplasmy and heteroplasmy
groups. They then examined activity in the mice, which are normally active
at night but not during the day. They found that both the 129 and NZB
animals were active at night but not during the day, while the heteroplasmic
animals “just sat there,” Wallace said. He characterized them as depressed.
Wallace went on to explain that if the researchers subjected the mice
to a color-cued task—providing them with an open field with differently
colored holes around the outside of the field, one of which contained a
black box where a mouse could hide—the homoplastic animals learned
over successive days where the black box was. Mice do not like to be in
open, exposed areas, he noted. The heteroplasmic mice learned where the
black box was as well, he reported, but it took them longer. Moreover, after
four trials, when the animals were removed from the field for 2 days and
then returned, the homoplasmic mice immediately ran and jumped into the
black box, having remembered where it was, but the heteroplasmic mice did
not, having, Wallace noted, learned nothing because they had no long-term
memory. “So simply converting a homoplasmic cell to a heteroplasmic cell,
of perfectly normal mitochondrial DNAs,” he said, “severely altered the
neuropsychiatric pattern of those animals.”
Geographic Constraints of Human Mitochondrial DNA

Wallace pointed out that because mitochondrial DNA can be transmit
ted only from mother to daughter, the only way it can change is by sequen
tial mutations. So, he explained, if he were to sequence the mitochondrial
DNA of any two individuals, the number of changes would be equivalent
to the generations since those two individuals shared a common mother.
Thus, he said, by sequencing the mitochondrial DNA from people around
the world, one can reconstruct their genetic relationships and migration
patterns.
According to Wallace, in humans, mitochondrial DNA arose about
200,000 years ago in sub-Saharan Africa. Today, he explained, the Khoisan
people in that region have the most ancient mitochondrial DNA lineage.
Two lineages that arose in Ethiopia—M and N—left Africa and colonized
the rest of the world. N went to the temperate zone and gave rise to a
number of European lineages (I, J, T, U, K, W, and Z), and also went to the
temperate zone of Asia, whereas M stayed in the tropics, south to Australia,
and later acquired new mutations to live in the temperate zone of Asia as
well. Lineages C and D from M and lineage A from N crossed the Bering
land bridge, from Chukotka, and colonized the Americas.
For Wallace, this geographic pattern is astonishing because nuclear
polymorphisms, in contrast, are found panmictically (occurring through
random mating) throughout all populations. The fact that mitochondrial
DNA variation is highly geographically constrained based on the geo
graphic origin of people’s ancestors, he explained, is why 23andMe is able
to analyze customers’ mitochondrial DNA and provide them with informa
tion about their relations in other parts of the world.
Wallace’s explanation for why geography constrains mitochondrial
variation is that people’s human ancestors evolved different adaptive muta
tions that allowed them to live in different environments and cope with
different problems. In Africa, for example, he imagines the need to run
away from lions, which would have required a great deal of ATP and thus
a tightly coupled mitochondrial system. In the north, by contrast, the prob
lem was not predation, he said, but freezing temperatures. Individuals there
accumulated mutations that decreased the efficiency of the mitochondria,
so that they were eating more calories for the same amount of ATP and
generating more heat. According to Wallace, this is why people in the north
still consume a high-fat marine mammal diet. “That’s their niche,” he said.
As an example of adaptive mitochondrial variation in humans, Wallace
mentioned lineage J, which he described as a tiny part of the European
lineage founded by two cytochrome B mutations, 15257 and 14798. The
latter mutation is conserved in all mesosomic animals, but is polymorphic
otherwise. In contrast, 15257 is conserved across evolution, yet Wallace
estimated that 5 percent of the workshop participants had a variant of this
gene. “That’s unheard of,” he said. “That is antithetical to what we think
about evolutionary biology. If something is conserved across evolution, it
should be homogeneous within a population. Not so for mitochondrial
variation.” He characterized mitochondrial variation as “our adaptive
engine. It allows us to adapt our energy to environmental changes.”
Wallace went on to talk about an A-to-G mutation that arose 10,000
years ago in Europe in the tRNA glutamine gene (Hutchin and Cortopassi,
1995). This mutation is found in only 0.4 percent of modern Europeans,
but in about 3 percent of individuals with Alzheimer’s disease, 5 percent of
those with Parkinson’s disease, and 7 percent of those with both diseases.
Wallace noted that other mutations are much more deleterious than even
this one—for example, ND1 methionine 31 valine (M31V), which causes

both Alzheimer’s and Parkinson’s diseases. He reported further that in a
study of European individuals with autism, mitochondrial variation was
shown to be correlated dramatically with that condition, with mitochondrial
haplogroups accounting for 55 percent of the risk. He added that mitochon
drial DNA variation has been associated with a range of other common
neurodegenerative, neurological, metabolic, and inflammatory diseases, as
well as with altitude adaptation, cancer, aging, and athletic performance.
Nuclear–Mitochondrial DNA Interaction

As an example of a nuclear–mitochondrial DNA interaction, Wallace
described a nuclear mutation, Ant1, in a Mennonite pedigree that af
fects the adenine nucleotide translocator isoform-1. The mutation arose in
Switzerland about 500 years ago and was carried to North America. It was
originally a recessive mutation, but then heterozygous individuals married
each other and gave rise to the affected homozygous mutants. What is inter
esting about this mutation, in Wallace’s view, is that some people with the
affected mutants have very mild cardiomyopathy, while others die of ful
minant, dilated cardiomyopathy. Compared with the heartbeat of cultured
cardiomyoctes derived from embryonic stem cells in a healthy individual,
the heartbeat in a mutant individual is highly dysrhythmic. According to
Wallace, the different phenotypes are explained by the fact that people with
severe cardiomyopathy have European mitochondrial lineage U, while those
with mild cardiomyopathy have European mitochondrial lineage H. “So it
is the mitochondrial DNA that is determining the severity of the disease,”
he said, “not the nuclear mutation.”
In mice with the same mutation, Wallace continued, it has been shown
that wild type mice (Ant1+/+) will continue to exercise until giving up,
while mutant animals (Ant1–/–) start running but fall down because of
the progressive accumulation of abnormal mitochondria. The mutant mice
also have been shown to exhibit highly dysrhythmic cardiomyopathy, as
opposed to the wild type. When the Ant1–/– mutation is combined with a
mitochondrial COI mutation, there is no significant change in phenotype,
but when it is combined with a mitochondrial ND6 mutation, mice develop
severe cardiomyopathy with half the life span. Wallace interpreted this to
mean, again, that mitochondrial DNA, not nuclear DNA, is determining
the phenotype.
In terms of behavior, Wallace continued, when these same mice were
put into a restraint to see how they would respond, the Ant1–/– mice with
the mitochondrial ND6 mutation had a much stronger corticosterone re
sponse relative to the wild type mice. Thus, he noted, this same mitochon
drial variant also affects brain development.
Closing Thoughts on the Mitochondrial View of Disease

Wallace closed by describing mitochondria as “the environmental sen
sors.” That is, when the environment changes, the epigenome changes,
which in turn reconfigures the mitochondrial genotype to maintain homeo
stasis. But if the environmental change is too great or if there are mutations
in the nuclear cytoplasmic system, Wallace explained, the mitochondria are
unable to adjust, leading to energetic deficiency and disease. Based on this
mitochondrial view of disease, he and his colleagues are now looking at
traditional Chinese therapeutics. For 5,000 years, he said, Chinese medicine
has been based on the idea of Qi (Chi), which he described as “vital force.”
He speculated that eastern therapeutics may act through mitochondrial
biology.
3
Personalized Nutrition in the Real World
C
ontinuing the session 1 discussion, four presenters discussed applica
tions of nutrigenomics “in the real world.” This chapter summarizes
their presentations and the discussion that followed, with highlights
provided in Box 3-1.
EXPLORING PERSONAL, DENSE, DYNAMIC DATA CLOUDS

AND THE FUTURE OF PERSONALIZED MEDICINE
Nathan Price, Institute for Systems Biology, addressed personalized
nutrition in the clinical setting. He began by emphasizing the complexity
of nutrition’s health effects, as reflected in the fact that different foods have
been shown to both prevent and cause cancer (Schoenfeld and Ioannidis,
2013). Given this complexity, he argued, “there is a need for person
alization, a need for understanding.” He referred to Patsy Brannon’s
opening presentation in session 1 and her discussion of the complex inter
relationships between diet and health, particularly when one considers the
molecular details of how the body processes food and how these molecular
details are related to disease (see Chapter 1 for a summary of Brannon’s
presentation). Additionally, he emphasized how the many different biologi
cal systems add to this complexity and the many different ways to think
about it, citing Douglas Wallace’s perspective on mitochondria and their
impacts as an excellent example (see Chapter 2 for a summary of Wallace’s
presentation).
29
BOX 3-1
• In contrast to the wellness industry, which has a mixed reputation because of the
many non-scientifically based approaches being applied, the goal of “scientific
wellness” is to provide an underpinning of rigorous science and dense, dynamic
data for the study of wellness, and to predict and prevent disease before it hap-
pens. To launch scientific wellness, the 100K Wellness Project was conceived,
focused on collecting a personal, dense, dynamic dataset for 100,000 indi-
viduals that can be observed over time for early warning signs of disease. (Price)
• Meanwhile, a 9-month feasibility study, the Pioneer 100 Wellness Project, has
demonstrated improvements in a number of clinical markers. Along with data
collection, wellness coaching was an important part of the study, reflecting the
critical role of behavior change in personalized nutrition. (Price)
• Research has explained arginine deficiency syndromes, mostly in relation to
sickle cell disease, an autosomal recessive inherited disease, but also trauma.
Both have distinct nutritional requirements that develop because of metabolic
abnormalities, and both may benefit from arginine replacement therapy. (Morris)
• Although the potential benefit of arginine therapy for sickle cell disease, as
well as for trauma, has been demonstrated in both mice and humans, most
of these studies are limited by methodological weaknesses. More research is
needed, including the identification of subpopulations that would likely benefit
the most from arginine replacement therapy. (Morris)
• Nutrigenomic studies are difficult not only because they are complex, but
also because proving causation from association is especially challenging in
the field of nutrition. Additionally, except for diseases caused by single gene
defects, it is very difficult to isolate which components of a disease phenotype
are related to nutrition. (Alpers)
• Because of these difficulties, many scientific approaches to studying links be-
tween genomics and nutritional phenotypes have relied on in vitro and in vivo
animal studies. A long lag time can be expected before strong human data are
available and nutrigenomics can be commercially implemented. (Alpers)
• Evidence from studies on the CYP1A2 genotype and coffee intake are “proof of
concept” that a single nucleotide polymorphism (SNP) can modify the associa-
tion between a dietary component and a variety of different health outcomes.
(El-Sohemy)
• There are problems with the ways in which nutrigenomics is portrayed in the
media and information about the field is communicated. An example is an
article in which a pediatrician who was interviewed said he was unaware of
evidence suggesting that people with different FTO gene variants respond
differently to low-protein versus high-protein diets. Yet not only does such
evidence exist, but it has been replicated. (El-Sohemy)
PERSONALIZED NUTRITION IN THE REAL WORLD 31
Scientific Wellness
The health care industry costs in the United States are approaching a
staggering $4 trillion per year, according to Price. But it has been estimated
that about 30 percent of a person’s lifetime health is attributable to genetics;
about 60 percent to behavior and the environment, a large part of which is
nutrition; and only about 10 percent to the health care system (Schroeder,
2007). “So there is a huge need, obviously, to focus on the 90 percent,”
Price said. Yet, physicians receive only about 2 hours of training in nutri
tion, he observed, and the “wellness industry” has a mixed reputation,
being characterized by many not very scientifically based approaches. Thus,
he and his colleagues have been advocating what he called “scientific well
ness.” He explained that the goals of scientific wellness are to provide a
data-rich basis for rigorously quantifying wellness, to try to predict and
prevent disease before it happens, and to focus on optimization of health
in the individual.
To help launch this new scientific wellness industry, Price and his col
league, Leroy Hood, announced in 2014 a project called the 100K Wellness
Project (Hood and Price, 2014). The project has one major goal: to collect
a dataset enabling observation of enough people over time to detect all of
the early warning signs for all of the major human diseases, and predict and
prevent those diseases to the extent possible. The initial vision was to col
lect dense information on 100,000 individuals, including data on genomics,
proteomics, metabolomics, the microbiome, and clinical chemistry, plus
data from wearable devices.
Price explained that, to test whether he and his team could collect all
the types of data they wanted to collect, they first conducted a prototype, or
feasibility, study called the Pioneer 100 Wellness Project. The results of that
9-month longitudinal study of 108 individuals were published in Nature
Biotechnology in 2017 (Price et al., 2017). As Price explained, multiple
types of data were collected on the participants at three different times.
Each time, the investigators measured about 150 clinical chemistries, about
700 metabolites, and about 400 proteins from blood; they also measured
stress hormones from saliva over the course of a day. The initial data collec
tion included whole-genome sequence data as well. In addition, individuals’
microbiomes were analyzed at three different times, and participants used
wearable devices for continual self-tracking and lifestyle monitoring. With
these data, Price and his team created what they call “personal, dense,
dynamic data (PD3) clouds” for each participant—personal in the sense
that they are individualized, dense because they include a large amount of
information, and dynamic because they change over time.
In addition to the data collection, Price continued, participants received
wellness coaching. He concurred with previous speakers on the critical role
of behavior change and the difficult challenge it presents, noting that his
team’s study engaged a behavioral coach as well as a study physician.
Price stressed that a key to retaining participants in a program like this
is making the data relevant. “How do you take these data,” he asked, and
make them “actionable for the person, in the moment?” In the long run,
he said, the researchers want to be able to mine PD3 clouds to enable new
health discoveries that can then be returned back to the participants.
Meanwhile, Price reported, just over the course of the 9 months of the
Pioneer 100 Wellness Project, the investigators saw improvements in a num
ber of clinical markers, including a 21 percent improvement in markers for
nutrition, a 33 percent improvement in markers for diabetes, a 12 percent
improvement in markers for inflammation, and a 6 percent improvement
in markers for cardiovascular disease. He noted that participants who have
stayed with the program, through Arivale,1 have shown continued improve
ments; for example, improvement in markers for cardiovascular disease
rose to 20 percent.
In addition to clinical markers, Price continued, his team monitored a
number of dietary factors. Through this monitoring, they discovered, for
example, that one individual who had high mercury levels also ate tuna sushi
three times a week. When this person switched to salmon sushi, the amount
of mercury in his blood had decreased by half within 3 months. After he had
remained with the program for 1 year, his mercury blood level had normal
ized completely. According to Price, there were a number of such cases.
Scientific Wellness and Discovery:
The Manifestation of Genetic Risk in the Body
In addition to mining the data and returning new health discoveries

back to the Pioneer 100 Wellness Project participants, Price and his col
laborators have been studying the nearly 4,000 correlations detected among
the different types of data collected, including associations between the
microbiome and metabolites, metabolites and proteins, proteins and life
style factors, and metabolites and genetic risk scores. “All these data types
had never before been measured simultaneously on a population of people,”
Price said. Given the complexity of the associations between these factors,
he argued, “this is just the tip of the iceberg in terms of understanding how
these things are interrelated.”
Price went on to acknowledge that some in the field of medicine believe
his team is collecting too many measures, a view with which he strongly
1 Price disclosed that he was co-founder of and on the board of directors at Arivale, a sci
entific wellness company that partially funded and may license discoveries from the Pioneer
100 Wellness Project.
disagrees. He explained, however, that it is important to distinguish what

he and his collaborators do with respect to discovery—trying to understand
how the human body is interconnected—from efforts focused on implemen
tation in populations as the field moves forward. The basis for the initial
study, he said, was the former. He clarified further that the relationships
among different data types can be modularized into subsets, each having
greater interconnectivity within than without, and those subsets then used
for further study.
As an example, Price used the relationship between cystine, the dimer
form of cysteine that is in the blood, and risk for inflammatory bowel dis
ease (IBD). He and his collaborators found that it is not the disease itself
but genetic risk for IBD that is related to differences in blood cystine levels.
In this particular case, the correlation detected by his team was a negative
one: on average, the higher the genetic risk score for IBD, the lower was the
amount of cystine in the blood. Price noted that case control studies have
shown that blood cystine level is also one of the best candidate biomarkers
for the disease itself. But what Price found interesting was that even without
the disease present, he and his collaborators found that this difference in
blood cystine level preexists across the life span, in individuals ranging
in age from their 20s through 89-plus, so the entire life span. He interprets
this finding to mean that this deficiency in cystine is genetic.
Another interesting aspect of this cystine–IBD relationship for Price
is that cystine lies upstream of the synthesis of glutathione, which is what
combats oxidative stress in the body, and that depressed cystine can lead to
an inability to process oxidative stress efficiently (Sido et al., 1998). Because
oxidative stress is a trigger for IBD, he explained, this depressed ability to
combat oxidative stress could be a potential mechanism for the association
between cystine genetics and increased risk for IBD. He suspects that over
a lifetime, individuals with a cystine deficiency are more likely to surpass
what he called their “reservoirs of resiliency,” thereby transitioning to some
sort of disease state. What is really fascinating to Price if this is true is that
an individual at high genetic risk for IBD could potentially change to one
at low risk for the disease through a shift in nutrition. Price termed this
finding “the manifestation of genetic risk in the body.” “Gene variants do
not mean anything in a test tube,” he remarked. “They mean something in
the body.” In his opinion, using a resource such as the PD3 clouds created
by his research team increases the chances of being able to see potential
interventions not suggested directly by genetics.

Price reported that Arivale, which, as noted above, was launched after
the successful completion of the Pioneer 100 Wellness Project, and which
collects the same types of data and provides the same type of wellness
coaching, now has 175 employees and has raised about $54 million, and
thousands of people are participating in the program. He added that the
Institute for Systems Biology has access to deidentified data from indi
viduals who participate in the program and who agree to donate their data
anonymously for research.
With respect to the value for participants, he said, “It’s really about
empowering them with data.” The program provides coaching to help
link the data collected with individuals’ behaviors so they can take action.
Technologies such as mobile apps and dashboards are used to amplify the
coaching relationship, Price noted, so that participants are receiving nearly
daily texts from their coaches. His hope is that people will remain with the
program over the course of their lifetime and that it will have an enormous
impact on their health.
Already, Price continued, there have been many cases in which partici
pants “have done the usual things,” such as lose weight and get healthier,
but there have also been people who have been directed to their physicians
because of early warning signs. As an example, he mentioned a woman
who had an early warning sign that led to the discovery of a stage III colon
cancer that was surgically removed just before it was likely to metastasize.
To provide workshop participants with a sense of other activities in
the scientific wellness space, Price briefly shared what is being done by
another personalized nutrition company, Habit, a spin-off of Campbell’s
and a company for which Price sits on the scientific advisory board. For
each individual, he reported, the company measures about 40–50 DNA
variants and blood biomarkers in participants, collects metabolic data after
they consume a “challenge shake” (a meal replacement drink), collects
information on their habits and goals, and then analyzes all these data.
Then, in a step Price characterized as very important, the company delivers
personalized food back to participants. This is important, he explained, be
cause integrating all of the information being provided and changing one’s
behavior is difficult. Thus in addition to telling customers that they need to
eat more x, y, or z, the company actually provides them with more x, y, or z.
In closing, Price observed, “We are starting to be able to gather im
mensely more kinds of data.” Additionally, the concept of the PD3 cloud
is already being put into practice. Price believes that “this kind of data can
be the foundation for the future of personalized medicine.”
SICKLE CELL DISEASE: AN ARGININE DEFICIENCY SYNDROME
WITH DISTINCTIVE NUTRITIONAL REQUIREMENTS
Claudia Morris, Emory University School of Medicine, began by stat

ing, “I am an emergency medicine physician. Most people scratch their
head wondering what I am doing talking about nutritional interventions.”

She explained that essential amino acids are dietary dependent, whereas
nonessential amino acids are not. But, she added, there are also condition
ally essential amino acids, which are nonessential but indispensable under
stress when the capacity of endogenous synthesis is surpassed. Arginine
is one of these amino acids. Morris explained that although she would be
talking mainly about arginine deficiency and its role in sickle cell disease
(SCD), she would also be discussing the role of arginine deficiency in
trauma. She noted that a number of other conditions are linked to ac
quired arginine deficiencies, including critical illness, burns, surgery, preg
nancy (where Morris observed that the deficiency is probably protective),
sepsis, pulmonary hypertension, asthma, and other hemolysis conditions
in addition to SCD (e.g., thalassemia, malaria).
What Is Arginine?
Morris explained that arginine is found naturally in the diet, with high
concentrations in meat, dairy products, seafood, nuts, and watermelon,
but it is challenging to obtain enough arginine from the diet to reverse
an acquired arginine deficiency. She noted that cardiovascular trials and
her studies in SCD utilize 7–10 grams two to three times per day, whereas
normal adult ingestion is about 2–7 grams per day. Arginine is available as
a nutritional supplement with a low toxicity and, according to Morris, is
now being marketed in the supplement world as a “natural alternative to
Viagra” in addition to its touted role in cardiovascular health.
Ultimately, Morris explained, arginine is the obligate substrate for
nitric oxide (NO) production via the NO synthase enzyme. NO, in turn, is a
potent vasodilator with multiple functions: it plays a role in blood pressure
modulation, but it also inhibits platelet aggregation, has immune response
and anti-inflammatory properties, and can be a signaling molecule.
Arginine is a substrate for arginase as well, Morris continued, which
means that arginase, an important intracellular enzyme in the urea cycle,
competes with the NO synthase enzyme (see Figure 3-1 for a schematic of
the metabolism of these different arginine processes). There are two mam
malian isoforms of arginase: arginase I, which is cytosolic, and arginase II,
which is mitochondrial. They are present in most cell types, including the
red blood cells, which, for Morris, makes arginase a very intriguing enzyme
to study in hemolytic disorders because when a red blood cell ruptures, the
arginase “gets dumped” into circulation in a physiologically active form. It
is also induced from inflammation by cytokines, she noted.
Morris went on to explain that in the presence of arginase, arginine is
converted to ornithine and urea. Interestingly, she remarked, arginine and
ornithine use the same amino acid transporters, CAT-1 and CAT-2, which
Hemolysis
Inflammation/cytokines
Liver damage
Genetic polymorphisms
Small Hypoxemia
intestine Kidney
Glutamine Citrulline Arginine
Renal
dysfunction
Inflammatory
cytokines
NOS Substrate
Arginase
competition
No consumption:
Hemolysis: cell-free Hb NO Ornithine
Uncoupled NOS
Superoxide → RNOS
Redox-active heme
Polyamines Proline
Vascular smooth muscle proliferation Collagen production/deposition

Airway remodeling Lung fibrosis
Airway remodeling
FIGURE 3-1 Metabolic pathways of the arginine processes, with arginine serving
as a common substrate for both nitric oxide (NO) and arginase.
NOTE: Hb = hemoglobin; NOS = nitric oxide synthases; RNOS = reactive nitric
oxide species.
SOURCES: Presented by Claudia Morris on December 5, 2017, from Bakshi and
Morris, 2016. Reprinted with permission from Dove Medical Press Limited.
means that when ornithine concentration is increased, it competitively

inhibits cellular uptake of arginine, thus limiting arginine bioavailability
and so decreasing NO bioavailability as well. As shown in Figure 3-1,
the downstream by-products of arginase activity are the polyamines and
prolines. The polyamines are involved in part in vascular smooth muscle
proliferation and airway modeling. The prolines play a role in collagen pro
duction and deposition, lung fibrosis, and airway remodeling, which Morris
identified as the kinds of structural changes seen in pulmonary hypertension
and asthma and as common complications in SCD.
Arginine is semiessential, Morris continued, because the body has the
ability to synthesize it through what is called “the intestinal renal axis.” The
amino acid L-glutamine is taken up in the diet, then converted into citrulline
in the enterocytes of the small intestine, and the citrulline is converted into ar
ginine in the kidney. Morris mentioned that glutamine was recently approved
by the U.S. Food and Drug Administration (FDA) for the treatment of SCD,
which makes it the first FDA-approved drug for pediatric SCD and only the
second FDA-approved drug for adults with the disorder. Morris clarified that
although glutamine is now considered a “drug” for treatment of SCD, it is
still an amino acid and a nutritional supplement. It is also what she called
“an arginine prodrug” through the intestinal–renal axis.
Turning to the bioavailability of arginine, Morris characterized it as
much more complex than the amount of arginine in the plasma. She added
that the term “global arginine bioavailability ratio”—arginine/(ornithine +
citrulline)—was coined to take into account a number of different mecha
nisms that impact arginine bioavailability, such as the effects of arginase
activity and renal dysfunction.
Amino Acid Deficiencies: Sickle Cell Disease as a Model

Morris defined SCD as an autosomal recessive inherited disease of the
red blood cells. The genetic mutation responsible for SCD, she explained, is
a single-point mutation, a substitution of valine for glutamic acid at the six
position of the beta unit of the hemoglobin molecule, which causes the
hemoglobin molecule to polymerize under stress or deoxygenation. This
“sickling,” in turn, causes a cascade of effects that ultimately decrease
blood flow. The tissue hypoxia that results causes both acute and chronic
damage to nearly every organ system, according to Morris. She added that
SCD affects about 100,000 individuals in the United States but millions of
people worldwide, and comes at significant economic cost. Interestingly, she
said, the clinical phenotype of SCD extends across a broad spectrum, from
mild to severe, far exceeding what would be expected from a single-point
mutation. So there are many other factors that come into play and that
contribute to disease severity.
In Morris’s opinion, SCD is an excellent model for distinctive nutri
tional requirements that develop from a metabolic process, the metabolic
process in the case of SCD being hemolysis. She noted that a decline in an
amino acid does not necessarily translate to a clinically significant defi
ciency. Rather, a nutritional deficiency requires a biological process that is
dependent on the nutrient that is being compromised. This compromise, in
turn, must lead to an abnormal physiological response that causes a poor
outcome, which needs to be reversible by replacement of the amino acid.
In the case of SCD, Morris elaborated, the low arginine bioavailability that
results from hemolysis is the nutritional deficiency; the endothelial dysfunc
tion is the biological process that develops in the presence of low arginine
bioavailability; pulmonary hypertension is one of the abnormal physiologi
cal responses that occurs as a result, and the one Morris said she would be
using as a model for the remainder of her presentation; and in SCD patients,
pulmonary hypertension is associated with increased mortality, which can
be reversed by amino acid replacement.
According to Morris, in addition to being a model for distinctive

nutritional requirements developing from a metabolic process, SCD is a
model for vasculopathy and endothelial dysfunction, as it involves not only
hemolysis but also inflammation, NO depletion, and arginine depletion.
With SCD-related vasculopathy and endothelial dysfunction depletion, NO
depletion takes “center stage,” she said. This is the case because with
hemolysis, all of the contents that are normally packaged within a red
blood cell dump into circulation when the cell breaks apart. These contents
include hemoglobin, which, now cell-free, rapidly consumes NO, as well
as arginase, which when dumped into circulation rapidly consumes the
obligate substrate for NO production. As arginine level depletes, Morris
continued, the NO synthase enzyme also begins to malfunction, uncoupling
and producing superoxide in lieu of NO and adding to what she described
as “this milieu of oxidative stress.” In sum, she said, there is a “global
dysfunction of the arginine-NO pathway,” with many of these breakdowns
occurring simultaneously.
Morris went on to explain that decreased NO bioavailability has sev
eral biological consequences, including endothelial activation, increased
endothelin-1 (a potent vasoconstrictor), increased vasoconstriction, and
increased platelet activation. There are several clinical consequences as well,
she observed, including pulmonary hypertension, asthma, stroke, renal in
sufficiency, priapism, and leg ulcers. Although she said she would go on to
focus on pulmonary hypertension in particular, she noted that all of these
clinical manifestations are hemolytic subphenotypes of both SCD and low
arginine bioavailability.
Also within the red blood cells, Morris noted, is lactase dehydrogenase
(LDH). She explained that LDH is commonly thought not to be of clini
cal significance when dumped into circulation, but makes for a convenient
biomarker of the hemolytic subphenotype of SCD first reported by Dr. Greg
Kato and colleagues (Kato et al., 2006).
Arginine Deficiency and Sickle Cell Disease

Morris went on to discuss her work with SCD and arginine insuf
ficiency, beginning with a 2005 study through which she and her research
team discovered that patients with SCD have a plasma arginine insuf
ficiency and elevated plasma arginase activity (Morris et al., 2005a). She
clarified that because arginase is an intracellular enzyme, it is released only
upon cell damage or cell death. “It just should not be in your plasma if
you are a healthy individual,” she said. As part of the same study, Morris
and colleagues (2005a) also examined the arginine-to-ornithine ratio, again
because in the presence of arginase, arginine converts into ornithine, and
they found a low arginine-to-ornithine ratio in patients with SCD compared
with normal controls. But “where it got interesting,” Morris said, was that
the lowest levels were found in the patients at highest risk for pulmonary
hypertension. She noted that not all patients with SCD develop pulmonary
hypertension—only about 10 percent—but that these results led her to pay
more attention to pulmonary hypertension.
Morris and her collaborators hypothesized, “if it is low, give it back.”
So they conducted a small study of arginine replacement and observed a
greater than 15 percent decrease in pulmonary systolic pressures, as esti
mated by Doppler echocardiography (Morris et al., 2003). Morris charac
terized this finding as “pretty impressive” (see Figure 3-2), noting that this
decline is similar to that observed with on-the-market pulmonary hyperten-
FIGURE 3-2 Changes in pulmonary artery systolic pressures before and after
arginine therapy (pulmonary artery systolic pressure reduced by a mean of 15.2
percent).
SOURCES: Presented by Claudia Morris on December 5, 2017, from Morris et al.,
2003. Reprinted with permission of the American Thoracic Society. Copyright ©
2018 American Thoracic Society. The American Journal of Respiratory and Critical
Care Medicine is an official journal of the American Thoracic Society.
sion medicine. She interprets this finding to mean that there is a condition
of endothelial dysfunction, manifesting as pulmonary hypertension, that
appears to be reversed with arginine therapy. In addition to being excited
about the decline shown in Figure 3-2, Morris and her team observed,
anecdotally, that leg ulcers started to heal on two of these patients, both of
whom had been experiencing chronic leg ulcers for years.
The next step, Morris said, was to consider another hemolytic anemia,
thalassemia, that was also known to be associated with a high prevalence
of pulmonary hypertension. So her team looked at some of their patients in
the thalassemia clinic and found a similar pattern of arginine dysregulation
(Morris et al., 2005b). More specifically, compared with controls, patients
with thalassemia had, on average, higher-than-normal arginase activity,
lower arginine-to-ornithine ratios, and elevated levels of the downstream
by-products proline and citrulline. The higher level of citrulline suggested to
Morris that there might be problems with converting citrulline to arginine.
Morris reported, however, that it was not until her team returned to
the thalassemia clinic 10 years later and looked specifically at patients who
were at risk for pulmonary hypertension that they found that some of the
thalassemia patients had completely normal arginine levels, and that it was
mainly patients who were at risk for pulmonary hypertension who had
dysregulated arginine metabolism (Morris et al., 2015). That is, compared
with thalassemia patients who were not at risk for pulmonary hypertension,
those who were at risk had low arginine levels, high arginase activity, low
arginine-to-ornithine ratios, and low global arginine bioavailability ratios.
In her studies of both SCD and thalassemia, Morris observed that that
the severity of pulmonary hypertension and cardiopulmonary dysfunction
correlated strongly with biomarkers of hemolytic rate. But what she char
acterized as “really fascinating” was that low global arginine bioavailability
was also associated with increased risk of death in adults with SCD: there
had been no deaths among patients with the highest bioavailability and the
greatest number of deaths among those with the lowest bioavailability. She
noted that Cox and colleagues (2018) obtained the same finding in children
with SCD in Tanzania. Additionally, she said, low arginine bioavailability
predicts early mortality in adults with malaria.
Morris reported that in separate work, Dr. Stan Hazen, a cardiologist,
and his colleagues followed a group of nearly 1,000 patients who were at
risk for cardiovascular disease and were undergoing right heart cardiac
catheterization. After 3 years, they found that a reduced global arginine
bioavailability ratio was prospectively associated with an increased in
cidence of major adverse cardiovascular events (Tang et al., 2009). The
researchers looked at death, myocardial infarction, and stroke. Addition
ally, Morris said, they found that the global arginine bioavailability ratio
was more predictive than cholesterol of cardiovascular disease, suggesting
to her, first, that this ratio is important for survival and, second, that it is
a biomarker of vasculopathy that goes beyond SCD.
Morris pointed out that, while there are a number of different mecha
nisms of arginine dysregulation, many acting simultaneously, a common
theme in arginine deficiency syndromes is excess arginase activity. So, she
stated, whether hepatic, immune, or from hemolyzed red blood cells during
hemolysis or transfusion reactions—that is, regardless of cellular origin—
the physiological effects and clinical consequences of excess extracellular
arginase are similar.
Arginine Deficiency and Trauma

In addition to conditions involving endothelial dysfunctions such as
SCD, Morris continued, are arginine deficiency–related conditions related
to T cell dysfunction, trauma being one example. Arginine is essential for
naïve T cell activation, she explained, and T cells are “exquisitely sensitive”
to arginine depletion. T cell proliferation is blunted and T lymphocyte–
mediated cytotoxicity and memory responses are almost entirely abolished
when arginine is depleted. But again, Morris said, “give it back, and you
fix the problem.” Indeed, providing arginine to culture media restores T
cell function.
As Morris had suggested earlier, T cell dysfunction may be protective in
pregnancy, when a women needs to suppress her immune system to protect
both herself and the fetus. But with trauma, she said, T cell dysfunction
increases susceptibility to infection. Plasma arginine levels decrease within
minutes to hours of a traumatic event and can remain low for up to a week
or longer. Morris pointed out that it was one of the pioneers in the field,
Dr. Juan Ochoa, who helped her and her team understand plasma arginase
activity increases in trauma patients as a result of myeloid-derived suppres
sor cells that express arginase I after trauma. So in contrast to SCD, she
continued, where it is the red blood cells that are dumping arginase from
hemolysis, the cell source in trauma is different, but it similarly increases
arginase. The increased arginase leads in turn to the arginine deficiency,
ultimately translating into T cell dysfunction and increased susceptibility
to infection.
Morris went on to observe that more than 15 million injuries occur
each year in the United States, and about 10 percent of trauma patients
develop wound infections. The infection rate increases to 30 percent for
patients who have been in an intensive care unit (ICU) for more than
48 hours. Infections are the leading cause of late organ failure, Morris
noted, and they contribute to about 10 percent of trauma deaths. Thus,
she suggested, strategies aimed at infection prevention after trauma should
result in significant decreased mortality, morbidity, and cost.
The Therapeutic Potential of L-Arginine

According to Morris, the therapeutic potential of arginine for SCD has
been studied for 20 years. She reported that in a sickle cell mouse model,
arginine supplementation has been shown to improve perfusion, increase
glutathione levels (with an effect on oxidative stress), decrease inflamma
tion, help heal lung injury, reverse micro-vascular vaso-occlusion, and
decrease mortality. However, what Morris finds interesting about a sickle
cell mouse model is that mice do not have arginase in their red blood cells
as do humans, yet they have increased arginase activity. So the arginase is
coming from a source other than the erythrocyte, she explained, and not
necessarily through the process of hemolysis.
Morris noted further that several human phase II studies have shown
that arginine therapy improves leg ulcers. Also in humans, she and her team
conducted a vaso-occlusive pain trial in which children with SCD admit
ted to the hospital with acute SCD-related pain were treated with arginine
versus placebo. She reported that those treated with arginine showed a
55 percent decrease in total opioid use (mg/kg) and lower pain scores at
discharge. She mentioned that she was currently working with FDA to com
plete a second phase II trial, with plans for a phase III multicenter study.
She also referred to data she had presented earlier showing decreased pul
monary hypertension with arginine therapy (see Figure 3-2). Anecdotally,
she added, arginine has improved priapism in the emergency room the few
times she has used it for that purpose.
With respect to trauma, Morris reported that arginine therapy has been
shown to enhance wound healing after trauma and hemorrhagic shock;
immunonutrition has been found to improve immune responses and T cell
function; and high arginine formulas have been shown to decrease infection
complications in critically ill patients, with the greatest benefit for surgical
patients. However, she added, there is also evidence of harm in sepsis and
following acute myocardial infarction. “So we don’t have all the answers
yet,” she said. Moreover, most of these studies have had a number of meth
odological weaknesses, and, as discussed below, there is a paucity of data
in children.
Immunonutrition in Critically Ill Children

Regarding immunonutrition in critically ill children, Morris said she
was shocked by results of a 2009 Cochrane review that found insufficient
evidence either for or against nutritional support in children during the
first week of a critical illness, mainly because the appropriate studies had
not been performed. She noted that some pediatric ICU doctors have inter
preted this finding to mean that some of the sickest children in the hospital
should not be fed—even trauma patients, some of whom, she said, are
basically being starved for days.
In addition to the Cochrane review, Morris mentioned a randomized
controlled trial of arginine/glutamine-fortified formula among 40 children
with traumatic brain injury (Briassoulis et al., 2006). The primary outcome
measure was mortality. The authors found no difference in mortality com
pared with standard formula. According to Morris, however, fewer than
10 percent of pediatric trauma patients die, so the study was severely under
powered for its primary outcome. What she did find enlightening was that 69
percent of patients who received fortified formula had a positive nitrogen bal
ance by day 5, compared with 31 percent of patients who received standard
formula. Morris cited another, multicenter prospective cohort study of more
than 1,000 mechanically ventilated children, in which Mehta and colleagues
(2015) found decreased 60-day mortality among patients who had adequate
protein intake. She reported that the same group recently published data
showing similar findings in surgical trauma patients (Velazco et al., 2017).
“This certainly gives me pause,” she said, “and it also suggests that we have
gotten it wrong all these years. It is not overall calories, but it is enteral pro
tein delivery [impacting important clinical outcomes].” She described enteral
protein delivery as “a modifiable risk factor for mortality that is in dire need
of a shift in our current practice, given the potential for improved outcomes.”
Therapeutic Strategies
Morris suggested several other therapeutic strategies to consider in
addition to arginine supplementation: arginine precursors such as citrulline
and glutamine; combination therapies that target multiple mechanisms; and
immunonutrition, particularly targeted enteral formulas, although the ideal
formulas for trauma, critical illness, hemoglobinopathies, and pediatrics do
not yet exist. She urged more research in this area.
Final Remarks
Morris concluded by listing several final points:
• Arginine is a conditionally essential amino acid that becomes essen

tial under conditions of stress and catabolic states, when the capacity
of endogenous amino acid synthesis is exceeded. This occurs in such
cases as critical illness, trauma, and hemolysis.
• SCD and trauma represent arginine deficiency syndromes, and they
pose a distinct nutritional requirement that develops because of
their metabolic abnormalities. Thus, they may benefit from arginine
replacement therapy.
• There are at least two broad categories of arginine deficiency syn

dromes: (1) T cell dysfunction (e.g., trauma), and (2) endothelial
dysfunction (e.g., SCD).
• The global arginine bioavailability ratio may be a novel biomarker
of arginine deficiency, and as such warrants further study.
• Arginine-fortified immunonutrition may be a treatment for acquired
arginine deficiencies. Morris called for future studies to identify sub
populations that would benefit most, with potential adverse events
being minimized.
Morris closed by stating, “Nutrition is medicine!”
PERSONALIZED NUTRITION IN THE REAL
WORLD: WHERE DO WE STAND?
David Alpers, Washington University School of Medicine, began his

presentation by saying, “We are in this room to try to figure out where
nutrigenomics is.” “We have heard a lot of evidence that has tremendous
promise,” he added, including evidence indicating that behavior has an
enormous influence on what people do in terms of nutrition and that this
behavior may be modifiable (Meisel et al., 2015). Yet, he asserted, despite
this evidence and despite the great number of genetic tests already avail
able, most based on single nucleotide polymorphisms (SNPs), few studies
are informative about how to influence clinical behavior in nutrition. He
discussed why useful studies will be difficult, but not impossible, and why
“we are just at the early stages of where we can utilize this information.”
According to Alpers, nutrigenomics studies are difficult, first, because
they require isolation of the effects of different individual genes and dif
ferent individual foods, initially by themselves and then in combination,
using adequate control arms. Thus far, he said, upon examination of either
isolated genes or isolated nutrients, such as antioxidants and vitamin A,
the results “have not been very impressive.” A second reason for the dif
ficulty of nutrigenomics studies is the challenge of proving causation from
associations, a challenge he discussed in more detail, as summarized below.
The Challenge of Nutrigenomics Studies: Proving Causation

Alpers explained how the Bradford-Hill criteria for causal association
are particularly difficult to achieve in nutrition-related studies (Bruemmer et
al., 2009). He noted that while the Bradford-Hill criteria are not “absolute
criteria,” they do provide a rough “scaling” of how to interpret associations.
For example, one of the Bradford-Hill criteria is that there be a strong
association. According to Alpers, however, this is not the case for many of
the associations that have been reported between nutrition and either genetic
or metabolic change. A second Bradford-Hill criterion is that the association
be constant. But at present, Alpers said, most nutrigenomics associations are
based on only a few studies, which makes it difficult to assess constancy. A
third Bradford-Hill criterion, Alpers continued, is that there be one cause
and one effect. He pointed out, however, that in nutrition, particularly in
nutrigenomics, where the goal is to prevent disease in relatively healthy
people, it is very difficult to narrow an association down to one cause and
one effect because there are so many components to the diet and because
those components interact, causing multiple metabolic changes to the diet.
He added that this complexity extends even to inherited diseases caused
by single genetic changes, such as what Morris had discussed. A fourth
Bradford-Hill criterion is that there be a dose-response relationship. Alpers
noted that although these relationships exist in genetic studies when one
allele is variably knocked out, they are not usually available for the sponta
neous SNPs found in association studies. A fifth Bradford-Hill criterion is
that there be scientific justification for an association. According to Alpers,
although there is always scientific justification for nutrition-related gene
associations, some of it quite convincing in his opinion, few of these justi
fications are based on clinical data. Most are based on in vitro and animal
data. A sixth Bradford-Hill criterion is that the association be coherent with
other data. In nutrition, however, other data are often quite limited, Alpers
explained. A final Bradford-Hill criterion is that interventions have been
tested in randomized controlled trials. Again, however, such studies are very
difficult to perform, Alpers said.
The Challenge of Nutrigenomics Studies: Isolating
Nutrition-Related Phenotypic Effects
Alpers continued by pointing out that, in addition to the challenge of

proving causation, another challenge to linking nutrition to genomics is the
fact that, except for diseases caused by single gene defects, it is very difficult
to isolate which components of the phenotype are related to nutrition and
which to other factors. He elaborated on this challenge in the context of
malnutrition, but remarked that his conclusions were just as applicable to
the prevention of disease.
Alpers observed that, although a number of organizations have devel
oped consensus criteria for malnutrition—that is, criteria that indicate
whether a person is malnourished (White et al., 2012)—in clinical practice
there are in fact two major types of malnutrition (Jensen et al., 2010). The
first is pure starvation with no or limited inflammation, whereby if nutrients
are given back, the phenotype is reversed. The second is malnutrition either
in chronic disease, where mild or moderate inflammation and/or other fac
tors are frequently superimposed, or in acute disease or injury with marked

inflammation.
Alpers explained that chronic diseases with malnutrition include, for
example, obesity, rheumatoid arthritis, inflammatory bowel disease, and
cancer. But in the case of chronic disease, he noted, clinicians can have no
idea what effect replacing nutrition will have on the phenotype. Although
there are certainly differences among individuals, he said, “usually by the
time we see a well-developed chronic disease, the effects of the disease itself
are more potent than that of nutritional deficiencies.” Acute diseases or
injuries with marked inflammation include trauma, as discussed by Morris,
and major infections and burns.
According to Alpers, many of these same kinds of chronic disease/
malnutrition conditions are the same disorders for which genomic links
have been sought in past studies (e.g., obesity, cancer, type 2 diabetes,
aging, even pregnancy). But again, he noted, most of these conditions
have a component of inflammation, and only conditions with no or lim
ited inflammation respond in a clear manner to nutrient supplementation.
Thus, he observed, any change in phenotype may be related to nutritional
supplementation only by chance or in part.
According to Alpers, the question then arises of what approaches have
been used to try to link genetic or genomic effects to nutritional phenotypes.
He referenced the large body of in vitro and in vivo animal studies carried
out to support the rationale for such a link. He cited the example of cancer
research, with many studies showing that curcumin, turmeric, garlic ex
tract, and other nutrient components have potent roles in preventing some
of the changes that occur during cancer in cells or in animals. But these
findings have yet to be translated into human data, he cautioned.
Alpers went on to point out that the few human data that do exist are
often less suggestive, citing studies on caffeine metabolism, omega-3 supple
mentation, and antioxidant supplementation. For example, he observed,
even though the antioxidant pathway has been well explicated in a variety
of diseases, including cancer and a number of degenerative diseases, the
antioxidant theory of human disease, which was quite prevalent many years
ago, has not yet been proven by clinical studies. He finds the mitochon
drial story potentially a very powerful one (see Chapter 2 for a summary
of Douglas Wallace’s presentation on mitochondria), but one without the
necessary clinical data at present.
Alpers observed further that with human data, some genetic factors
that can be detected—such as human leukocyte antigen (HLA) subtypes for
celiac disease—are not sensitive enough. It is known, he pointed out, that
the two subtypes found in almost all cases of celiac disease are also highly
prevalent among individuals who do not have celiac disease. Sometimes, he
noted, more information is needed than just the genetic change.
Alpers also pointed to other genetic factors that add little to clinical
information. To illustrate this point, he explained that while it has been
known for decades which genetic changes are determinative of lactose
intolerance in humans, this same determination can be made clinically by
removing milk products from an individual’s diet and seeing whether the
person responds. “So we have not needed that information yet to get per
sonalized in that particular condition,” he said.
Alpers cited as a final challenge to the scientific approaches link
ing genomics to nutrition that again, many chronic diseases—obesity in
particular—are also related to the phenotype of chronic inflammation/
malnutrition. He identified as the challenge with obesity and other nutri
tional disorders, including to some extent even diabetes, that management
with the standard-of-care nutritional advice is difficult by itself and often
is not fully implemented. While the use of individual coaches is, he said,
“a wonderful thing” (see the summary of Price’s presentation earlier in this
chapter), with such coaching being what trained dietitians provide, he be
lieves the field will need to move much further along in terms of its use of
cell phones and other technologies before individualized coaching becomes
a widespread phenomenon.
Alpers expects a long lag time before strong nutrigenomics data be
come available, and he predicted that such data would become available
one disease at a time. “There is not going to be any great breakthrough,”
he said. “I think we need definite effects on a clinical basis before we can
really implement these things fully commercially.”
Exploring Current and Future Directions of Personalized Nutrition

Alpers identified three current and future trends in personalized nutri
tion. First, many currently available personalized Internet services provide
people with information based on an analysis of their dietary patterns,
although, according to Alpers, none of these services have anything to
do with genomics (Gibney and Walsh, 2013). Moreover, he asserted, the
dietary patterns reported by individuals are often biased, although he be
lieves this perhaps could be changed with education. He suggested that the
difference between meal-based and food component–based information
also will need to be addressed. He added that many of these services are
mobile phone–based. Thus at present, the uptake of these systems has been
much greater among adolescents, who have grown up with cell phones,
than among adults, Alpers expects this situation will change with time and
as the population becomes more accustomed to the technology. And despite
these challenges, he predicts that in the future, personalized Internet services
will become a potent method for modifying behavior, potentially leading to
changes in clinical outcomes (once those changes in clinical outcomes have
been identified). He cautioned, however, that recidivism may be a problem,

as it currently is with weight loss diets, noting that “it is very hard to keep
up a change in behavior that hasn’t been lifelong up until now.” He added
that while these programs have as yet nothing to do with genomics, if
it can be shown that behavior is changed in a meaningful way, those lessons
can be incorporated into what is learned in the future about the role of
genetics in modifying disease phenotypes.
A second personalized nutrition trend discussed by Alpers is the use of
phenotypic data. He remarked that although the phenotype is more difficult
to study than the genome because of the difficulty of conducting a large
phenotypic study with clear clinical relevance, there are a few examples
of such studies. He cited a study in which monitoring urine sodium and
decreasing sodium-containing foods was found to have an effect on blood
pressure (Yamasue et al., 2006). This intervention appeared to work, he ob
served, although in the face of relatively high sodium intake, indicating that
the effect of altering sodium intake is modest. He cited another example
involving the use of a wristwatch accelerometer to monitor physical activ
ity and deliver relevant information (Hurling et al., 2007). He described
these studies as being among a number of wellness programs, suggesting
that such programs do work. But again, he stressed, what is missing is
knowledge of whether this type of program will actually change a disease
phenotype, as well as how long people will stay with the program. As a
final example, Alpers cited a number of studies of blood tests that are used
to analyze metabolites and develop metabolic profiles. He clarified that
these are metabolic analyses, not metabolomics analyses, which he said “are
coming.” One of these studies looked at the effect of vitamin D supplemen
tation, finding no effect on metabolites (O’Sullivan et al., 2011). In sum,
Alpers stated that these types of studies have many problems that he did
not have time to discuss during his presentation, but that such studies will
be necessary to examine personalized nutrition with respect to phenotypic
changes.
The third and final trend Alpers discussed is personalized nutrition
based on genomic data. He observed that at present, most of the informa
tion in this area comes from observational studies linking SNPs to dietary
patterns. “That’s not really enough in itself,” he argued. While it has been
shown, he elaborated, that certain SNPs can cause metabolic changes—such
as in the methylenetetrahydrofolate reductase gene, MTHFR—that have
been shown to change homocysteine levels in TT individuals who receive
riboflavin supplementation (McNulty et al., 2006), again that association
has yet to be translated into a change in disease phenotype.
Alpers emphasized that, with all three of these approaches, it is dif
ficult to predict the extent to which a user will want just a “one-off” result
or will maintain the service in the long term. In his opinion, some of the
programs currently available are providing good incentives for people to

stay with them, but what is needed is a service that can be delivered over
the long term and will eventually show that its delivery leads to a change
in disease progression or occurrence. While just making people feel good is
worthwhile, he said, “that is not really what we are talking about [in this
workshop].”
In closing, Alpers mentioned that some Food4Me studies under way
in the European Union are developing data on consumer responses. These
include a study just published in the American Journal of Clinical Nutri
tion in which individuals who were told that they had the FTO variant
associated with risk of obesity lost more weight over 6 months relative to
individuals who were not told whether they had the variant (Celis-Morales
et al., 2017). The difference was small, Alpers said, but he suspected that
it would have been greater if the study had lasted longer than 6 months.
Additionally, he noted that members of the control group were told nothing
about their genetic risk and that to serve as a real control group, they
should have been told something definite but unrelated.
In closing, Alpers stated, “The concept of genomics for personalized
nutrition is a sound one, and many of the strategies are in place. What is
missing is the data that translate those strategies or the preclinical work to
actual clinical outcomes. It will occur. It will be difficult but it will occur
slowly. We just need to be patient.”
IS GENETIC TESTING FOR PERSONALIZED NUTRITION
READY FOR PRIME TIME?
Ahmed El-Sohemy, University of Toronto, began by saying that he

would be discussing some of the translational activities under way at a
company, Nutrigenomix, he had founded and for which he serves as chief
science officer. He also holds shares in the company. He clarified that
Nutrigenomix is not a direct-to-consumer genetic testing company, but
provides a service to health care practitioners, mainly registered dietitians
but also some physicians who practice functional and integrative medicine.
At the time of the workshop, the company was serving more than 6,000
practitioners in 35 countries and providing reports in 8 languages.
El-Sohemy asserted that genetic testing for personalized nutrition is
indeed ready for prime time. While he agreed with many of Alpers’s com
ments, he said he would also be presenting evidence to support his opinion
that many of the skeptics’ criticisms “are actually not true.” However, he
acknowledged that the field is not without controversy, as there are many
different kinds of operators, and the evidence base behind much of what
is being offered is quite varied. He characterized some of what is being of
fered as “on the fringe or not really rooted in robust scientific evidence.”
He pointed to the many articles in the media questioning the validity of

personalized dietary tests, and while he agrees that it is important to keep
these companies honest, he asserted, “It is also not right to lump all of them
in one basket and say that the whole field is all just snake oil.”
Part of the controversy, in El-Sohemy’s opinion, is due to the different
kinds of tests on the market. He emphasized the importance of distinguish
ing between disease risk genes, which are often identified through genetic
association studies, and what he refers to as modifier, or metabolic, genes.
The latter are genes that are not by themselves related to any phenotype
or health outcome, but modify the effect of an environmental factor on a
phenotype or health outcome. El-Sohemy cited as an example that a genetic
variant for a drug-metabolizing enzyme or a drug transporter does not
necessarily cause any adverse effect by itself, but if someone with one of
these particular genetic variants is prescribed a certain drug, he or she may
experience an adverse reaction. He noted that although this analogy is from
pharmacogenetics, it applies to nutrition as well.
Why Are Genetic Differences Important for Nutrition?

With respect to why it is important to look at genetics in the field
of nutrition, El-Sohemy remarked that if one looks at the link between
virtually any nutritional factor and any health outcome for which there
have been enough observational studies, one will see a heterogeneity of
responses, with some studies showing increased effects, some no effect, and
others completely opposite effects. There are, he observed, many reasons
for the inconsistencies among studies, but an important consideration is the
genetics of the groups or population being studied. For example, he noted,
some people who go on a low-sodium diet actually experience an increase
in blood pressure. These people used to be thought of as outliers, he said,
but these so-called outliers are increasingly being recognized as very real.
“So what if you are an outlier,” he asked, “and the advice that we are giving
you is actually causing harm?” If there is a way to identify these individuals
and find alternative strategies for them, he suggested, that is something to
consider. “One size does not fit all,” he pointed out.
As proof of concept, El-Sohemy described some of his early work on
caffeine and cardiovascular disease. He and his collaborators found that
in fast metabolizers (CYP1A2 AA), moderate coffee consumption was
associated with a lower risk of myocardial infarction, whereas in slow
metabolizers (CYP1A2 AC + CC), consumption of even two to three cups
per day was linked with a higher risk of that outcome (Cornelis et al., 2006;
see Figure 3-3). A couple of years later, he reported, these findings were
replicated by a research group in Italy, looking not at myocardial infarction
but at the risk of developing hypertension (Palatini et al., 2009). Theirs was
4
<1 cup/d *
1 cup/d
3 2-3 cups/d *
Odds Ratio
≥4 cups/d
2
1
* *
0
AA AC + CC
CYP1A2 Genotype
* P<0.05
FIGURE 3-3 The difference in risk of myocardial infarction between fast metabolizers
(AA) and slow metabolizers (AA + AC).
SOURCES: Presented by Ahmed El-Sohemy on December 5, 2017, from Cornelius
et al., 2006.
a prospective study, he explained, for which the researchers recruited people

who were prehypertensive, genotyped them, assessed their coffee consump
tion, then monitored them over a few years. They found a similar pattern,
with the fast metabolizers being protected against the risk of hypertension,
while the slow metabolizers experienced the opposite effect. The pattern
was replicated yet again a few years later with respect to risk of prediabetes,
with coffee consumption being found to increase the risk of impaired fast
ing glucose among slow metabolizers but not among fast metabolizers
(Palatini et al., 2015). More recently, El-Sohemy’s group collaborated with
the Italian research group to look at kidney function and again found a
similar pattern, with no increased risk of impaired kidney function (as mea
sured by glomerular filtration rate) among fast metabolizers but a strong
increased risk among slow metabolizers.
In addition to these observational studies, El-Sohemy and his team
conducted a randomized controlled intervention trial of endurance per
formance in athletes. They recruited individuals and, based on genotype,
randomized them to receive either placebo or one of two different doses
of caffeine. They found that fast metabolizers benefited more from the caf
feine, whereas slow metabolizers showed no improvement in performance
(Guest et al., 2018).
In summary, El-Sohemy said, myocardial infarction, hypertension, pre
diabetes, and kidney function all show the same pattern. “If you are a slow
metabolizer,” he observed, “you should probably limit your intake to no

more than two cups a day. If you are a fast metabolizer, you are lucky. You
can follow the general recommendations, which suggest that you can drink
up to four cups a day.”
Media Messages
El-Sohemy then showed the image of a headline for a 2015 The Wash
ington Post article: “Government panel said drinking coffee is harmless.
Why that might be wrong.” The subheadline read: “A U.S. panel said
coffee can be part of a healthy diet. That might be true for only half of
us.” According to El-Sohemy, the journalist cited some of the work on fast
versus slow metabolizers and wondered why these one-size-fits-all recom
mendations are still be being issued when the science suggests otherwise
(Whoriskey, 2015).
El-Sohemy added that one of the quotes in the article was from
Sander Greenland, an epidemiology professor emeritus at the University of
California, Los Angeles, who said, “There are spectacular metabolic differ
ences in people, and to expect that coffee will have the same health effects
on everyone is absurd.” El-Sohemy agreed with this assessment. He found it
interesting that the journalist also interviewed a member of the government
panel, who said, “Unfortunately, because genetic testing is expensive and
rarely done, most people have little idea which gene variant they carry.”
El-Sohemy agreed that this, too, was a fair observation, saying, “There is
no point in making recommendations based on a bit of information that
people do not have access to.”
For El-Sohemy, this quote by the panel member is significant because
it implies that, if genetic testing were inexpensive and everyone knew what
gene variant he or she had, the recommendation about drinking coffee
would to some extent have taken the science into account. Such issues that
relate to the economic and social aspects of genetic testing, such as how to
make the information accessible to everyone, are very legitimate topics of
discussion, in his view. He believes “there are some really good examples
of proof of concept at how . . . a single SNP can modify the association
between a dietary component and a variety of different health outcomes.”
El-Sohemy then cited a paper that appeared in The BMJ just prior to
the workshop. Poole and colleagues (2017) conducted a review of about
200 meta-analyses of coffee consumption and multiple health outcomes and
concluded that the totality of the evidence suggests a protective effect for
a number of these outcomes. A BBC News article responding to this was
headlined, “Three cups of coffee a day may have health benefits” (Roxby,
2017). Unfortunately, El-Sohemy said, “at the end of the day, people want
to know what they can do for themselves, and when they see headlines like
this, they falsely assume that coffee is safe to consume.” But he emphasized
that if slow metabolizers were to follow those recommendations, they
would actually increase their risk for multiple health conditions. He as
serted that the conclusion of the review suggests that the majority of partici
pants in the studies included in the review were probably fast metabolizers.
He pointed out that if a study population comprised only 60 percent fast
metabolizers and 40 percent slow metabolizers, the fast metabolizer effect
would still predominate. “We need to move away from these kinds of
studies,” he argued. “Bigger is not necessarily better. You have to look at
the quality of the scientific evidence.”
To this end, El-Sohemy and Raffaele De Caterina wrote what he said
was the first consensus article of the International Society for Nutrigenetics
and Nutrigenomics reviewing the scientific evidence that would enable
DNA-based dietary advice on the consumption of caffeine (De Caterina
and El-Sohemy, 2016). He mentioned another article, published recently
in Genes and Nutrition, in which he and his co-authors propose certain
guidelines for evaluating the scientific evidence for formulating DNA-based
dietary advice (Grimaldi et al., 2017). He also cited an article that appeared
in The New York Times headlined “For Coffee Drinkers, the Buzz May
Be in Your Genes.” Although the research had been completed several
years earlier, he added, the journalist reminded readers that the association
between coffee and health appears to be dependent on individual genetic
variation (O’Connor, 2016).
Still, El-Sohemy continued, there is no shortage of articles that ques
tion the validity of the entire field, referring in particular to an article that
had appeared in the week just prior to the workshop titled “DNA-Based
Diet Advice Is Big Business with Little Scientific Support” (Entis, 2017).
He pointed out that one of the individuals interviewed in this article was
a pediatrician and author of The Bad Food Bible (Carroll, 2017). The
journalist wrote:
There’s no evidence that some people respond better to high-fat diets while
others are more receptive to diets packed with protein or complex carbs.
“It doesn’t exist,” [Carroll] says. Even if it did, “there’s no evidence we
could detect it” through DNA sequencing. Metabolic illnesses and disor
ders such as celiac disease or lactose intolerance aside, humans’ genes are
very similar. We have evolved to be able to eat the same foods.
El-Sohemy reminded the workshop participants, however, that José

Ordovás had already presented evidence showing an association between
APOA2 and saturated fat (see Chapter 2 for a summary of Ordovás’s
presentation). El-Sohemy cited other studies as well, such as the POUNDS
LOST study, a 2-year randomized controlled trial comparing the effects of
a high-protein versus a low-protein diet, that have found similar associa

tions. He reported that, as part of the POUNDS LOST study, Zhang and
colleagues (2012) had found a significant loss of fat mass after 2 years of a
high-protein diet, but only among individuals with an FTO AA genotype.
Individuals with an AA genotype showed no change in fat mass on a low-
protein diet, and individuals with either a TT or TA genotype showed no
change in fat mass on either a high- or low-protein diet. “When it comes
to the gold standard of scientific evidence,” El-Sohemy asserted, “I think
this is pretty robust.” He added that this evidence has since been replicated
in a distinct population in Spain. In that study, de Luis and colleagues
(2015) showed that a high-protein diet is effective for weight loss only in
individuals with the AA genotype. El-Sohemy and his team have replicated
these findings yet again, in a distinct, East Asian population, in which indi
viduals with the AA genotype had a waist circumference roughly 10 cm
greater when not on a high-protein diet (Merritt et al., 2018). What these
findings show, El-Sohemy argued, is that while FTO has been used in the
past as a predictor for obesity, it is also a modifier gene that indicates
whether someone is likely to benefit from a high-protein diet.
Personalized Dietary Advice Versus Public Health Recommendations

El-Sohemy agreed with Patsy Brannon’s prediction that the future
would likely see the integration of personalized dietary advice with public
health recommendations (see Chapter 1 for a summary of Brannon’s presen
tation). In the meantime, he said, there is some disagreement about whether
providing people with genetic information is actually helpful. Some argue
that if a person knows that something is “in my genes,” he or she will not
be motivated to do anything in response. Others argue the opposite: that
someone aware of having a particular gene will be motivated to watch what
he or she eats. For example, people who knew they were slow metabolizers
of coffee would cut back on coffee. Likewise, people told that they have the
risk variant for salt-sensitive hypertension would lower their sodium intake.
El-Sohemy and his collaborators decided to put this notion to the
test and conduct a randomized controlled trial comparing DNA-based
dietary advice with standard recommendations (Nielsen and El-Sohemy,
2012). They found that those who received the DNA-based dietary advice
actually understood the recommendations to a greater extent relative to
those who received the standard recommendations, and were motivated
to change their eating habits. In fact, El-Sohemy reported, they did change
their eating habits and had maintained those changes 1 year later (Nielsen
and El-Sohemy, 2014). The biggest effect, he noted, was with salt-sensitive
hypertension in individuals told that they had the risk variant for that
phenotype.
That DNA-based dietary advice can motivate behavior change has since
been replicated by a group in Finland, El-Sohemy continued, with a differ
ent kind of genetic information and different outcomes (Hietaranta-Luoma
et al., 2014), as well as in the Food4Me trial (Celis-Morales et al., 2017;
Livingstone et al., 2016). He cited yet another study of behavior change in
response to receiving genetic information, in which Green and Farahany
(2014) showed that 42 percent of people surveyed reported positive changes
in their health behavior. Many people reported changing their exercise
habits (61 percent), and the vast majority reported changing their dietary
patterns (72 percent). Finally, El-Sohemy cited a recent study by Nielsen
and colleagues (2017), showing again that while not everyone changes be
havior in response to receiving genetic information, providing people with
the right kind of information can be a very useful way to get at least some
people to change their eating habits.
What Do the Skeptics Say?

Again, El-Sohemy posed the question, What do the skeptics say? He
mentioned the Academy of Nutrition and Dietetics’ position paper on nutri
tional genomics, which states: “Applying nutritional genomics in clinical
practice through the use of genetic testing requires that registered dietitian
nutritionists understand, interpret, and communicate complex test results
in which the actual risk of developing a disease may not be known” (Camp
and Trujillo, 2014). El-Sohemy questioned the use of the word “complex”
and remarked that risk in nutrition is always relative, never actual, viewing
this as a message to “spook” dietitians away from this type of testing. He
noted that the position paper had been pulled a couple of months prior to
the workshop so that the scientific evidence could be re-reviewed.
More generally, El-Sohemy continued, a frequent comment is that
single SNPs are useless. In his opinion, there are a number of good examples
of single SNPs that modify the effects of specific dietary factors. Another
skeptics’ argument, he noted, is that people are not going to change their
behaviors, and he reiterated that research has shown the contrary to be
true. He also asked the question of when this has ever been an issue, point
ing out that some people still smoke, and it is unlikely that they have not
heard that smoking causes cancer. Finally, he observed, some skeptics argue
that “it’s all about the microbiome.” Yet, he argued, there is good evidence
that host genetics determines to a large extent the kinds of bacteria that
colonize the gut (Blekhman et al., 2015; Goodrich et al., 2016; Turpin et
al., 2016). Although he did not go into detail, he remarked that there are
other criticisms that also are not necessarily valid.
Where Are We Today?

El-Sohemy closed by stating that, while the current dietary recommenda
tions are based on science, he believes they are based on what he considers
“old science.” The question this raises for him is, How much more science
do we need before we can actually start using DNA-based information? “It
is not meant to be revolutionary,” he said. “It is just meant to be evolution
ary.” In his opinion, yes, DNA-based dietary advice is ready for prime time.
DISCUSSION
Following El-Sohemy’s presentation, he and the other session 1 speakers
(including those whose presentations are summarized in Chapter 2) partici
pated in an open discussion with the audience, summarized here.
Unintended Consequences of Information Provided to Consumers

Session moderator Naomi Fukagawa asked the speakers to reflect on
the potential unintended consequences of providing consumers with genetic
information and on ways to achieve a balance such that dietary recommen
dations do not end up being punitive—that is, with people feeling guilty
about their dietary choices when they know they have an SNP that increases
their risk for a particular health outcome.
Douglas Wallace replied that providing genetic information without
genetic counseling can be highly problematic. He commented on recre
ational genetics2 companies that sequence various parts of an individual’s
DNA, including mitochondrial DNA, and then provide that sequence to
the consumer. It is quite common, he suggested, for people to search the
Internet and scan the literature to see whether their nucleotides have been
correlated with any kind of clinical problem. He receives phone calls from
people who have done just that, asking him what they should do to “save
themselves from this terrible disease.” People can find information on al
most any nucleotide, he observed, with either positive or negative associa
tions. “Without appropriate genetic counseling,” he said, “we are not doing
people a real service to give them this kind of information.”
Fasting and the Mitochondria

Panelist Tim Morck commented on what he called a “new genre” of
weight loss—fasting, not just fasting intended to mimic diets but also fast
2 Recreational genetics refers to direct-to-consumer genetic testing for genealogy and health
diagnostic services.
ing itself, that is, going without any nutrients. He wondered whether fasting
affects the mitochondria.
There is no question, Wallace replied, that periodic fasting changes
one’s metabolic state, and it has been shown repeatedly in model organisms
and in some primate studies to affect longevity and other risk factors. There
is also clear evidence, he added, that fasting affects mitochondrial metabo
lism by increasing antioxidant defenses and respiration rate. Additionally,
he explained, people make more mitochondria during fasting because they
are trying to cope, first, with low carbohydrates, and then with what is basi
cally a high-fat diet (from stored fats). According to Wallace, these aspects
of fasting have generated a great deal of interest, as has the question of
whether fasting increases mitophagy—the way the body pulls out the accu
mulation of defective mitochondrial DNA—and how it might be related to
longevity. “But I think there is still a huge amount of unknown information
that we need to really understand this in any causal way,” he said.
When Morck asked about potential stem cell stimulation in particular,
Wallace replied that in fact, some of the most interesting studies have in
volved introducing mutations into the nuclear-encoded mitochondrial DNA
polymerase that increased mitochondrial DNA mutation rates and caused
premature aging. But the main effect, he said, was on stem cell biology. “So,
yes,” he said, “there is a lot of interaction there.”
Behavior, Behavioral Feedback, and the Brain

In response to the emphasis placed by many speakers on the importance
of behavior, Morck asked about the need for better markers of improve
ment that could help reinforce behaviors. He asked whether “true” metabo
lomics panels that show benefit might be sufficient to help motivate people.
Nathan Price agreed that behavioral feedback is important and pointed
out that it is a focus of Arivale and was emphasized in the Pioneer 100 Well
ness Project. The risk of a disease in the far future is not very motivating to
individuals, he observed, and at present, the company does not explicitly
provide people information on disease risk. But with the markers provided,
individuals can see changes in their body that are happening now. “In our
experience,” he said, “we have seen that to be quite motivating for people.”
Wallace identified as a problem in clinical medicine that “if we don’t
have a test, it is invisible to us.” In the field of what he called bioenergetic
medicine, there are no good outcome variables, making it difficult to know
whether an individual has a low- or high-energy state and whether a nu
traceutical or other kind of intervention is actually having an effect. He
mentioned that a great deal of time is currently being spent on developing
microelectronic and nanoelectronic systems with which to monitor bioener
getics in tissues so there can be some kind of quantifiable outcome variable.
While the discussion was on the topic of behavior, David Alpers ob
served, “The organ that has been left out of this whole discussion is the
brain.” He stressed that many behavior changes are dependent on an indi
vidual’s makeup. What drives or motivates a person to stay in a program
is not always a test, he asserted; sometimes it is a feeling the person has
or something about the way he or she looks. “So that is an enormously
important part of the whole equation,” he said, “which usually isn’t looked
into very often in this particular setting.”
Behavior and Coaching

An audience member asked about the longitudinal follow-up of the
coaching that Price had described, wondering whether he and his team had
followed participants beyond 6 months to see whether they continued to
show improvement either with or without continued coaching. Price replied
that many of the Pioneer 100 Wellness Project participants had entered
Arivale’s commercial program. So yes, he and his collaborators do have a
couple of years of follow-up data on those participants. But, he acknowl
edged, there was also a gap between the end of the Pioneer 100 Wellness
Project and participants’ entry into the program, during which they received
no coaching. During that period, many participants had reverted back, he
said, so they had not done so well when they were not receiving coaching.
When they reentered the program, however, they improved again.
Questions About the Pioneer 100 Wellness Project

In response to the previous question about whether the microbiome
sequencing conducted during the Pioneer 100 Wellness Project was
metagenomic sequencing, Price replied that, while metagenomic sequenc
ing is better and he is advocating for a switch, 16S sequencing was used
in the project because of cost considerations. Another audience mem
ber asked about the demographics of the project’s population, including
diversity of socioeconomic status, and what Price hopes the demographics
will be for the 100K Wellness Project. Price replied that the population
in the Pioneer 100 Wellness Project was representative of Seattle, so in
terms of ethnicity, it was heavily Caucasian, with some Asians and a few
representatives of other lineages. With respect to the Arivale program,
he explained that, because it is a commercial program, it is “definitely
heavily biased socioeconomically.” He said the company would love to
launch the program among groups of lower socioeconomic status and had
attempted to do so in West Virginia, for example, but the financing
had fallen through. He added that the company is exploring different
models of payment in cases where individuals, including those of low

socioeconomic status, are at very high risk for disease, and there are other
parties with a financial interest in their health.
Caffeine Fast Metabolizers Versus Slow Metabolizers

An audience member commented that most cardiologic health events
are multifactorial, not single-factor events. She asked El-Sohemy whether
studies on fast metabolizers versus slow metabolizers of caffeine had
collected nutritional information other than caffeine intake, such as tea
intake and overall diet, and whether they had considered the concentra
tion of the coffee people were drinking. El-Sohem 3y acknowledged that
many factors determine the “chemical soup” of a cup of coffee, such as
type of bean, the extent of roasting, and other factors. In his opinion,
however, those other factors are just “noise,” because whatever the fast
metabolizers are drinking, or misreporting (e.g., their cup sizes), the
slow metabolizers are drinking or misreporting as well. He explained
that the gene he had discussed, CYP1A2, does not affect preference—for
example, whether someone prefers Arabica, which has less caffeine than
Robusta. Regarding other sources of caffeine, in one of his group’s study
populations, 90 percent of caffeine intake came from coffee, even with
the consumption of cola beverages and tea. With regard to consumption
of other nutrients, he commented that in the myocardial infarction study
he had referenced (Cornelis et al., 2006), the reported odds ratios were
multivariate adjusted odds ratios that accounted for several confounding
factors (e.g., sugar added to coffee, physical activity, smoking). Session
moderator Fukagawa added that there are other bioactive compounds in
coffee and coffee products that could have had salient interactions as well.
Treating Specific Nutritional Deficiencies

In response to a question about when the field will begin treating the
type of very specific nutritional deficiencies discussed by Morris—that is,
those with clear causality constructs—Morris reframed the question as, Are
we really replacing a nutritional deficiency, or is arginine, or glutamine,
working and functioning as a drug that works for everyone? Her personal
experience in patients with SCD was that glutamine supplementation had
the greatest effect on those who were the most glutamine deficient and
that glutamine deficiency in those patients’ red blood cells was correlated
strongly with their tricuspid regurgitant jet velocity on Doppler echo
cardiography (a measure of pulmonary hypertension risk). So her bias, she
said, is that the patients who should be targeted first are those with the
most severe deficiencies.
Additionally, Morris has learned from her studies that the global argi
nine bioavailability ratio is predictive of clinical outcome years ahead. Thus
while children, for instance, have normal arginine levels at baseline, their
levels drop acutely during times of pain crisis. Morris was involved with
a phase II study that showed that administering arginine to these children
during a pain crisis had an impact on pain outcomes.
Finally, when Morris and her collaborators gave arginine to SCD
patients at baseline, they saw no effect on NO bioavailability. In fact, they
observed a paradoxical decrease in NO that was not overcome by dose. But
when they gave arginine to the same patients during a vaso-occlusive pain
episode, they saw a rise in NO. “So again,” Morris said, “the patients who
have a deficiency are probably the ones who are most likely to respond.”
Ordovás added that, regarding the genetic component, criticism is often
raised that there is no clinical proof of benefit. He mentioned a long-term
nutrition intervention study of people at high risk of cardiovascular disease,
in which participants were administered either a Mediterranean or a low-fat
diet. Using the gene TCF7L2, which is related to diabetes, Ordovás and col
leagues found that even in people who were aged 60 and older, there was a
benefit to using what he described as “the right diet for the right genotype”
in terms of reducing the number of cardiovascular events that occurred over
the 5 years of the study (Corella et al., 2016).
4
Nutrigenomics Applications:
Dietary Guidance and Food
Product Development
B
efore introducing the first speaker of session 2, moderator Wendy
Johnson, Nestlé USA, reflected on a few highlights from the morn
ing’s presentations and discussion that she found particularly interest
ing. She mentioned Patsy Brannon’s discussion of the circular relationship
among the genome, diet, and health outcomes; José Ordovás’s description
of evidence suggesting that where people live can influence their genetic
makeup; Claudia Morris’s remarks on the elusive defined nutrition require
ment that appears to change according to various disease states; discussion
of how little is known about how behavior impacts nutrigenomics; and
several participants’ thoughts on what can be done commercially with
personalized medicine to help people, but also the complexity of making
nutrigenomics a practical alternative for consumers. Now in session 2,
Johnson continued, the focus would be shifting to “how we really take
that information and move it forward in a way that makes a difference in
people’s lives.” This chapter summarizes the session 2 presentations and
discussion, with highlights provided in Box 4-1.
NUTRIENT REQUIREMENTS AS COMPLEX TRAITS:
WHAT CONSUMERS NEED TO KNOW
Patrick Stover, Cornell University, began his presentation by describ

ing an incident that had recently taken place when he missed a flight and
was sent an Uber driver to accommodate his changed travel plans. It was
about 1:00 AM, but the driver was quite chatty, he recalled. She told him
about her family and how she had started a career as a personal training
61
BOX 4-1
• The food environment has been one of the most powerful selective pressures
on human evolution. (Stover)
• Not only does nutrition-related genetic variation exist, but it matters in public
health. An example is how knowledge of an MTHFR polymorphism that affects
folate status impacted World Health Organization guidelines for optimal folate
levels. (Stover)
• In addition to matching diet to genotype, another “precision nutrition” strategy
to consider is leveraging real-time, personalized readouts through the use of
apps or point-of-care diagnostic devices. However, questions remain regarding
what kind of guidance to provide to individuals and whether systems biology
can be applied to the tremendous amount of data that individuals are collecting
on themselves through these apps and devices. (Stover)
• Much is known about many of the metabolic pathways that nutrients must
transit, the genes upon which those pathways depend, and how certain vari-
ants of some of these genes (i.e., single nucleotide polymorphisms [SNPs])
act as “roadblocks” in metabolism. Given this knowledge, one could develop
nutritional solutions, or medical foods, to bypass roadblocks known to be asso-
ciated with particular nutrition-related health outcomes. (Zeisel)
• An example is how premenopausal women with a polymorphism of the PEMT
SNP require more dietary choline than premenopausal women without that
polymorphism. (Zeisel)
• Single SNP analysis is useful, but as the field of nutrigenomics evolves, com-
panies may need to start recognizing the complexity of metabolic pathways
and the involvement of multiple SNPs. Nonetheless, one could still intervene
with a medical food that delivers the nutrient(s) affected by a multiple SNP-
defective pathway. (Zeisel)
coach and amassed a large clientele. When she learned that Stover was
in the nutrition field, she told him that nutrition was the most important
guidance she provided to her clients who were morbidly obese. “I use the
blood type diet,” Stover remembered her saying, adding, “that’s the single
most important thing that improves their health: the blood type diet.”
Stover noted that the blood type diet is based on Peter D’Adamo’s book Eat
Right 4 Your Type, and remarked that his experience with the Uber driver
NUTRIGENOMICS APPLICATIONS 63
reflects where he thinks a lot of consumers are in terms of their knowledge

of nutrition and health.
Stover then showed a picture of the front cover of a 2010 issue of
Nature with the headline “Can Science Feed the World?” That is, can sci
ence feed the 9 billion people who will be on this planet in 2050? The same
issue, Stover continued, contains an article on diabetes. He explained that
for him, the question is not whether we can feed that many people, but,
“Can we feed them in a way that keeps diabetes off the cover of Nature?”
He suggested that another way to frame the question, given today’s un
precedented capacity to formulate the food supply in any way desired, is,
“What are our expectations of the food supply? That is, when we think
about setting dietary and nutrient guidance and recommendations, what are
the outcomes we really want to achieve? And what is achievable?” In fact,
Stover observed, the U.S. federal government has asked these questions, as
indicated by the request to the National Academies that a committee be
assembled to develop a consensus report on developing guidance on dietary
reference intakes (DRIs) based on chronic disease endpoints (NASEM,
2017a).
Stover went on to stress that making connections between food and
disease prevention poses several challenges. He cited as the first of these
that few chronic diseases are affected by a single nutrient or a single path
way. Thinking about the relationship between food and chronic disease, he
argued, requires considering systems, or networks of pathways, rather than
individual pathways, and how these pathways and nutrients converge and
interact. This means, he observed, that thinking about biomarkers requires
thinking not about single nutrient biomarkers, but about integrative bio
markers that are the endpoints of systems where pathways and nutrients
interact and impact chronic disease. Additionally, he stated, as called for
in the above-referenced National Academies report (NASEM, 2017a), it
means considering DRIs as ranges, not point estimates. He noted further
that, beyond considering integrative biomarkers, thinking about chronic
disease endpoints requires considering biomarkers of aging and how they
interact with biomarkers of nutrition. As a final challenge, he mentioned
that the above report (NASEM, 2017a) recommends use of the Grading
of Recommendations Assessment, Development and Evaluation (GRADE)
Working Group’s standards of evidence. But, he pointed out, this is a field
that is driven primarily by observational data, most of which are not at the
GRADE level of evidence needed to set chronic disease endpoints. He added
that, given that half of the adult population in the United States is under
the care of a physician for some sort of chronic disease, combined with the
fact that the DRIs are intended for healthy people and therefore may not
apply directly to what is essentially half of the population, the National
Academies convened a separate committee to plan a public workshop to

examine nutritional requirements in disease states.1
Stover continued by arguing that, while the DRIs are highly focused on
the nutritional needs of healthy individuals, nutritionists need to start think
ing about the totality of nutritional requirements and how to classify and
evaluate human nutrient needs from health, through disease prevention, to
disease management. Acknowledging that there are many markers available
that can be used in attempting to understand the nutrient needs for health
and disease prevention, he asserted that other types of indicators will need
to be considered as nutrition scientists work to understand the connection
between food and disease management (see Figure 4-1). These include
indicators of tissue-specific nutritional status, because chronic disease often
exhibits tissue-specific effects that may not relate to whole-body effects;
restoration of function, as addressed by Claudia Morris in her presentation
on conditionally essential amino acids (as summarized in Chapter 3); and
tissue regeneration (i.e., the unique nutritional needs of stem cells as they
repair damaged tissue). Stover suggested that in thinking about the connec
tion between food and disease management, one can begin to think about
distinct nutritional requirements (DNRs) instead of DRIs. He noted that
these requirements would include medical foods, which provide nutrients
that may not be accessible from the food supply in the quantity or quality
one needs.
Dietary Requirements as Complex Traits

Like previous speakers, Stover described dietary requirements as com
plex traits. That is, many physiological processes inform the nutrient needs
of an individual (i.e., absorption, catabolism, excretion, metabolism, stabil
ity, transport, bioactivation, energetic state, nutrient storage), all of which
interact with each other as well. He added that nutrient requirements also
are affected by a number of modifiers and sensitizers, including disease, but
also epigenetics, the food matrix, genetics, nutrient–nutrient interactions,
pharmaceuticals, toxins, age and physiological decay, the microbiome,
pregnancy, and sex. He noted that although the topic of the workshop
was genetics, it does not make sense to consider any one of these modi
fier or sensitizer variables in the absence of the others, given that nutrient
requirements are what he described as “true complex traits.” Of course,
he continued, this has been recognized for many years, as indicated by the
American Society for Nutrition’s 2013 research agenda, on which one of
1 For information on this April 2–3, 2018, workshop, see http://www.nationalacademies.org/
hmd/Activities/Nutrition/ExaminingSpecialNutritionalRequirementsinDiseaseStatesWorkshop.
aspx (accessed April 23, 2018).
Health Disease Prevention Disease Management

Groups
Primary - Secondary –Tertiary Acute - Chronic
Whole Body Nutritional Status

Normal Physiological Function
Indicators
Clinical Outcomes
Predictive Biomarkers
Tissue Specific Nutritional Status
Restoration of Function
Tissue Regeneration
Dietary Reference Intakes Distinct Nutritional Requirements
(DRIs) (DNRs)
FIGURE 4-1 Indicators, or biomarkers, that could be used to classify and evaluate
nutrient needs from health through disease prevention and management.
SOURCE: Presented by Patrick Stover on December 5, 2017.
the top priorities is to understand variability among individuals in response

to diet and food (Olhorst et al., 2013). More recently, he added, the U.S.
federal government released the National Nutrition Research Roadmap,
2016–2021, which also focuses not just on the connection between nutri
tion and disease prevention, but on the importance of understanding indi
vidual differences in nutritional status as well (Interagency Committee on
Human Nutrition Research, 2016).
Genetics as a Modifier of Nutritional Status

Stover went on to emphasize the importance of remembering, when
thinking about the effects of genetics on nutrition, that the purpose of
the Human Genome Project was not only to inventory all of the genes
in the human genome, as well as variations in these genes, but also to as
semble and understand cellular networks, or circuits; variation in these
circuits; and how they can be manipulated by inputs, whether these be
drugs or nutrients. The impact of genetics on diet is rooted in evolution
ary biology, he observed. He showed the cover of a 2002 issue of Scientific
American with the headline “Food for Thought.” The article is about
dietary change as a driving force in human evolution (Leonard, 2002).
Stover explained that the molecular basis of the evolution of a species is
the evolution of genes, but not all genes evolve, or change over time, at the
same rate. Genes that evolve quickly are those that enable adaptation to a
local environment, he noted, adding that upon examination, it appears that
one of the most powerful selective pressures in genome evolution is diet.
Thus, he argued, today’s human genome—not just its primary sequence, but
also genome programming and gene expression—is suited to a particular,
historical nutrient environment. When the genome is exposed to a changed

nutrient environment, he said, people experience food intolerances, special
dietary requirements, and susceptibility to disease.
Stover explained that there are two major contributors to all of the
variation in today’s human genome. First is the introduction of the genome
of archaic humans into that of what are now modern humans. More spe
cifically, with the recent sequencing of the Neanderthal genome, it appears
that about 500,000 to 1 million years ago, probably through the male
germline, Neanderthal DNA was integrated into the human genome. He
added that, based on identification of the Denisovan archaic humans, it is
now known that Denisovan DNA also became integrated into the modern
human genome. Further, he said, it is likely that a third, unknown hominid
also contributed DNA to the current human genome. He suggested that, in
addition to contributing to understanding of why humans across the planet
are so genetically variable, knowing which Neanderthal and Denisovan
genes became integrated into the modern human genome and how they
affect human traits is of interest to consumers. He cited as an example
23andMe, which offers a genetic test whereby consumers can learn not
just about their ancestry but also what percentage of their genome is
Neanderthal or Denisovan.
Stover identified as a second major source of human genetic variation
mutation events that subsequently extended though a population via either
selection or drift. He explained how computers can identify genes or regions
in the genome in which what he called a “selective sweep” occurred—that
is, where a mutation enabled some sort of selective advantage that displaced
all of the preexisting variation. Many of the genes that show evidence of
selective sweep are related to nutrition, metabolism, or immunity, he noted,
which he interprets as good evidence that nutrition has played an active role
in much of the variation that exists today.
Importantly, however, in Stover’s opinion, the relationship between
nutrition-related genetic variation and phenotype is not a one-to-one cor
respondence. The one gene in the human genome that shows the strongest
evidence for this type of selection, he observed, is the lactose tolerance gene,
with a mutation in the promoter allowing the gene to be expressed through
adulthood, and therefore allowing a source of nourishment inaccessible to
the rest of the population. However, he noted, when the geographic distri
bution of this gene is overlaid on a map of the phenotype of lactose intoler
ance, the two overlap fairly well but not completely (Itan et al., 2010). “No
one gene variant completely determines what the phenotypic expression is
going to be,” he said.
Stover added that there is also evidence of evolution of nutrition-related
copy number variants (CNVs), such as amylase CNVs. Across human
populations, he elaborated, individuals have between one and nine copies
of the gene. Those with high copy numbers are from populations with a
history of an agrarian lifestyle (for improved digestion of starch), he ex
plained, whereas those with low copy numbers are from populations with
a history as hunter-gatherers. Stover pointed to this as another example of
an adaptation that has been driven by the food supply.
Stover went on to observe that many other diet-related genes, such as
the calcium transporter gene, have similarly displayed genomic signatures
of adaptive evolution by selection (Stover, 2007). He finds it interesting
that selection for the lactose tolerance gene appears to have occurred before
selection for the calcium transporter gene. That is, only after the lactose
tolerance gene arose and expanded and enabled milk consumption did the
calcium transporter mutation arise and expand.
Stover suggested that while all of this evidence provides a strong bio
logical premise for the link between nutrients and health, one rooted in
evolutionary biology, “what we are not so sure about” is the strength,
or penetrance, of the effect. Again, he stressed, dietary requirements are
complex traits, and genetics is only one of many factors that determine the
relationship among food, nutrition, and health. For Stover, this uncertainty
raises the question of whether all of this genetic variation really matters in
public health. He went on to describe an example in which, in fact, it does.
The MTHFR polymorphism is a fairly common variant in human
populations, Stover explained, with about 80 percent of individuals hav
ing a C allele, which codes for alanine, and the other 20 percent having a
T allele, which codes for valine. The T allele protein is less stable and less
active, and individuals carrying that variant have a lower folate status and,
all other things being equal, a higher folate requirement and greater risk for
birth defects and miscarriage. However, Stover observed, if individuals with
the T allele survive to adulthood, their risk of colon cancer is reduced by
70 to 80 percent if they maintain adequate folate status (Ma et al., 1999).
He noted that this finding has been replicated in several cohorts. “This is
a very powerful effect from a single nucleotide polymorphism,” he said.
The C and T allele frequencies at the MTHFR polymorphism vary
across the globe, Stover added. He explained that the polymorphism clearly
arose after migration out of Africa, but it does not show a signature of
selection, so it either accumulated through drift or entered the human
genome from another archaic human.
Stover stated that there is also good evidence from controlled feeding
trials that the variant can affect nutrient requirements for folate. When
Solis and colleagues (2008) fed adult Mexican men the recommended daily
allowance (RDA) for folate, they found that initially, serum folate levels
dropped for both CC and TT individuals, but by the end of 12 weeks, the
CC individuals had significantly higher levels of serum folate relative to
the CC individuals. In addition, homocysteine level, which is a functional
biomarker of folate metabolism, did not change over time among CC indi
viduals but rose markedly among TT individuals. According to Stover,
“This is an example of one single polymorphism that definitely affects
nutrient requirements.” In fact, he suggested that the RDA is probably not
adequate for Mexican American men who harbor the TT genotype. But
again, he asked, whether these findings have affected policy. The answer,
he said, is yes.
In 2015, the World Health Organization (WHO) published a guideline
for optimal serum and red blood cell folate levels to prevent birth defects
(WHO, 2015). Stover explained that this action was taken in response to
member states approaching WHO and asking how much folate they should
be adding to their food supplies. He described the WHO (2015) committee’s
work as remarkable because it represented the first time a chronic disease
endpoint was being used to help establish a nutrition reference value, and
because big data integration was used to reach this conclusion. Regarding
the latter point, he explained that there was a paucity of data linking folic
acid intake to risk of neural tube defects and that what data did exist were
of low quality. However, there were data linking folic acid intake to folate
concentration in red blood cells. So through Bayesian modeling, Stover
explained, the WHO (2015) committee was able to derive a computed dose-
response curve predicting estimated risk of neural tube defects as a function
of folate concentration in red blood cells (Crider et al., 2014). He added
that, although the curve was computer generated, data from the one empiri
cal study that does exist, a small study in an Irish population, align with
the big data curve of Crider et al. (2014) and the WHO (2015) committee.
He highlighted this as a case in which evidence of a single polymorphism
was used to generate a guideline, in this instance on what the optimal level
of folate should be to prevent neural tube defects.
Genetic Testing: What Consumers Will Need to Know

Stover pointed out next that consumers have available to them a range
of genetic tests that are providing not only ancestry information but also,
increasingly, health information. He raised the question of what consumers
really need to know to use this information.
It has been suggested, Stover observed, that individuals be classified
into subgroups for diets, which he noted had already been discussed earlier
in the workshop. He referenced the recently released National Academies
report on redesigning the process for the Dietary Guidelines for Americans
(DGA), which emphasizes not only the prevention of chronic disease but
also the need to take into account a range of individual factors, including
age, gender, and metabolic health (NASEM, 2017b). He identified as a
challenge to this approach, however, that although there have been many
studies on various types of diets and how they affect health in human
populations, most of those studies are based on observational data, and
very few are long-term.
Stover cited a recent long-term study in inbred mice, in which Barrington
and colleagues (2018) fed the mice one of four diets—American, Mediter
ranean, ketogenic/Maasai, or Japanese—for much of their lifetime and com
pared the diets’ effects on metabolic health. Additionally, they measured
certain health-related metabolic and epigenetic markers over time. Stover
reported that the study showed that the best diet for maintaining health
varied depending on both the health outcome of interest and the genetic
background of the mouse. So, for instance, among mice fed the Mediter
ranean diet, HDL cholesterol levels were at very healthy levels in one strain
but not another (see Figure 4-2). In Stover’s opinion, these findings provide
a good biological premise for matching diet to genotype. “Of course,” he
said, “the challenge is, how are we going to classify people? Because we
can’t classify them based on inbred strain, if you will.”
FIGURE 4-2 (a) Diet ingredient profiles and geographic origins for the four diets
fed to the mice in the Barrington et al. (2018) study; (b) comparison of metabolic
phenotypes in each strain of mice fed the Mediterranean, Japanese, and ketogenic/
Maasai mouse diets relative to the American mouse diet.
NOTE: A = A/J strain mice; ALT = alanine aminotransferase; B6 = C57BL/6J strain
mice; Chol. = cholesterol; FVB = FVB/NJ strain mice; GTT = glucose tolerance test;
HDL = high-density lipoprotein; LDL = low-density lipoprotein; NOD = NOD/
ShiLtJ strain mice; TG = triglyceride.
SOURCES: Presented by Patrick Stover on December 5, 2017, from Barrington et
al., 2018. Reprinted with permission from the Genetics Society of America.
Instead of classifying subgroups of people by diet, Stover continued, it

has been suggested that subgroups be classified by nutrients. This approach,
he explained, is based on the precision medicine model, in which a prog
nostic test related to a risk for some chronic disease predicts whether a
drug will work or which drug will work, as well as how to dose the drug.
According to Stover, however, this approach has been somewhat problem
atic for nutrition thus far. He cited the example of diabetes, which is such
a complex trait affected by so many nutrition-related variables that it that
it has made classifying individuals difficult. He asked, “Does it really make
sense to split the pie up in so many pieces?”
In fact, in Stover’s opinion, it may not even matter. Instead of classify
ing subgroups by either diet or nutrient, he elaborated, the trend toward
real-time personal readout has created a third possibility. He pointed out
that people are collecting a tremendous amount of data on themselves, with
apps available to record how many steps they have taken, what their blood
pressure is, and so on. Increasingly, he added, high-resolution biomarker
data are being collected and will be available to almost everyone. Still, he
suggested, the questions are what guidance will be provided to individuals
and whether systems/network biology can be applied. He then cited one
example of point-of-care measurement of nutrition-related biomarkers, ex
plaining that his colleagues at Cornell University have developed what they
call the Nutriphone, a smartphone-based microfluidic device. He described
this device as much like a pregnancy test, except that it provides a real-time
readout of 8–10 nutrient status markers, functional biomarkers, chronic
disease markers, and infectious disease markers (Lee et al., 2016). Accord
ing to Stover, the price of the device will eventually fall to a few dollars, but
again, he raised the question of what consumers will do with the informa
tion collected.
In an attempt to understand how best to help consumers with the
genetic and other information now emerging, Stover and his group have
been working with researchers at the University of Toronto to develop
a stochastic model for understanding metabolism networks. They have
recreated the entire folate network, running the simulation for hours or
days at a time, with different inputs, until the system reaches equilibrium,
and they are using the model to conduct sensitivity analyses for changes
in gene expression and enzyme levels (Misselbeck et al., 2017). Stover
described this as the type of algorithm that will be needed to manage all of
the data coming from cell phone apps. He envisions plugging one’s phone
into some sort of computational model and then receiving guidance on how
to optimize the function of one’s own network.
In closing, Stover mentioned that he was helping to organize the First
International Conference on Precision Nutrition and Metabolism in Public
Health and Medicine (September 21–26, 2018, in Crete, Greece), with the
goal of bringing together people in the fields of nutrition, engineering, and

computer science to address how a systems-level understanding of nutrition
can be used to provide better guidance to consumers.
GENE-GUIDED NUTRITION INTERVENTIONS

Steven Zeisel, University of North Carolina at Chapel Hill, began by
saying that he would be sharing his thoughts on how to develop a nutri
genomic application in industry based on his work with a number of com
panies that are doing just that. Additionally, he himself was involved in the
early startup phase of Zthera, a gene-guided medical foods company.
“We’ve heard over and over again how metabolically different we
are,” Zeisel said, noting that each individual has about 50,000 common,
inherited single nucleotide polymorphisms (SNPs) out of the millions that
exist. Because people have inherited these SNPs from their ancestors, he
explained, the distributions of many of them differ among populations. As
an example, he cited the distributions of the GG, GC, and CC genotypes
of the PEMTrs12325817 polymorphism. These genotypes vary worldwide,
with their proportions differing among populations in Africa, Asia, Europe,
and America. Zeisel noted that the C allele is associated with inefficient
choline production.
But because so much is already known about metabolism, Zeisel con
tinued, there is no need to be overwhelmed by such complexity. Scientists
understand the metabolic pathways, he elaborated; they know that nutri
ents have to transit these pathways; they know that each of these pathways
depends on a number of genes; they know what these genes are; they know
how the different pathways interact with each other; and they know that
the polymorphisms that affect the function of a gene in a specific pathway
will have a metabolic marker, such as buildup of a precursor or less final
product. “So we can cut down on the complexity of what we look at,” he
said, “and increase the power by having pre hoc hypotheses based on our
understanding of metabolism.”
Zeisel pointed out that some polymorphisms that are functionally ac
tive will create “roadblocks” in metabolism—for example, by changing the
affinity site of the enzyme or by changing the regulator of a gene, thereby
making metabolism inefficient. “If we know this,” he said, “we can ask,
how do we step around this? . . . How could you develop nutritional solu
tions or medical foods, if they meet all the other Food and Drug Adminis
tration (FDA) criteria, that are specifically designed to bypass each of the
roadblocks that you identify as being associated with a health condition
related to nutrition?”
Zeisel went on to observe that not all SNPs cause functional change.
For example, more than 1,000 polymorphisms for the gene PEMT have
been identified in humans, but only a selected subset—about 10 thus far

that have been identified—are functionally important (i.e., because they
change, for example, the binding site or a response element). But if one
of those SNPs that are functionally active causes a roadblock, Zeisel ex
plained, it creates a bottleneck such that less metabolite is being produced
and more precursor is building up, unless diet hides this fact. That is, if
someone has a metabolic inefficiency because of one of these SNPs but is
eating enough of the relevant nutrient to push through the bottleneck, the
SNP will not manifest as functionally important (see Figure 4-3). It is only
when one is challenged by having low amounts of the nutrient in one’s
diet that an inefficiency becomes important. Zeisel said he would be giving
an example of this from his research with choline (see the following sec
tion), but first he argued that this is why genome-wide association studies
(GWASs) have been “so abysmal” at identifying nutritionally relevant
SNPs. By failing to consider dietary intake, he elaborated, GWASs combine
people who are consuming large amounts of a nutrient with people who are
challenged for the nutrient, thus canceling out any significant effect among
those who are challenged.
Metabolism
Metabolite
Nutrient
No SNP
Metabolite
Nutrient metabolite
Metabolite
SNP
DIET DELIVERS METABOLITE
FIGURE 4-3 By delivering large amounts of a metabolite, diet can bypass, and
“hide,” a metabolic roadblock caused by a single nucleotide polymorphism (SNP).
SOURCE: Presented by Steven Zeisel on December 5, 2017.
Gene-Guided Nutritional Intervention: Choline as an Example

Zeisel began his discussion of choline by remarking that anyone can do
with another nutrient what he and his colleagues have done with choline—
that is, identify genetic polymorphisms that explain the difference between
responders and nonresponders to a nutritional intervention. He then men
tioned that in addition to an adequate intake (AI) recommendation set by
the Institute of Medicine (IOM, 1998), choline has had approved FDA
labeling since 2016. He also explained that choline is important for both
the liver and muscle. It can be made in the liver through the enzyme coded
by PEMT, and it is contained in such foods as liver and eggs, as well as
other high-cholesterol foods. But Zeisel cited National Health and Nu
trition Examination Survey (NHANES) data (2009–2014) showing that
most Americans are not meeting the recommended AI for choline, which
is about half a gram per day for adults, a finding with especially impor
tant implications for pregnancy and lactation, as he would explain later.
He noted that only small children, who drink a great deal of milk, come
close to achieving their recommended AI, making choline what he called a
“problem nutrient.”
In one of his first choline studies, Zeisel and his team questioned
whether the half a gram per day requirement was really necessary. To ex
plore this question, they removed the nutrient from their study participants’
diets to see if they would develop fatty liver or liver or muscle damage
caused by apoptosis. In the process, they noticed that young women needed
less choline relative to both men and postmenopausal women (Fischer et
al., 2007). After 42 days without choline, only 44 percent of the young
women got sick. In contrast, most men (77 percent) and post-menopausal
women (80 percent) got sick. Most of the participants who fell ill presented
with fatty liver and liver damage, and only about 10 percent presented with
muscle damage.
So Zeisel and his collaborators asked the question of what is differ
ent about young women. Why is it, they asked, that 56 percent of young
women do not need choline? Estrogen appeared to be an obvious answer,
Zeisel recalled. Indeed, the researchers found that PEMT is induced by
estrogen and is turned on at exactly the concentrations of estrogen that
are achieved during pregnancy (Resseguie et al., 2007). But if that is the
case, Zeisel’s team asked—that is, if women can turn on PEMT to make
their own choline when estrogen is present—why do 44 percent still get
sick when deprived of choline? According to Zeisel, it turns out that there
is a polymorphism, or set of polymorphisms, in the estrogen response ele
ment for PEMT that prevents PEMT from responding to estrogen even
if a woman’s estrogen level is high (Resseguie et al., 2011). Women who
are homozygous for the C allele at PEMTrs12325817 do not respond to
estrogen at all, he reported, in contrast to women who are homozygous for

the G allele, who do respond, and heterozygotes, who respond somewhat.
Because women who are CC at this polymorphism cannot increase their
production of choline during the high-demand period of pregnancy and
lactation, he added, they need to ingest choline. Zeisel explained that it
was because of this kind of data—that a polymorphism can help predict
which women will need choline in their prenatal diet—that the American
Medical Association (AMA) voted for the first time in 2017 to recommend
that prenatal vitamins contain choline.
As Zeisel had mentioned earlier in his presentation, the different geno
types at the PEMTrs12325817 polymorphism are distributed differently
around the world. In Europe and America, 72 percent of women have one
or more alleles of the C allele, and 22 percent are homozygous for it. In
contrast, very few women in The Gambia have the C allele. Zeisel explained
that the indigenous diet in The Gambia is very low in choline, which he said
is an indication that the C allele was selected against. Among the Maasai
in Kenya, by contrast, where the diet is higher in choline, the C allele is as
common as it is in Europe, where there was enough choline in the diet (e.g.,
in eggs) so that presumably there was no such selection (Silver et al., 2015).
Regarding the effects of low choline on the fetus, Zeisel shared results
from a mouse study showing that when pregnant mice were fed a low-cho
line diet, their offspring had significantly fewer neural progenitor cells rela
tive to the offspring of control mice (Wang et al., 2016). This phenotype,
he explained, has a lifelong effect on memory in mice and probably occurs
in humans as well. It has been shown, he reported, that maternal choline
intake during the first and second trimesters of pregnancy is correlated with
performance at age 7 years on a cognitive test known as the Wide Range
Assessment of Memory and Learning, 2nd Edition (WRAML2), with an
apparent dose-response (Boeke et al., 2013).
Based on this cumulative evidence, Zeisel envisioned a company form
ing around this scenario: a gene test (for the PEMT SNP), an obvious inter
vention (dietary choline), and a common mutation (72 percent of women
in the United States having at least one allele for this gene).
Recognizing the Involvement of Multiple SNPs

While single SNP analysis is useful, Zeisel continued, as the field of
nutrigenomics evolves, companies will need to start recognizing the com
plexity of metabolic pathways and the involvement of both multiple path
ways and multiple “hits” within pathways. He explained that with choline,
for example, other SNPs besides the PEMT SNP can alter sensitivity to low
choline and put people at greater risk of becoming depleted and develop
ing liver or muscle problems. In addition to this observation having been
demonstrated in his own work with multiple SNPs (da Costa et al., 2006,
2014; Kohlmeier et al., 2005), Caudill and colleagues (2009) showed that
MTHFR alters sensitivity to low choline and increases one’s choline require
ment. According to Zeisel, these other SNPs can be found at almost every
step of the choline pathway.
Another question that has interested Zeisel is why choline deficiency
presents differently, with 90 percent of individuals developing fatty liver
and the other 10 percent developing muscle damage. So again, he and his
research team examined the responders and nonresponders to see what
was different about them and found that people who are choline deficient
cannot export fat from the liver as very low-density lipoprotein and thus
develop fatty liver (Corbin et al., 2013). He explained that this is because
choline is needed to export fat from the liver. That is, the liver makes
a “wrapper” out of phosphatidylcholine to export the fat, and without
this wrapper, the fat remains in the cytosol. But given that a number of
pathways affect how fast the liver can package fat and how much choline
is needed, Zeisel and his team genotyped the liver tissues of a population
of individuals who had provided liver biopsies, for various reasons. They
found a number of SNPs in other pathways (e.g., genes related to choline
metabolism, folate metabolism, fatty acid transport, and bile synthesis)
that were also associated with fatty liver (Corbin et al., 2013). When they
included these genes from the other pathways in their prediction model,
they were able to predict susceptibility to liver disease with 95 percent
accuracy, compared with 70 percent when they included only the choline
polymorphisms. Additionally, however, they found that the predictive
power of these polymorphisms was what Zeisel termed “totally useless”
in lean people, because lean people are not making a large amount of fat
in their liver and can afford to be inefficient at exporting it. Thus it is
only individuals with a high body mass index (BMI) for whom export of
fat from the liver is important because their liver produces much more fat
from the excess calories they consume, and for whom these polymorphisms
predict the development of fatty liver.
As a result of this research, Zeisel’s team now has a gene test for 19
SNPs in women and 21 in men that predict susceptibility to developing fatty
liver with 90 percent accuracy among people gaining weight. According to
Zeisel, a nutritional intervention that bypassed the choline-related SNPs
probably would be about 70 percent effective, while an intervention that
bypassed all of the roadblocks probably would be about 90 percent effec
tive. In his opinion, given the difficulty of delivering all of these metabolites
with a normal diet, the best intervention likely will be a medical food. The
idea, he reiterated, is that by giving people whatever metabolite they are
unable to make because of a metabolic roadblock, the problem is solved
theoretically. And in fact, he asserted, in the case of choline it works: when
people who are choline deficient and who have developed fatty liver are
given choline, their fatty liver resolves.
Zeisel then turned to the 10 percent of people who are choline deficient
and have developed muscle defects. It turned out, he reported, that everyone
in his team’s study who developed muscle damage (rhabdomyolysis2) had
SNPs that resulted in a problem in the transport of choline into the muscle
cells and in phosphorylating choline once it had entered the muscle cells. He
explained that, as with glucose, choline metabolism entails phosphorylating
the choline to give it a charge so that it cannot leak out of the cell. In addi
tion to the choline polymorphisms he had discussed, the MTHFD1 poly
morphism also appears to predict who is going to develop rhabdomyolysis,
as measured by leakage of creatine kinase from muscle cells (da Costa et al.,
2014). More specifically, he continued, during exercise, people break down
their muscles more if they have these polymorphisms and are eating a diet
lower in choline. So again, he predicted the opportunity for another medical
food as a solution to a blocked metabolic pathway, or pathways—in this
case the SNPs responsible for muscle breakdown during exercise.
SNPs and Sperm Dysfunction:
Another Example of Gene-Guided Intervention
Zeisel went on to explain that when a study is conducted in humans

and polymorphisms are identified that appear to be important, as was the
case with choline deficiency, those polymorphisms can be knocked out
in mice and other effects examined. So he and his team knocked out the
choline dehydrogenase gene, Chdh, in mice because it was one of the genes
that affected the choline requirement in humans, and they found that the
mice developed what he characterized as horrible-looking mitochondria
in their sperm (Johnson et al., 2010). The sperm were infertile, unable to
swim, and unable to make adenosine triphosphate (ATP). The researchers
then found that they could restore sperm function in the mice by giving
them the metabolite (betaine) that was being blocked from production.
Although Chdh is a nuclear gene, Zeisel noted, the protein resides in the
mitochondria.
Zeisel’s team next examined this same polymorphism in men (Johnson
et al., 2012). It is a common polymorphism, he observed, existing in about
5–9 percent of men, depending on lineage. The researchers found that
men who are homozygous for the T allele make little ATP in their sperm,
and heterozygotes can make only half as much ATP as GG homozygotes.
Although the sperm in the men with the T allele “look terrible,” as they did
in mice, Zeisel and his team have yet to test whether they are less fertile.
2 Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down.

He suspects that they are, as their sperm do not swim well. “So again,” he
said, “you can imagine if you were trying to think of a company, you could
genotype men who are unable to have a baby, predict poor sperm function
using ATP in sperm as a biomarker, and conduct a clinical trial to see if
their low sperm ATP is reversible by delivering the metabolite that bypasses
the genetic roadblock.” And again, he emphasized his underlying thought
process: “Take what you know about metabolism and use that to predict
what nutrigenetic test and treatment should work.”
Future Developments: Medical Foods as a
Starting Point for Developing Nutrigenomic Products
To move forward, Zeisel called for better methods for working with
complex metabolic pathways involving multiple SNPs. He remarked that
he had been focusing on choline because that is his area of expertise. But
he argued that the same approach could be used to study vitamin D, for
example, to design interventions that would bypass specific inefficiencies in
metabolism that contribute to the problems people have with vitamin D.
Additionally, Zeisel called for a better way to include diet informa
tion in GWASs. He remarked that, as part of many precision medicine
initiatives, researchers are going to be measuring genes and metabolome,
but, he said, “they are not thinking of collecting nutritional data.” Yet
without those data, he asserted, it will be impossible to know who is being
challenged by low or high intake. If people with a polymorphism are not
being challenged, he added, they will look the same as people without the
polymorphism.
Finally, Zeisel encouraged the workshop participants to think about
medical foods, as defined by FDA, as a potentially good starting point for
developing nutrigenomic products. He referred to José Ordovás’s descrip
tion of what Zeisel called the “prototype medical food”—a food for rare
mutations that cause aminoacidopathies, such as phenylketonuria. He ar
gued that the same strategy could be used for metabolic roadblocks, ex
cept that instead of bypassing a rare mutation, the medical food would be
bypassing a common polymorphism. In his opinion, an intervention that
specifically bypasses a multitude of blocked pathways would not be easily
deliverable in a normal diet; indeed, it would not even necessarily be easy
to calculate, he opined. Therefore, he said, “it is the perfect fit to the FDA’s
current definition of what a medical food should be.”
DISCUSSION
Following Zeisel’s presentation, he and Stover participated in an open
discussion with the audience, summarized here.
Questions About the Potential Role of Medical Foods in Nutrigenomics

Much of the discussion revolved around the potential role of medi
cal foods in nutrigenomics, beginning with a question from an audience
member about Zeisel’s rationale for working toward developing choline as
a medical food when it could be a dietary supplement. Zeisel agreed that if
choline alone were the issue, a dietary supplement would be a good nutri
tional solution, but he argued that when multiple pathways are involved,
a medical food makes more sense. The advantage of a medical food, he as
serted, is that a physician or other health professional would be overseeing
the interpretation of the gene test for its need. Additionally, he observed,
physicians understand prescription medicine, and a gene test tells them
what to prescribe. The test, he elaborated, validates that there is a problem
and that they are really treating something, providing both physician and
consumer with more confidence. He added that, because developing this
type of nutritional intervention will require research and investment, it
would be beneficial to make it something (i.e., a medical food) that brings
slightly higher returns to account for that extra cost.
Another audience member, noting that “Food Product Development”
was in the title of this session, questioned how nutrigenomics tools will
impact what kinds of food products become available, how widely used
these products will be, and what the regulations around them will be. She
pointed to gluten-free foods as an example of a class of food products that
has become very mainstream and is related to a medical condition that she
presumed could be predicted with nutrigenomics tools.
“I would say we are at a frontier,” Zeisel replied. He predicted that
someday, it will be obvious how to develop foods that are not commodi
ties, that is, foods that have a little extra value because they are designed
specifically to deal with a health problem. They may or may not be based
on genetics, he added. “We’re going to have a lot of snake oil,” he ac
knowledged, “but we have a lot of snake oil diets with regular foods.”
He emphasized that he liked the idea of medical foods as a starting point
because FDA has already set some ground rules in this area. The agency
has not fully defined the problem, he remarked, but with what it has de
fined, there is at least some oversight. At the same time, he characterized
the development of a medical food as “kludgy,” requiring a much greater
financial investment and being more difficult relative to developing a dietary
supplement. Yet, he said, using the term “medical foods” is a way to dif
ferentiate these products from those developed by what he called “mom
and pop operations” that sell products that do not work. Once it can be
shown that a nutrition intervention works as a medical food, he suggested,
one can work backward and consider how to make it an over-the-counter
intervention and distribute it to the public at large.
Douglas Wallace remarked that one of the goals of nutrigenomics

is to minimize chronic disease. “The pharmaceutical industry would love
to develop drugs that have the same effect,” he said. He asked how these
conflicting perspectives on how to deal with chronic disease are going to
be managed when an estimated 50 to 60 percent of the population is being
prescribed pharmaceuticals to minimize a chronic disease.
Stover replied that FDA is very clear about the effect of chronic disease
treatment on nutrition; that is, if a pharmaceutical changes one’s require
ment for a nutrient, the change must become part of the formulation for the
drug. He suggested that perhaps this rationale needs to be revisited given
how widespread use of these drugs is today, but that is how it currently
stands. With respect to which is going to play the bigger role in lowering
rates of chronic disease—food or drugs—Stover expressed the view that
both need to move forward, but, he said, “I think a lot of the evidence is
that these are diet-driven, and in the long run, the diet-driven approaches
are going to be the best approaches in terms of lowering rates of chronic
disease without side effects and without the added health care cost.” At the
same time, he added, those are decisions made by politicians, not scientists.
Tim Morck agreed with Zeisel that medical food appears to be an
appropriate category for nutrigenomics products. However, he observed,
not everyone is familiar with what he described as “all the narrowness”
that this characterization entails from a regulatory standpoint. Choline is
a nutrient, he said, “so at least it gets that part of the box checked.” But
he argued that many people are trying to make medical foods out of things
that are not actually nutrients. He identified as a second challenge with
the medical food category that although medical foods require medical
supervision, which he agrees is an appropriate approach, it is important to
emphasize that these products are for nutritional management. One would
not be able to say, he elaborated, that they are being used to treat a disease
because that characterization is allowed only for drugs; instead, one would
have to say that they are being used to address the nutritional imbalance
a patient has by virtue of a genetic condition, or in some cases, a disease
impact. He argued that this then calls into question how to talk about nutri
tional balance, or normalization—in other words, the restoration of normal
metabolism—rather than about a pathological condition. Keeping this in
mind, he said, medical foods are the only categorization that would allow
for a nutritional treatment for patients with disease, as dietary supplements
can only help support normal function.
Zeisel clarified that he was not suggesting a medical food is the only
way to start implementing nutrigenomics; rather, he was suggesting that
it might be the best way to get the field started. It is credible, he argued,
because it has science behind it. Moreover, he suggested, given the com
plexity of nutrigenomics, developing a medical food rather than focusing
on dietary advice is a way to simplify and focus on a small problem with

a well-understood outcome. He predicted that eventually, products will be
developed that address multiple problems, and the idea that nutritional
intervention works will begin to permeate medicine. At that point, physi
cians will be able to tell their patients, “Go out and eat more eggs.” (During
his presentation, he had mentioned eggs as a dietary source of choline.) But
at present, in his opinion, most physicians would not be comfortable tell
ing their patients, “Go out and eat more eggs”; they would be more com
fortable with conducting a genetic test and then prescribing a nutritional
intervention on the basis of its results.
The audience member observed that, given the direction this field
appears to be going, it eventually will require the involvement of both
clinical nutrition and clinical genetics, as well as medical supervision. Yet,
she asserted, even adults who have inborn errors of metabolism caused by
single gene defects are not well handled right now in what she described as
“the great hospitals of America.” She acknowledged that perhaps children
with these disorders are being well handled, but argued that their adult
counterparts are not being integrated into internal medicine, adding that
she was unaware of the situation with surgery. She asked, “How is this all
going to be handled, this brave new world?”
Medical foods fit the precision medicine model, Zeisel replied. He
described precision medicine as a powerful movement at present, with the
support of both federal researchers and many large medical schools, and as
a subject being taught to every medical student today. “I think everybody
will be practicing that way,” he said, so “this will just look the same to
them.”
Stover suggested that the formulated medical foods being used to treat
loss of function in individuals with inborn errors of metabolism also serve
as a model. In the case of inborn errors of metabolism, he noted, the loss
of function is due to a single-gene defect, and many chronic diseases are
similarly due to a loss of function, not in a single gene, but across multiple
genes, and other factors, such as inflammation. Thus, he argued, just as
medical foods are used to restore function in individuals with single-gene
inborn errors of metabolism, they could also be used to restore function in
people with chronic disease.
Foods: From Wellness to Therapeutics

Naomi Fukagawa called attention to what she called a “spectrum” of
classifications for food, from wellness to therapeutics, and asked how cat
egories of food along this spectrum will be differentiated from each other
and from supplements.
Stover clarified that some chronic disease can be initiated prior to
conception. It is a trajectory over time, he said, and nutrition can change

or modify that trajectory. He suggested that complete prevention may not
be possible in all cases, and the idea of the food supply and wellness does
not always align well with the idea that chronic disease manifests over a
lifetime as the result of multiple factors, including genetics and others, in
addition to diet. For Stover, the question to ask is when the requirements
of an individual fall outside the realm of what can be achieved through a
natural, food-based diet because of genetic or other age-related factors. For
example, he observed, depending on one’s genetic makeup, one may not
be able to get enough folate from the food supply without fortification or
supplementation to prevent the risk of neural tube defects.
Zeisel suggested that another way to think about Fukagawa’s question
is that without a challenge, a person may be phenotypically healthy, but
when challenged, that person’s genetic or other limitations are revealed, and
they get sick. For example, he noted, there is no need to worry about fatty
liver in someone who is not consuming excess calories or is not making a
large amount of lipid in the liver. In that case, he said, transport of fat out
of the liver does not matter; it becomes important only when a person is
challenged. Thus, he observed, one could anticipate the fatty liver pheno
type appearing as a person moves toward becoming overweight, which is
when the need to transport fat out of the liver increases. So the question for
Zeisel is, What is the challenge that is going to reveal someone’s metabolic
inefficiency? The limitation of this approach, he added, is that it misses
things that were never conceived as being likely. The other approach, which
will reveal things not anticipated to be present, is to measure everything
and see what is correlated with health outcomes. But this approach, Zeisel
argued, is limited by the fact that the results will be associational and not
based on an understanding of the person’s biochemistry and metabolism.
Nutrigenomics in the Context of Preexisting Conditions

An audience member asked about the future of genomics, metabolomics,
and proteomics given that preexisting conditions may cause a problem with
insurance for today’s children. Stover responded that insurance coverage is
one of the greatest challenges with medical foods—for example, for children
with inflammatory bowel disease who are dependent on a liquid diet for their
survival. It is very difficult, he observed, for those families to get insurance
to pay for these products. He stated that political interest in this issue is cur
rently growing, and a bill now pending, the Medical Nutrition Equity Act of
2017, would address the problem. The question is, he suggested, What will
be the standard of evidence that justifies this huge expansion in reimburse
ment, that demonstrates these products actually work and are meaningful for
managing disease? “That is something that this community is going to have

to wrestle with,” he said.
In Zeisel’s opinion, if someone already has a problem, such as fatty
liver or rhabdomyolysis, his or her physician is already looking for the
optimal treatment at the lowest cost. He argued that testing is standard
for physicians, and if a test comes back positive, the physician feels con
fident prescribing a treatment. If a test shows that someone has a specific
metabolic effect, for example, and there is a medical food designed to treat
that effect, Zeisel would argue that prescribing that medical food as an
intervention poses no greater risk than would be the case if there were no
such option.
Zeisel suggested that eventually, babies will be genotyped at birth.
Thus, for example, if a person were prescribed warfarin later in life, that
person would not need to be genetically tested because his or her geno
type would be on file. Zeisel cautioned, however, that legislation will be
necessary to ensure that this type of screening does not place people at a
disadvantage. He mentioned a study in which he was involved with the
National Aeronautics and Space Administration (NASA), in which 16 of
32 astronauts who spent more than 16 months in space were found to
have permanently lost visual acuity by the time they returned. It is not
clear why, he said, but the best clue is that they have higher homocysteine
levels, not out of the normal range, but still higher than those of the other
astronauts who did not lose visual acuity. They have some polymorphisms
as well, he added. Once NASA knows the genotype associated with lost
vision, he observed, it will not want to send those astronauts to Mars. So
again, he added, there is a risk to genetic testing, and there must be either
legislation or a treatment. He mentioned a similar situation with the U.S.
Army Special Forces, among whom a significant percentage have developed
rhabdomyolysis and had to be sent home from the field. Again, he noted,
the army would like to avoid rhabdomyolysis in those people, so soldiers
are not going to want to be genotyped. On the other hand, he said, if there
is a solution related to the genotype that cures the problem such that muscle
breakdown does not develop, it will be worth being genotyped.
Implications for Dietary Guidelines

Wendy Johnson posed the question of what understanding of genetic
variation and how the environment impacts gene expression means for
dietary guidance. Will dietary guidelines still exist in “this new world,” she
asked, or are they to be abandoned altogether and replaced with something
more progressive?
For Stover, the question is whether the focus will be on clinical nutri
tion in a patient or in a population. “I think the answer is both,” he said.
He referred to the description in his presentation of the WHO recommen

dation for fortifying the food supply to prevent neural tube defects, and
how the WHO committee included in its model the effects of the MTHFR
polymorphism on folate status and the prevalence of the polymorphism in
the population. He explained that the question will always be the degree to
which any sort of modifier or sensitizer (e.g., the MTHFR polymorphism)
affects the requirement for a given nutrient. If there is an identifiable group
that falls outside of the normal population distribution, he observed, then
either the value for the nutrient will need to be changed to accommodate
that minority group, or the group will need to be considered a separate sub
group with separate nutritional requirements. Then the question becomes,
he suggested, how many subgroups there can be. “But there is no way I
think we are going to be able to walk away from having population-based
nutritional requirements,” he asserted, “because that’s the basis of the food
supply. The question is, how do we deal with people who fall outside the
distribution?”
In Zeisel’s view, a polymorphism found in 72 percent of U.S. women
(i.e., those with at least one PEMT C allele), represents a large enough
identifiable group to be accommodated. On the other hand, he suggested,
a polymorphism that occurs in only 1 percent of the population may be
too infrequent to accommodate. As far as what accommodation entails, he
said it could involve a genetic test indicating whether someone needs, for
example, more of a particular nutrient, or it could involve extending the
upper limit of the nutrient to meet that higher nutritional requirement. He
cautioned that the latter approach would be pushing toward toxicity.
With respect to the number of identifiable groups, Zeisel suggested that
the next step for the dietary guidelines may be to base recommendations on
haplotypes. He described a haplotype as a “lumping of genes that tend to
travel together with an ancestry,” and remarked that there are many fewer
of them than SNPs.
Stover urged the workshop participants to keep in mind, especially
when thinking about chronic disease endpoints for either dietary or nutrient
guidelines, that the risk factors for chronic disease include genetics, but they
also include age and diet and the interactions among genetics, age, and diet.
“The aging genome has just as much effect on a chronic disease, and maybe
even on nutritional requirements, as genetics,” he asserted.
Consolidation and Collaboration

Nathan Price remarked that both Stover and Zeisel had addressed the
notion of “genetics under challenge,” which he subscribes to as well. He
noted that for GWASs, a 1 percent effect is considered large, yet speakers in
this session had presented examples of much larger effects under challenge.
He asked about the degree to which this information has been catalogued
or consolidated such that other people can learn from it. Additionally, he
asked how the field can move beyond a few examples to begin studying
genetics under challenge on a large scale.
Stover replied that many databases are available to aid in developing
the architecture of a metabolic network, such as those for gene expression,
SNPs, the proteome, and the transcriptome, any of which can be used to set
a range for or circumscribe the magnitude of an effect at any one node. Yet,
he added, although the information is available, one must have some famil
iarity with the field to understand it. Once the dynamic range of an effect
is known, he observed, one can perform a sensitivity analysis to determine
how different inputs of nutrients affect the range of responsiveness. But,
he added, there has been no coordinated effort to examine and determine,
node by node, the degree of stochasticity of expression that is associated
with each node, something he believes is clearly needed.
Zeisel called for greater collaboration between experts who know
how to measure the genome or metabolome but do not really under
stand metabolism and experts in nutrition and other fields who understand
metabolism and know the inputs, outputs, and challenges along a pathway.
He stressed that most GWASs are focused only on statistical association,
without accounting for the fact that both challenged and unchallenged
individuals are involved.
5
Nutrigenomics: Regulatory, Ethical, and
Science Policy Considerations
I
n session 3, moderated by Patsy Brannon, speakers considered a range
of policy and ethical issues in personalized nutrition. Their presentations
took a close look at the nature and strength of nutrigenomic evidence in
terms of both what it needs to be and what it is, and at consumer perspec
tives, behaviors, and ethics. This chapter summarizes the session 3 presenta
tions and discussion, with highlights provided in Box 5-1.
SCIENTIFIC BASIS OF
GENETICALLY PERSONALIZED NUTRITION:
ETHICAL IMPLICATIONS OF METHODOLOGICAL LIMITATIONS
To begin her discussion of the ethical implications of the methodologi

cal limitations of the scientific evidence for personalized medicine, Cecile
Janssens, Emory University, remarked that she had presented a similar
lecture at the 2008 Evaluation of Genomic Applications in Practice and
Prevention (EGAPP) meeting in Atlanta, Georgia. The title of that talk
was “A Critical Appraisal of the Scientific Basis of Commercial Genomic
Profiles Used to Assess Health Risks and Personalize Diet and Lifestyle
Interventions.” At the time, she recalled, there were many companies selling
personalized diet DNA tests via the Internet, with many people believing
what Janssens referred to as the “myths about weight loss.” For example,
Genotrim was among the first companies to introduce a DNA-customized
“solution” for weight, telling consumers that the advice being provided
would last a lifetime because, the company claimed, “your genes are not a
85
BOX 5-1
• A 10-year-old critical appraisal of the scientific evidence behind seven different

companies’ dietary recommendations concerning the health risks associated
with certain genes found, for example, that almost half of the 56 genes tested
by these companies were not supported by robust evidence. Because such a
comprehensive review of the evidence has not been conducted for the genetic
tests currently being offered, the field, while promising, is not ready for prime
time. (Janssens)
• There is a discrepancy between what genetic testing companies’ advertise-
ments claim and what their disclaimers reveal. Companies need to communi-
cate more respectfully with consumers regarding the prematurity of genetically
personalized nutrition recommendations. (Janssens)
• In the future, the nutrition community will be using a stratified approach to
develop nutrition recommendations—that is, with individuals being clustered
into groups based on how they respond to particular dietary interventions (as
opposed to personalized, or individual, nutrition). This approach has an anal-
ogy in cancer treatment. (Schork)
• One can envision greater leverage of N = 1 and other emerging trial designs that
collect an individual’s phenotypic information over time to establish personal, as
opposed to population, thresholds for change in health status. (Schork)
• In the context of nutrigenomics, there are differences among the Clinical
Laboratory Improvement Amendments (CLIA) standards; the U.S. Food and
Drug Administration’s (FDA’s) authority under the medical device provisions
of the Federal Food, Drug and Cosmetic Act, as well as FDA’s regulation of
the safety and labeling of food; and the Federal Trade Commission’s (FTC’s)
authority. (Roller)
• Key regulatory issues that merit further consideration as nutrigenomics moves
forward in a commercial context include the adequacy of the existing FDA
regulatory framework to accommodate nutrigenomics claims for foods without
triggering “drug” status. (Roller)
fad.” Some of the genomic profiles being sold by those companies, Janssens
noted, focused on specific diseases or disease categories, such as heart
health, bone health, or inflammation health, while others were what she
characterized as a potpourri of gene variants supposedly statistically asso
ciated with some kind of health outcome. She added that the companies
would then provide dietary recommendations based on having detected, for
REGULATORY, ETHICAL, AND SCIENCE POLICY CONSIDERATIONS 87
example, an increased risk for heart disease. Her presentation began with a
review of the evidence behind these claims.
Reviewing the Evidence Behind Company Claims That
Gene Variants Are Associated with Disease Risk
In an article published in the American Journal of Human Genetics,

Janssens and colleagues (2008) review the scientific literature for evidence of
any association between the gene variants being tested by those early com
panies and disease risk. Janssens explained that she and her colleagues did
not limit the outcomes of their search to certain classifications of disease.
For example, if a company was using a gene to provide consumers with
information about heart health, they searched for evidence of an association
between that gene and any disease, not just heart disease. Additionally, they
required that the evidence be robust, so they reviewed only meta-analyses,
not single studies. Specifically, they investigated the claims of seven differ
ent companies, pooling all patients tested for a total of 69 polymorphisms
in 56 genes. Of those 56 genes, they found no evidence at all for almost
half (24); that is, none of those genes had been included in a meta-analysis.
Another 7 of the 56 genes had been analyzed in meta-analyses but showed
no statistically significant association with any disease. The remaining 25
genes also had been included in meta-analyses and had been shown to be
significantly associated with disease, but with 28 different diseases, and
most of the reported effects were small. What Janssens characterized as the
two most amazing findings of this review were, first, that the genes being
used to construct consumers’ cardiogenomic profiles were more frequently
associated with noncardiovascular than with cardiovascular diseases; and,
second, that two of the five genes used to construct consumers’ osteo
genomic profiles (i.e., risk for bone diseases) were associated not with bone
disease but with Alzheimer’s disease, asthma, non-Hodgkin’s lymphoma,
obesity, psoriasis, and systemic lupus erythematosus.
While this review was conducted 10 years ago, Jannsens continued,
“I’m not really very positive that the situation at this moment is very much
different.” In a recent commentary, Janssens and colleagues (2017) describe
their observation of two nutrigenomic studies in which the investigators
had tested all participants for the APOE gene in order to tailor recom
mendations on saturated fat intake, but without telling them that one
of the APOE alleles is a major risk factor for Alzheimer’s disease. Thus
now, she explained, all of the people tested in one of these studies know
whether they carry either one or two copies of the risk allele, and all of the
people tested in the other study know whether they carry at least one copy.
And, she added, as soon as they search for and read about APOE on the
Internet, they will know they carry an allele that is associated with a risk
for Alzheimer’s. For Janssens, that they were not told about this risk is an
indication that too few clinical genetics experts were involved in the studies.
In her opinion, even a clinical geneticist in training would have recognized
the association between APOE and an increased risk for Alzheimer’s dis
ease. She believes this example of the APOE allele illustrates many ethical
issues, such as those of informed consent, privacy, data sharing, and return
of results.
Janssens went on to describe another study similar to Janssens et al.
(2008), conducted by a team of researchers in Greece (Pavlidis et al., 2015).
She explained how they identified several nutrigenomics companies, exam
ined whether the genes included in the companies’ profiles were associated
with any disease or pathological condition, and found no single statistically
significant association for any of the 38 genes of interest. In cases in which
a weak association was demonstrated, she noted, the evidence was based
on only a limited number of studies. These authors concluded, “As solid
scientific evidence is lacking, commercially available nutrigenomics tests
cannot be presently recommended.”
Janssens remarked that, as a critical reviewer of scientific literature, she
is always aware of confirmation bias. She acknowledged that the results
of the Pavlidis et al. (2015) review accord with her skepticism about
nutrigenomics, but she also expressed the view that the review was not very
well conducted. The investigators conducted their search of the literature
using the following combination of terms: “nutrigenomics,” “[gene name],”
and “[disease name].” Thus, the only articles that appeared in their search
results were articles with “nutrigenomics” in their title or abstract. But
Janssens pointed out that many of the possible associations of relevance to
the 38 genes of interest could have been studied by researchers who were
not interested in nutrigenomics, in which case that term probably would not
have appeared anywhere in their papers. She said she was unsure whether
the results of the Pavlidis et al. (2015) meta-analysis would have been any
different if the investigators had conducted a more thorough search.
Regarding what is argued by researchers working in the field, Janssens
quoted the Academy of Nutrition and Dietetics’ position paper on nutri
tional genomics (Camp and Trujillo, 2014): “Although the discipline of
nutritional genomics holds promise for tailoring diet to a person’s genotype
and influencing chronic disease development, the science is still develop
ing.” She noted that this paper was being updated with new evidence,
but did not know whether the updates would alter this conclusion. She
also cited another paper, written by Görman and colleagues (2013), the
principal investigators of the Food4Me study, a large nutrigenomic trial in
Europe, who concluded “There is convincing evidence that common diet-
related diseases are influenced by genetic factors, but knowledge in this
area is fragmentary and few relationships have been tested for causality.
The evidence that genotype-based dietary advice will motivate appropriate

behavior changes is also limited.” Janssens interpreted these papers to mean
that the field is “not ready for prime time” yet. “It was premature in 2008,”
she said, and “it’s still premature in 2017.”
Company Claims Versus Disclaimers

Despite this lack of what she characterizes as robust evidence, Janssens
continued, companies advertising genetic testing for consumers continue to
claim that insights from their DNA can help them eat a healthy diet best
suited to their genetic makeup, metabolism, and lifestyle, or simplify diet
ing with a personalized nutrition plan based on their DNA. One company
claims that people’s DNA plays a large role in determining how their body
interacts with food, affecting preferences, sensitivities, and metabolism. But
does DNA really play such a large role?, Janssens asked. Her answer was
no. These companies, she asserted, are not providing recommendations—
they are promising genetically personalized eating plans. In her opinion,
their claims are too optimistic and can be misleading.
In contrast to their claims, Janssens continued, these companies’ dis
claimers are very transparent with regard to the limitations of the testing
they provide and the marginal role of genetics in how the body responds
to diet. As an example she cited Helix, an online marketplace that sells
nutrition-related DNA testing applications, whose disclaimer states, “Genetic
variants related to nutrition are connected by the way that your body pro
cesses food, but they do not guarantee that you will or will not be successful
with any given diet plan. Your DNA may help you narrow in on new diet
plans that you might prefer or find more successful than others, or even just
a better understanding of your existing preferences. Everyone, regardless of
their genetics, will benefit from a well-balanced diet.”1
Janssens went on to point out that all of these companies provide legal
disclaimers, although consumers must scroll down to the bottom of their
terms of service pages to find this information, and when they do, the
information is in legal language. To illustrate, she showed a screenshot of
a disclaimer that reads,
This site and the information, services and materials contained on this site
are provided on an “as is” basis and your use of this site is at your own
risk. . . . Neither Vitagene nor its affiliates warrant that the information
on this site is accurate, reliable or current. . . . Neither Vitagene nor its
affiliates nor any third party supplier can be assured that the user, in using
this site, has selected an appropriate service provider. Again, you should
1 See https://www.helix.com/shop/dnafit-mealplanner (accessed April 17, 2018).

use this site for general informational and educational purposes only and
should direct any further inquiries to a professional health care provider.2
The point is, Janssens said, “if you put this on the bottom of your site, you
can get away with any test.”
For Janssens, the content of these claims and the way these disclaimers
are being communicated is where ethical principles come into play. The
ethical norms of both medicine and marketing, she stressed, basically say
the same thing: do good with the best intentions, and treat your patient or
customer with honesty, responsibility, and transparency. In her opinion, the
companies whose claims and disclaimers she had described are not meet
ing these criteria. She elaborated on two ethical principles in particular, as
summarized below: doing good (beneficence) and autonomy.
Beneficence
Janssens explained that beneficence, which is the intent of doing good,
involves, first, developing and maintaining skills and knowledge and con
tinuously updating them to reflect the best of what is available; and, sec
ond, considering the individual circumstances of all patients. She expressed
uncertainty as to how the latter criterion should be applied on the Internet,
but asserted that at least the first criterion can be met. But an important
question for her is whether, given that nutrigenomics research is still so
young, the commercial offers of these companies are in the best interest of
customers or the best interest of the companies. She highlighted as another
important question whether there is any evidence on how to “compensate”
genetic effects with diet, to which, in her opinion, the answer is no. “The
knowledge that we have does not provide enough evidence for those kinds
of tests,” she argued.
To explore further the concept of beneficence in personalized nutrition,
Janssens described the analytic framework used by the U.S. Preventive
Services Task Force (USPSTF) to investigate whether a screening program
provides a benefit to persons at risk—for example, whether a glucose
test used to screen obese individuals for prediabetes results in improved
health after a dietary or exercise intervention (Melnyk et al., 2012) (see
Figure 5-1a). She remarked that, while many studies link diet and genes to
final outcomes—which in the glucose/prediabetes example include reduced
diabetes, cardiovascular disease, and mortality—clear evidence linking diet
and genes to an intermediate outcome—which in the glucose/prediabetes
example would be weight loss—should be adequate for personalized nutri
tion (see Figure 5-1b). The problem, she emphasized, is that there is no
2 See https://vitagene.com/consent/terms_of_use (accessed April 17, 2018).

FIGURE 5-1 Analytic framework used by the U.S. Preventive Services Task Force
(USPSTF) to investigate (a) whether a screening program (e.g., glucose test) pro
vides a benefit to a person at risk (e.g., an obese individual); and (b) whether DNA
testing (combined with a survey and other lab tests) provides a benefit to healthy
consumers.
NOTE: CVD = cardiovascular disease.
SOURCES: Presented by Cecile Janssens on December 5, 2017, adapted from
USPSTF, 2017.
evidence showing that a genetic disadvantage can be compensated by

changing one’s diet. In other words, as represented by the question marks
in Figure 5-1b, there is no evidence showing that personalized nutrition is
associated with any beneficial intermediate outcomes, let alone final out
comes. “I think that’s where the science is lacking,” Janssens asserted—not
with gene–disease associations, but with the solution that is being offered
by these companies to break these associations.
Janssens reiterated, “I think there is not enough evidence yet to offer
those tests online.” She believes that if people want to purchase these tests,
they should be able to do so, but they should also be provided with the
information necessary to make informed decisions about whether to make
such a purchase.
Autonomy
In addition to beneficence, Janssens views autonomy as an ethical
problem with current nutrigenomics companies. She explained that many
websites use proprietary algorithms that provide consumers with no insight
into how the company makes its recommendations based on a consumer’s
DNA profile. This means, she stated, that neither consumers nor scientists
can verify whether the information being provided makes sense, nor can
anyone verify what the company is doing with the algorithm. For Janssens,
this raises the question of whether a company is using an advanced algo
rithm to develop a personalized diet based on multiple SNPs with small
effects, or using a simple list of specific recommendations, or rules (e.g., the
rule for one SNP might be “eat more broccoli,” and for another, “consume
more vitamin D”), and then combining them into a personalized combina
tion of recommendations. Janssens argued that to build trust, it is essential
to provide some insight into how advanced a company’s algorithm is.
If the companies are not using advanced algorithms, Janssens con
tinued, they are providing essentially the same services that were offered
10 years ago, when, for example, it was recommended that an individual
with variation in MTHFR, MTRR, MTR, or CBS add a supplement con
taining 800 mcg folic acid, 15 mg vitamin B6, and 20 mcg B12 (Arkadianos
et al., 2007). Basically, she elaborated, there was a specific recommenda
tion for every gene, and one’s personalized diet was the combination of all
of these specific recommendations. “But that was 2008,” she said, adding
that, by 2017, one would have expected the field to have advanced further.
Janssens called for companies to be straightforward when evidence
is lacking, as she said 23andMe has been. She described how she had her
DNA tested by 23andMe in 2009 and how the information she received
from the company indicated that, while her risk for diabetes, for example,
was what it was at the time of the testing, evidence was accumulating
that could alter her risk. Additionally, the company provided her with
exact information about the volume of patients used to predict her risk
for diabetes and how her risk would increase or decrease if she had other
genotypes. In her opinion, that was enough information to verify what the
company was doing and to draw a conclusion about whether the informa
tion being provided made sense.
Final Remarks
In closing, Janssens called for better and more relevant scientific studies,
especially those showing whether personalized nutrition improves inter
mediate outcomes. Additionally and more important, in her opinion, she
called for companies to show more respect to consumers. She cautioned
against “spoiling the field” before personalized nutrition matures, noting
that it is lacking an appropriate scientific basis.
VETTING PERSONALIZED AND GENOMICALLY GUIDED

NUTRITION: ISSUES AND STRATEGIES
Delving more deeply into the vetting of personalized, genomically
guided nutrition, Nicholas Schork, J. Craig Venter Institute,3 began by list
ing the three themes he would be covering during his presentation: (1) how
to leverage trends in the biomedical sciences in nutrition-based health care,
touching on themes addressed by previous speakers; (2) how to identify,
verify, and vet nutrition strategies for individuals, borrowing strategies used
in cancer and chronic disease management; and (3) how to apply N-of-1,
aggregated N-of-1, and personal threshold–based trials.
Leveraging Trends in Biomedical Science in Nutrition-Based Health Care

Schork identified four trends in today’s biomedical science that he
believes could be leveraged in nutrition-based health care: (1) personalized
health care; (2) a number of emerging technologies that could facilitate
personalized health care, such as DNA sequencing, proteomics, wireless
technologies, and novel imaging technologies; (3) big data and the use of
information technology to identify patterns in the massive amounts of data
that are being collected at the population level; and (4) emerging strategies
in artificial intelligence. He identified as the goal for nutrition-based health
3 Schork was chair of the planning committee for the 2006 National Academies workshop
on nutrigenomics (IOM, 2007). The workshop summary is available at https://www.nap.edu/

catalog/11845 (accessed March 23, 2018).
care combining these trends such that something compelling can be said
about the nutritional needs of individuals.
However, Schork continued, these trends also raise some questions,
beginning with what he termed the “garbage in, garbage out principle”:
that unless data are of sufficient quality, an analysis of those data will
not yield reliable results. In the context of vetting nutritional strategies,
he elaborated, a number of questions need to addressed, including how
to develop these strategies in the first place, how to test them in humans,
and how to deploy them at the population level. Additionally, he raised
the question of what these nutritional strategies are trying to optimize—
individual outcomes; cost savings for the community as a whole, such as
by reducing the incidence of disease in the population at large; or quality
of life. He encouraged the workshop participants to keep these questions
mind as he proceeded and suggested that they could shed light on some of
the controversies he would be describing.
In addition to these emerging trends in biomedical science, Schork
mentioned recent, relevant changes at the U.S. Food and Drug Adminis
tration (FDA). He predicted that some of these changes will bear on the
claims one can make in the future about nutritional interventions. Specifi
cally, he was referring to the 21st Century Cures Act, signed into law by
President Obama in December 2016, which under certain conditions allows
companies to provide “data summaries” and “real-world evidence,” such
as results of observational studies, insurance claims data, patient input,
and anecdotal data, rather than full clinical trial results (FDA, 2017a). The
data must be compelling and collected in a sophisticated way, although
definitions of “compelling” have yet to be proposed. Nonetheless, Schork
characterized this as “a complete game changer.” He noted that FDA has
issued a number of white papers on various aspects of this new legislation
that he thinks may be worthy of consideration by nutritional scientists.
Identifying, Verifying, and Vetting Nutrition Strategies for Individuals

For Schork, a key question to consider when thinking about how to
leverage this new legislation and new technologies to identify, verify, and
vet nutrition strategies for individuals is what is actually being tailored to
what. Is a gross diet, such as the Atkins or Mediterranean diet, being tai
lored to an individual’s genetics? Or are refined nutrient recommendations
being tailored to an individual based on the collection of many different
types of data?
Schork described four levels of nutrition strategies for individuals. First
is the traditional, one-size-fits-all strategy, which involves simply provid
ing everyone with the same diet. Second is stratified nutrition, which may
involve using a couple of biomarkers of relevance to nutritional response
to place people in homogeneous categories and then providing each cat

egory, or subgroup, with a specific diet. Third, taking that strategy one
step further, multiple biomarkers could be used to refine the subgroups, an
approach Schork referred to as “precision nutrition.” Finally, at the indi
vidualized, or personalized, nutrition level, every individual is provided a
uniquely nuanced diet based on his or her genetic or biochemical profile.
But, again, Schork suggested, these possibilities raise questions: Which of
these four levels works best? How does one define “best” (e.g., economics,
patient benefit, scientific understanding)? And how does one prove that one
or another approach is best?
As an example of work in this area, Schork referenced a study by Zeevi
and colleagues (2015), who developed a strategy for collecting a large
amount of data on a group of individuals and then matching those profiles
to certain dietary recommendations in an attempt to identify subgroups
of individuals who would respond best, or optimally, to particular dietary
interventions. Additionally, the authors took their study one step further to
pursue what Schork said amounted to a small randomized controlled trial
that showed that in fact, the strategy had value.
Schork went on to state that this stratified approach has an analogy in
the cancer space. The cancer community knows, he explained, that certain
drugs can overcome the defects induced by certain genetic perturbations
(i.e., mutations) often found in tumors (Simon and Roychowdhury, 2013).
But to test, or vet, each drug–perturbation match would require what
Schork described as “a zillion small clinical trials,” which no one is likely
to pay for or pursue. So, he said, the cancer community has developed a
few strategies for vetting drug–mutation matches. As an example, he cited
the “basket trial,” whereby patients who are enrolled in a trial are steered
toward whatever treatment “basket” is most relevant, or most likely to
counteract the defect(s) caused by their mutation profile, based on an a
priori scheme, or algorithm, for matching patients to drugs. He emphasized
that it is not the individual drugs that are being tested in these basket tri
als, but the a priori scheme for matching a drug to a mutation. Based on
his conversations with FDA, he remarked that this same vetting strategy is
applicable not just to cancer but to all diseases, and that people can be pro
filed not just at the genomic level but on the transcriptomic and proteomic
levels as well. He predicted that in the future of nutrition, it will be these
algorithms that will be tested, not individual nutrients versus individual
profile characteristics.
Schork noted that in his discussions with FDA, another issue that arose
was that this type of study often does not take into account insights derived
outside of a trial. According to historical FDA standards, he elaborated,
someone initiating a trial to test a particular matching scheme would not
be able to incorporate any new information with bearing on the drug or
nutrient being tested that emerged over the course of the trial. According
to Schork, this potentially could result in a disservice to the individuals
participating in the trial. In the future, he argued, some discussion will
need to take place around how to make these trials more adaptive such
that they can incorporate data external to a trial into whatever strategy is
being vetted.
Schork stated that in his opinion, it should not be obligatory to test
the algorithms being used to develop nutrition strategies for individuals
(e.g., via legislation or regulatory oversight at some level)—that is, to show
that people who are provided therapies based on an algorithm have better
outcomes than those resulting from the standard of care or experienced by
some comparator group. However, he suggested further that if a company
is not curious enough about or confident enough in its technologies to want
to see if its algorithm works, that company should probably be approached
“with major caution.”
N-of-1, Aggregated N-of-1, and Personal Threshold–Based Trials

Finally, Schork considered several emerging trial designs that focus
on the well-being of an individual rather than that of the population at
large (Schork, 2015). He characterized the basic idea behind these trials as
fairly simple. He explained that one may want to measure an individual’s
phenotype and then modify it through intervention, but not know what
intervention would be useful. So one could measure the phenotype; sub
ject the individual to a particular intervention, or diet; take the individual
off the diet; then subject him or her to a comparator diet; and finally
measure the phenotype over the course of these alternating applications.
Then on this basis, Schork stated, objective claims could be made about
which intervention worked best for that particular individual. He added
that the same N-of-1 study on a different individual might yield a differ
ent result; that is, the second individual might respond better to a different
intervention.
Schork noted that although N-of-1 studies have been pursued in the
literature (Lillie et al., 2011), only some have dealt with dietary manipula
tions. But he envisioned the approach being used more in nutrition in the
future, leveraging wireless technology to collect phenotypic information
continuously.
There are several different N-of-1 study designs, Schork continued, in
cluding the sequential design (i.e., making decisions in real time), as well as
aggregated N-of-1 studies (Schork and Goetz, 2017). He explained that the
latter design involves aggregating results from multiple N-of-1 studies so
that patterns can be detected, and subsets of individuals with the same kind
of response can be identified. Then the next question would be, he said,
What is it about one subset that differentiates it from another? It could be,
for example, that individuals in that subset possess a particular genotype, or
perhaps they were exposed to something that was not accounted for when
the study was started. Schork suggested thinking about N-of-1 studies as a
way to identify phenotypes for later detailed study.
Schork cited as an example of an N-of-1 study the work of David and
colleagues (2014), who collected information on one of the investigator’s
own microbiomes, as well as information on his diet, every day for more
than 1 year. At the end of the study, they found a number of compelling
associations—such as that between fiber in the diet and changes in the
microbiome—that they believed might provide insights into how one can
optimize one’s diet. Schork himself conducted an N-of-1 study on the effects
of interventions on blood pressure. In this study, he and his colleagues
found that one of two drugs had a greater effect, but they were unable to
discern whether the individual’s drop in blood pressure was due to the ef
fect of that one drug or to weight loss, because over the course of the study,
the individual had become more health conscious and had lost 10 pounds.
Schork also was involved in another N-of-1 study that helped identify an
optimal strategy for treating a genetically mediated sleep disorder.
In closing, Schork differentiated between population and personal
thresholds. He defined population thresholds are those defined on the basis
of epidemiological studies; if a person’s biomarker level exceeds the popu
lation threshold, he or she is at risk. Personal thresholds, in contrast, are
based on an individual’s personal average (with error bars), obtained from
historical or legacy measures of the biomarker in that individual, with any
deviation over time being an indication of a health status change even if the
person’s biomarker level remains below the population threshold. Schork
concluded by observing that, as demonstrated by Drescher and colleagues
(2013), using a personal as opposed to a population threshold can minimize
the amount of time a person might have latent disease.
POTENTIAL REGULATORY POLICY
CONSIDERATIONS PRESENTED BY NUTRIGENOMICS
IN THE COMMERCIAL CONTEXT
The third and final speaker of this session, Sarah Roller, Kelly Drye
& Warren, LLP, shared her thoughts on key regulatory issues she believes
merit further consideration as nutrigenomics moves forward commercially.
She began by providing an outline of her talk. First, she would provide an
overview of the current federal legal framework that governs genetic test
ing and health benefit claims for the types of foods that might be used in
the context of nutrigenomics. She noted that she would not have time to
cover state law, but emphasized that states have regulatory authority that is
comparable to federal law and in some cases is even more stringent. Next,
she would be highlighting recent legal developments related to commercial
direct-to-consumer genetic testing. Finally, she would be highlighting some
key regulatory considerations for the commercialization of nutrigenomics
moving forward.
Federal Legal Framework for Health-Related Genetic Testing

Roller explained that all laboratories that perform health-related test
ing, including genetic testing, are subject to federal regulatory standards
administered by the Centers for Medicare & Medicaid Services (CMS)
under the Clinical Laboratory Improvement Amendments (CLIA). These
standards, she noted, govern how tests are performed, the qualification of
laboratory personnel, and quality control procedures for each laboratory.
She added that they are designed to ensure the analytical validity, but not
the clinical validity, of genetic testing in laboratories that perform health-
related testing.
In contrast, Roller continued, FDA regulates genetic testing kits and
components that are sold to clinical laboratories or other persons under
the Federal Food, Drug and Cosmetic Act (FDCA), which requires that
products be cleared by FDA before marketing. In accordance with the
definition of “device” in the statute, FDA’s authority to regulate medical
devices covers in vitro reagents and any genetic testing kit or related article
that is intended for use in the diagnosis of disease or other conditions or
in the cure, mitigation, treatment, or prevention of disease. Roller noted
that, while there is some controversy concerning the precise scope of FDA’s
authority to regulate tests that are developed in house by laboratories (i.e.,
laboratory-developed tests, or LDTs), FDA has taken the legal position that
laboratories offering LDTs are subject to both the CLIA and the FDCA,
yet FDA has generally exercised enforcement discretion and refrained from
enforcing the pre-market clearance requirements for LDTs.
Roller went on to point out that in 2015, FDA issued a report on its
findings from an evaluation of 20 publicly available case studies involving
what it called “problematic LDTs,” including some genetic tests (FDA,
2015). According to Roller, none of the problematic LDTs appeared to
have been related to nutrigenomics, but among those 20 cases, FDA iden
tified a number of critical issues posed by LDTs that had not been cleared
by the agency, including lack of evidence supporting clinical validity, lack
of pre-market review of performance data, and unsubstantiated product
claims. In the specific context of genetic tests, she reported, FDA found
that some tests yielded too many false positives and others too many false
negatives, some detected factors that had no clear relevance to the disease
at issue, some linked to treatments that were based on disproven scientific
concepts, and others had problems with lack of validation. She pointed
out that all of these 20 problematic LDTs had met the minimum CLIA
standards.
Roller emphasized that only health-related genetic tests qualify as medi
cal devices. So, for example, Helix’s many applications, which she noted
that Janssens had also mentioned during her presentation (in the context of
her discussion of the contrast between companies’ claims and disclaimers
about the genetic tests they are selling), are classified as entertainment
applications of genetic testing. To illustrate this point, Roller observed that
through Helix, one can order genetic testing to gain insight into the types
of wine one is likely to prefer based on taste preference, how much “the
Neanderthal genome” is reflected in one’s own genome, or whether one’s
metabolism is more farmer or hunter based. She added that consumers
can even purchase socks, scarves, or tartans that are color-coded to reflect
their personal genetic profile. Because these are not health applications, she
reiterated, they do not qualify as medical devices, so FDA does not have
jurisdiction to regulate the tests involved under the medical device provi
sions of the FDCA.
Direct-to-Consumer (DTC) Genetic Testing

Roller went on to point out that, while a number of personal test kits
have been cleared by FDA for DTC marketing, the very first DTC genetic
test—23andMe’s Genetic Health Risks (GHR) test(s)—was not cleared
until early 2017. She noted that the initial set of approved GHR tests was
intended for use in determining an individual’s genetic predisposition to
10 diseases, and as far as she was aware, that initial set had already been
expanded by the time of the workshop. She explained that the tests analyze
DNA from a saliva sample and provide results intended to help individuals
make decisions about lifestyle choices or inform discussions with their
health care providers.
FDA cleared the 23andMe tests through the de novo premarket review
pathway, which Roller explained is available for devices that are novel,
that is, not substantially equivalent to an already legally marketed device,
and that present low to moderate risk. The conditions of approval were
designed to provide reasonable assurance of the safety and effectiveness of
both the initially approved and similar GHR tests produced by 23andMe.
According to Roller, the agency intends to exempt additional 23andMe
GHR tests from pre-market review and may also exempt GHR tests of
other makers after they submit their first pre-market notification. Because
of the higher risks associated with diagnostic tests, she added, FDA ap
proval excluded diagnostic tests from its scope.
Regulatory Considerations for the Commercialization of Nutrigenomics:

Health Benefit Claims for Foods
Under the FDCA, FDA also regulates the safety and labeling of food,
Roller continued. “Food” is a broad category, she noted, defined as “articles
used for food or drink,” “chewing gum,” and “components” of these
articles. “Food” encompasses conventional foods and beverages, including
nutritionally fortified and enriched foods; dietary supplements, which are
foods that are not in conventional food form and are consumed to supple
ment the diet with an essential nutrient or other dietary ingredient; foods
for special dietary use, which Roller noted is a very old category, one that
includes foods designed to serve particular dietary needs due to a physical,
physiological, pathological, or other condition, such as disease convales
cence, pregnancy, lactation, food allergy, underweight, or overweight; and
medical foods, which are foods that are formulated to be consumed or ad
ministered orally under the supervision of a physician and are intended for
the specific dietary management of a disease or condition for which distinc
tive nutritional requirements have been established that cannot be satisfied
by dietary modification alone (FDA, 2017b). Roller cited Lofenalac4 for
people with phenylketonuria as an example of a medical food.
Roller stressed that, regardless of category, a food may also be a drug
because the FDCA defines a drug as “(B) articles intended for use in the
diagnosis, cure, mitigation, treatment, or prevention of disease in man or
other animals [excludes FDA-cleared ‘health claim’].” Thus, she elaborated,
if a vendor makes a claim for a food product suggesting that the food has
benefits with respect to diagnosing, curing, mitigating, treating, or prevent
ing a disease, FDA may regulate that product as a drug unless the particular
claim has been cleared by the agency as a health claim. If the product is ap
proved on the basis of a health claim instead—that is, if the claim suggests
that a food has health maintenance or health promotion benefits rather than
disease prevention benefits—the marketer must instead substantiate the
claim under what Roller described as the structure/function claim carve-out
from the drug definition.
According to Roller, while FDA historically has interpreted the drug
provisions of the FDCA very broadly so as to limit the range of disease-
related claims that can be made for food products without triggering drug
status, the agency also has broad authority to interpret and enforce the
statute and regulations flexibly. She offered a few examples in which FDA
has relied on this authority to exercise enforcement discretion and refrain
from enforcing the letter of the statute or agency rules. She cited as a
4 Lofenalac is an oral powder prescribed to replace milk in the diets of infants and children
with phenylketonuria; it has been regulated as a food since 1972.

recent example FDA’s guidance allowing “healthy” claims for higher-fat

foods that contain a healthy balance of fatty acids, even though the rule
in the Code of Federal Regulations (CFR) does not include this provision,
adding that this guidance was partly in response to the most recent dietary
guidelines. She referred to qualified “health claims”—truthful health claims
substantiated by credible evidence that does not meet the “significant sci
entific agreement” evidence standard—as a second example. Finally, as a
third example she pointed to FDA currently allowing medical device data
systems (MDDSs) and many medical apps to be marketed without meeting
the requirements for medical devices, even though their makers call their
products medical devices. This latter policy, she remarked, is intended to
avoid overregulation of promising lower-risk health information technology
(HIT) applications.
Regulatory Considerations for the Commercialization of Nutrigenomics:

Federal Trade Commission (FTC) Authority
Finally, in addition to CLIA and FDA standards and regulations, Roller
discussed FTC’s broad authority under the Federal Trade Commission
Act (FTCA) to prohibit unfair and deceptive acts and practices, including
false advertising. In contrast with FDA, she elaborated, the scope of FTC’s
authority does not cover products, only acts and practices. In the context
of nutrigenomics, she explained, FTC authority encompasses advertising
claims for genetic testing and food products and services, as well as data
security practices of companies that produce and store personal consumer
information (e.g., social security numbers and personal genetic test results).
Roller went on to point out that based on a large body of FTC false
advertising case law, FTC has developed detailed policies and guidance un
der the FTCA concerning requirements for claim substantiation. She then
highlighted a few of these policies.
First, Roller noted, both expressed and implied claims must be accu
rate and substantiated before they are used. Second, Roller continued, a
claim must be supported by evidence that provides a reasonable basis for
the claim. The basis need not be complete, she clarified, just reasonable,
and the reasonable basis standard is flexible. She explained that FTC takes
several factors into account when determining the nature and amount of
evidence required, including the type of product and claim, the benefits of a
truthful claim, the consequences of a false claim, the cost and feasibility of
developing claim substantiation, and the nature and amount of evidence
that experts in the relevant field believe is reasonable to support this kind
of claim. For Roller, the last criterion is especially important. “It’s what
people like you believe would be necessary for there to be a reasonable
basis,” she said.
Roller identified as a third FTC policy concerning claim substantia

tion that “competent and reliable scientific evidence” is generally required
for health-related claims. This means, she clarified, that studies must be
conducted objectively by qualified persons using investigative procedures
generally accepted in the relevant scientific community, such as randomized
controlled trials. She added that even in the context of this “competent
and reliable scientific evidence” standard, there is flexibility regarding the
amount and type of evidence, quoting FTC guidance (FTC, 2001):
A guiding principle for determining the amount and type of evidence

that will be sufficient is what experts in the relevant area of study would
generally consider to be adequate. The FTC will consider all forms of
competent and reliable scientific research when evaluating substantiation.
As a general rule, well-controlled human clinical studies are the most
reliable form of evidence. Results obtained in animal and in vitro studies
will also be examined, particularly where they are widely considered to
be acceptable substitutes for human research, or where human research
is infeasible. . . . Although there is no requirement that a . . . claim be
supported by a specific number of studies, the replication of results in
an independently conducted study adds to the weight of the evidence. In
most situations, the quality of studies will be more important than quan
tity. When a clinical trial is not possible (e.g., in the case of a relationship
between a nutrient and a condition that may take decades to develop),
epidemiologic evidence may be an acceptable substitute for clinical data,
especially when supported by other evidence.
As an example of recent FTC enforcement, Roller reported that in

2013, FTC took an enforcement action against Genelink, Inc., and foruTM
International Corporation, alleging that both companies had violated the
FTCA by making false and unsubstantiated health benefit claims about
their genetic tests and genetically customized dietary supplements, and by
using inadequate data security practices, putting consumers at risk of iden
tity theft. Roller did not delve into the details of the allegations, but pointed
out that they addressed both the claims and the characterizations of the
evidence, as well as the companies’ data security and data sharing practices
falling short of requirements to protect private consumer information. The
cases were settled in 2014.
Roller cited as another example that, although 23andMe’s GHR tests
were recently cleared through FDA, it sent the company a warning letter in
2013 because 23andMe was marketing the tests without their having yet been
cleared. The company successfully responded to that warning letter in 2014
following a cascade of class action litigation inspired by the letter. According
to Roller, the complaints that were filed in those lawsuits (all of which were
or are being settled, she noted) were similar to consumer protection issues
raised by FTC, such as misrepresentation to the consumer (e.g., the market

ing of the product implied to consumers that it had scientific support and
FDA approval) and inadequate data security practices (e.g., consumers were
unaware that third parties would have access to their genetic information).
Summary
In closing, Roller recapped issues that she believes merit further consid
eration as nutrigenomics moves forward, such as the adequacy of
• existing CMS and FDA frameworks for regulating genetic tests,

including LDTs that are used in DTC products and services;
• existing FDA regulatory framework to accommodate nutrigenomics
claims for foods without triggering “drug” status;
• existing claim substantiation guidance with respect to claims pro
moting genetic tests and foods in the context of nutrigenomics, such
as what “competent and reliable scientific evidence” should mean in
this context; and
• data security and disclosure practices concerning the personal ge
netic information that is being collected.
DISCUSSION
Following Roller’s presentation, she, Janssens, and Schork participated
in an open discussion with the audience, summarized here.
Nutrition in the Disruptive Frontier: Innovation Versus Regulation

An audience member commented on how the “disruptive frontier”
being described at the workshop really challenges the way nutrition is under
stood. As examples, she mentioned Steven Zeisel’s discussion of medical
food as a potential category for classification in the context of nutrigenomics
(Zeisel’s presentation is summarized in Chapter 4) and Schork’s discussion of
N-of-1 studies and real-world evidence as new ways to measure the impact
of nutritional interventions. She asked the speakers to reflect on the balance
between maintaining a long-term outlook and continuing to foster this type
of innovation so that nutrigenomics products can reach the people who
really need them, as well as the need for oversight to control these develop
ments from food safety and communication perspectives.
Roller responded, “I think that right now is about as favorable an
environment for bringing those questions to the FDA as we have had in a
number of years.” In addition to the 23andMe clearance showing “some
creativity,” she mentioned a health claim that had been cleared earlier in
2017 concerning a food allergen, commenting on how the claim addressed

the kind of health condition for which previous health claims had not been
cleared. She cautioned, however, that while the environment is favorable,
it is important to be very particular when requesting a response from FDA.
Schork added that relatively little time had elapsed since the 21st
Century Cures Act was introduced, so the fact that there have not yet been
many examples of such requests may simply reflect the fact that investiga
tors have not had enough time to develop new study designs or ways to
collect data in the real world. He agreed with Roller that currently, FDA is
willing and eager to listen to the scientific community, more so than it has
been in the past. As another example of a new development, he mentioned
that it is now possible to register digital therapeutics (e.g., apps on smart-
phones) with FDA as health technologies, so that if approved, they can be
prescribed by physicians instead of pills. “So there’s a lot of really forward
thinking that goes on,” he said, adding that “of course the data is going to
have to pass muster, but there’s a lot of receptivity for novel ideas.”
The Flexibility of the FDA Regulatory System

An audience member observed that currently, risk is structured by
“put[ting] things very neatly into boxes with boundaries.” For example,
there is a definition for food, a definition for dietary supplements, and so
on, and FDA is structured that way as well; that is, devices and biologics
and drugs are each considered separately. Yet, the audience member pointed
out that the discussion at the workshop had revolved around a systems
approach whereby testing “that” leads to “this” and to “this.” “But we
don’t have a regulatory system that puts those puzzle pieces together,”
she said, or an agency that is structured to deal with a holistic approach.
She asked how, moving forward, the systems-level, or holistic, nature of
nutrigenomics will be managed from a regulatory perspective when the
regulatory system is not structured to handle such an approach.
Roller replied that, although FDA has customarily interpreted its stat
utes in particular ways, in fact this simply reflects a general principle of
administrative law. That is, she explained, when an agency interprets its
own statute, the courts will defer to the agency. So if the agency has been
interpreting a statute in a particular way but decides that the world is
changing and a different approach is needed, it can change its approach—it
simply needs to justify the change. Roller again emphasized the flexibility
and authority FDA has to be creative.
The audience member also commented on the fact that there is no
established format for labeling medical foods, in contrast with dietary
supplements and conventional foods. The term “medical food” does not
appear on foods that are intended to be medical foods, she elaborated,
while many foods in the marketplace that do not meet the definition of
medical food are labeled as such. Thus, she said, consumers cannot tell
by looking at the package whether a food is a medical food (as defined by
FDA). Roller replied that only one kind of food is required to have a label
indicating what it is, and that is dietary supplements. For all the other food
categories, she explained, what is important is that the product meet the
requirements for that kind of food. She reiterated that FDA has flexibility,
in this case with its approach to medical foods. In her opinion, something
not being well defined can actually be a “good thing.”
Transparency of 23andMe
Ahmed El-Sohemy commented on Janssens’s approval of 23andMe’s
handling of its DTC genetic testing. Janssens clarified that she has, in fact,
criticized 23andMe many times in the past and that there are still things
about the company she does not like, mainly in relation to its presenta
tion of health risks. But she does like its transparency and how clearly it
informs consumers that their risks will need to be updated as new material
becomes available, and that their current risks are based only on “what
the science at this moment knows about your genes.” She recalled that her
own thrombosis risk “decreased” from 24 percent to 9 percent when the
company refined incidence rates to be sex-specific.
The Ethics of Sharing Information with Patients

An audience member commented on the many medical centers in the
United States that ask their patients to provide DNA so they can conduct
whole-exome sequencing and then bank those data. He asked whether it
was ethical not to give that information back to the patients. To him, it ap
pears that information is being collected about many SNPs, or alleles, that
could be of value to people’s health but is not being shared.
“That is a difficult question,” Janssens replied. After clarifying that
only data are collected and that data do not become information until they
are interpreted by an algorithm or specialist, she expressed uncertainty
about whether it was ethical not to share that information. She posed a
different question: Is it ethical to give something to the patient when the
patient does not know what to do with it? “I think in health care,” she
said, “doctors should give answers to questions, and not just answers, but
that’s a personal opinion.”
Roller added that, based on her observations and in the context of
litigation at the federal level, it appears that genetic information is being
treated in much that same way as social security numbers. In other words,
she clarified, disclose all the material facts and ensure that consumers know
what they are getting. But for her, the question is, Is it the same kind of
information, or is it something more significant? Right now, she observed,
there is no legal framework for dealing with these kinds of ethical issues.
She added that in the complaints she had mentioned during her presenta
tion, people have mentioned property rights. “It’s not settled right now,” she
said, “but I do think it’s an issue that does deserve further consideration.”
Janssens added that the American College of Medical Geneticists has
developed a list of variants that it calls “actionable mutations.” These
are variants, she clarified, that need to be returned when people undergo
sequencing, such as the BRCA mutation for breast cancer.
Is Nutrigenomics Premature or Is It Ready for Prime Time?:
The Level of Evidence Needed
In response to points made by Janssens during her presentation,

El-Sohemy pointed out, first, that the Academy of Nutrition and Dietetics
had formally withdrawn its position on nutrigenomics and was not just
updating it, as Janssens had mentioned; and, second, that some letters to the
editor have asserted that the Pavlidis et al. (2015) study, which Janssens had
discussed, should be retracted. Additionally, El-Sohemy pointed out that his
company, Nutrigenomix, has been asked by practitioners to provide APOE
testing to predict response to blood lipids, but that the company decided
not to include that gene in its panel because of the potential for unintended
consequences (i.e., due to its association with a risk for Alzheimer’s disease).
He then asked Janssens what kind of evidence she would need to see to
agree that nutrigenomics should be available and used.
Janssens replied that in her opinion, proper evidence does not stop with
demonstrating a robust gene–diet outcome association. That is the start,
she said, “but you need to show that changing a diet really compensates
that genetic disadvantage.” So, for example, if a certain genotype has been
shown to be associated with higher blood pressure, she believes it needs to
be demonstrated that by changing diet, blood pressure in individuals with
that genotype can be lowered to a level that is similar to that associated
with other genotypes. Whether developing this evidence requires a ran
domized controlled trial or an observational study, she suggested starting
with the latter; then, when sufficient observational evidence exists, see if
a randomized controlled trial is still needed. She explained that she holds
this view because the field is changing too rapidly to rely on randomized
controlled trials. She emphasized that in her opinion, what is not needed
is more evidence on clinical outcomes, and thus she discouraged the type
of long study needed to show whether a change in diet affects clinical out
come. “If you can show that the intermediate factor changes, for me, that’s
enough,” she said.
6
Rethinking the Relationship

Between Diet and Health:
Can Nutrigenomics Help?
T
his chapter summarizes session 4 of the workshop, a panel discus
sion involving Cecile Janssens, Douglas Wallace, Steven Zeisel, and
Tim Morck, Spectrum Nutrition, LLC. The goal of the discussion,
said moderator Patrick Stover, was to address the question: Where do we
go from here, in terms of both where the field is moving and new expecta
tions for nutrition?
Before introducing the panelists, Stover summarized the workshop
as “an update to where the field of nutritional genomics is, based on the
last meeting we had 10 years ago.” The field has evolved rapidly in his
opinion, with respect to not only new knowledge about the role of genetics
in nutrition but also expectations for nutrition in terms of chronic disease
outcomes. In addition to the bar being raised for outcomes, that is, moving
beyond functional indicators as discussed by Patsy Brannon in her opening
presentation (see Chapter 1), he called attention to the fact that the bar
has also been raised with respect to the type of evidence that is needed.
He noted that a recent National Academies publication on chronic disease
outcomes calls for grading evidence such that nutrition recommendations
would have to have at least moderate evidence (NASEM, 2017a). Although
he believes that observational data, which he said drive this field, can reach
that level of moderate evidence, large sample sizes and a dose dependence
will be required to demonstrate any effect of an intervention. Thus, he said,
“we have a lot of challenges in front of us.”
107
THE USEFULNESS OF THE PRECISION
MEDICINE PARADIGM IN NUTRITION
To initiate the discussion, Stover asked the panelists how they viewed
the role of precision medicine, that is, being able to classify individuals as
responders versus nonresponders (i.e., to a drug), as a paradigm for nutri
tion. Zeisel did not answer the question immediately but stressed that now
is a critical time to introduce nutrition into precision medicine, as major
medical centers are beginning to establish data collection systems upon
which precision medicine will be based. Yet, he said he was unaware of
anyone who was thinking seriously about the nutrition information that
would be collected, adding that this information is often viewed as being
too difficult to collect. “But if we don’t insert ourselves into the field so that
the data is collected,” he asserted, “nutrition will never be part of precision
medicine. It’s a critical time.”
Regarding the appropriateness of the precision medicine paradigm for
nutrition, in Zeisel’s opinion, the field of epidemiology “is being turned on its
head by recognizing that people are different.” Before today’s nutrigenomics
tools were available, he observed, one would have concluded, for example,
that half of young women need a particular intervention and the other half
do not. He stated that this type of result cannot be used to make a recom
mendation. With the new technology, however, what he described as “finer
cuts” can be made. Now, he elaborated, one can examine the 50 percent that
respond and the 50 percent that do not and determine why different people
respond differently. Doing so will “get the noise out of nutrition data,” he
said. Then, he suggested, it will be possible to develop targeted interventions
that work more predictively on subpopulations with unique genetic charac
teristics or some unique combination of genetic and other characteristics.
Janssens cautioned, however, that a challenge to classifying people on
the basis of their profiles is that “we very easily become unique.” As soon
as everyone becomes unique and there is no other “me” from whom to
learn, she argued, it is very difficult to say what the best treatment or diet
is for an individual. In other words, she said, profiling can reach a point
at which “there is no one else with that profile,” and the only way to test
interventions is through trial and error. She was curious as to whether any
one had any ideas on how to address this challenge, saying, “That, for me,
is the limiting factor both in precision medicine and in precision nutrition.”
In contrast, Zeisel expressed optimism and the view that many of the
ways in which people are unique have little to do with the profiling factors
used to characterize individuals as responders or nonresponders. He ex
plained that it is possible to identify profiling factors that make significant
contributions to determining whether an individual will be a responder or
a nonresponder, although a decision must be made about what constitutes
RETHINKING THE RELATIONSHIP BETWEEN DIET AND HEALTH 109
significant: Is a 1 percent contribution sufficient, or should it be 10 per

cent? “We arbitrarily decide how close we need to be to make a recom
mendation,” he noted. He referred to José Ordovás’s comment earlier in
the workshop about perfection being the enemy of good. In his opinion,
if enough profiling factors can be identified that predict 92 percent of
responders versus nonresponders, that is probably good enough, whereas if
the prediction rate is only 32 percent, more work should probably be done
to characterize response.
Janssens stated that she was not convinced the question is that simple.
When a large amount of data is collected, she said, the data reflect many
different profiles that distinguish “me” from others. In her opinion, it is
very difficult to identify what accounts for why different people respond to
different treatments.
Wallace suggested that there may be a continuum of variants, with dif
ferent variants (i.e., what Zeisel termed profiling factors) having different
impacts. Some act like single genes, he elaborated, which is the basis for
newborn screening whereby a particular variant is identified, and a specific
nutrient is given to compensate for that variant. In contrast, he continued,
mitochondrial medicine, a field in which physiological processes are af
fected by broad groups of related genes, requires a more general approach.
Depending on the pathway that is affected, he explained, certain kinds of
defects may require a more glucose-rich diet, for example, while others may
require more fatty acids in the diet. The more interesting challenge, in his
opinion, is the percentage of variance that can actually be controlled with
diet. He wondered whether there may be too much noise, or too much
variation, to control a risk for a disease such as Alzheimer’s or diabetes.
Zeisel pointed out that even in medicine, efficacy is quite low. If 30 per
cent of people who receive a drug treatment benefit, he argued, “we’ve done
well.” He cautioned against holding nutrition up to a more stringent stan
dard. Given that the goal of precision medicine is to try to do better than
this 30 percent, he asserted that if personalized nutrition guidelines could
be developed for a reasonably sized subpopulation with the understand
ing that the guidelines could be wrong for any given individual, “you’d be
doing really well.”
In that respect, Janssens said, the term “precision nutrition” is mislead
ing. She suggested instead “stratified nutrition,” which she believes presents
a more realistic picture of what can be expected.
Zeisel argued that adopting the same terminology used by the medical
community will be necessary to ensure that nutrition is actually used by
that community. If “precision medicine” is the term medical professionals
recognize, he stated, then only by using the term “precision nutrition” will
nutrition be recognized as “every bit as important as knowing what dose
of a drug to give.”
BEHAVIORAL ASPECTS OF NUTRIGENOMICS
Stover observed that the discussion to this point had focused on the clas
sification of nutrition at a clinical level. He asked Morck about the impact
of nutrigenomics on population as opposed to clinical nutrition.
“My bias is that the field of nutrition encompasses a pretty broad
spectrum of health,” Morck replied. Nutrition is not just about food, he
stated—it includes absorption, digestion, and all the other kinetic and
dynamic processes that Patsy Brannon had laid out in her opening pre
sentation. It also includes education (knowing what good nutrition looks
like) and selection (actually making good food choices), he added. Even
with all the genetic information and medical advice available, he said, “If
we are not motivated to take that advice, it is worthless.” He emphasized
the behavioral aspects of nutrigenomics that Brannon, Ahmed El-Sohemy,
and Nathan Price had all touched on in their talks. For nutrigenomics
to be successful, he asserted, the field needs to find a way to convince
people that it is not just beneficial but may be imperative to change their
diet should something be discovered about their genes that indicates risk.
Without that motivation, he claimed, change will not happen. He pointed
to smoking as an example of something that is known to be “bad,” but
that people still do. Lifestyle factors need to be taken into account as well,
he cautioned. With respect to precision nutrition, he imagined someone
having a recommended precision diet based on genetic information, but
then attending a family Thanksgiving dinner. He reminded the audience
that people eat food in social settings, and suggested that precision nutri
tion could inadvertently impose a level of social isolation by not taking
that fact into account.
For Morck, the personalization of nutrition is the personalization of
one’s approach to incorporating nutrition into one’s lifestyle and as an
important part of one’s future. He noted, for example, that the Mediter
ranean and Paleo diets provide guidelines, but posed the question of what
will guide people to making better choices on an incrementally more fre
quent basis. Additionally, he stressed the importance of having validated
biomarkers that are sensitive enough to show a metabolic or physiologic
benefit when people make the effort to change their diet. At present, he
asserted, the tools available are too crude to provide that type of reinforce
ment, and body weight, blood pressure, and cholesterol levels, for example,
are not specific enough. He believes that metabolomic markers hold prom
ise for providing patterns specific enough that people will be able to see
changes within a few months and perceive the value of continuing the new
dietary trends they began. He expressed the view that “the feedback is
really critical . . . in making significant, long-term nutritional changes that
are expected to produce real benefits.”
Zeisel suggested that there may be a biological component that helps

explain why some individuals are willing to change their diet while others
are not. Moreover, he suggested that this component may not be just
genetic. For example, he observed, when the feces of a person with anorexia
are transferred into another person, the other person starts behaving as
though anorexic.
Wendy Johnson, session 2 moderator, agreed with Morck, saying,
“We definitely have to have a behavioral piece . . . so that we can have the
benefit of these new discoveries.” She referred to Zeisel’s earlier remark
that nutrition needs to be included in precision medicine studies, or it will
be left behind. She posited that the same is true of behavior—it needs to be
included as well. She emphasized the importance of behavioral phenotyping
and of understanding what causes people to adhere, whether that cause is
genetic or something else.
WHY THE FOCUS ON GENETICS IN THIS
ERA OF DATA INTEGRATION?
Stover pointed out that, in addition to genetics, several speakers had

discussed epigenetics (Ordovás), the microbiome (Price), and other mea
surable features. He asked whether it made sense to continue the focus on
nutrigenetics in this era of data integration.
Zeisel remarked that the nutrigenetics toolset is 5 years ahead of other
toolsets, which in his opinion is the only reason it has become the priority.
The microbiome is much further behind, he added, given that it attracted little
attention until about 10 years ago, and the problem with epigenetics is that
target tissues cannot be collected, only blood samples. “I think it is a mistake,”
he argued, “to try to push too hard when you don’t have the toolset yet.”
Wallace wondered how metabolomic biomarkers in particular will be
found in the future, given the inherent variability of humans. In his own
research, he works with inbred mice and therefore is able to remove most of
the variance so that significant chemical signatures can be identified. With
that knowledge, he asserted, one should then be able to study that same
chemical signature in humans and identify which groups of individuals
show variation and which do not. “We have to go back and define . . . what
the real markers of relevance are,” he said, “then go back to the [human]
population and stratify the population.”
Zeisel added that in his opinion, the “challenge test” will be an impor
tant tool for nutrition metabolomics. He suggested that it may be the only
way to see metabolic variation because unless a system is challenged, the
body’s homeostatic mechanisms are capable of managing any variation in
metabolism. A challenge test pushes the system and reveals weaknesses, he
added.
Wallace agreed that in mitochondrial medicine, when a nutritionist

believes it is appropriate, administering a challenge test such as the glucose
challenge can help identify which part of the metabolic pathway is most
impaired. With that knowledge, he explained, dietary recommendations
can be tailored to meet that need. “That’s a really important tool for us,”
he said.
THE RELEVANCE OF NUTRIGENOMICS
TO LOW-INCOME POPULATIONS
Stover commented on how it has been estimated that nutrition-related

chronic diseases cost the U.S. economy about $1 trillion annually. Thus, he
asserted, one of the goals in nutrition is to lower rates of chronic disease,
with much of the discussion at the workshop being relevant to those efforts.
Yet, he observed, chronic disease is present mainly in low-income commu
nities that are least likely to benefit from nutrigenomics and have bigger
problems to deal with. He asked, “How do we deal with the equity issue
as we begin to think about advancing the science toward reducing chronic
disease when the target population that is driving the chronic disease may
be the least receptive to what we have to offer?”
Wallace commented on the importance and difficulty of studying differ
ent ethnic groups. He mentioned that he and his team have been conducting
fairly large studies on macular degeneration and glaucoma, which he char
acterized as having very different risk states in African Americans, Asian
Americans, Native Americans, and European Americans. Thus, he stated, it
is necessary to stratify by ethnicity, then substratify within each group, so that
variable(s) that are contributing to the differences in disease can be identified
and the percentage of variance due to those variables determined. Addition
ally, he and his research team have been very interested in studying Asian
Americans in California, but have spent almost all of their budget just as
sembling a population that would be representative of both first- and second-
generation Asian Americans. “I think this is important,” he said, “but there
are also constraints, and I don’t know how we are going to manage that.”
Another point to be made, Wallace continued, is that there is an inher
ent assumption that a person of lower socioeconomic status has a clinical
problem because of his or her socioeconomic status. He views that assump
tion as a sociologist’s perspective, and as a geneticist, he disagrees. He cited
as an example the assumption that African Americans have a higher rate of
preterm birth because they do not receive good health care. But a study in
Chicago stratified African Americans by socioeconomic status and showed
that preterm birth was the same regardless (Collins et al., 2007). Wallace
interpreted those results to mean that in fact, there may be much more
going on genetically than has been assumed in the past.
Zeisel mentioned studies conducted in Great Britain showing that

socioeconomic status in early life modifies epigenetic markers and ex
pressed concern that corporate databases are being built from people who
can afford to buy genetic tests, so that the data will be heavily biased
toward rich people. He suggested that because health care systems have
proposed collecting data on all patients, perhaps the collection and analy
sis of those data could be funded in a way that would allow for the data to
be correlated not only with outcomes but also with socioeconomic status.
He mentioned the National Institutes of Health as a possible source of
such funding.
For Janssens, the question of equality is so important that she feels
uncomfortable discussing nutrigenomics and puzzling over such detailed
tweaking of diet when there is an enormous nutrition problem in society
that will likely require completely different types of solutions. “I’m sure
that when I walk out of the building here later, and I see the people on the
street,” she said, “that I’ll question myself, ‘What have I been doing this
entire day? Why have I not tried to solve a bigger problem for them, instead
of trying to find a little benefit in nutrigenomics?’”
Ordovás asserted that “most of the time, the people who are missing
from this discussion are the policy makers.” He mentioned how the policy
of subsidizing meat, for example, is known to have affected the nutritional
health of certain neighborhoods. Additionally, he observed, it is known
from human breastfeeding data that the quality of milk varies among neigh
borhoods depending on socioeconomic status. Given these circumstances,
the component that is missing from the nutrigenomics discussion, in his
opinion, is public policy making.
Janssens agreed with Ordovás, but only partly. “I think also,” she said,
“to find a solution for the people who need it, we have to first ask ourselves
whether the solution for them is in nutrigenomics.” In her opinion, this is
not likely.
Zeisel disagreed. He characterized data studies as noisy, generating a
great deal of variability. Results of one study will come out and lead to
a new policy, for example, to recommend eating more cocoa; then another
study will lead to a different policy because it was based on a different
population. These discrepancies, Zeisel argued, turn people away from
nutrition and from using it in policy at all. In his opinion, imprecise, noisy
data lead to bad policy. Thus, he said, “I think everything we can do to
refine our ability to explain the noise and to understand why some people
respond and others do not is useful.” “Sure,” he added, “the big problems
are going to be solved by policy, but [policy makers] won’t come up with
the right answers unless our research techniques are refined.”
Johnson wondered whether a cost-effectiveness or cost-utility analysis
of some sort could be carried out and the results used to talk with policy
makers about whether genetic testing is a good investment in populations

that cannot otherwise afford it.
TRUST—AND DISTRUST—IN NUTRIGENOMICS

An audience member described how a genetics lab in Texas used DNA
to perform facial reconstruction and how law enforcement officials, in turn,
used the facial reconstruction to arrest a suspect for a crime. Historically,
she pointed out, communities such as the black community have experi
enced what she called “medical malfeasance.” “So there’s a lot of distrust in
wanting to give genetic information,” she said, even if it is for science. She
asked the panelists how this distrust would impact nutrigenomics.
In Zeisel’s opinion, the use of DNA in facial reconstruction is the same
as asking a witness to describe a suspect. The only difference, in his view, is
that instead of being obtained from an observer, information is being sought
from DNA based on what is known about genetic differences among, for
example, different ancestries. Regarding medical malfeasance, he mentioned
the Tuskegee study, in which black people were infected with syphilis to
study its effects, greatly harming credibility. Today, by contrast, there is
an expectation and a requirement that researchers consider a community’s
interests. He cited the example of his own research team, which, especially
with studies pertaining to genetic testing, solicits input from a community
advisory board. He described the members of the board as members of
the local community who can provide perspectives that the researcher
may not be able to perceive. He also emphasized the importance of good
communication and the sharing of benefits with respect to the knowledge
generated by a study. He stated that participants should be told about the
uses of the data, and they must give permission for the data to be used for
other research purposes.
“But in the end, you are taking a risk when you give your genetic
data,” Zeisel continued. For example, he noted, concern has been raised
that if an investigator were to be subpoenaed by the U.S. court system, he
or she would have to release study data even if the research subjects had
been promised that their data would be confidential. He stated that for this
reason, some investigators have been storing their genetic data on servers
outside of the United States. He emphasized the importance of investigators
informing individuals of the risks of their participation in a study and what
is going to be done to mitigate those risks. Then, he said, individuals can
decide whether they want to participate.
THE RELEVANCE OF AGRICULTURE TO NUTRIGENOMICS

An audience member asked about the potential impact of the con
sumption of genetically modified foods on a person’s long-term genetics.
Zeisel replied that the genetics used to modify a plant has little to do with
nutrigenomics, except for the fact that better data on people’s nutritional
needs could be used to try to design better foods. He added that traditional
breeding is a form of genetic manipulation. In the past, farmers chose
plants with the largest fruits, for example, and bred those plants, whereas
with the new techniques available today, they are making plants artificially
instead of breeding. But he said that in terms of the genes being inserted
into those plants, other than the effect of any food on one’s genetics, he
was unaware of any inserted gene that could also enter the human genome
upon consumption.
While the discussion was on the topic of agriculture, Naomi Fukagawa
pointed out that much of the genetic variation in humans also exists in
plants, animals, and the food that is produced from those plants and ani
mals. In her opinion, agricultural production goes hand in hand with efforts
in medicine aimed at wellness and the prevention of disease. She noted that
even Hippocrates, who is credited with the precept “first do no harm,” also
stated, “food is thy medicine.”
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A
Workshop Agenda
Nutrigenomics and the Future of Nutrition
Food Forum Meeting
December 5, 2017
National Academy of Sciences Building
2101 Constitution Avenue, NW, Washington, DC
Lecture Room
8:30 AM Welcome and Food Forum Member Recognition

Sylvia Rowe, M.A., Food Forum Chair
8:40 AM Setting the Stage: Introduction and Overview

Patsy Brannon, Ph.D., R.D., Cornell University
SESSION 1: Nutrigenomics and Chronic Disease Endpoints

Moderator: Naomi Fukagawa, M.D., Ph.D.,
U.S. Department of Agriculture
9:00 AM Genotypes and Disease Risk: What Do We Currently Know

About Nutrition and Epigenetics?
José Ordovás, Ph.D., Tufts University
127
9:30 AM Mitochondrial Genetics and Disease Risk: What Is the

Current Evidence?
Douglas Wallace, Ph.D., University of Pennsylvania
Perelman Medical School
10:00 AM BREAK
10:15 AM Personal, Dense, Dynamic Data Clouds and the Future of

Personalized Nutrition
Nathan Price, Ph.D., Institute for Systems Biology
10:35 AM Sickle Cell Disease: An Arginine Deficiency Syndrome with

Distinctive Nutritional Requirements
Claudia R. Morris, M.D., Emory University
10:55 AM Personalized Nutrition in the Real World: Where Do We

Stand?
David Alpers, M.D., Washington University (via WebEx)
11:15 AM Is Genetic Testing for Personalized Nutrition Ready for

Prime Time?
Ahmed El-Sohemy, Ph.D., University of Toronto;
Nutrigenomix
11:35 AM Moderated Discussion
12:05 PM Food and Nutrition Board Member Recognition

Bert Garza, M.D., Ph.D., Food and Nutrition Board Chair
Ann Yaktine, Ph.D., R.D., Food and Nutrition Board Director
12:15 PM LUNCH
SESSION 2: Nutrigenomics Applications: Dietary Guidance and Food

Product Development
Moderator: Wendy Johnson, Ph.D., M.P.H., R.D., Nestlé
1:15 PM Nutrient Requirements as Complex Traits—What Consumers

Will Need to Know
Patrick Stover, Ph.D., Cornell University
APPENDIX A 129
1:45 PM Gene Guided Nutrition Interventions

Steven Zeisel, M.D., Ph.D., University of North Carolina at
Chapel Hill
2:15 PM Moderated Discussion
2:45 PM BREAK
SESSION 3: Nutrigenomics: Regulatory, Ethical, and Science Policy

Considerations
Moderator: Patsy Brannon, Ph.D., R.D., Cornell University
3:00 PM Scientific Basis of Genetically Personalized Nutrition:

Ethical Implications of Methodological Limitations
Cecile Janssens, M.Sc., Ph.D., Emory University
3:20 PM Vetting Personalized and Genomically Guided Nutrition:

Issues and Strategies
Nicholas Schork, Ph.D., J. Craig Venter Institute; University
of California, San Diego (via WebEx)
3:40 PM Regulatory Policy Considerations Presented by

Nutrigenomics in the Commercial Context
Sarah Roller, J.D., R.D., M.P.H., Kelley Drye & Warren, LLP
4:00 PM Moderated Discussion
SESSION 4: Rethinking the Relationship Between Diet and Health: Can

Nutrigenomics Help?: A Panel Discussion
Moderator: Patrick Stover, Ph.D., Cornell University
4:30 PM Panelists:
• Cecile Janssens, Ph.D., Emory University
• Tim Morck, Ph.D., Spectrum Nutrition, LLC
• Douglas Wallace, Ph.D., University of Pennsylvania
Perelman Medical School
• Steven Zeisel, M.D., Ph.D., University of North Carolina
at Chapel Hill
5:15 PM ADJOURN
About Us
The Food Forum convenes scientists, administrators, and policy makers from
academia, government, industry, and public sectors on an ongoing basis to dis-
cuss problems and issues related to food, food safety, and regulation and to iden-
tify possible approaches for addressing those problems and issues. The Forum
provides a rapid way to identify areas of concordance among these diverse inter-
est groups. It does not make recommendations, nor does it offer specific advice.
It does compile information, develop options, and bring interested parties together.
The Food and Nutrition Board (FNB) established the Food Forum in 1993 to
allow selected science and technology leaders in the food industry, top administra-
tors in the federal government, representatives from consumer interest groups,
and academicians to periodically discuss and debate food and food related issues
openly and in a neutral setting. The Forum provides a mechanism for these
diverse groups to identify possible approaches for addressing food and food
safety problems and issues surrounding the often complex interactions among
industry, academia, regulatory agencies, and consumers.
About the FNB: The FNB falls within the Health and Medicine Division of
the National Academies of Sciences, Engineering, and Medicine. The National
Academies are private, nonprofit institutions that provide independent, objective
analysis and advice to the nation to solve complex problems and inform public
policy decisions related to science, technology, and medicine. The National Acad-
emies operate under an 1863 congressional charter to the National Academy of
Sciences, signed by President Lincoln.
http://www.nationalacademies.org/foodforum
B
Acronyms and Abbreviations
ABCA1 ATP-binding cassette transporter

acetyl CoA acetyl coenzyme A
ADH1B alcohol dehydrogenase 1B
ADP adenosine diphosphate
APOA2 apolipoprotein A-II
APOE apolipoprotein E
ATP adenosine triphosphate
BMI body mass index
CFR Code of Federal Regulations

CH congenital hypothyroidism
CLIA Clinical Laboratory Improvement Amendments
CMS Centers for Medicare & Medicaid Services
COI cytochrome c oxidase I
CoQ coenzyme Q
CYP1A2 cytochrome P450 1A2
DRI dietary reference intake

DTC direct-to-consumer
EAR estimated average requirement

EFSA European Food Safety Authority
131
EGAPP Evaluation of Genomic Applications in Practice and Prevention

EPA eicosapentaenoic acid
FDA U.S. Food and Drug Administration

FDCA Federal Food, Drug and Cosmetic Act
FTC Federal Trade Commission
FTCA Federal Trade Commission Act
FTO fat mass and obesity associated
GHR test Genetic Health Risks test

GOLDN Genetics of Lipid Lowering Drugs and Diet Network
GRS genetic risk score
HDL high-density lipoprotein

HIT health information technology
HLA human leukocyte antigen
IBD inflammatory bowel disease

ICU intensive care unit
LDH lactase dehydrogenase

LDT laboratory-developed test
M31V methionine 31 valine

MDDS medical device data system
miRNA micro RNA
MTHFR methylenetetrahydrofolate reductase
NAD nicotinamide adenine dinucleotide

ND1 NADH-ubiquinone oxidoreductase core subunit 1
NGS next-generation sequencing
NO nitric oxide
PASP pulmonary systolic pressure

PD3 clouds personal, dense, dynamic data clouds
RCT randomized controlled trial

RDA recommended dietary allowance
SCD sickle cell disease

SNP single nucleotide polymorphism
APPENDIX B 133
TCA cycle tricarboxylic acid cycle

TCF7L2 transcription factor 7-like 2
UL tolerable upper intake level

USPSTF U.S. Preventive Services Task Force
C
Speaker and Facilitator Biographies
David H. Alpers, M.D., is a professor of medicine at Washington University.

He is a graduate of Harvard College and Harvard Medical School, and
received his initial medical training at the Massachusetts General Hospital
(MGH), a Harvard teaching hospital. After training in molecular biology
at the National Institutes of Health, he returned to the Gastroenterology
Division at MGH before leaving to become chief of the Division of Gas
troenterology at Washington University School of Medicine, a post he held
for 28 years. He has served as editor-in-chief for the American Journal of
Physiology/GI Liver Physiology and Current Opinion in Gastroenterology
(Small Intestine/Nutrition); as associate editor for the Journal of Clinical
Investigation and American Journal of Clinical Nutrition (2008–2017); and
on the editorial board of the Journal of Biological Chemistry, the Journal of
Gastroenterology, and many other journals. He is the author of 223 peer-
reviewed scientific/clinical papers and is the senior author of the Manual
of Nutritional Therapeutics (6th edition, 2015), and he was an associate
editor of Yamada’s Textbook of Gastroenterology through its first five edi
tions. He has served on many scientific advisory committees, including for
MGH (chairman); the Bill & Melinda Gates Foundation (zinc absorption
in third-world countries); and most recently the Alimentary Pharmabiotic
Centre, University College Cork, Ireland, and the Sackler Center for Bio
medicine and Nutrition Research at The Rockefeller University. He has
been involved for decades as a consultant in drug development on assets
related to gastroenterology and nutrition, most often with GlaxoSmithKline
135
(Digestive Diseases), Takeda North America (Digestive Disease Therapeutic

Unit), and Pfizer Pharmaceuticals (Rare Disease Research Unit).
Patsy M. Brannon, Ph.D., R.D., is a professor in the Division of Nutri

tional Sciences at Cornell University, where she has also served as dean
of the College of Human Ecology. Prior to moving to Cornell University,
Dr. Brannon was chair of the Department of Nutrition and Food Science at
the University of Maryland. She has also served as visiting professor in the
Office of Dietary Supplements at the National Institutes of Health (NIH).
Her research focus includes nutritional and metabolic regulation of gene
expression, especially as it relates to human development, the placenta, and
exocrine pancreas. She chaired an NIH initiative to plan effective federal
research related to the health effects of vitamin D, and co-chaired the NIH
program “Vitamin D and Health in the 21st Century: Update Conference,”
as well as the vitamin D roundtable associated with the conference. She
also served on the Institute of Medicine’s Committee to Review Dietary
Reference Intakes for Vitamin D and Calcium. Dr. Brannon is a member of
a number of professional and scientific associations and has served on the
executive board of the American Society for Nutrition. She has received
numerous awards, including the Pew Faculty Scholar in Nutrition award
and the Centennial Laureate award from Florida State University. She re
ceived her Ph.D. from Cornell University in nutritional biochemistry. She
is a registered dietitian.
Ahmed El-Sohemy, Ph.D., is a professor at the University of Toronto and

has held a Canada Research Chair in Nutrigenomics. He earned his Ph.D.
in nutritional sciences from the University of Toronto and completed a
postdoctoral fellowship at Harvard. He returned to Toronto in 2000 to
establish a research program in nutritional genomics. The goal of his re
search is to elucidate the genetic basis for variability in nutrient response
in health and performance. Dr. El-Sohemy has published more than 130
peer-reviewed articles and has given more than 200 invited talks around
the world. He is on the editorial board of 10 scientific and medical journals
and served as an expert reviewer for more than 30 other journals and 12
granting agencies. He has more than 4,200 citations with an H-index of
38. Dr. El-Sohemy has served on Health Canada’s Scientific Advisory Board
and several international expert advisory panels. He has made numerous
appearances on television, on radio, and in print media. He was voted one
of the top 10 people to watch in 2004 by the Toronto Star, Canada’s largest
daily newspaper, and in 2007 was nominated for Canada’s Top 40 Under
40 award. In 2013, Dr. El-Sohemy was named one of the top 10 inventors
of the year by the University of Toronto, and the following year he was
awarded the Centrum Foundation New Scientist Award for Outstanding
APPENDIX C 137
Research by the Canadian Nutrition Society. Last year he was awarded the
Mark Bieber Professional Award by the American College of Nutrition.
He is the founder of Nutrigenomix and chairs the company’s International
Science Advisory Board.
Naomi K. Fukagawa, M.D., Ph.D., is the director of the U.S. Department

of Agriculture’s (USDA’s) Beltsville Human Nutrition Research Center in
Beltsville, Maryland. She previously served as professor of medicine and
acting director of the Gerontology Unit at the University of Vermont,
Burlington. Dr. Fukagawa is a board-certified pediatrician and an expert
in nutritional biochemistry and metabolism, including protein and energy
metabolism; oxidants and antioxidants; and the role of diet in aging and
chronic diseases, such as diabetes mellitus. She has served on numerous
National Institutes of Health (NIH) review panels, served as chair of the
NIH study section for General Clinical Research Centers, and completed
a 5-year term on the NIH Integrated Physiology of Obesity and Diabetes
study section. Her national/international recognition is demonstrated by her
membership in the American Society for Clinical Investigation; election as
president of the American Society for Clinical Nutrition (American Society
for Nutrition); and service as an associate editor for the American Journal
of Clinical Nutrition, as editor-in-chief of Nutrition Reviews, and as vice-
chair of the 2010 Dietary Guidelines Advisory Committee of USDA and
the U.S. Department of Health and Human Services. Her clinical training
included residency at the Children’s Hospital of Philadelphia, University of
Pennsylvania; chief residency at the University of Vermont; and nutrition/
gerontology fellowships at the Children’s Hospital and Beth Israel Hospital,
Harvard Medical School. Dr. Fukagawa has maintained an active research
laboratory where her work ranges from cells and animals to in vivo studies
in human volunteers. Her present work focuses on the impact of environ
mental stressors (metabolic or physical) on human health, specifically the
health effects of exposure to petrodiesel and biodiesel exhaust. She received
her M.D. from Northwestern University and her Ph.D. from the Massachu
setts Institute of Technology in Cambridge.
A. Cecile J. W. Janssens, M.A., M.Sc., Ph.D., is a professor of epidemiology

in the Department of Epidemiology of the Rollins School of Public Health,
Emory University, Atlanta, Georgia. Her research concerns the translation
of genomics research to applications in clinical and public health practice,
and focuses on the polygenic prediction of multifactorial diseases such as
diabetes, cardiovascular disease, and cancer, in particular on theoretical
and methodological questions in the assessment of the predictive ability
and utility of genetic testing. She regularly publishes on research methodol
ogy, research integrity, and research ethics. As the result of a serendipitous
finding, she is currently investigating a novel search method for scientific

literature. Dr. Janssens has published more than 180 papers in international
scientific journals. She is a lecturer in graduate and postgraduate courses in
local, national, and international programs. She holds degrees in econom
ics, psychology, and epidemiology and received her Ph.D. from Erasmus
University in Rotterdam, the Netherlands.
Wendy Johnson, Ph.D., M.P.H., R.D., is the vice president of nutrition,

health, and wellness at Nestlé USA; the past chair of the food and nutri
tion section of the American Public Health Association; and a recognized
public health researcher. She is known for her focus on diverse communities
and on ensuring that parents have the information and resources they need
to give their children a great start. In her current role, she is charged with
setting and implementing the cross-cutting Nutrition, Health and Well
ness Strategy for the U.S. Nestlé businesses. Dr. Johnson is a member of
the advisory board of the Newark Start Healthy Stay Healthy community
program, which educates families on how to close nutrition gaps for young
children. She received her Ph.D., M.P.H., and B.A. from the University of
North Carolina at Chapel Hill.
Timothy A. Morck, Ph.D., is the president and founder of Spectrum Nutri

tion, LLC, a firm that provides expertise in nutrition-related basic/clinical
research, product development, regulatory and public policy, and global
scientific affairs. His career includes clinical nutrition practice, research,
and medical school faculty appointments; scientific association manage
ment; entrepreneurial personalized nutrition startups; and executive and
senior management positions at several global nutrition and pharmaceuti
cal companies. His unique multidisciplinary perspective integrates science
and business objectives with a passion for personalized approaches to
improving health. Dr. Morck received a B.S. in animal science from The
Pennsylvania State University, followed by M.S. and Ph.D. degrees in nutri
tion (biochemistry and physiology minors) from Cornell University.
Claudia R. Morris, M.D., FAAP, is an associate professor of pediatrics

and emergency medicine at the Emory University School of Medicine. She
is also a pediatric emergency medicine attending physician at Children’s
Healthcare of Atlanta. Dr. Morris has been involved in sickle cell disease
(SCD) research for more than 20 years; has a history of National Institutes
of Health (NIH)-, U.S. Food and Drug Administration (FDA)/R01-, and
industry-sponsored funding; and has led several single- and multicenter tri
als. She has a special interest in translational research that targets inflamma
tion and oxidative stress. From the start of her career, Dr. Morris’s research
endeavors have focused on nutritional interventions based on specific meta
APPENDIX C 139
bolic pathways that cross disease disciplines, identifying alterations in

the arginine metabolome in SCD, thalassemia, asthma, and pulmonary
hypertension. She also published the first randomized, blinded, placebo-
controlled trial of arginine therapy to treat pain in children with SCD. Dr.
Morris’s efforts have always encompassed an integrative approach to the
practice of medicine. She is a firm believer in nutrition as medicine, and
appreciates the growing need to address distinctive nutritional require
ments provoked by some acute and chronic illnesses, with SCD as an ideal
paradigm.
José M. Ordovás, Ph.D., is a professor of nutrition and genetics at Tufts

University and a senior scientist at the U.S. Department of Agriculture
(USDA)-Human Nutrition Research Center on Aging at Tufts University
in Boston, where he also is director of the Nutrition and Genomics Labo
ratory. He is a senior collaborating scientist at the Centro Nacional de
Investigaciones Cardiovasculares and the Madrid Institute of Advanced
Studies Alimentacion (Madrid, Spain). Dr. Ordovás’s research focuses on
the genetic and epigenetic factors predisposing to cardiovascular disease
and obesity and their interaction with environmental and behavioral fac
tors, with an emphasis on diet. He has published more than 770 scientific
articles in peer-reviewed journals and written several books on these topics.
He is considered one of the most distinguished world experts in gene–diet
interactions related to cardiovascular traits. Moreover, he has trained in his
laboratory roughly 60 scientists from all continents. Throughout his career,
Dr. Ordovás has received multiple honors for his scientific achievements,
including the USDA Secretary’s Award, the Centrum American Nutrition
Society Award, the Danone Foundation Award, and the Gold Medal of the
Spanish Society of Cardiology. He has been awarded an honorary degree
in medicine bestowed by the University of Cordoba in Spain and is a
member of the Spanish Royal Academies of Sciences, Medicine, Nutrition
and Pharmacy. He serves on multiple editorial, advisory, peer-review, and
steering committees. Dr. Ordovás was educated in Spain at the University
of Zaragoza, where he completed his undergraduate work in chemistry and
his Ph.D. in biochemistry. He did postdoctoral work at the Massachusetts
Institute of Technology, Harvard, and Tufts.
Nathan Price, Ph.D., is a professor and the associate director of the Insti
tute for Systems Biology in Seattle, Washington. He is also affiliate faculty
in the Departments of Bioengineering, Computer Science and Engineering,
and Molecular and Cellular Biology at the University of Washington. He is
the co-founder and on the board of directors of Arivale, Inc. (“Your Scien
tific Path to Wellness”), which was named Geekwire’s 2016 Startup of the
Year. Dr. Price has won numerous awards for his scientific work, including
a National Institutes of Health Howard Temin Pathway to Independence

Award, a National Science Foundation CAREER award, and a young inves
tigator award from the Roy J. Carver Charitable Trust. He was named one
of the inaugural “Tomorrow’s PIs” by Genome Technology and a Camille
Dreyfus Teacher-Scholar. Most recently, he received the 2016 Grace A.
Goldsmith Award from the American College of Nutrition, given each year
to a researcher under the age of 50 for significant contributions to nutri
tion science. Dr. Price has produced more than 120 peer-reviewed scientific
publications and serves on the editorial board for many leading scientific
journals, including Science Translational Medicine and Cell Systems. He
also serves on advisory boards for a number of companies and institutes,
including Roche (personalized medicine division), Cleveland Clinic’s Center
for Functional Medicine, Sera Prognostics, Inc., the Novo Nordisk Founda
tion Center for Biosustainability, Trelys, Inc., and the University of Wash
ington’s Public Health Genomics. He is a fellow of the European Society
of Preventive Medicine.
Sarah Roller, J.D., is a partner in the Washington, DC, office of Kelley Drye
& Warren, LLP, and the chair of the firm’s Food and Drug Law practice.
For more than 25 years, her practice has focused on the representation of
U.S. and global companies and industry trade organizations that are in
volved in the development, manufacture, labeling, and marketing of foods,
beverages, dietary supplements, and other health products. She represents
companies in proceedings before the U.S. Food and Drug Administration,
the U.S. Department of Agriculture, the Federal Trade Commission, the
Tax and Trade Bureau, and state governmental bodies, and serves as coun
sel in litigation matters involving product safety, labeling, and advertising
regulation. Ms. Roller is a registered dietitian and received her B.S. from
the University of Wisconsin–Madison and her M.P.H. from the University
of Minnesota. She received her J.D. from The George Washington Univer
sity. Ms. Roller has been recognized nationally as a leading practitioner by
Chambers USA and selected as one of The Best Lawyers in America.
Nicholas J. Schork, Ph.D., is a distinguished professor of quantitative medi

cine at the Translational Genomics Research Institute (TGen) in Phoenix,
Arizona, and the co-director of the City of Hope/TGen IMPACT Center;
professor and director of human biology at the J. Craig Venter Institute
(JCVI) in La Jolla, California; and adjunct professor of psychiatry and fam
ily medicine and public health (Division of Biostatistics) at the University of
California, San Diego. Prior to joining JCVI, Dr. Schork held faculty posi
tions at The Scripps Research Institute, the Scripps Translational Science
Institute, and Case Western Reserve University. His interests and expertise
are in quantitative human biomedical science and integrated approaches
APPENDIX C 141
to complex biological and medical problems. He has published more than

500 scientific articles and book chapters that consider novel data analysis
methodology, study designs, and applications. He also has mentored more
than 75 graduate students and postdoctoral fellows, holds 8 patents, and
has helped establish 10 different companies in biomedical sciences and ap
plications. Dr. Schork is a former member of the National Academies of
Sciences, Engineering, and Medicine’s Food and Nutrition Board, a member
of several scientific journal editorial boards, and a frequent participant
in National Institutes of Health–related steering committees and review
boards. He has also served as director of the quantitative components of
a number of national research consortia, including the National Institute
on Aging–sponsored Longevity Consortium and the National Institute of
Mental Health–sponsored Bipolar Consortium.
Patrick J. Stover, Ph.D., is a professor and the director of the Division of

Nutritional Sciences at Cornell University. He teaches three classes for grad
uate students—Grant Writing; Translational Research and Evidence-based
Policy and Practice in Nutrition; and the B-vitamin metabolism section of
Micronutrients: Function, Homeostasis, and Assessment. He was elected in
2015 as a member of the National Academy of Sciences and in 2014 as a fel
low of the American Association for the Advancement of Science. In 2014,
he received the State University of New York Chancellor’s Award for Excel
lence in Scholarship and Creative Activities; the Osborne and Mendel Award
for outstanding recent basic research accomplishments in nutrition from the
American Society for Nutrition; and a MERIT award from National Insti
tute of Diabetes and Digestive and Kidney Diseases, National Institutes of
Health. In 1996, Dr. Stover received the Presidential Early Career Award for
Scientists and Engineers from President Clinton, the highest honor bestowed
by the U.S. government on outstanding scientists and engineers beginning
their independent careers. He has been selected as an Outstanding Educator
four times by Cornell Merrill Presidential Scholars. He is editor of Annual
Reviews of Nutrition. He graduated from Saint Joseph’s University with a
B.S. in chemistry and was awarded the Molloy Chemistry Award at gradu
ation. He received a Ph.D. in biochemistry and molecular biophysics from
the Medical College of Virginia and performed his postdoctoral studies in
nutritional sciences at the University of California, Berkeley.
Douglas C. Wallace, Ph.D., is the Michael and Charles Barnett endowed

chair in pediatric mitochondrial medicine and metabolic disease, the direc
tor of the Center for Mitochondrial and Epigenomic Medicine at Children’s
Hospital of Philadelphia, and a professor in the Department of Pathology
and Laboratory Medicine at the University of Pennsylvania. He founded
the field of human mitochondrial DNA (mtDNA) genetics and demon
strated that mtDNA variation has profound implications for human health
and disease, the origins and ancient migrations of our ancestors, human and
animal adaptation, and perhaps the origin of species. In recognition of
his seminal contributions to human and mammalian genetics, Dr. Wallace
was elected to membership in the National Academy of Sciences in 1995,
the American Academy of Arts and Sciences in 2004, and the National
Academy of Medicine in 2009. He received the William Allan Award from
the American Society of Human Genetics in 1994, the Passano Award for
Mitochondrial Genetics (with G. Attardi) in 2000, the Metropolitan Life
Foundation Award for Medical Research in Alzheimer’s Disease in 2000,
and the Pasarow Award for cardiovascular disease in 2006. In 2012, he
received the Gruber Genetics Prize, the world’s highest genetics honor, as
well as the American College of Physicians Award for “Outstanding Work
in Science as Related to Medicine.” In 2015, he was awarded Doctor Ho
noris Causa, Universitè Angers, France, and was elected to the Accademia
Nazionale delle Scienze detta dei XL (National Academy of Sciences of
Italy). In 2017, he received the Franklin Institute’s prestigious Benjamin
Franklin Medal for the Life Sciences and the Paul Janssen Award for Bio
medical Research.
Steven H. Zeisel, M.D., Ph.D., is the Kenan distinguished university profes

sor in nutrition and pediatrics; the former chairman, Department of Nutri
tion; director, Nutrition Research Institute; and the director, University of
North Carolina at Chapel Hill (UNC) Nutrition Obesity Research Center at
UNC. The Nutrition Research Institute focuses on using genetic, epigenetic,
and metabolomic methods to discover why there is individual variation in
responses to and requirements for nutrients. The UNC Nutrition Obesity
Research Center is one of 12 centers of excellence in nutrition research
funded by the National Institutes of Health. Dr. Zeisel’s research focuses on
dietary requirements for the nutrient choline, genetic variation as a source
of individual differences in requirements for and responses to nutrients,
effects of choline and folate on stem cell proliferation and apoptosis, and
resulting effects on cancer and neurogenesis. His research team works with
cells, mouse models, and human clinical studies. Dr. Zeisel is the author of
more than 250 peer-reviewed scientific papers. He is on the editorial board
of the FASEB Journal and is an editor of the nutrition textbook Present
Knowledge of Nutrition, Volume 10. He is a leader in the development of
an innovative nutrition curriculum used by more than 150 medical schools.
He received an M.D. from Harvard University (1975) and a Ph.D. from the
Massachusetts Institute of Technology (1980).

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NUTRIGENOMICS

AND THE FUTURE OF NUTRITION

Leslie Pray, Rapporteur

Food and Nutrition Board

Health and Medicine Division

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001

International Standard Book Number-13: 978-0-309-47764-2

Copyright 2018 by the National Academy of Sciences. All rights reserved.

Printed in the United States of America

Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2018.

The National Academy of Medicine (formerly the Institute of Medicine) was

The three Academies work together as the National Academies of Sciences,

Proceedings published by the National Academies of Sciences, Engineering, and

NUTRIGENOMICS AND THE FUTURE OF NUTRITION1

PATSY M. BRANNON, Professor, Division of Nutritional Sciences,

1 The National Academies of Sciences, Engineering, and Medicine’s planning committees

SYLVIA ROWE (Chair), SR Strategy, LLC, Washington, DC

Health and Medicine Division Staff

JOHANNA DWYER, Tufts University, Boston, Massachusetts

Although the reviewers listed above provided many constructive com­

2 NUTRIGENOMICS AND CHRONIC DISEASE ENDPOINTS 11

3 PERSONALIZED NUTRITION IN THE REAL WORLD 29

4 NUTRIGENOMICS APPLICATIONS: DIETARY GUIDANCE

Gene-Guided Nutrition Interventions, 71

5 NUTRIGENOMICS: REGULATORY, ETHICAL, AND

SCIENCE POLICY CONSIDERATIONS 85

Scientific Basis of Genetically Personalized Nutrition:

Ethical Implications of Methodological Limitations, 85

Vetting Personalized and Genomically Guided Nutrition:

Issues and Strategies, 93

Potential Regulatory Policy Considerations Presented by

Nutrigenomics in the Commercial Context, 97

6 RETHINKING THE RELATIONSHIP BETWEEN DIET

AND HEALTH: CAN NUTRIGENOMICS HELP? 107

The Usefulness of the Precision Medicine Paradigm in

Behavioral Aspects of Nutrigenomics, 110

Why the Focus on Genetics in This Era of Data Integration?, 111

The Relevance of Nutrigenomics to Low-Income Populations, 112

Trust—and Distrust—in Nutrigenomics, 114

The Relevance of Agriculture to Nutrigenomics, 115

A WORKSHOP AGENDA 127

B ACRONYMS AND ABBREVIATIONS 131

C SPEAKER AND FACILITATOR BIOGRAPHIES 135

2 NUTRIGENOMICS AND THE FUTURE OF NUTRITION

SETTING THE STAGE: INTRODUCTION AND OVERVIEW

Highlights from Patsy Brannon in Her

• A risk assessment approach is central to current population-based dietary

An Overview of Population-Based Dietary Guidance:

The Centrality of the Risk Assessment Framework

Brannon began by discussing the risk assessment framework, which she

Step 1: Synthesizing the Evidence

Step 2: Characterizing Dose-Response Relationships

FIGURE 1-1 The distribution of intake requirements (bell-shaped curve) upon

SOURCE: Presented by Patsy Brannon on December 5, 2017.

risk increases with increasing intake (right).

NOTE: RDA = recommended dietary allowance; UL = tolerable upper intake level.

SOURCES: Presented by Patsy Brannon on December 5, 2017, from NASEM,

6 NUTRIGENOMICS AND THE FUTURE OF NUTRITION

Nutritional Kinetics, Dynamics, and Requirements

as nutrients are consumed. Adverse or beneficial effects, Brannon observed,

Although the reviewers listed above provided many constructive com

“Why can’t we understand or cure the common metabolic and degen

Claudia Morris, Emory University School of Medicine, began by stat