Mysteries of The Microscopic World

Mysteries of the
Microscopic World
Bruce E. Fleury, Ph.D.
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Bruce E. Fleury, Ph.D.

Professor of the Practice, Department of
Ecology and Evolutionary Biology,
Tulane University
rofessor Bruce Edward Fleury is Professor

of the Practice in the Department of
Ecology and Evolutionary Biology at Tulane
University. He received his B.A. in Psychology and
General Science from the University of Rochester
in 1971 and his M.A. in Library, Media, and Information Studies in 1979
from the University of South Floridas library school. Dr. Fleurys career as a
college reference librarian led him to Tulane in 1983, where he became head
of the university librarys Science and Engineering Division. While taking
classes toward a masters degree in biology to enhance his subject skills as
a librarian, he rediscovered his interest in the natural world. He received his
M.S. in Biology in 1989 and his Ph.D. in Biology in 1996.
Dr. Fleury wrote his doctoral dissertation on the link between the explosive
growth of colonial wading birds like herons, egrets, and ibises and the rise of
the crawsh aquaculture industry. He teaches between 600 and 700 students
a year, and his course offerings include ornithology, introductory general
biology and environmental biology, the history of life, and evolution in
human health and disease. He has authored numerous articles and newspaper
columns, both popular and professional, and the reference book Dinosaurs:
A Guide to Research.
Dr. Fleury has won several teaching awards and has appeared in Whos Who
among Americas Teachers. Between 2001 and 2003, the Tulane chapter of
the Mortar Board National College Senior Honor Society awarded him twice
for outstanding teaching. In 2008, he was a guest speaker at the Mortar Board
Last Lecture Series, where favorite professors are invited to give a lecture as
if it would be their last. He admits it was disconcerting to receive an ofcial
letter that begins, Congratulations, you have been invited to present your
Last Lecture at Tulane University.
i
Most recently, Dr. Fleury worked as a consultant for Warner Bros. space
epic Green Lantern, working on several classroom and laboratory scenes,
and serving as a consulting xenobiologist on alien life in general. He reports
that the movie business is an odd combination of Disneyland and the
Department of Motor Vehicles.
Having grown up in the shadow of the Adirondack Mountains in upstate New
York, Dr. Fleury admits he was always a student of the natural world, and
only recently got around to making it ofcial. He says, As a child, I only
wanted to be 2 things when I grew up (you can ask my mom)a librarian
and a teacher. He considers himself quite fortunate to have been both.
You can nd Dr. Fleurys home page at: http://www.tulane.edu/~beury. It
includes links to several of his humorous columns on life in the Big Easy and
to the courses he is currently teaching.
ii
Table of Contents
INTRODUCTION
Professor Biography ............................................................................i
Course Scope .....................................................................................1
LECTURE GUIDES
LECTURE 1
The Invisible Realm ............................................................................3
LECTURE 2
Stone Knives to Iron Plows.................................................................7
LECTURE 3
The Angel of Death ........................................................................... 11
LECTURE 4
Germ Theory ....................................................................................15
LECTURE 5
The Evolutionary Arms Race ............................................................19
LECTURE 6
Microbial Strategies ..........................................................................23
LECTURE 7
Virulence...........................................................................................27
LECTURE 8
Death by Chocolate ..........................................................................30
LECTURE 9
Bambis Revenge .............................................................................33
LECTURE 10
The Germ of Laziness ......................................................................37
iii
Table of Contents
LECTURE 11
The 1918 FluA Conspiracy of Silence ..........................................41
LECTURE 12
The 1918 FluThe Philadelphia Story.............................................45
LECTURE 13
The 1918 FluThe Search for the Virus .........................................49
LECTURE 14
ImmunitySelf versus Nonself ........................................................53
LECTURE 15
Adaptive Immunity to the Rescue .....................................................58
LECTURE 16
AIDSThe Quiet Killer .....................................................................63
LECTURE 17
The Deadly Strategy of AIDS............................................................68
LECTURE 18
AutoimmunitySelf versus Self .......................................................72
LECTURE 19
Allergies and Asthma ........................................................................76
LECTURE 20
Microbes as Weapons ......................................................................80
LECTURE 21
Pandoras Box ..................................................................................84
LECTURE 22
Old World to New .............................................................................88
LECTURE 23
Close Encounters of the Microbial Kind............................................92
iv
Table of Contents
LECTURE 24
Microbes as Friends .........................................................................96
SUPPLEMENTAL MATERIAL
Glossary .........................................................................................100
Bibliography .................................................................................... 119
vi
Mysteries of the Microscopic World

Scope:
his course will take you on a guided tour through an invisible

realma hidden world as close as your ngertips and as unfamiliar
as the bottom of the sea. Our lives are shaped and nurtured, and
sometimes threatened by this world and its inhabitants: countless millions of
microorganisms, creatures as alien to us as we are to a ea.
In this course, we follow the long path of our coevolution with our microbial
friends and foes, starting with our descent from the trees on the prehistoric
plains of Africa. The simple act of setting foot on solid ground exposed us
to a wealth of new microscopic parasites. As we evolved from nomadic
hunter-gatherers to settled agriculturalists, we changed the way we related
to microbes and the ways in which they could relate to us. As we settled into
permanent camps and began to grow crops, our populations grew, making us
vulnerable to crowd diseases like plague, u, and smallpoxgreat epidemics
of the ancient world that claimed millions of lives.
One of the deadliest microbes of the ancient world was Yersinia pestis,
the bubonic plague, which swept through Europe in the 14th century as the
Black Death. We look at how a subtle weave of history, biology, and human
behavior made us vulnerable to the plague and try to imagine living through
such an epidemic with no idea why everyone around us is dying. Is it divine
retribution? Perhaps it is caused by an imbalance of the bodily humors, or
uids; or perhaps a miasma, an invisible cloud of disease emanating from
unhealthy habitats and people, is to blame. We review such early ideas about
disease as we trace the rise of germ theory, the growing realization that
diseases were caused by microorganisms.
In the second set of lectures, we contrast the strategies humans have
evolved to defend ourselves against microbial invaders with the strategies
that microbes have evolved for attacking us. We examine how the rise of
civilization has altered our environment and how microbes have rapidly
adapted to take advantage of those environmental changes, leading to
1
diseases like Lyme, Legionnaires, toxoplasmosis, and death by chocolate.

We also look at the effects of natural environmental changes, such as an El
Nio weather pattern, on microbes.
Its hard to imagine how tiny creatures like bacteria and viruses could cause
such dramatic changes in the lives of large and powerful beings like ourselves,
but we will consider 2 examples of how microbes may have altered the course
of human history. Well learn about hookworm, the so-called germ of laziness,
which held back the economic development of the American South and may
have cost it the Civil War, and the 1918 Flu, the worst epidemic in human
history, which helped to set the stage for World War II.
In the third set of lectures, we roll up our sleeves and delve into the
complexities of the immune system, our best protection against microscopic
invaders. This knowledge will enable us to better appreciate the subtle and
insidious strategy of the AIDS virus, which directly targets the immune
system. We also explore the causes and consequences of autoimmune
diseases like multiple sclerosis and lupus, when the body turns on itself and
treats its own cells and tissues as if they were foreign invaders.
Scope
In the fourth set of lectures, we follow Christopher Columbus and the

European explorers across the Atlantic Ocean and witness the devastation of
New World native populations from the microbial hitchhikers they carried.
Then we consider the possibility of another great microbial exchange as
we prepare to cross the nal frontier into outer space. What new forms of
microscopic life might be waiting for us between the stars?
Finally, we see how microbes shaped the world in which we live by creating
our oxygen atmosphere, by enriching the soil for plants to grow, and by
opening an evolutionary pathway leading to the cells that make up our body.
We consider the many ways in which microorganisms continue to make our
world a healthier, tastier, and more protable place in which to live. By the
time weve completed our journey together, you will better understand the
diverse ways in which microbes affect our lives and will have gained a deeper
appreciation for the marvels and mysteries of the microscopic world.
The Invisible Realm

Lecture 1
There are roughly 100 trillion cells in the human body, but roughly
90 trillion of them9 out of every 10are different kinds of bacteria.
These microorganisms do both good things and bad things for us and
to us. We interact with microbes as competitors and companions, as
predator and prey.
Along the journey from

the plains of Africa to
the towers of midtown
Manhattan, we humans Even the cleanest human mouth is home to
countless but fragile bacteria.
changed from nomadic
hunter-gatherers to settled
farmersa change that forever altered our relationship to the microbial
world. As we built great cities, dense urban populations triggered the great
plagues of antiquity.
For centuries weve been engaged in an evolutionary arms race with an
invisible foe. Microbes have evolved strategies to invade and exploit us,
including resistance to our most powerful antibiotics, just as weve evolved
ways to ght back, including our complex immune system.
Hemera/Thinkstock.
here are more bacteria in your mouth right now than the total number
of men, women, and children that have ever existed on Earth since
humans separated
from the great apes some
610 million years ago.
But individual pathogens
are pretty fragile creatures.
You can wipe out entire
populations of bacteria
with nothing more than a
teaspoon of antibiotics.
Not all microbes are pathogens; some are essential to our health and welfare:
They created the air that we breathe; they created the type of cells that make
up our bodies. Frankly, wed be hard-pressed to survive without them.
Will we ever reach a balance where both man and microbe can safely
coexist? Probably not. Bacteria evolve much more rapidly than we do
because they can exchange genetic
information in little snippets called
plasmids, without that lengthy
Modern ecologists have
and often messy process of sperm
learned to appreciate that
meeting egg.
nature is often not in balance.
Lectuire 1: The Invisible Realm
The idea that nature keeps itself in

balance isnt new; it is at least as
old as the golden age of Greek philosophy. In fact, the original meaning of
evolutionfrom the Latin evolutio, meaning to unroll; to unfoldwas
the unfolding of the divine plan for nature. Many theologians thought that
the balance of nature was the most eloquent argument you could make to
prove the divine plan and worriedas Darwin didabout the cosmic forces
that preserved that delicate balance between organism and environment.
How can a mere 6 billion humans hope to prevail against countless
trillions of microbes? To answer that question, we need to understand the
ways populations are controlled and regulated by their interactions with
other organisms and with the Earth. These extrinsic limiting factors
include sunlight, water, nutrients, food supply, competitors, predators, and
availability of symbiotic partners.
Modern ecologists have learned to appreciate that nature is often not in
balance. Ecosystems are frequently disturbed by forces like storms, res,
oods, hungry animals, and diseases. These ecosystems adapted so well to
disturbance that they often come to rely on ita phenomenon ecologists call
nonequilibrium theory.
Humans are subject to the same fundamental laws of nature as other
organisms; we have to compete with one another, and with other species, for
the limited resources that we need to survive. Two species cant peacefully
4
coexist if they both need the same essential limiting resource. If one
species is a better competitor than another, it might even eliminate its rival
altogetherwhat we call competitive exclusion.
Competition can be intraspecic (between members of the same species), or
it can be interspecic (between members of different species). Intraspecic
competition is more intense because each organisms needs almost exactly
match the needs of other members of its species; they share the same
ecological niche.
Microorganisms like bacteria are so amazingly small that they actually live in
a very different physical universe from us. Theyre buffeted by microscopic
physical and chemical forces in ways that are hard for us to even appreciate.
Most microorganisms are so small they dont need specialized biological
equipment to exchange gases, get rid of wastes, or move chemicals through
their cells. The ability of microbes to sense the presence of food or danger
depends on their ability to sense the concentration gradient of certain
molecules, and to orient themselves and navigate accordingly.
Microbes accomplish all these chores and more through diffusion. Due to
their small size, bacteria have a relatively large surface area for diffusion.
As objects get smaller, they have relatively less volumeless interior
with respect to surface area. This greatly enhances their ability to rely on
diffusion.
Important Terms
bacteria (sing. bacterium): Primitive unicellular organisms; when
capitalized, refers to one of the 3 taxonomic domains of living things.
competitive exclusion: A situation in which one species or population
outcompetes its rival to the point where the rival is locally eliminated.
diffusion: The movement of atoms and molecules from an area of higher
concentration to an area of lower concentration.
extrinsic limiting factor: A limiting factor that comes from outside the
individual or population, such as sunlight, water, or nutrients.
niche: The functional role that an organism plays in an ecosystem; also, the
sum total of a speciess needs and the range of conditions within which it can
survive.
nonequilibrium theory: The idea that certain ecosystems are not harmed by
disturbance but rather thrive on it.
pathogen: The umbrella term for disease-causing organisms, including
bacteria, viruses, ukes, and nematode worms, and so forth.
plasmid: Tiny loops of genes freely exchanged between bacteria, often
bearing useful traits.
Suggested Reading
Crawford, The Invisible Enemy.
Dobson, Disease.
Questions to Consider
1. How does the original meaning of the word evolution (from the Latin
Lectuire 1: The Invisible Realm
evolutio) reect the way pre-Darwinian scholars saw the natural world?
2. In what way, mathematically speaking, is small size an advantage for a

single-celled organism like a bacterium?
Stone Knives to Iron Plows

Lecture 2
As humans changed the way we lived and consequently changed our

environment, microbes had to adapt or perish. In many ways, these
changes left us vulnerable to a host of new microbial invaders and new
microbial strategies.
lagues were not always a problem for humankind. Epidemics

couldnt spread very far when we lived in scattered nomadic tribes,
but when we started gathering together to build villages, raise crops,
and domesticate animals, we changed our niche and altered our habitat.
About 4 to 7 million years ago, vast ice sheets began to spread over North
America and Eurasia. The tropical African climate became much cooler
and drier. This new environment favored creatures such as our distant
ancestor Australopithecus, who could live in the trees yet still cross the open
grasslands to forage. But contact with the ground meant contact with an
entirely new group of microbes.
Why didnt all these new pathogens wipe out our distant ancestors? What
probably saved us was our small population size. Humans lived in nomadic
bands of 12 dozen individuals, perhaps fewer. Bands rarely crossed paths
and were never in one place long enough to pollute the area. The occasional
disease outbreak was self-limiting; once the disease had burned through the
tribe, it had nowhere to go. Only diseases carried by insects and animals or
diseases able to persist in the soil would have caused any serious problems
for early man.
The human population made a sudden leap from 7 or 8 million people in
10,000 B.C. to about 100 million by 5000 B.C. This Neolithic population
boom probably marks humanitys transition to a radically different lifestyle,
from nomadic hunting and gathering to settled agriculture.
The agricultural revolution allowed us to build up large urban settlements
that would not only become the basis for the great civilizations of antiquity
7
and the nodes in a vast web of trade; they also served as a breeding ground
and transit network for many of our worst microbial foes. Food storage,
water and soil contamination, deforestation, and accumulation of personal
possessions all provided new environments for disease, especially those
carried by insects and rodents.
Lecture 2: Stone Knives to Iron Plows
The results of urbanization

were measles, smallpox,
typhus, plague, syphilis,
scarlet fevera long and
growing list of epidemic
diseases that would shape the
entirety of human history.
cycles are affected by numerous
For example, Thucydides Disease
factors, including the presence of vector
wrote what may be the rst organisms, like mosquitos.
description of a pandemic
in his History of the Peloponnesian War. No one knows what microbe was
responsible for this plague, but it devastated the Athenian army and citizenry
and contributed to the end of the golden age of Greek civilization.
Its no accident that epidemic diseases seem to wax and wane throughout
history. Many microbes cant survive for long outside of a human body. An
epidemic disease will infect everybody in the population in a relatively short
period of time, and the victims either die or recover and have immunity. The
pattern that results from all this is a series of population cycles between host
and pathogen. The microbe quickly uses up all its available hosts, and has to
travel to another population to survive.
iStockphoto/Thinkstock.
About 6000 years ago, human population density became high enough for 2
entirely new types of population regulation to kick in: density-dependent
limiting factors, factors related to the intensity of the competition for limited
resources, and intrinsic
limiting factors, changes in
an individuals reproductive
physiology or behavior that
reduce population size.
Disease cycles can be very complex. They are affected by political,

economic, and climactic factors. They can even be affected by the presence
of other diseases; tuberculosis, for example, was nearly eradicated by the
end of the 20th century, but the spread of HIV/AIDS gave the disease a new
set of vulnerable hosts to infect.
Today, the worlds population stands at over 6 billion and is rapidly
increasing. By 2025 we could be near 8.5 billion people; India alone could
have 600 million more people, Nigeria 200 million more people, and China
357 million more people. Our growing population will have a tremendous
effect on the environment, creating a wealth of new opportunities for
microorganisms.
Important Terms
density-dependent limiting factor: A limiting factor whose effects are
directly proportional to the density of a population, such as predation or
disease.
epidemic: An outbreak of disease that exceeds the expected norm, usually
applied to an infectious disease that appears suddenly and moves rapidly
through a population.
immunity: Disease resistance acquired by exposure to a pathogen. The
immune system remembers the encounter by keeping some antibodies
around from each disease it defeats, in case the same pathogen returns.
intrinsic limiting factor: A limiting factor that operates from within
the individuals of a population, affecting reproductive physiology or
reproductive behavior.
pandemic: An epidemic that occurs over a wide geographic area.
Suggested Reading
Crawford, Deadly Companions.
Karlen, Man and Microbes.
McNeill, Plagues and Peoples.
1. How is immunity different from genetic resistance?
2. Why were epidemic diseases not a big problem for early human
Lecture 2: Stone Knives to Iron Plows
populations of hunter-gatherers?
10
The Angel of Death

Lecture 3
The Medieval Warm Period allowed for a rapid increase in European

population, but the following Little Ice Age led to a collapse in
agriculture, leading to generations of famine and malnutrition, and
helped to make medieval Europe especially vulnerable to the deadly
clutches of the Black Death.
any of the most devastating epidemics come from vector-borne

diseases, like typhus, malaria, and dengue fever. A vector is
any organism that carries a microbe that causes a disease. Most
vector-borne diseases are carried by arthropodsies, eas, ticks, lice,
and mosquitoes, and some rely on multiple vectors. Unlike crowd-borne
diseases, they have no difculty surviving without secondary hosts.
Between A.D. 950 and A.D. 1250, Europe basked in one of the most fruitful,
productive, and disease-free periods in its history, the Medieval Warm
Period. But this warm spell was followed by an extended period of damp,
chilly weather called the Little Ice Age, which lasted from about 1350 to
about 1850.
Symptoms of the coming climate shift were evident by the early 14th century;
summers in northern Europe became too cool and damp for grain to fully
ripen, leading to the Great Famine (13151317). Severe storms, oods, and
droughts became more frequent as the Little Ice Age set in, and it became
harder and harder to grow crops. Millions starved; thousands of villages
simply disappeared. Social and political structures broke down.
Into this already dismal period came the Black Death, a pandemic that would
kill half the remaining population of Europe. Caused by an ancient vectorborne microbe carried by oriental rat eas, this particular outbreak began in
Central Asia or China around 13201340, then spread to India and Africa
along the Silk Road. Italian soldiers who were exposed to the microbe during
the Siege of Caffa in the Crimea brought it to Sicily and then mainland
Europe. The disease reached Britain, its furthest port of call, in 1348.
11
Lecture 3: The Angel of Death
There are 3 distinct forms of plague:

bubonic, pneumonic, and septicemic.
Modern antibiotics and modern
vaccines are effective against all 3.
x
Bubonic plague is a disease Black rats are hosts for oriental rat
eas, which in turn are hosts for the
of the lymphatic system with Black Death.
u-like symptoms, followed
by swelling of the lymph glands, delirium, convulsions, coma,
and often deathabout 4060 percent mortality in 28 days if left
untreated.
x
In pneumonic plague, the disease spreads to the lungs and can then
be spread through coughing and sneezing. Additional symptoms
include coughing up blood, progressive pneumonia, and shock.
The fatality rate is over 90 percent, and death occurs in as little as
12 days.
x
In septicemic plague, the bacterium enters the bloodstream, where

a bacterial toxin interferes with clotting. Victims quickly bleed to
death internally. It kills virtually 100 percent of its victims, most of
them in less than a day.
Successive waves of Black Death struck the Old World over the centuries.
A pandemic that began in China around 1890 has since claimed 15 million
lives and nally circled the globe, entering the United States through Chinese
12
Weakened by generations of famine

and crowded into cities fouled by
garbage, sewage, and rats, European
populations were sitting ducks for the
Black Death. Populations fell 4060
percent, with up to 75100 million
dead in the 14th century alone. The
plague ebbed and owed throughout
Europe for the next 300 years.
workers in San Francisco. By that time, however, we were aware of germ

theory and were eager to hunt down this ancient enemy.
A Swiss-born, Paris-based doctor named Alexandre Yersin went to Hong
Kong in 1894 to investigate the disease. Working in a primitive grass hut
laboratory because the British authorities would not let him use their state-ofthe-art hospitals, he identied and isolated the bacterium Pasteurella pestis,
later renamed Yersinia pestis in his honor, and determined that it was carried
by black rats. Then Paul-Louis
Simond, a French colonial army
doctor, proved that it was the bite Weakened by generations of
of the oriental rat ea, Xenopsylla famine and crowded into cities
cheopis, that transmitted the fouled by garbage, sewage,
infection from host to host.
and rats, European populations
The pandemic that began in 1890 were sitting ducks for the
is still going on today but has been Black Death.
relatively mild. Several cases of
plague are reported every year
worldwide, but it never spreads very far. Part of the reason may be that rats
are scarcer than they used to be. Todays rats are also more domesticated;
they tend to stay in one house or one neighborhood, so the plague never
spreads beyond the local rodent population.
Important Terms
Great Famine: A famine in Europe between A.D. 1315 and 1317 that
claimed millions of lives.
Little Ice Age: A 500-year climate aberration (A.D. 13501850) during
which temperatures in Europe were signicantly colder than normal; the
period was characterized by extreme and intense weather, such as oods
and droughts.
Medieval Warm Period: A climate aberration preceding the Little Ice Age,
during which average temperatures were signicantly higher than normal.
13
vaccine: A therapeutic technique that introduces foreign antigens into an

animal to help improve immune response to a particular pathogen; usually
made from dead microbes, fragments of dead microbes, or microbial toxins.
vector: Any organism that carries a pathogen.
Suggested Reading
Gottfried, The Black Death.
Scott and Duncan, Return of the Black Death.
Tuchman, A Distant Mirror.
Ziegler, The Black Death.
1. Why have some biologists suggested that the Black Death and the
bubonic plague are different diseases?
2. Bubonic plague is very much alive and well and living in the American
Lecture 3: The Angel of Death
Southwest. Why do you rarely hear of an outbreak of plague in

modern times?
14
Germ Theory
Lecture 4
Before we could begin to solve the puzzle of disease, we rst had to

realize that diseases were caused by tiny little creatures feeding on our
bodies. With the realization that microbes were the cause of human
diseases came a growing awareness that we were engaged in an ongoing
evolutionary struggle with these microscopic creatures.
n the days before the invention of the microscope, before the rise of
modern medicine, the common explanations for epidemics involved
cosmic forces beyond human control, the whims of gods and demons, or
simple astrological fate. More earthly-minded theorists blamed an imbalance
of bodily uids called the humorsblack bile, yellow bile, phlegm, and
blood. Still others blamed a miasmabad air.
Girolamo Fracastoroa Renaissance

doctor, mathematician, astronomer,
geographer, and poetsuggested
in On Contagion and Contagious
Diseases (1546) that diseases were
caused by tiny spores that could be
spread by contact. But Fracastoro
was too far ahead of his time, and his
ideas faded away. In 1683, Antony
van Leeuwenhoek was the rst to
use a microscope to observe the tiny
creatures of the microbial world.
But Leeuwenhoek didnt connect
microorganisms to disease or to decay.
Photos.com/Thinkstock.
All these ideas might sound foolish, but up until the late 17th century, no one
on Earth had ever actually seen a microbecreatures so small, we have to
measure them in microns (thousandths
of a millimeter). Typical bacteria are
only about 0.25 microns across.
Louis Pasteur convinced the scientic

world of the importance of microbes.
15
The germ theory of disease wasnt accepted until the late 19th century. Louis
Pasteur was the rst to prove that wine fermentation was caused by a living
organism, the yeast Saccharomyces cerevisiae. Along the way, he also saw
other microorganisms in wine, beer, and vinegar. He concluded that different
microbes could have different effects.
John Tyndall and Joseph Lister studied Pasteurs results and concluded
that microbes must also be the cause of human diseases, but it fell to
Robert Koch to rmly establish germ theory in the 1870s. Koch connected
anthrax, tuberculosis, and cholera to specic bacteria. Seeking to tell
bacteria apart and how to tell the benecial ones from the dangerous ones,
Koch also invented the agar plate for culturing bacteria that is still used in
modern laboratories.
Kochs postulates are a series of steps to prove which specic microbe
is causing a particular disease: (1) The bacteria must be present in every
case of the disease; (2) it must be isolated and cultured from an infected
person; (3) injecting the cultured bacteria into a healthy host must cause
the disease; and (4) one must be able to recover the bacteria from the
newly infected host.
Lecture 4: Germ Theory
Ignaz Semmelweis was a germ theory pioneer who paid a huge price for
his efforts to ght puerperal (childbed) fever. In 1846, he was appointed
assistant to the professor of the maternity clinic at the Vienna General
Hospital. When one of his male medical colleagues died a few days after
pricking his nger during an autopsy on a young mother, the colleagues
body was riddled with the same type of damage seen in victims of
childbed fever.
Semmelweis realized the connection: Medical students were going
straight from performing autopsies to assisting at births, unintentionally
spreading the disease. He was able to show that the death rate among
new mothers was much, much lower if doctors and nurses washed their
hands with chlorinated lime between patients. Sadly, rather than thank
Semmelweis for his discovery, the medical community shunned him, and
his boss red him for suggesting that doctors and medical students were
killing patients.
16
Despite all Semmelweiss efforts, doctors who dont wash their hands are still
a problem today. Around 2 million hospitalized people every year acquire
infections that are due to doctors and nurses who dont wash their hands.
Important Terms
fermentation: An ancient metabolic pathway evolved by cells before the
formation of an oxygen atmosphere. Fermentation produces alcohol as a
byproduct.
germ theory: The theory that microorganisms were the cause of human
diseases, nally established in the late 19th century.
humors: Bodily uids whose imbalance was once thought to be the cause
of human diseases. The 4 humors were black bile, yellow bile, phlegm, and
blood. The theory of humors was inspired by the 4 elements of the ancient
Greeks (earth, air, re, and water).
Kochs postulates: A series of steps established by physician Robert Koch
to prove that a particular microbe causes a particular disease.
miasma: A noxious vapor once believed to be the cause of human disease.
microbe: Any organism small enough to require a microscope to clearly see it.
Suggested Reading
De Kruif, Microbe Hunters.
Nuland, The Doctors Plague.
Waller, The Discovery of the Germ.
17
1. What were some of the ways people explained infectious diseases before
we discovered the microscopic world? Can you think of an alternate
explanation not covered in the lecture?
2. Why, according to the medical theory of humors, was there no such
Lecture 4: Germ Theory
thing as a specic disease?
18
The Evolutionary Arms Race

Lecture 5
Leigh Van Valens Red Queen hypothesis states that organisms are
doomed to extinction if they cant evolve apace with the organisms they
interact with. He argues that genetic variation by denition is nite but
the environment never stops changing, so sooner or later every species
fails to keep up.
icrobes and humans are locked in a perpetual evolutionary arms

race, a cycle of coevolution wherein each change in one organism
leads to an evolutionary change in the other, advantage for
advantage. Even our ultimate weapons, penicillin and antibiotics, have only
driven microbes to greater evolutionary extremes.
Although Sir Alexander Fleming is usually credited with discovering

penicillin in 1928, Ernest Duchesne, a French medical student, was the
rst to document the connection between Penicillium molds and healing
in 1897. His research was inspired by noticing that the Arab stable boys at
the French army hospital stables intentionally stored saddles in damp, dark
rooms to encourage mold growth, which they knew promoted the healing
of saddle sores.
Even earlier, the Roman scholar Pliny the Elder recommended using
mushrooms to treat wounds. The ancient Egyptians used beer and bread
therapeutically; the brewing and baking methods they used caused the
development of tetracycline in the nal product. But Duchesne was the rst
person to conduct true scientic experiments on molds medicinal properties
and the rst to publish his results.
Penicillin turned out to be a very effective killer. It doesnt actually kill
bacteria outright; it keeps them from reproducing, which amounts to the
same thing in the long term.
Mass production of penicillin began in the last days of World War II, but
producing penicillin in large quantities turned out to be a major challenge.
19
Some strains were more effective and more productive than others.
Penicillium chrysogenum, discovered by lab technician Mary Hunt at a U.S.
Department of Agriculture lab, turned out to have the best combination of
effectiveness and ease of production.
Penicillin was soon followed by a host of other new wonder drugs. Gerhard
Domagk discovered Prontosil, the rst sulfa drug, in 1935. In 1943, Selman
Waksman isolated streptomycin from soil bacteria, receiving the 1952 Nobel
Prize for his efforts. Tetracyclines were isolated from Streptomyces soil
bacteria in 1945 and a synthetic form patented in 1955.
Lecture 5: The Evolutionary Arms Race
But bacteria quickly evolved into strains resistant to tetracycline and every
new antibiotic that we could invent, including, unfortunately, penicillin.
Antibiotics are becoming less and less effective against more and more
diseases. By the late 1980s, antibiotic resistance had reached alarming
proportions, and multiple drug resistant (MDR) and extensively drug
resistant (XDR) strains appeared. Methicillin-resistant Staphylococcus
aureus (MRSA) alone is responsible for 17,00018,000 deaths or more
per year.
Bacteria can evolve resistance to antibiotics in several ways: a change in the
permeability of their cell walls; disguising themselves by altering the surface
of their cell membranes; altering the binding site the drug usually attaches to;
or developing a bacterial enzyme to neutralize the drug. All of these changes
are inheritable, and bacteria evolve 1000 times faster than we do.
One of the secrets of bacterial success is conjugationthe exchange of
plasmids that code for a particular trait, like resistance to an antibiotic. A
plasmid evolved by any one bacterium can soon be passed to billions of
others; each bacterium can have several hundred copies of each plasmid,
and with a little help from us, plasmids can be carried around the globe in a
matter of hours.
Interestingly, fungi like Penicillium and bacteria like Streptomyces didnt
evolve their antibiotic properties from their war against us; these properties
evolved from their continual war with one another. Microbes have been
20
competing with one another for billions and billions of years, yielding some
very exotic and very effective chemical weapons.
The constant game of evolutionary one-upmanship is not only frightening;
it is also costly. By the 1980s, resistant strains of bacteria were costing
hospitals $30 billion per year because only the newest, most powerful, and
therefore most expensive drugs have a hope of treating MDR and XDR
infections. Meanwhile, a large share
of the worlds population simply
cant afford treatment, so the bacteria
The constant game of
spread on and on.
evolutionary one-upmanship
is not only frightening; it is
The hidden cost of antibiotics is that
also costly.
they are completely indiscriminate
killers of bacteria. They kill the
normal bacterial symbiontshelpful
(mutualistic) or neutral (commensal) strainsthat live inside of us. Killing
the helpful and neutral strains gives the harmful (parasitic) strains more
freedom to do their worst.
What lessons can we learn from antibiotic resistance? Doctors should limit
antibiotic use whenever possible; shouldnt prescribe antibiotics unless they
know what the disease is; and should break up prescription patterns to avoid
constant selection pressure on any one drug; Patients must use the full dosage
prescribed to completely kill the bacteria. Farmers should stop feeding
massive amounts of prophylactic antibiotics to healthy cattle and poultry.
Finally, the medical industry should retire certain antibiotics altogether to
allow vulnerable, treatable strains to reemerge and compete with the MDR
and XDR strains.
Important Terms
antibiotic: Any substance that either kills microbes outright or slows down
their population growth.
antibiotic resistance: The evolutionarily acquired ability of microbes to
either neutralize or withstand an antibiotic.
21
coevolution: An evolutionary change in one organism that leads to an

evolutionary change in another organism that interacts with it.
commensalism: A form of symbiosis in which one partner is helped and the
other is neither helped nor hindered, such as Spanish moss hanging on trees.
mutualism: A form of symbiosis in which both partners are helped by
the relationship (the traditional meaning of symbiosis), such as a lichen, a
fungus cooperating with a green algae or cyanobacteria.
parasitism: A form of symbiosis in which one partner is helped and the
other is harmed.
prophylactic antibiotic: Antibiotics given without a clear indication of
disease as a preventative measure.
Red Queen hypothesis: Theory of biologist Leigh Van Valen that there is an
upper limit to adaptation. The genetic resources of any species are nite, and
because the environment never stops changing, every species will eventually
exhaust its ability to adapt to those changes and will go extinct.
Lecture 5: The Evolutionary Arms Race
Suggested Reading
Lapp, Evolutionary Medicine.
Spellberg, Rising Plague.
1. How does the prescription of prophylactic antibiotics promote bacterial
resistance?
2. Why should you always nish the antibiotics the doctor prescribes for
you to the last disgusting drop, even if you already feel better?
22
Microbial Strategies
Lecture 6
Both sides in the war between humans and microbes have evolved
many strategies of attack and defense. Humans strategies are avoiding
exposure to microbes, keeping microbes out of the body, and destroying
microbes that do get in. Microbes strategies are to evade the hosts
defenses; attack the hosts defenses; and change the hosts behavior to
benet itself.
ne of the most important microbial strategies is one of the easiest to

overlook: their innate ability to make a lot more of themselves in a
very short period of time. Some bacteria can divide as often as once
every 20 minutes. At that rate, the offspring of a single bacterium in just 2
days would outnumber the entire human raceand that includes everyone
who has ever lived.
This staggering reproductive output is critical for microorganisms because
they live in a very perilous world. Almost everything we do, great or small,
in the course of our everyday lives destroys thousands upon thousands
of microbes. Bacteria and other microbes are therefore called r-selected
speciesspecies that rely on rapid reproduction for survival.
Human beingsand large vertebrates in generalare called K-selected
species. K stands for carrying capacityhow many individuals of a species
can be sustained by a given environment. K-selected species are adapted to
stable or predictable environments; r-selected species, like microbes, are
much better adapted to unstable or ephemeral environments. If its species is
going to survive, it needs a way to move from one environment (or person)
to the next.
Just as microbes have evolved a wide variety of strategies to attack us and
exploit us, weve coevolved an equally impressive array of strategies to keep
them at bay, like fever. The bodys thermostat goes up a few degrees, just
enough to kill the invading bacteria or virus. But fever comes with a price.
23
High fevers can lead to hallucinations, delirium, permanent organ and tissue
damage, and even death.
Lecture 6: Microbial Strategies
Skin is humans rst line

of defense in keeping
microbes out of the body,
a mechanical and chemical
barrier against infections. Bacteria need a steady supply of iron to
survive. Avoid iron supplements and iron-rich
Next, receptors on our foods when you have a bacterial infection.
tongues and in our stomachs
are hard-wired to detect certain toxins; if we do eat something thats bad for
us, we get rid of it as quickly as possible. Finally, if microbes breach our
defenses, our immune systems ag them for destruction.
One strategy microbes use to thwart our immune system is to adopt a secret
identity. Under normal circumstances, a cell can take a piece of an invading
microbe and stick it on its exterior like a little ag to let the immune system
know it has been invaded. Adenoviruses, a common cause of colds and sore
throats, make a protein that interferes with the host cells ability to make
these cellular ags, so the infected cells become safe houses for the virus.
The rabies virus attaches nerve cell receptors; the immune system thinks the
virus is a neurotransmitter molecule and leaves it alone. African sleeping
sickness, caused by protozoan called Trypanosoma brucei, changes its
surface proteins every 9 days, so the immune system loses track of it.
24
Hemera/Thinkstock.
Iron is an essential nutrient for both humans and bacteria, so humans have
developed various strategies for iron withholding. When were sick,
we often develop strong
aversion to iron-rich foods.
Human breast milk is rich
in an iron-binding protein
called lactoferrin, which
helps breast-fed babies ght
off infection by starving
invading bacteria.
Some microbes use the direct approach to breach our defenses: Streptococcus
kills white blood cells outright. HIV, the human immunodeciency virus,
goes for helper T cells, killing the heart of the immune system.
The most intriguing microbial attack strategy of all is host manipulation.
Y. pestis, which causes the bubonic plague, makes infected eas ravenous
so they bite harder and regurgitate concentrated wads of bacteria into their
victims. Rabies invades the neurological system and causes aggression in its
host, leading the host to bite and pass the rabies virus on.
Vector microbes, like the bubonic plague, use an intermediate organism to
disperse themselves and infect new hosts. Although this can be an effective
strategy for wide and rapid spread, the more links in a microbes dispersal
chain, the more things can go wrong.
Important Terms
host manipulation: A microbial strategy in which the parasite alters host
behavior in a way that signicantly benets the parasite.
iron withholding: Adaptive response in which the human body sequesters
or binds iron so that it is not accessible to bacteria, for whom it is a limiting
nutrient.
virus: A microscopic organism consisting of a core of RNA or DNA in a
protein capsule, which can only reproduce by invading a living cell and
using its protein synthesis mechanisms to make and assemble copies of the
virus.
white blood cell (a.k.a. leukocyte): An immune system cell that helps ght
infectious diseases or foreign proteins. The presence and number of these
cells is often used in the diagnosis of disease. White blood cell types include
neutrophils, dendritic cells, lymphocytes, and macrophages.
25
Suggested Reading
Finlay, The Art of Bacterial Warfare.
Nesse and Williams, Why we Get Sick.
1. Whats the medical wisdom in the old folk saying feed a cold, starve a
fever?
2. How is it possible to drive a parasite into extinction without actually
Lecture 6: Microbial Strategies
killing all of them?
26
Virulence
Lecture 7
The vector strategy, despite its hazards, is a clear winner in the war
between microbe and host. Vector-borne diseases are so virulent
because as long as the vector population is doing well, the microbe does
well. This suggests a strategy to tame such diseases: Isolate the vectors
from the hosts.
ooperation and coexistence often prevail in nature, thanks to

coevolution. But if nature tends towards peaceful coexistence,
then why do so many infectious diseases like cholera, malaria, and
anthrax continue to be so virulent?
Competition and coevolution can cause some diseases to gradually lose

their sting. Other diseases seem to come out of nowhere, ravage the world,
and then disappear as mysteriously as they arose. Diseases ebb and ow for
many reasons, but we can tease out some interesting patterns: Successful
organisms nd a balance over time with their competitors.
Imagine a new species of bacteria, an effective and virulent killerin
clinical terms, virulent means it kills a large percentage of its victims.
But killing an entire population of hosts isnt a good long-term strategy;
the microbe needs some hosts to survive and make contact with a fresh
population of victims. Logic suggests that pathogens should coevolve with
their hosts to become more benign strains, and with many diseases, like
syphilis and scarlet fever, thats exactly what has happened.
How can we use our knowledge of competition, predation, and coevolution
tip the balance of the evolutionary arms race in our favor? One effective
strategy is the virulence antigen strategy: using targeted drugs and
vaccines, rather than a broad-spectrum attack, to target virulent strains and
leave more benign ones to ll the niche. Instead of trying to wipe out a
microbe altogether, we need to focus our efforts on targeting those precise
virulence factors that are unique to the bad strains but are not found in the
more benign strains.
27
Another important aspect of virulence is dispersal. Getting into a victim is

only half the battle; unless the microbe can escape to infect another victim,
every host is going to be a dead end. If the microbe is too virulent, dispersal
is sharply limited because nobody is left standing to spread it around.
Lecture 7: Virulence
With vector-borne diseases, however, an immobile host is less of a problem.

In malaria, for example, semicomatose victims cant wave off the mosquitoes
that feed on them and spread the disease to other hosts. Therefore, vectorborne diseases can be more virulent than diseases that rely solely on physical
contact. In fact, diseases that are
spread by contact often evolve to
become less virulent, while vector- Diseases that are spread by
borne diseases can evolve toward contact often evolve to become
more virulence.
less virulent, while vectorDirect transmission does have a borne diseases can evolve
few advantages; it doesnt rely toward more virulence.
on intermediate hosts. It doesnt
expose the microbe to risks while
getting from the vector to the host and back again. It is the strategy of
choice in dense human populations. Life is tougher for vector-borne
diseases; they face risks during vector-host and host-vector journeys.
There are more links in the chain and hence a greater risk of failure. But
the advantage for vector-borne diseases is that they can immobilize or kill
a host with relative impunity.
Some diseases, like cholera and anthrax, are highly virulent but arent carried
by vectors. These diseases can enter the water supply, most commonly
through human waste and through washing or disposing of contaminated
bedding and clothing. Water takes over the role of the vector, so the virulence
of water-borne disease can remain high.
Similarly, nosocomial infectionsthat is, hospital infections like childbed
fever before the 20th century and MRSA todaycan spread from one
immobile patient to another through direct contact with nurses, doctors,
other patients, and so on. Other people become the vectors.
28
Pathogens like anthrax that are more durableones that can survive outside
a host for a signicant period of timecan also be much, much more virulent
than more mobile but less sturdy microbes.
Understanding the nature of vector-borne diseases suggests a very basic
strategy to tame them: Simply make it more difcult for the vector to reach
the host. Virulent strains are competing with more benign strains of their
own and related species; anything that slows down the vector should tip
the competitive balance in favor of the more benign strains. But microbial
strategies are adaptations to a shifting landscape. Thats the nature of
evolutionary adaptation: Its always responding to a never-ending series of
environmental changes.
Important Terms
benign strain: A species or subspecies of microbe that is less harmful than
competing strains of the same species.
nosocomial infection: A hospital-acquired infection.
virulence: The intensity of a particular infectious disease as measured by its
mortality rate.
Suggested Reading
Ewald, Evolution of Infectious Disease.
Gluckman, Beedle, and Hanson, Principles of Evolutionary Medicine.
Infectious Disease: A Scientic American Reader.
1. What do a hospital worker, a mosquito, and a river all have in common?
2. Why is high virulence an evolutionary trade off for a microorganism?
29
Death by Chocolate
Lecture 8
Human civilization gave microbes countless new dispersal routes,

from highways to hypodermic needles, and new habitats, from kitty
litter to air conditioning. Agriculture in particular has led to ecosystem
disturbance and increased human contact with opportunistic microbes.
he trade routes and roads of antiquity were interstate highways for

microbes, taking them from populations with herd immunity to new,
nave populations. The movement of bubonic plague from East to
West and smallpox from Old World to New, for example, were just such
virgin soil epidemics.
Transportation isnt the only technology that created new ways for microbes
to disperse. Hypodermic needles, rst used in 1844, have given microbes
a new express route into
our bloodstream via blood
transfusions, allergy injections,
and illegal narcotics. This is a
particularly serious problem
in less developed countries,
where needles are relatively
rare, very expensive, and often
reused by doctors and nurses.
New technology has also
created new microbial habitats.
Kitty litter, for example, has
30
Air conditioning gave bacteria that cause

Legionaires disease a new dispersal route.
Comstock/Thinkstock.
Lecture 8: Death by Chocolate
Spanish explorers and the transatlantic slave trade brought smallpox,

measles, u, bubonic plague, diphtheria, typhus, cholera, scarlet fever,
chickenpox, yellow fever, and whooping cough to the New World. These
diseases were big contributors to the estimated 97 percent drop in the Native
American population between about A.D. 1500 and 1900; now, railroads and
airplanes can transport microbes even faster than sailing ships did.
given toxoplasmosis a route to spread from cats to humans. The rst known
major outbreak of Legionnaires disease, caused by the bacterium Legionella
pneumophila, was tracked to a hotel air conditioning system. The microbe
was not new, but technology has given it a new aerosol dispersal route.
Global climate change will create some new health problems and worsen
some old ones, like allergies. Its already changing the natural ranges and
distributions of a wide variety of species, including many microbes and
their vectors: Mosquitoes, ticks, and other tropical and subtropical vector
organisms are being found farther north, at higher altitudes, and in greater
numbers.
One of the most profound effects of agriculture is how it changes habitats,
primarily through deforestationthat is, clearing land for pastures and
cropswhich brings humans into contact with entirely new species of
pathogens. Any such disruption in an ecosystem can give some species the
opportunity for rapid population growth.
Which brings us to the subject of death by chocolate: Chocolate is a dry
fruit, botanically speaking, whose owers are pollinated by tiny midges. The
product we eat comes from the seeds of the Theobroma cacao plant. Most
chocolate comes from West Africa, but a big portion of it comes from the
Caribbean and from South America.
In Belm, Brazil, in the early 1960s, over 11,000 residents came down
with a mysterious ulike illness. The disease turned out to be Oropouche
fever, a vector-borne illness rst described among the people of Trinidad
and Tobago.
What caused the sudden outbreak in Belm? Land had been cleared
for chocolate plantations along the then-new Blem-Brasilia road. This
clearance disturbed the habitat of the forest midge Culicoides paraensis, a
vector for Oropouche fever. The midge found a new habitat in the discarded
fruit shells from the plantations, and the microbe found virgin soil among
the plantations workers. The story of Oropouche fever demonstrates how
ecosystem disturbance can become an evolutionary opportunity, particularly
for r-selected species like microbes.
31
Important Terms
disturbance: Any force or factor that perturbs the normal functioning of an
ecosystem.
herd immunity: A complete or partial immunity in the surviving population
(the remaining herd) after an epidemic.
nave population: An isolated population that has not been systematically
exposed to an infectious disease.
virgin soil epidemic: An epidemic in a population not previously exposed to
that disease.
Suggested Reading
Despommier, West Nile Story.
Garrett, The Coming Plague.
1. In addition to those discussed in our lecture, can you think of any
Lecture 8: Death by Chocolate
other ways that technology and modern lifestyles have created new
opportunities for microorganisms?
2. What are some of the ways in which agriculture encourages the

evolution and spread of infectious diseases or parasites?
32
Bambis Revenge
Lecture 9
Human innovations from agriculture to warfare present new

opportunities for the microbes that surround us. The great epidemics
of tomorrow may already be lurking in some forgotten corner of Earth,
waiting for an unwary victim to carry them far and wide.
ntil World War II, microbes killed far more soldiers than ever
died in battle. During wars, public health and sanitation programs
grind to a halt; malnutrition is widespread; soldiers, prisoners, and
refugees live in crowded, unsanitary conditions; and local environments
suffer profound disturbance. Invading troops bring new diseases to native
populations and take new diseases home with them after the war.
Why
the
sudden
mysterious
appearance and rapid spread of Lyme
disease? Deforestation for agriculture
led to an explosion in the white-tailed
deer population across North America.
The expansion of suburbs into cleared
farmland brought large numbers of
people into regular contact with deer
habitats, where infected ticks were
waiting in the grass.
Comstock Images/Comstock/Thinkstock.
War, however, is not the only cause of disturbance and exposure.

Suburbanization is an equal culprit. In 1975, children in Old Lyme,
Connecticut, began reporting aches
and pains in their bones and joints,
mild fevers, general malaise, and
memory problems. The syndrome
became known as Lyme disease,
caused by the bacterium Borrelia
burgdorferi, carried by deer ticks of
the genus Ixodes.
Deforestation brought deer ticks

into closer contact with humans.
33
When a new microbe comes into contact with humans, there is a danger
that it will prefer human hosts to its original hosts. African relapsing fever,
carried by Borrelia duttoni, is a disease related to Lyme disease that now
occurs only in ticks and humans; it has bypassed all the intermediate hosts
it used to prefer. There is a chance this could happen with the Lyme disease
microbe as well.
Agriculture has also altered microbe habitats through irrigation. Fluke
worms like Clonorchis and Schistosoma take advantage of irrigation farming
to reach human hosts, especially in developing nations, where human
waste may be used as fertilizer.
Clonorchis sinensis infects 20
million East Asians and can cause
The great epidemics of
severe jaundice and liver cancer.
tomorrow may come from
Schistosoma can cause anemia,
diarrhea, brain damage, and
similar technology- and
damage to many other organs, with
weather-driven changes in the
a fatality rate of about 25 percent.
ecosystem. We have already
had several close calls.
Natural changes in the environment
Lecture 9: Bambis Revenge
can also create new opportunities

for microbes. Take, for example,
the hantavirus. Of the 22 types found worldwide, 18 are found in the New
World, all associated with rodent vectors. Many New World strains cause
hantavirus pulmonary syndrome (HPS)fever, muscle aches, headaches,
and cough. HPS strains are extremely virulent and eventually progress to
respiratory failure and death in about 50 percent of all victims.
The primary vector for the Sin Nombre hantavirus, an HPS strain identied
in the American Southwest in 1993, was the deer mouse Peromyscus. The
vector and microbe were not new to the area, but the environmental effects
of El Nio fueled rapid growth of vegetation that fed the mice. Thus the
mouse population exploded, bringing mice into closer contact with the
nearby human population.
The great epidemics of tomorrow may come from similar technologyand weather-driven changes in the ecosystem. We have already had
34
several close calls. A sample of virus that causes Lassa fever, a form of
hemorrhagic fever that arose in Nigeria in 1969, was brought to a Yale
University laboratory and infected a researcher. That one infection could
have spread the disease to New England and beyond had the victim not
been quickly isolated and treated.
One of the latest forms of hemorrhagic fever to emerge is Ebola, named after
the Ebola River in the Congo, where it was rst described in 1976. It is a
zoonosisa disease that can infect both animals and humans. Ebola is a
savage killer, with a fatality rate between 50 and 90 percent. Its emergence
may be yet another example of expanding agriculture bringing people into
more frequent contact with the original hostin this case, fruit bats.
One of the 5 known types of Ebola, now called Ebola-Reston, almost
escaped into the United States in October 1989 from infected monkeys at
Hazleton Laboratories in Reston, Virginia. The army and the U.S Centers for
Disease control had to be called in to contain the outbreak.
Perhaps the most frightening aspects of the Reston incident were that 6 lab
workers tested positive for Ebola antibodies but displayed no symptoms, and
2 of those workers had no direct contact with infected monkeys, indicating
that the microbe might have actually gone airborne. Luckily, Ebola-Reston
turned out to be harmless to humans, but the next zoonosis may not be
so benign.
Important Term
zoonosis: A disease that pass directly from a vertebrate animal to humans
and back, with no intermediate vector such as an insect.
Suggested Reading
Harper and Meyer, Of Mice, Men, and Microbes.
Karlen, Biography of a Germ.
Preston, The Hot Zone.
35
1. How does warfare promote the spread of infectious diseases?
2. Why is the emergence of so many different diseases connected to
Lecture 9: Bambis Revenge
deforestation?
36
The Germ of Laziness

Lecture 10
A microscopic worm may have altered the course of American history

by contributing to the defeat of the Confederate army in the Civil
War. The eradication of this so-called germ of laziness not only helped
individuals but improved the social, political, and economic prospects
of the entire American South.
ematode worms, also called roundworms, are among the most

abundant, most diverse, and least understood creatures on this
planet. A typical shovel full of garden soil could hold over a million
worms, and a single acre of farmland might shelter a billion. Ninety percent
of the life on the ocean oor consists of nothing but different species of
nematode worms.
Many
nematodes
are
carnivorous,
eating
tiny
creatures like algae, but about
16,000 species of nematodes
are
parasites.
Necator
americanus, the American
hookworm, is a parasite that
causes millions of people to
be labeled ignorant, lazy, and
Hemera/Thinkstock.
We think of dirt as something solid, but on a microscopic scale, its riddled

with tiny irregular spaces between the fragments of minerals, dead vegetation,
bits of bugs, and other natural
materials. Nematodes wriggle
through this complex maze
of tiny irregular spaces, this
interstitial habitat, keeping soil
loose and open, letting water and
air into the dirt, and easing the
passage of roots.
Nematodes are necessary for soil fertility,

but they can cause diseases as well.
37
shiftless. In the early 20th century, it was dubbed the germ of laziness
by the New York Sun, much to the chagrin of its discoverer, Charles
Wardell Stiles.
Hookworms are extremely common and globally distributed. Roughly
10 percent of the planets population is currently infected. Hookworm
disease was known to the ancient Egyptians and was described at length
by the Persian physician Avicenna in the 11th century A.D. N. americanus
probably arrived in the New World
with the slave trade. Today, its
Hookworm infected about 40
found throughout the tropics, in the
Southwest Pacic, in Africa, and
percent of all Southerners,
throughout Asia.
primarily in poor rural areas.
But this widespread infection
and suffering was virtually
unrecognized.
Lecture 10: The Germ of Laziness
The female hookworm lays up to

30,000 eggs a day in the intestine
of an infected person. The eggs are
shed in feces. Young worms can live
in the soil for several weeks. When
a bare foot rests on the soil, the worm burrows into the skin. Once in the
body, it migrates through the blood. When it arrives in the small intestine, it
attaches itself to the intestinal lining, starting the cycle again.
Victims of hookworms become pale, anemic, and suffer severe digestive

problems. Their muscles become weak and their abdomen may protrude.
They have unusual dietary cravings for chalk paper, and dirta phenomenon
called pica. Severe infections retard growth and leave the victim shrunken
and malformed. Hookworm victims appear gaunt and haggard, with a
sallow complexion.
The poor condition of Southern soldiers with chronic hookworm infections
due to unsanitary camp conditions may have contributed to the outcome of
the Civil War. The soil, climate, primitive sanitary conditions, and little to
no medical care provided a nearly perfect breeding ground for hookworms
in the old South. At its peak in the late 19th and early 20th century, hookworm
infected about 40 percent of all Southerners, primarily in poor rural areas.
But this widespread infection and suffering was virtually unrecognized.
38
Charles Wardell Stiles discovered N. americanus in Texas in 1902 while

working for the U.S. Department of Agriculture. After describing this new
species, he toured the South looking for hookworm; to his surprise, he found
it everywhere, with infection rates ranging from 40 to 82 percent. With funding
from John D. Rockefeller, he founded the Rockefeller Sanitary Commission for
the Eradication of Hookworm Disease and set about eradicating the infection.
Fortunately, hookworm is easy to cure with thymol, an extract from the thyme
plant. Unfortunately, it is also too easy for a patient to be reinfected. Stiles
not only had to treat the victims; he had to convince whole communities
to adopt lifestyle changes like shoe wearing and indoor plumbingboth
expensive prospects among the rural poor at that time.
The commissions eventual, hard-fought success created a healthier
Southern working class, which enabled the growth of industry in the South.
School attendance and school performance also increased, as did agricultural
productivitya happy ending to a sad story.
In what may be the oddest twist of fate, hookworm infection has recently
been proposed as an experimental cure for asthma. Hookworms produce
immunosuppressants that could be useful in treating not only asthma but
diseases such as ulcerative colitis, Crohns disease, and multiple sclerosis.
Important Terms
interstitial habitat: A habitat within and among the grains of soil in
terrestrial or aquatic habitats.
pica: A dietary craving for nonfood items such as chalk and dirt; sometimes
a symptom of nematode infection.
Suggested Reading
Brown, Rockefeller Medicine Men.
Ettling, The Germ of Laziness.
Wray, Not Quite White.
39
1. Was John D. Rockefellers gift of $1 million to fund hookworm
eradication primarily philanthropic, or was he making a calculated
nancial investment in a new industrial base?
2. If nematodes are so incredibly abundant and widespread, why have
Lecture 10: The Germ of Laziness
most of us never seen one?
40
The 1918 FluA Conspiracy of Silence

Lecture 11
The deadliest epidemic of all time was 1918 Flu, which killed 50100
million people. The story of the epidemic shows us, for better or worse,
how society responds to a public health crisis. By learning how and why
we were so vulnerable, we may be better equipped to save ourselves
when the next global pandemic strikes.
he Spanish inuenza epidemic of 1918 was one of the great

watershed events in the history of the world. Flu was nothing new in
1918. The rst global u pandemic occurred in 1580, starting in Asia
and sweeping across Europe. Between 1700 and 1900 there were at least 16
major u epidemics. The last major pandemic was in 18891890, the rst of
what were later called the Asian us.
Nobody knows exactly where the 1918 Flu began, but Dr. Loring Miner
of Haskell County, Kansas, reported dozens of patients stricken by an
unusually virulent form of the u between January and mid-March of 1918.
There it might have ended in such an isolated community, but America was
at war, and in wartime, people move between populations more often and in
greater numbers.
Twenty-four of the 36 largest U.S. army camps reported an outbreak of
u in the spring of 1918, along with 30 of the countrys 50 largest cities.
Meanwhile, over 1.5 million American soldiers were being sent to Europe,
the largest troop movement in the history of the world, and many of them
were unknowingly incubating the disease.
The u soon spread to French and British troops, and Allied soldiers took
it home to civilians while on leave. The virus spread rapidly to Germany,
Russia, China, India, southeast Asia, and Spain, becoming a true global
pandemic. It was dubbed the Spanish Flu only because the press started to
take notice as it hit Spain.
41
Something happened aboard the troopships or in the foul and crowded

trenches that turned a mild u into a savage killer. It is possible that a new
and entirely different strain of u from the Kansas virus had emerged; a
genetic mutation may have altered
the original strain; or 2 different
viruses may have fused to create a
Within 10 hours of infection,
new strain.
that cell can release 100,000
to 1 million or more new
u viruses.
Lecture 11: The 1918 FluA Conspiracy of Silence
Viruses generally consist of a core

of RNA or DNA surrounded by
a membrane or capsule. Unlike
cells, viruses cannot replicate by
themselves; they take over the protein factory of a living cell and reprogram
it to make copies of the virus. Inuenza is an RNA virus whose membrane
is covered 2 kinds of antigen spikes: H spikes and N spikes. (Different u
strains are named for their spike congurations, like H5N1.) The H spikes,
made of hemagglutinin, cause red blood cells to clump, or agglutinate. The
N spikes are neuraminidase, an enzyme.
Every organism has a different pattern of antigens on the surface of its cells.
The immune system recognizes these antigens as cellular ID tags and uses
them to separate self from nonself. Small changes in antigen structure, called
antigenic drift, create variant strains. Larger changes, called antigenic
shifts, create subtypes. Antigenic shifts are responsible for major new
outbreaks of u.
The u virus uses its H spikes like grappling hooks to attach itself to the
outside of a cell. The cell absorbs the virus through phagocytosis, wrapping
the virus in a bubble of cell membrane. Once inside the cell, the virus sheds
its envelope and releases its RNA genes, which hijack the cellular protein.
Within 10 hours of infection, that cell can release 100,000 to 1 million or
more new u viruses. Then new viruses N spikes chemically slice through
the cell membrane and go in to infect new cells.
In the case of the 1918 Flu, the fact that survivors of the rst mild wave
had some immunity to later waves tells us that the second wave wasnt an
entirely new strain but an altered form of the rst virus with different surface
42
antigens. An RNA virus, like the u, has hypermutabilitya mutation rate

thousands and thousands of times higher than a DNA virus.
This altered strain the u struck with amazing intensity. Symptoms were so
severe that doctors often misdiagnosed the u as malaria or dengue fever.
The immune system reaction was so strong that it often created a disastrous
feedback loop called a cytokine storm, destroying the lungs ability to
exchange gas. Some survivors were left with permanent nerve damage and
even psychosis.
Casualty gures for the fall of 1918 show the brutal power of the virus:
nearly 23,000 u deaths in military hospitals, and well never know how
many thousands or tens of thousands more in foxholes and trenches on the
front. But the battle with the 1918 Flu did not end on the battleelds of
Europe, as we will soon see.
Important Terms
antigen: A fragment of a cell or protein that can be detected by the immune
system; also, a molecule or cell with an epitope in its structure.
antigenic drift: A signicant alteration in the structure of the surface proteins
of a virus, effectively disguising it from the immune system. Usually refers
to inuenza, especially the structure of H spikes and N spikes.
antigenic shift: A dramatic alteration in the structure of the surface proteins
of a virus sufcient to trigger an epidemic.
cytokine storm: A cascade reaction of defensive proteins that can prove
fatalthe immune systems equivalent of a thermonuclear attack.
enzyme: A protein that can act as a chemical catalyst, mediating a reaction
without being changed by it. Enzymes control the rate, direction, synthesis,
and degradation of many biochemical reactions in the body. Most of what
our genes actually code for are different kinds of enzymes.
43
hypermutability: The tendency of certain organisms, such as the inuenza

virus, to mutate at a relatively high rate.
mutation: A random alteration of genetic information that can occur in RNA
or DNA.
RNA virus: A virus whose genetic material consists solely of RNA (not
DNA). Because such viruses lack the proofreading mechanism that governs
the reproduction of DNA, they mutate at a very high rate.
Suggested Reading
Barry, The Great Inuenza.
Crosby, Americas Forgotten Pandemic.
Pettit and Bailie, A Cruel Wind.
Lecture 11: The 1918 FluA Conspiracy of Silence
1. Because inuenza is an RNA virus, it lacks the proofreading mechanism
that a DNA virus would have, and its control over replication and
reverse transcription is rather messy. Why does this sloppiness turn out
to be a big advantage for the virus?
2. What makes a virus fundamentally different from a bacterium when it

comes time to reproduce?
44
The 1918 FluThe Philadelphia Story

Lecture 12
The city of Philadelphia is a case study of how American cities

responded to the 1918 Flu pandemic, but the u also hit isolated
native populations especially hard. Everyone on Earth at one time
was probably exposed to the virus; in the end, the pandemic only
subsided because it had no new hosts within the human population.
ost authorities think that the American u mutated into a killer

in its new European population. The new strain likely re-entered
the United States on August 12, 1918, via the Norwegian
passenger ship the Bergensfjord, which entered New York harbor with 200
sick passengers who disembarked and scattered into the New York City
population. Over half a million Americans would die in their wake.
One of the reasons the u was so terrifying at that time was that no one had
any real idea of what had caused it. After the 18891890 u pandemic, Dr.
Richard Pfeiffer had isolated a bacterium now known as Pfeiffers bacillus. Its
a very dangerous microbe but not, as it turned out, the cause of the 1918 Flu.
There was also little to be done for the sick. Medical treatment consisted
mostly in comforting and isolating the patient if possiblein other words,
basic nursing. Public health responses included fumigation, urging people to
wear gauze masks, campaigns against spitting and sneezing, warnings about
public gatherings, and a general prescription for rest and fresh air. Folk cures
abounded; snake oil salesmen were everywhere.
Philadelphia was typical of big cities ravaged by the u. Overcrowding,

inadequate social services, and squalid living conditions amongst the poor
made the city the perfect breeding ground for infection. Inuenza entered the
city in mid-September 1918 via the navy yard. On September 27, some 200
u cases had been reported, 123 of them among civilians. Nonetheless, the
city fathers refused to cancel the Liberty Loan Parade, designed to sell war
bonds, scheduled for the next day.
45
Library of Congress, Prints and Photographs Division, LC-USZ62-108266.
Lecture 12: The 1918 FluThe Philadelphia Story
An inrmary at Camp Devens, Massachusetts, full of soldiers infected with the

1918 Flu. At its peak, the Devens outbreak claimed 100 lives per day.
The us incubation period is typically 2448 hours. By September 30,

several hundred people had fallen ill. Twelve emergency hospitals would
eventually open to receive the growing number of the sick and dying. The
call went out for retired doctors to come back to work; all 5 Philadelphia
medical schools closed and sent their third and fourth year students to help.
On October 3, the government ordered all schools, churches, and theaters
to close and banned all public gatherings. Most grocers were closed and
few stores of any kind were open. Absentee rates ran from 20 to 40 percent
for those businesses and factories still functioning. As the epidemic peaked
during the week of October 16, 4597 people died759 of them on October
10 alone.
The city resorted to burying the poor in mass graves. Citizens were given
wooden boxes and instructed to leave their dead on the front porch. Some
bodies were heaped into wagons, reminiscent of scenes from the Black
Death. People often had to live with dead bodies in their homes for several
46
days. Every social agency in the city chipped in to help as best they could,
without regard to race, creed, or color.
By October 18, the worst was over and emergency hospitals began to close.
Churches reopened on Sunday, October 27, and schools reopened the next
day. On October 30, bars and theaters reopened.
A third and nal wave followed in late 1918 and ran through early 1919.
The virus seems to have gradually mutated into a weaker strain at this point
because the third wave was short
and sharp but relatively mild.
Estimates of American
Estimates of American dead run
dead run to 675,000 out of
to 675,000 out of a population of
a population of 105 million.
105 million. Britain lost 228,000.
Britain lost 228,000. The best
The best global estimate is 50100
global estimate is 50100
million dead out of 1.8 billion.
million dead out of 1.8 billion.
Nave native populations were
especially hard hit because they
lacked previous exposure and immunity. American Samoa survived without
a single victim because of its early quarantine, and Australia had the lowest
global death rate because of its relative isolation. But, for example, in the
Fiji Islands, 14 percent of the population died in 16 days. In Alaska, many
Inuit villages sustained an 85 percent casualty rate or higher. Over 20 million
people are thought to have died in India alone.
Those who survived the 1918 Flu developed immunity to it and resistance to
similar strains. Thus in the end, the virus had no place left to go; it couldnt
maintain itself in the human population. Fortunately for the u virus (and
unfortunately for us), it doesnt need humanity to sustain itself. Birds are its
primary host, and as long as bird populations are healthy, the u will always
nd a home.
47
Important Terms
incubation period: Period of time between infection and the rst symptoms
of an infection. Sometimes called the latency period, although that term
usually refers to the time between infection and becoming infectious to
others.
resistance: A physiological trait that helps prevent infection by pathogens.
Although often used as synonym for immunity, resistance is a physical
feature that can be directly inherited (like lacking a certain protein on the cell
wall that a virus could use to enter the cell), whereas immunity is a cellular
memory of a disease in the form of stored antibodies.
Suggested Reading
Duncan, Hunting the 1918 Flu.
Lecture 12: The 1918 FluThe Philadelphia Story
Kolata, Flu.
1. What does the response of Philadelphias citizens to the u epidemic tell
us about how people in general behave in a medical crisis?
2. Why did a greater proportion of native tribes in isolated areas die from
the 1918 Flu versus urban populations?
48
The 1918 FluThe Search for the Virus

Lecture 13
In 1918, the u was a horror story; today, it is a detective story,

as scientists search for an intact virus. This is no mere intellectual
exercise; in the wrong hands, the virus could make a formidable
weapon; if we can decode its genes, we might nd a way to ght it or
any similar strain.
ne surprising, lingering effect of the 1918 Flu was how it helped set
the stage for World War II. President Woodrow Wilson began the
treaty negotiations with a harsh stance against the aggressors. But
after his struggle with the u in April 1919, those close to Wilson reported
a dramatic personality change. Soon, Wilson made every concession he had
previously refused.
Historians speculate that Wilson suffered a mild stroke during the talks,
but the 1918 Flu left many of its victims with permanent mental and
neurological damage. Whatever the case, the Treaty of Versailles did not
solve the problems of World War I and helped to create the conditions that
led to World War II.
What if the 1918 Flu or a similar strain were to return today? Would we be
prepared to ght it? In many ways, we are more vulnerable than ever. The
1918 Flu spread rapidly by rail and ocean liner; modern highways and global
airlines would disperse such a killer even more effectively. Our increasingly
interconnected global trade system leaves each nation less self-reliant, so a
global pandemic might trigger a cascade of economic collapse, leading to
shortages of critical items, even food.
Being more vulnerable means we have to be better prepared, starting with
a better understanding of what made this strain so dangerous. The U.S.
Army preserved many lung tissue samples from dead soldiers. Jeffery
Taubenberger and Ann Reid of the Armed Forces Institute of Pathology
have begun trying to isolate the virus from such a sample. Pathologist Johan
Hultin found samples in a mass grave at Brevig Mission, Alaska, in 1997 in
49
Lecture 13: The 1918 FluThe Search for the Virus
a victim he dubbed Lucy, from which Taubenberger was able to sequence

several viral genes.
Several mysteries surrounding the 1918 Flu remain unsolved. Normally, the
u is most deadly to those with the weakest immune systemsthe young,
the old, and the already ill. Some doctors think the massive lung damage seen
in young victims of the 1918 Flu was partly due to a deadly cytokine storm.
On the other hand, young adults in
1918 may have had especially high
A multi-billion dollar
levels of tuberculosis, leaving their
damaged lungs ripe for invasion
international effort is currently
by inuenza.
underway to study H5N1
and prepare for a possible
Flu is driven by herd immunity
future outbreak.
to undergo major antigenic shifts
every 2 or 3 years. But the 3 waves
of the 1918 Flu were very close
together; in a few places, its hard to say when one ended and the next began.
That tight spacing lends some support to the argument that that second wave
was a hybrid virus or a mutant strain, sufciently different to overcome the
partial immunity of survivors of the rst wave. Cycles of the 1918 Flu were
so out of step that many scientists have come to doubt the validity of the
whole idea of epidemiologic cycles, at least where the u is concerned. Or
perhaps we are missing a much larger pattern.
Flu is a rather unusual microbe in that new subtypes of u tend to drive
all old subtypes into extinction; only one subtype and one variant tends to
exist in humans at a time. This may be because each new subtype provokes a
general partial immunity to u viruses. So when older strains cycle back into
fresh populations, the door may be already closed.
The molecular evidence suggests that the 1918 Flu was H1N1, a novel strain
of bird u which later spread to swine and humans. The 1976 swine u was
an H1N1 variant, which is why it caused an international panic, and a record
40 million people got a u shot that year. If nothing else, that 1976 swine u
scare prepared us for another epidemiological nightmare: A modern outbreak
50
or a terrorist attack with weaponized u would require a similar scheme of

mass inoculation.
In 1997, an explosive outbreak of avian u struck in Hong Kong. This was a
new strain called H5N1. Six out of every 18 infected people died. That could
have been the beginning of a serious new pandemic, but rapid quarantine
and the destruction of every single chicken in Hong Kong stopped it in its
tracks. H5N1 is currently the most dangerous type of u in circulation. A
multi-billion dollar international effort is currently underway to study H5N1
and prepare for a possible future outbreak.
The 2009 Swine Flu virus was an H1N1 subtype, like the 1918 Flu, which
is one reason why doctors overreacted so strongly to that outbreak. Initial
analysis of the 2009 swine u pandemic indicated a higher mortality rate
for young adults, just like the 1918 Flu, and once again caused by extreme
cytokine storms. If the 1918 Flu or a similar strain does return, we may be
prepared for it this time. An experimental DNA vaccine developed by the
U.S. National Institutes of Health has been found to be effective against a
live reconstructed 1918 virus.
Important Terms
DNA vaccine: Plasmids that code for a critical protein in the life cycle of a
particular microbe.
epidemiologic cycle: The demographic pattern of infection or mortality over
time in a given population.
Suggested Reading
Blakely, Mass Mediated Disease.
Jones, Inuenza 1918.
51
1. Why doesnt our annual u shot always work?
2. In what way are we more vulnerable during a major u epidemic, as
Lecture 13: The 1918 FluThe Search for the Virus
individuals and as a society, than our parents generation?
52
ImmunitySelf versus Nonself

Lecture 14
You might be starting to wonder why humans arent all sick all of the
time. For that, you can thank your immune system, your rst line of
defense against infection. This extremely complex system saves our lives
every day, but it can also turn on us, sometimes with fatal consequences.
here are thousands and thousands of tiny organisms whose only goal
in life is to survive and reproduce in or on you. All kinds of creatures
can live in the diverse habitats that exist inside our cells, and theyve
evolved many strategies for exploiting the human body. We need a complex
immune system to deal with that endless diversity.
The immune system has evolved to master the difcult art of telling the
difference between self and nonself. Thats not as easy as you might think. It
must recognize and kill invaders without harming the host. In other words, it
must learn self-tolerance.
Our immune system consists of many specialized cells. One of the most
important defensive cells is the leukocyte, or white blood cell. Leukocytes
actually can be found not just in the blood but all throughout the body.
There are many different types with many different functions, but the 3 main
types are phagocytes, or eating cells; cytotoxic cells, or killing cells; and
inammatory cells, which are responsible for local inammation.
Phagocytes literally wrap themselves around microbes and pinch off a little
part of their outer membrane to enclose the microbe in a tiny little sphere
called a vesicle or a vacuole. Once inside, lysosomes, organelles that hold
digestive enzymes, are used to kill and digest the microbes. That simple act
of good cells killing bad cells is part of what we call cellular immunity.
Russian zoologist lie Metchnikoff won the Nobel Prize in 1908 for
discovering cellular immunity. His focus was comparative embryology,
but while studying the larvae of starsh, he became curious about groups
of amoeba-like cells he saw moving through the starsh larvae. He thought
53
these eating cells formed a primal digestive system in the early evolution
of animal body plans. He also reasoned that these cells might be part of the
larvaes defense system.
One of phagocytes many functions is to devour all the dead cells and the
debris at the site of wounds or infections. Recent studies suggest they also
have a much broader role in maintaining our tissues, like ensuring the
structural integrity of vascular tissue.
Phagocytes, along with cytotoxic cells and inammatory cells, are part
of what we call innate immunity. But the white cells involved in innate
immunity are very unusual in one key respect: Theyre the only cells in our
body that arent associated with a specic tissue or organ.
Lecture 14: ImmunitySelf versus Nonself
Defensive cells recognize invaders the way a lock recognizes its key.
Phagocytes are covered in surface receptors; if they encounter a microbe
with surface molecules that t one of their receptors, they can latch on to it.
Cytotoxic cells are our second line of defense. Cytotoxic cells dont poison
microbes, as the name implies; they stab them to death. Natural killer (NK)
cells are cytotoxic cells unique to vertebrates. NK cells dont kill microbes
directly but rather kill the cells that those microbes have invaded. They
specialize in tumor cells or cells that have been infected by a virus. They
release a protein called perforin that perforates the cell walls of the infected
cells, through which the NK cells send molecules that cause the infected cell
to commit suicide, taking any invading microbes along with it. NK cells also
release cytokines.
NK cells look for cells that lack a cellular ID card called the major
histocompatibility complex (MHC). MHC molecules haul bits and pieces
of the cells proteins to the surface of the cell where they are visible to any
passing NK cell. If a virus is at work, pieces of viral proteins will be hauled
to the surface as well, where they will be spotted by passing killer cells.
The inammatory cells, our third line of defense, create an inammatory
response that is local and nonspecic. The chemicals that cause local
swelling attract swarms of phagocytes, cytotoxic cells, and defensive
54
In addition to defensive
cells, our bodies have
evolved many different
proteins that can attack
microbes. Interferon, for
example, attacks viruses.
The complement system,
a more primitive proteinbased defense system, is a
group of about 25 proteins The immune system identies bacteria, like
these Haemophilus inuenzae, by their cellthat build up on the surface surface molecules.
of a microbe. They may
destroy the microbe themselves or may release chemicals to attract other
immune cells. They also opsonize invading cells, coating them with proteins
that help phagocytes bind to them.
Higher animals have adaptive immunity as well as innate immunity. Their
immune systems arent limited to recognizing a small number of basic
patterns. Rather than looking for patterns of sugar molecules like those
found on a bacterial cell wall, they look for pattern differences in proteins
specically, for groups of amino acids called epitopes, unique molecules
found on the surface of antigens. The adaptive immune system has to
make a different type of antigen receptor to match each different epitope
potentially over 100 million different epitopes.
55
CDC.
proteins called antibodies. The most important inammatory cells are mast
cells and basophils They respond to injury or attack by releasing chemicals
like histamine that cause our
capillaries to dilate, making
them more permeable,
which allows the phagocytes
to pass through.
Important Terms
adaptive immunity: A type of immunity evolved by higher animals that
doesnt look for general patterns of shared structure but rather for minute
differences in molecules shared by hosts and microbes.
antibody: A protein that can attach to a corresponding epitope and ag a cell
or molecule for destruction by the immune system.
cytotoxic cell: A type of defensive cell common to all animals that effectively
stabs foreign cells to death by punching holes through their cell walls.
epitope: A fragment of protein from a cell or molecule that can be detected
by the immune system.
Lecture 14: ImmunitySelf versus Nonself
inammatory cell: A cell involved in the inammatory response that is

densely packed with granules loaded with potent chemical mediators like
histamine.
innate immunity: A primitive type of immune system common to a wide
variety of animals that gives certain cells the ability to identify foreign cells
by recognizing patterns of sugar molecules in their cell walls. Phaogocytes,
cytotoxic cells, and inammatory cells are components of innate immunity.
major histocompatability complex (MHC): A receptor site on the outside
of every vertebrate cell that can hold onto an epitope or antigen so that
immune system cells can recognize it.
mast cell: An inammatory cell that releases the cytokine histamine.
natural killer cell (NK cell): A cytotoxic cell that seeks out and destroys
cells invaded by microbes; NK cells specialize in attacking cancerous cells
or cells invaded by a virus.
opsonization: Part of the complement system; a process through which an
invading cell is coated with proteins that help phagocytes bind to them.
56
phagocyte: An amoeboid eating cell found in all types of animals that can
engulf and consume other microbes.
Suggested Reading
Clark, In Defense of Self.
Playfair, Living with Germs.
1. I have type O blood and my friend has type AB. When it comes to
blood transfusion, why am I the universal donor, and why is he the
universal recipient?
2. What is it about larger, more complex animal bodies that made the
adaptive immune system necessary?
57
Adaptive Immunity to the Rescue

Lecture 15
Defensive cells have to master the ne art of recognizing epitopes to

ght off foreign invaders. Once an epitope is recognized, this sets off a
virtual army of different cells in a coordinated response that destroys
the microbe and stores the memory of the attack for use in the future.
O
Lecture 15: Adaptive Immunity to the Rescue
ur cells can potentially detect over 100 million different kinds of

epitopes thanks to our lymphocytes, which are types of leukocytes.
There are 3 basic types of lymphocytes: NKT cells, T cells, and
B cells. NKT, or natural killer T cells, act just like NK cells but also act as
messengers, releasing cytokines to stimulate the immune response.
Lymphocytes, among other cell types, are made by bone marrow stem cells.
Each stem cell has several hundred genes that code for antigen receptor
shapes. Every new lymphocyte gets a starter kit, a random set of 5 or 6 of
these receptor genes, just enough to put together one unique antigen receptor.
A few hundred genes, parceled out this way can easily make more than 100
million different antigen receptors. But this clever system has a hidden cost:
Among those millions of random variations will be a handful that match our
own antigenswhat we would call a self-reactive epitope.
Any unique epitope could be recognized by any of several different kinds of
lymphocytes, a process called presentation. But there are so many different
kinds of lymphocytes, the body cant keep more than a few of each type
around at any one time. When an invader is recognized, the matching
lymphocyte has to copy itself to create an army, a process called activation.
This phase of the infection is called the primary immune response.
To thwart future attacks from that same microbe, the adaptive immune
system makes memory cells that are matched to that particular microbe.
These memory cells can live for several years, and if the invader returns,
we can build up a new population of cloned soldiers so quickly that we
might not even have any symptoms of infection at all. We are now said to
58
B cells and T cells are especially important in this process. Both are made
in bone marrow; B cells mature in the marrow, while T cells migrate and
mature in the thymus gland. The B cells are the deputies; they check cellular
IDs for known villains
and they mark them with
antibodies. Antibodies can
directly neutralize some
toxins made by microbes
and can prevent some
microbes from binding to
our cells. But their most
important function is to pin
a ag on invading microbes
to call out the possethe T
cells, which release a wide
array of chemicals that
marshal the attack on an
invading microbe.
Lymphocytes act as killer cells, destroying
microbes directly, and as messengers to other
cells, stimulating the immune response.
At any given moment

there are roughly 900
billion lymphocytes moving through your body. Most of the time, they are
concentrated in the lymph nodes. When needed, a network of capillaries
transports them through the lymphatic uid throughout the body. When
you have a swollen lymph node, its a sure sign that the body is ghting off
an infection.
The immune system uses messenger cells called antigen-presenting cells
(APCs)including macrophages, B cells, and dendritic cellsto signal to
T cells that an infection has begun. APCs run the invading microbes epitope
up their own molecular agpole, the MHCspecically MHC class II.
APCs then approach the nearest lymph node and present the foreign antigen
to the T cells, hoping to nd one whose antigen receptor ts. If it nds a
match, the T cell activates. Different groups of APCs tend to patrol each
59
Hemera/Thinkstock.
be immune to that disease. This return engagement phase is called the

secondary immune response.
particular part of the body. T cells can recognize each group and know where
to nd the infection.
There are 2 kinds of T cells: helper T cells (TH cells) and killer T cells (TC
cells). APCs release the cytokine interleukin-1, which activates the TH cell
and stimulates the hypothalamus to raise body temperatures, causing a fever.
Fever stimulates the macrophages to start eating bacteria and causes the
liver and the spleen to begin iron
withholding. The TH cell releases
interleukin-2, which triggers the
At any given moment there
activation of TC cells and B cells.
are roughly 900 billion
lymphocytes moving through
The activated TC cell clones itself
your body.
and goes off to seek the enemy. The
B cells split into 2 lines: plasma
cells and memory cells. The plasma
cells make antibodies, and the memory cells hold onto the proper receptor
site in case the invader ever returns. The point when antibodies appear in the
bloodstream is called the humoral response.
The terms immunity and resistance are often used interchangeably, but
they dont quite mean the same thing. Resistance comes from a structural
change in a cell or in a moleculechanges that are coded for in our genes
and can therefore be inherited. Immunity is learned resistancesomething
we acquire only by encountering a new disease. It does not change our
genes, and we cannot inherit it or pass it on.
Important Terms
antigen-presenting cell (APC): Immune system cells that act as messengers
by carrying antigens on their major histocompatability complex to the
corresponding T cells for activation. APCs include macrophages, B cells,
and dendritic cells.
B cell: A type of lymphocyte whose function is to produce antibodies for
specic antigens and to form memory cells to guard against any future
encounters with that same antigen.
60
dendritic cell: A type of lymphocyte in mammals that functions as an

antigen-presenting cell, helping to bridge the gap between the innate and
adaptive immune systems.
helper T cell (a.k.a. TH or CD4+ cells): A critical immune system T cell
that, when activated, coordinates a wide range of immune processes through
the secretion of messenger molecules called cytokines.
humoral response: Part of the primary immune response; the activation of
B cells by helper T cells to make antibodies (plasma cells) and memory cells.
killer T cells (TC or CD8+ cells): Cytotoxic T cells that are especially good
at killing cells that are cancerous or have been infected with a virus. See
cytotoxic cell and helper T cell.
lymphocytes: Cells involved in adaptive immunity.
macrophage: An immune cell common to most animals that eats
pathogens. Macrophages can travel almost anywhere in the body, devour
pathogens, and carry them to the lymph nodes to trigger an immune response.
memory cell: An activated B cell that is relatively long-lived and can be
rapidly cloned if the same antigen or invader returns.
natural killer T cell (NKT cell): A cell that acts like a regular natural killer
cell but can also mediate adaptive immune responses by releasing messenger
chemicals called cytokines.
T cell: A lymphocyte that plays many key roles in the immune system and
has a receptor on its cell surface that lets it recognize antigens bound to the
major histocompatability complex. Types include cytotoxic T cells, helper T
cells, and natural killer T cells.
61
Suggested Reading
Mak and Saunders, Primer to the Immune Response.
Sompayrac, How the Immune System Works.
1. How can a nite number of animal genes make a sufciently large
number of proteins to match up with millions of possible microbial
epitopes?
2. Why do we often get sick for a day or two when we catch a disease
were supposed to be immune to?
62
AIDSThe Quiet Killer

Lecture 16
AIDS may be the most virulent disease in human history. Caused

by a retrovirusa type of virus that alters its hosts DNAthe
disease cripples the immune system by destroying TH cells,
making every cell in the hosts body a safe haven for the virus.
o one has ever truly survived infection with HIV, the virus that
causes acquired immunodeciency syndrome (AIDS) in humans.
Once symptoms emerge, the fatality rate is 100 percent. There is no
cure; the most we can do is slow it down. Without treatment, victims have
about 11 years to live from the time of infection.
HIV relies on the uid route for transmission, namely blood and semen.
Microbes that travel in the blood often rely on insect vectors like mosquitoes
or their technological counterpart, the hypodermic needle. But the trifecta
for the uid route is sex; saliva, semen, and sometimes blood are all owing.
Throw in intimate bodily contact, and you have the ideal mode for dispersal.
Unsurprisingly, many of the deadliest diseases are sexually transmitted.
HIV produces no killer toxins, no violent symptoms. Instead, it cripples the
immune system by striking at its most vulnerable partthe TH cells that
orchestrate the adaptive immune response. Once the virus kills enough TH
cells, the immune system can no longer coordinate an attack. AIDS victims
dont die from AIDS; they die from cancer or a secondary infection.
Because an AIDS victims body can no longer recognize a cancerous cell, any
cancerous growth can be fatal. More AIDS victims die of cancer than from
any other cause; 3040 percent of AIDS victims will develop a malignant
tumor. In fact, AIDS was rst discovered from a cluster of Kaposis sarcoma
cases in the gay community of San Francisco in 1981.
Like so many of our worst diseases, AIDS came out of the jungle, specically
from increased human contact with other primates. Recent genetic analysis
puts the viruss origin in West Africa sometime between 1930 and 1950
63
during a period of deforestation. As rural populations expanded, they became

increasingly reliant on bush meat and were more likely to keep monkeys
as pets.
Lecture 16: AIDSThe Quiet Killer
Viruses usually consist of strands of

RNA or DNA that are wrapped in a
protein coat called a capsid. Every
kind of virus is coded to attach to a
particular type of cell, so they can
target specic tissues and organs.
A virus attacks by attaching to the
outside of the cell, injecting its genetic
code into the cell, taking over the
cells machinery, and using the cell to
make more viruses.
The ultimate origin of viruses is a
complete mystery, though there are 3
main hypotheses: the cellular origin,
or vagrancy, hypothesis, which claims The hypodermic needle is the hightech counterpart to the mosquito,
viruses are rogue bits of genetic acting as a vector for blood-borne
material escaped from an intact cell; viruses like HIV.
the coevolution hypothesis, which
suggests viruses coevolved with cells; and the degeneracy, or regressive,
hypothesis, which claims viruses are degenerate cells.
Viruses are strange little creatures to begin with, but HIV is strange, even
for a virus. HIV is a retrovirus. Its core is a strip of RNA, and it uses an
enzyme called reverse transcriptase (RT) to stitch its RNA into the host
cells DNA. In this way, it not only forces the host cell to make copies of
itself; when the host cell reproduces, it passes that viral RNA on to all of its
64
BananaStock/Thinkstock.
One of the reasons that AIDS is so deadly is that its so new. A scant 50
years have passed since the rst cases appearednot much time for humans
to evolve defenses, nor for AIDS to
coevolve to a less virulent strain.
daughter cells. Even if the immune system kills every single active virus in
the body, the instructions for making more will live on.
DNA contains the instructions our cells use to make proteins. RT reads the
cells DNA and maps it onto a strand of messenger RNA (mRNA). This
strand is a set of instructions for building a protein from amino acids. The
mRNA travels to the cytoplasm, like a foreman bringing plans to the factory
oor, where ribosomal RNA (rRNA) will read them and transfer RNA
(tRNA) will use them to assemble
a protein.
The ultimate origin of viruses
DNA is a chain of molecules called
is a complete mystery.
nucleotides, of which there are
4 types. A group of 3 nucleotides,
called a codon, is used to code for each of the 20 amino acids used in making
proteins. The amino acids used and the order in which they are assembled
determine the nal shape of the protein and thus its chemical properties.
By changing the amino acid sequence, you change the proteins ability to
interact with other chemicals. So in essence, retroviruses like HIV change
the codons of the hosts DNA, getting the cell to build the proteins needed to
make a new virusan elegant act of biological piracy.
Important Terms
codon: A series of 3 genetic nucleotides that code for a particular amino
acid. The sequence of codons determines the proper sequence of amino acids
needed to assemble a particular protein.
DNA: Two strands of complementary nucleotides attached to a molecular
backbone of sugar and phosphate molecules. The sequence of nucleotides
codes for the synthesis of proteins.
messenger RNA (mRNA): A form of RNA used in the synthesis of proteins
that is assembled by matching complementary nucleotides (A/T, C/G) to
replicate the sequence of nucleotides on a strand of DNA.
65
nucleotide: A biomolecule whose many important functions include carrying

the genetic code. The 4 nucleotides used in DNA are adenine, guanine,
cytosine, and thymine (abbreviated A, G, C, and T). RNA substitutes uracil
(U) for thymine (T).
retrovirus: A virus that uses an enzyme called reverse transcriptase to
convert its RNA into DNA, which is then incorporated into the hosts DNA.
reverse transcriptase (RT): An enzyme used to turn viral RNA into DNA,
which is then stitched into a hosts DNA. This is the reverse of the normal
process of transcription, in which the genetic message contained in a strand
of DNA is copied or transcribed onto a strand of messenger RNA. The
enzyme is used by viruses like HIV and feline leukemia virus.
ribosomal RNA (rRNA): A type of RNA that reads a strip of messenger
RNA to allow transfer RNA to identify and fetch the next amino acid coded
for. This in turn allows a ribosome to create a chain from the amino acids
supplied by transfer RNA that will subsequently roll up into a functional
protein.
Lecture 16: AIDSThe Quiet Killer
RNA: A single strand of nucleotides attached to a molecular backbone of

sugar and phosphate molecules. The nucleotides code for synthesis of a
particular protein.
transfer RNA (tRNA): A form of RNA that to transfers amino acids from
the cytoplasm to the ribosomes to be added to a chain of amino acids that
will form a protein. It has a binding site on one end that matches up with a
codon on messenger RNA and a binding site for the corresponding amino
acid at the other.
Suggested Reading
Davis, Defending the Body.
Shilts, And the Band Played On.
66
1. AIDS may be the ultimate killer, yet no one has ever actually died from
it. How can this be true?
2. Based on what weve learned about how humans acquire animal

diseases, how would the rapid growth of biomedical research during the
1940s and 1950s have increased the odds of the emergence of a disease
like AIDS?
67
The Deadly Strategy of AIDS

Lecture 17
By attacking the immune system, AIDS gets a double bonus. The HIV
virus itself is protected, and other invading microbes stimulate TH cell
production, giving the virus more cells to attack. At the moment, there
is little hope for a vaccine against HIV or a cure for AIDS; we need to
focus on prevention.
s evolutionary strategies go, HIVs is a clear winnerand an

ironic one. Macrophages carry fragments of the virus to our lymph
nodes and present them to the TH cells, leading them to their doom.
Infected macrophages can live for years, carrying the virus to every system
in the body. The more our bodies try to ght HIV, the sicker we get.
Lecture 17: The Deadly Strategy of AIDS
This systematic destruction of TH cells cripples the victims immune system.

HIV can destroy 1 to 2 billion TH cells every dayroughly 30 percent of the
bodys supply. Even a trivial infection could become fatal because there is no
longer any way to ght back.
As if this werent bad enough, opportunistic microbes have coevolved
to take advantage of HIVs assault on the immune system. There is a real
danger that these strains might spread to the general population. But the true
nightmare scenario is HIV becoming airborne. Since HIV can mutate up
to 1 million times faster than a standard DNA virus, anything is possible.
There is a long latency between HIV infection and the appearance of AIDS
symptomssometimes as long as a decadeso theres plenty of time for the
virus to mutate within an individual. The more people infected with HIV, the
greater the odds of an aerosol mutation become.
That said, even in the worst-case scenario, not everyone on Earth would die.
A small handful of individuals can carry the HIV virus but arent infected
by itthey never develop AIDS. These individuals have a mutation that left
their cells with a deformed or missing fusin coreceptor, so HIV cant get
a grip on the surface of their cells to get inside. A handful of HIV-positive
individuals are long-term nonprogressorspeople with no symptoms 10
68
or more years after infection. These individuals are still losing TH cells,
though at a much slower pace.
The AIDS pandemic is increasing at an astounding rate. Over 33 million
people worldwide are infected, with over 25 million deaths so far. There
are about 1.5 million AIDS victims in North America, 2.25 million in
South America, and 22.4 million in sub-Saharan Africa. Worldwide, there
were 7400 new cases of AIDS every day in 2008; 1200 of those new cases
were in children under the age of 15. Over 2 million children worldwide are
currently living with AIDS. Nearly
half of the newly diagnosed cases
in 2008 were in womenso much
A small handful of individuals
for the gay plague.
can carry the HIV virus but
arent infected by itthey
never develop AIDS.
One of the reasons AIDS is raging

through Africa today is that
HIV is riding on the coattails of
malaria, which stimulates TH cell
production. Another reason that the virus is ourishing in Asia and in Africa
is social unrest. In the wake of war, anarchy, famine, and civil strife, social
fabrics unravel. Casual sex with multiple partners becomes much more
common, as does sharing of hypodermic needles, both of which rapidly
spread the virus.
We ght AIDS with a wide variety of drugs. The current best drug is
azidothymidine (AZT), which slows viral reproduction but doesnt kill the
virus. The gold standard of AIDS therapy today is highly active antiretroviral
therapy (HAART), a drug that combines a reverse transcriptase inhibitor
with a protease inhibitor. However, HAART costs approximately $10,000
per year and is out of reach for most of the worlds victims. The newest
drugs are fusion inhibitors, which bind to HIVs fusion proteins and stop
the virus from attaching itself to cell surfaces. But fusion inhibitors have to
be injected twice a day and cost around $25,000 a year per patient.
Why dont we have an AIDS vaccine? Vaccines work by challenging the
immune system with a small dose of fragmented or dead microbe. Because
HIV only needs one active virus to get started, nobody wants to take a
69
chance, even with a dead virus vaccine, because one live virus could slip
through. Attempts to make HIV vaccines based on viral fragments, or
epitopes, have so far been unsuccessful. Scientists are researching the use
of a DNA vaccine to enhance the ability of TC cells to kill HIV. Others are
looking at some newly discovered antibodies from AIDS victims that seem
effective against 90 percent of all known HIV strains and variants.
Our best hope to stem the AIDS pandemic is to change human behavior.
The virulence of AIDS changes with changes in the frequency of sexual
contact. In a population with high monogamy and low promiscuity rates,
a sexually transmitted diseases best strategy is to mutate into a strain that
keeps the host alive as long as possible to wait out a new contact. A less
virulent strainHIV-2is already circulating in West Africa. Reducing the
frequency of unprotected sexual contacts should help nudge AIDS toward
more benign strains. Distributing free condoms and free sterile needles
would go a long way toward slowing down the AIDS pandemic.
Important Terms
Lecture 17: The Deadly Strategy of AIDS
fusion inhibitor: A type of AIDS drug that prevents HIV from fusing with
the surface of a cell to inject its contents.
long-term nonprogressor: An HIV-positive individual who has avoided
developing the symptoms of AIDS for 10 years or more.
Suggested Reading
Barnett and Whiteside, AIDS in the Twenty-First Century.
Epstein, The Invisible Cure.
Levenson, The Secret Epidemic.
70
1. Why was it already too late to stop the AIDS epidemic when the
rst cases were recognized? What factors helped to prolong the
delayed response?
2. Why are vaccines based on dead viruses so much more dangerous than a
vaccine based on viral fragments?
71
AutoimmunitySelf versus Self

Lecture 18
The immune system can be a fair-weather friend. When things are

going well, we arent even aware of all the microbial bullets that were
dodging until we the system fumbles and we get hit. In autoimmune
diseases, however, the immune system turns on us, attacking our own
cells as if we were our own enemy.
The whole idea of autoimmune disease might seem a little strange. Why
hasnt natural selection weeded out those individuals whose immune
systems cant make that critical distinction? In fact, autoimmunity isnt
entirely a bad thing. Self-reactive B cells can be found throughout the blood
in small numbers. Its as if the immune system needs to constantly challenge
itself in order to stay sharp.
However, a little challenge
can go a very long way.
Self-reactive cells are like
ticking time bombs in the
immune system.
A critical period for learning
self versus nonself occurs
very early in embryonic
development. Every fetus
is the product of 2 parents,
which means every fetus
has both parents antigens
on every cell, so the fetus
72
Lecture 18: AutoimmunitySelf versus Self
he acceptance of self, the bodys own tissues, is called immunological

self-tolerance. Usually, our bodies do a pretty good job of learning
friend and foe. But sometimes this self-learning mechanism breaks
down; then our friendly guard dog changes into a rabid beast, causing
diseases like rheumatoid arthritis, multiple sclerosis, lupus, myasthenia
gravis, and type 1 diabetes.
In rheumatoid arthritis, the body fails to

recognize its own cells and attacks itself.
must tolerate both sets. Mothers have to acquire maternal-fetal tolerance

so the fetus isnt attacked in the womb as an invader, possibly causing
a miscarriage.
Its not enough to nip those self-reactive cells in the bud while were still
babies; adaptive immunity is a lifelong learning process. The immune
system has to police every new generation of T cells as we grow. The bone
marrow and thymus winnow out selfreactive and nonreactive B and T cells,
There are genetic
respectively, before they are released
into the body.
predispositions and
environmental triggers
to certain autoimmune
diseases, but the details are
very poorly understood.
When self-tolerance fails and the

immune system reacts to its own
antigens, we may be witnessing the
strategy of an agent provocateura
microbe provoking the immune
system into triggering an autoimmune
response. Common microbes that can cause an autoimmune response
include those of the genera Syphilis, Chlamydia, Salmonella, Shigella,
Staphylococcus, and Borrelia.
Molecular mimicry may be the missing link between microbial infection
and autoimmune diseases. A bacterial antigen could be similar enough to one
of our own that the immune system attacks both microbe and body cells.
Even after the microbe is gone, the self-reactive cells may continue to attack
us. Molecular mimicry is the main, although not the only, suspect in multiple
sclerosis and rheumatoid arthritis.
Is molecular mimicry the result of a shared cellular heritage, or is it a clever
strategy evolved by microbes? We just dont know. There are so many
different kinds of autoimmune diseases that its hard to nd any patterns. We
know, for example, that there are genetic predispositions and environmental
triggers to certain autoimmune diseases, but the details are very poorly
understood. We also know that 75 percent of people with autoimmune
diseases are female, so we assume there is a hormonal connection as well.
73
One recently discovered common thread is the superantigen (SAg). SAgs

are antigens that activate many different kinds of T cells. A normal antigen
will activate 1 in 10,000 to 1 in 1,000,000 T cells; a SAg will activate 1 in
50. Unfortunately, they also seem to reactivate the silenced clones of selfreactive cells, ooding the body with cells that are self-reactive to many
different tissues. This would explain why some autoimmune diseases can
affect so many different parts of the body at the same time.
The damage done in lupus, rheumatoid arthritis, and some other autoimmune
diseases is done by the accumulation of the immune complexa cluster
of interlocked antibodies and antigens. Macrophages usually eat these
byproducts, but in autoimmune disease, the macrophages cant keep up
because the supply is essentially unlimited, so they remain in the body,
causing tissue damage. The causes of other autoimmune diseases are even
more mysterious; many genetic and environmental factors may be involved.
Lecture 18: AutoimmunitySelf versus Self
There are no treatments for most autoimmune diseases, though a wide

variety of immunosuppressants and anti-inammatory drugs are commonly
prescribed. For most autoimmune diseases, all we can do is try to treat
the symptoms.
Important Terms
autoimmune disease: The failure of the immune system to properly
distinguish self from nonself, causing the immune system to attack the
bodys own cells and tissues.
molecular mimicry: The similarity between epitopes in our cells and those
in various microbes, probably resulting from a shared genetic heritage; these
similarities may be exploited as a microbial strategy.
self-tolerance: The immune systems tolerance for the bodys own cells.
self-reactive cell: An immune system cell that reacts to the bodys own cells
as if they were foreign.
74
Suggested Reading
Albert and Inman, Molecular Mimicry and Autoimmunity.
Fehervari and Sakaguchi, Peacekeepers of the Immune System.
Lagerkvist, Pioneers of Microbiology and the Nobel Prize.
1. Why do we keep the same relative risk of getting multiple sclerosis that
we had when we were a child if we move to a region where the risk is
different?
2. What could explain molecular mimicryan unfortunate resemblance

between body cell epitopes and viral or bacterial epitopesother than
sheer (and improbable) coincidence?
75
Allergies and Asthma

Lecture 19
Allergies and asthma are immune system overreactions to harmless

foreign substances. For some, they are a seasonal nuisance; for others,
they can be life threatening. The culprit is immunoglobulin Ean
antibody that lives in mucus membranes and can cause local or bodywide inammation.
he word allergy comes from the Greek allos (other) and ergon
(work or action). In medical terms, refers to hypersensitivity to
any foreign substance to which most people dont react, called an
allergen. When the term was coined in 1906 by Dr. Clemens von Pirquet,
allergies were rare, almost fashionablea rich persons disorder.
Lecture 19: Allergies and Asthma
Immunology was a brand-new eld in Pirquets day. His contemporaries

Paul Ehrlich and Emil von Behring won the rst Nobel Prize in Medicine
in 1901 for curing diphtheria with blood serumantibody-carrying blood
from which the blood cells and clotting factors have been removed. Some
of their patients developed serum sickness; their immune systems became
hypersensitive to the serumthat is, they developed an allergy to it.
People who suffer from allergies are called atopic. Atopy is hereditary. If
either parent is atopic, you have a 25 percent greater risk of being atopic
yourself. If both parents are atopic, your risk goes up to 50 percent. Some
5060 million Americans suffer from allergies; about 1 in 5 in the developed
world have allergies.
For many people, allergies are a serious medical problem, requiring
regular injections and avoidance of certain foods, objects, or environments.
An allergen with a mild effect on one person could be fatal to another.
Anaphylaxis, a whole-body inammatory reaction, is the most severe form
of allergic reaction. Symptoms can include respiratory problems, vomiting,
diarrhea, hives, and loss of bladder control. Blood pressure drops so quickly
that victims sometimes slip into shock and die.
76
Desensitization
depends
on
2
antibodies:
immunoglobulin G (IgG)
and
immunoglobulin
E (IgE). IgG makes up
roughly 7580 percent of
all antibodies in circulation
at any one time; they ght
viruses and bacteria. IgE Asthma may be a disease of civilization. The
immune system overreacts to minor threats
antibodies are found in the because it has too few major ones to combat.
skin, mucous membranes,
and lungs; theyre best
at handling allergens like pollen, fungal spores, or parasitic worms. Small
doses of IgG provoke a low-level immune response, and continued doses
can gradually override the more hypersensitive IgE response.
There is relatively little IgE in the body compared to the IgGroughly
a ratio of 1 to 100,000but this tiny amount of IgE can do an incredible
amount of damage. IgE stimulates mast cells to release histamine, triggering
an inammatory response, leading to itching, a runny nose, and so forth.
Allergies are on the increase worldwide; one theory behind this is our
lifestyle in the developed world, living in airtight homes lled with objects
that retain allergens, like upholstered furniture, carpets, drapes, bedding,
mattresses, and stuffed animals. Surrounded by allergens from an early
77
Tom Le Goff/Digital Vision/Thinkstock.
In anaphylaxis, the rst contact with the allergen causes a reaction. This socalled sensitizing dose causes the immune system to overreact if it encounters
that same allergen later onthe shocking dose. Researchers are experimenting
with exposing bee venom
sensitive to increasingly
large amounts of bee venom
and reduced the chance of
shock to 2 percent after 3 to
5 years of regular treatment.
This type of therapy is
called desensitization.
age, we become sensitized. This so-called hygiene hypothesis is still a bit

controversial, but there are interesting statistics behind it.
Asthmatics have unusually high levels of IgE in their blood and are
hypersensitive to common allergens, stress, and exercise. During an asthma
attack, airways become tightly constricted, causing wheezing. Severe attacks
can require hospitalization and can even be fatal. Like allergies, asthma
diagnoses have risen over the past several decades. The incidence of asthma
and allergies may continue to increase in the near future due to rising levels
of carbon dioxide in the atmosphere.
The current approach to treating allergies and asthma is almost entirely
pharmaceutical; theres little emphasis on environmental intervention
and control, although that approach might offer more hope. Asthma in
particular may be a disease of civilization. Individuals with heavy loads
of parasitic wormswhich we think IgE evolved to combatrarely get
asthma. IgE may be overreacting to various allergens because it has no
worms to combat.
Important Terms
allergen: Any environmental substance that provokes an allergic reaction.
Lecture 19: Allergies and Asthma
allergy: Hypersensitivity to a foreign substance to which most people do not

react.
anaphylaxis: A severe type 1 hypersensitivity reaction; it can lead to
anaphylactic shock, in which widespread leakage in ne blood vessels
results in a rapid drop in blood pressure and a critical condition.
atopy: Susceptibility to allergies.
histamine: An inammatory cytokine produced by mast cells and cells
called basophils that causes capillaries (tiny blood vessels) to dilate, which
in turn increases blood ow and lets lymphocytes and defensive proteins get
to the site of the injury. As a result, the injured area becomes red and swollen
and feels warm to the touch.
78
IgE and IgG: Two immunoglobulins (Ig) that lie at the heart of the allergic
reaction. IgG antibodies, which make up about 7580 percent of the
antibodies in circulation, are good for ghting viruses and bacteria, and IgE
antibodies, found in skin, mucous membranes, and the lungs, are best at
handling allergens like pollen, fungal spores, and parasitic worms.
Suggested Reading
Adams, The Asthma Sourcebook.
Jackson, Allergy.
1. Is raising children in clean and airtight houses in articial urban
environments a good idea from the standpoint of the immune system?
2. Why does our immune system overreact to such an extreme when we

experience a bad attack of asthma?
79
Microbes as Weapons
Lecture 20
Biological and biochemical warfare are as old as human conict. What

humans lack in natural weaponsno fangs, no claws, no venom
weve made up for by using our intellect to imitate the adaptations of
all the other predators.
nimals ght with horns, hooves, tooth, and claw; Plants ght quieter
battles, as do fungi and bacteria, using exotic chemical compounds
to stop an enemy in its tracks. Humans dont have sharp fangs nor
slashing claws, but we can forge knives and swords. We cant secrete venom
but can borrow venom from other animals.
Lecture 20: Microbes as Weapons
We know that the use of animal venom as a weapon goes back at least as
far as classical Greece. Homer describes warriors using poisoned spears and
arrows in his epic poems. In legend, Hercules used the Hydras venom to
poison arrows to slay the centaur Nessus; later, that same poison was used
Just as animals constantly struggle against each other for dominance, so

humans have adopted the tools of animals to ght each other.
80
to kill Hercules. Hannibal, the Carthaginian general, bombarded his enemy

with clay pots full of poisonous snakes; meanwhile, the Romans did the
same to their enemies with beehives.
Centuries before we had any inkling of the existence of microscopic
creatures, we were using them in combat. The rst known use of germ
warfare occurred during the Anatolian War, around 13201318 B.C., when
the Hittites drove sheep and donkeys infected with tularemia into enemy
territory. Some 3000 years later, the Black Death entered Europe in a similar
way. Turkish mercenaries besieging the Genoese army in the Crimean city
of Caffa (modern-day Feodosiya) used catapults to launch plague-infected
corpses into the city until the defenders sickened and died. The surviving
Genoese soldiers scattered to ports all across the Mediterranean, bringing the
Black Death with them.
The very rst act of native-versus-colonist biological warfare in the New
World may have been committed by a group of Iroquois. In the early 1700s,
an angry tribe threw animal pelts into a stream used for drinking water by
English troops, killing over 1000 soldiers. We know the British deliberately
distributed smallpox-infected blankets to Native American tribes during the
colonial era; the British may also have used smallpox against colonial troops
and civilians during the American Revolution.
Smallpox was widespread in urbanized Europe; virtually everybody was
exposed at an early age and developed immunity. Colonial America was
comparatively rural and its populations isolated; many people had never
been exposed to the disease. As rumors of British germ warfare tactics
arose, George Washington decided to inoculate incoming recruits to the
Continental Army; despite his caution, at one point about a third of his army
was down with smallpox or with the inoculation. This tiny little virus nearly
cost us the Revolutionary War; an outbreak certainly cost us the Battle of
Quebec in December 1775 when the British commander, Sir Guy Carleton,
used the germ against the colonial troops.
These crude tactics of our ancestors pale before our modern-day ability
to cultivate the deadliest microbes on the planet. In World War I, gas
was the preferred biological weapon: Gas attacks by the Germans caused
81
Lecture 20: Microbes as Weapons
91,000 Allied casualties and an unknown number of German casualties

from Allied counterattacks. The Germans also employed a limited
form of biological warfare in World War I, cultivating anthrax and a
cattle disease called glanders, which a German spy named Dr. Anton
Casimir Dilger brought to Washington DC in 1915 in an unsuccessful
attempt to destroy Americas horse
population. The Nazis ran a secret
germ warfare program in World
These crude tactics of
War II, experimenting with malaria,
our ancestors pale before
hepatitis A, and Rickettsia bacteria.
our modern-day ability
The use of chemical and biological
to cultivate the deadliest
weapons was outlawed by the Geneva
microbes on the planet.
Protocol of 1925, but possession
and research remained legal, so this
provision was essentially toothless.
Whats more, the Geneva Protocol arguably started our modern biological
arms race. It gave a Japanese microbiologist named Shiro Ishii the idea that
biological weapons might actually be both feasible and very powerful. Ishii
became the mastermind behind the Japanese biological weapons program.
His tool kit included cholera, typhus, dysentery, salmonella, typhoid fever,
botulin toxin, gangrene, smallpox, tuberculosis, and anthrax. The death toll
from Ishiis experiments and attacks is estimated at over 400,000 people.
For many reasons, anthrax has been a perennial favorite in every nations
biological arsenal and has been recently adopted as a tool of bioterrorism.
Caused by the bacterium Bacillus anthracis, its symptoms begin with a
cough and progress to shortness of breath, high fever, convulsions, bleeding
from bodily orices, and a rapid and painful death within 1224 hours of
exposure. What is more, anthrax spores can remain viable for up to 4080
years in soil, allowing anthrax to be highly virulent.
The U.S. chemical and germ program ofcially began in 1942 under the
auspices of the Chemical Warfare Service (CWS), later called the Army
Chemical Corps, but several sources allege that clandestine biowarfare
research was already well underway in 1941. The program was centered at
Fort Detrick, the Army Medical Research Institute of Infectious Diseases,
82
where it is still located today. Britain and Canada later joined the program. In
1942, the British military used Gruinard Island, off the coast of Scotland, to
test anthrax; it devastated the tiny island and even crossed to the mainland. It
took 47 years to clean up the mess.
Important Term
inoculation: Introduction of a serum or vaccine into the body of an animal.
Suggested Reading
Harris, Factories of Death.
Koenig, The Fourth Horseman.
Mayor, Greek Fire, Poison Arrows, and Scorpion Bombs.
1. Does Lord Amherst really deserve the blame for the incident in which
native Americans were given blankets infected with smallpox?
2. Are we ever justied in developing biological weapons, even as a

deterrent?
83
Pandoras Box
Lecture 21
Following World War II, the United States and the Soviet Union
launched massive germ warfare research programs; today, both nations
and non-state militants have access to deadly microbial weapons.
This threat raises many questions, from the practical (What can we
do to prepare for biological attacks?) to the ethical (Is it right to arm
ourselves with bioweapons?).
s weve seen, biowarfare is probably as ancient as warfare itself.

Theres no better example of this than the 2002 decision of Indias
defense ministry to perform modern research on the substances
described in the ancient Indian text Arthashastra. Some of these formulas
are said to help night vision and ght hunger and fatigue, but it also contains
lists of snake, insect, and plant poisons, including detailed instructions for
their preparation and use.
Lecture 21: Pandoras Box
The American and Soviet germ warfare research programs were among the
worst-kept secrets of the Cold War. Both the Americans and the Russians
developed an anthrax bomb during the war; after, emphasis shifted from
weapons production to researchespecially eld testing. In September
1950, the U. S. Navy bombarded San Francisco with a supposedly harmless
bacteria and measured the bacterias progress through the citys population.
We now know that bacterium, Serratia marcescens, which causes that pink
slime found on bathroom tiles, is harmful, causing low-level infections like
conjunctivitis and urinary tract infections, as well as more serious ones like
meningitis and pneumonia. Nobody knows how many similar attacks were
made on the U.S. population by its own government.
By the late 1960s, both the United States and Soviet Union had stockpiled
several tons of biological weapons. In 1972, a new international treaty
was written to replace the 1925 Geneva Protocol: the Biological Weapons
Convention (BWC). To date, 163 countries have ratied it, although Israel
still refuses to sign. The BWC declared that bacteriological methods
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of warfare must be stopped, because using such weapons would be

repugnant to the conscience of mankind. However, it makes no provision
for inspections; it prefers to rely on the honor system.
It didnt take long for the Soviets to violate the treaty; the head of their
biowarfare program, Dr. Kanatjan Alibekov, defected to the United States
in 1992 and revealed, among other frightening statistics, that the Soviet
program employed 30,000 scientists
and had engineered a strain of plague
that was totally resistant to every For better or worse,
known antibiotic.
microbes dont make
particularly good weapons.
The U.S. military concluded that if
the Russians were violating the treaty, Theyre too unpredictable,
it was all right to do the same. Under too hard to control.
President Ronald Reagan, the federal
government ofcially spent $100
million a year under on developing biological weaponsand thats just what
was on the books. American stockpiles included tularemia, brucellosis, Q
fever, and Venezuelan equine encephalomyelitis. America also stockpiled
plant pathogens to use against crops and weaponized several toxins,
including staphylococcal enterotoxin B, saxitoxin, ricin, and botulinum.
The U.S. Ofce of Technology Assessment reported in 1995 that 17 other
nations were actively engaged in bioweapons research, including Iraq, Iran,
Libya, Syria, North Korea, Taiwan, Israel, Egypt, Vietnam, Laos, Cuba,
Bulgaria, India, South Korea, South Africa, China, and Russia. Among
modern nations, the United States, Russia, and Iraq have had the most
ambitious and well-developed programs.
For better or worse, microbes dont make particularly good weapons. Theyre
too unpredictable, too hard to control. Neither side wants to be the rst to
use them for fear of reprisal; theyre only effective in the hands of someone
who has nothing to lose. In that sense, biological weapons are custom made
for terrorists. They spread chaos, fear, and death, and they provide the most
bang for the buck; microbes are cheap compared to nuclear and chemical
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weapons and dont require elaborate missile systems to disperse, just access
to your enemys air and water.
There are many ways to tamper weaponize microbes, even with common,
normally harmless bacteria like Escherichia coli. You could try to create
an MDR strain, to alter its surface structure, to increase its growth rate,
reproductive rate, or virulence, or the amount or the potency of the toxin that
it can produce. But your weapons effectiveness will still depend on many
random factors: weather, wind speed, humidity, dispersal location, and so on.
Bioweapons are the last resort of the desperate and the foolish. The bad news
is there are a lot of desperate and foolish people out there. Bioterrorism
has become a constant threat. During the past century, there have been at
least 52 cases where biological weapons were sought, obtained, or used by
bioterrorists, with almost 1000 victims and 9 deaths.
What can we do to prepare for bioweapon attacks? Surveillance and arrests
are not enough. Mandatory vaccinations may be required, which, in the
United States at least, may not go over well with the populace. Bioweapons
also pose a moral dilemma: Whether we continue to develop these weapons
or not, other nations and groups will. Does this make it right to arm ourselves
with these same horrible weapons?
Lecture 21: Pandoras Box
Important Terms
Biological Weapons Convention (BWC): A 1975 agreement extending
from the 1925 Geneva Protocol that bans the production and stockpiling of
biological agents for use as weapons.
bioterrorism: The use of biological weapons in terrorist activities.
weaponize: To convert or prepare a biological agent for use in warfare.
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Suggested Reading
Cole, Clouds of Secrecy.
Mangold and Goldberg, Plague Wars.
1. If all organisms have a right to life, should we prevent the extinction of
species like the polio virus or the smallpox virus?
2. What aspects of microorganisms makes them less than ideal as weapons?
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Old World to New

Lecture 22
Columbus, de Soto, and Corts carried deadly Old World microbes to

the New World, bringing about the destruction of some of the greatest
civilizations this world has ever known. It wasnt just the guns, armor,
and horses that defeated the Native Americans; Europeans were able to
conquer the Americas because of the microbes they brought with them.
hile the Columbian Exchange brought many American crops to

the Old World, such as tomatoes and chocolate, as far as diseases
go it was a very one-sided affair. Why didnt European explorers
bring devastating virgin soil epidemics back from the New World? Part of
the answer may lie in the domestication of animals.
Lecture 22: Old World to New
Many of our worst Old World epidemic diseases came from domestic
animals, but the New World had relatively few species that could be
domesticated. Most of the large animals in North and South America were
wiped out by the end of the Pleistocene, some 12,000 years ago. Paul Martin,
a prominent geoscientist, claimed that this extinction event was due to the
rst organized human hunting.
The most abundant large New World mammal was the buffalothe
American bison. Buffalo were so abundant, you didnt need to domesticate
them. If you wanted one, you just went out back and got one. The only New
World animals available for domestication were llamas, alpacas, guinea pigs,
turkeys, Muscovy ducks, and dogs. None of these animals were kept in large
numbers and none were used for milk.
The Old World had much greater diversity of animals for domestication,
as well as a much larger land area, than the New World. Our large herds
of cattle and ocks of poultry became giant incubators for new strains.
Century after century of constant and intimate contact with animals gave
these microbes ample opportunity to jump from cattle or poultry to humans.
Among the diseases that made the leap are measles, tuberculosis, inuenza,
whooping cough, and malaria.
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Agriculture turned out to be a microbial bonanza in the Old World, too. It

provided microbes with new habitats, new dispersal routes, and new hosts.
Meanwhile, it allowed us to build up dense urban populations, which made
us sitting ducks for crowd diseases like u and smallpox.
The rst waves of colonists

brought with them at least
partial immunity to smallpox
from centuries of exposure
in Europe. But as time went
on, more nave populations
emerged,
especially
in Buffalo were so abundant in pre-Columbian
America that they were easy to hunt; thus the
isolated rural areas, where natives had no need to domesticate them.
crowd diseases quickly
reach a dead end. Then, as American settlements grew larger, they reached
a critical mass where smallpox and similar diseases could return in waves.
One of the unsung heroes of the colonial smallpox epidemics was Cotton
Mather. Most people know him as the stern and implacable inquisitor
of the colonial witch trials; however, he was also a well-respected
scholar and a member of the Royal Society of London. Mather had heard
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Thinkstock/Comstock/Thinkstock.
None of these Old World diseases existed in the New World. Native
Americans were a nave population, and many virgin soil epidemics
swept
through
the
population:
smallpox,
measles, tuberculosis, u,
typhus, malaria, diphtheria,
mumps,
yellow
fever,
and plague. The New
World population, estimated
at roughly 20 million at
the time of European
contact, declined by more
than 90 percent during
the
century
following
Columbuss voyage.
about inoculation in 1706 from a slave who had received it as a child in

Africa. Mather became a champion of inoculation in the colonies and
experimented successfully with variolation, which uses live smallpox
virus, in several patients.
Smallpox is caused by the Variola virus, a DNA virus and one of the
largest viruses known. Its a member of the Orthopox family, which
includes smallpox, cowpox, camelpox, gerbilpox, and monkeypox. It
spreads via aerosol dispersal, entering a new host through the nose or
mouth. The rst symptoms appear
in about 1012 dayshigh fever,
intense headaches, and backaches, As American settlements grew
followed by a characteristic rash. larger, they reached a critical
The fatality rate ranges between 1
mass where smallpox and
and 30 percent; there is no effective
treatment once the rst full-blown similar diseases could return
symptoms appear. You either in waves.
survive or you die.
Lecture 22: Old World to New
Despite its historic ravages, smallpox turned out to be relatively easy to

control. Victims are highly infective, but for only about a week after the
onset of the rash. Smallpox requires close exposure to spread, so quarantine
in the early stages is very highly effective. Its a very stable virus, unlike the
u virus, which makes it much easier to eliminate by a simple vaccination.
This stability might also explain why it never has coevolved into a more
benign strain.
Mathers variolation could prevent smallpox, but it was dangerous. It fell
to a British country doctor named Edward Jenner to develop the rst safe
vaccine in 1796. His inoculation was made from pus from a milkmaids
cowpox sorescowpox being a nondeadly infection in humans that
conferred immunity to its cousin smallpox. The word vaccination, in
fact, comes from the Latin vacca, meaning cow, for this reason.
Thanks to Jenner, smallpox is no longer the scourge of civilization. A series
of global initiatives begun in the 1950s by the United Nations World Health
Organization ofcially eradicated smallpox in December 1979. This was the
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rst time in history that the human race took aim at a single microorganism,
with the sole intent of wiping it out of existence, and won.
Important Terms
Columbian Exchange: The exchange of trade goods, cultures, ideas, crops,
livestock, and diseases between the Old World and the New World following
the voyage of Columbus.
crowd disease: A disease that requires a dense population to sustain itself.
pus: A mixture of dead and dying neutrophils, microbes, and body cells that
forms at the site of an infection.
variolation: Intentionally introducing smallpox into a human body to
provide immunity.
Suggested Reading
Crosby, The Columbian Exchange.
Diamond, Guns, Germs, and Steel.
Martin, Twilight of the Mammoths.
1. Why do we rarely catch diseases directly from other animals, yet many
of our worst human diseases came from animals?
2. Why was smallpox such a big problem for the American colonists when
so many of their parents and grandparents were born in Europe, where
immunity to smallpox was relatively common?
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Close Encounters of the Microbial Kind

Lecture 23
When we voyage into the nal frontier of outer space, will our bacterial
hitchhikers nd alien races waiting for their deadly microbial sting? Or
will we bring back an alien microbe that will spell doom for the human
race? In fact, microscopic creatures could make our long journey to the
stars possible and help turn our destination into a new Eden.
Lecture 23: Close Encounters of the Microbial Kind
e live our lives surrounded by millions of creatures as alien to us

as we are to an ant. Take the curious case of the bacterium that
wasnt. Bacteria are primitive cells called prokaryotes with rigid
cell walls, no nuclei, and a single loop of DNA, with many of their important
genes carried on plasmids. For many years we thought all prokaryotes
were alike.
Using the new tools of DNA analysis, microbiologist Carl Woese discovered
in the late 1970s that some bacteria werent bacteria at all. He named them
archaebacteria, later shortened to archaea, Greek for ancient things.
They were a totally different kind of microscopic life, as distantly related to
bacteria as bacteria are to man.
Archaeans form 1 of the 3 domains of living things: Bacteria, Archaea, and
Eukaryawhich include the plants, animals, fungi, algae, and protozoa.
Were actually more closely related to the archaeans than we are to bacteria.
Theyre like prokaryotic bacteria in their basic morphology and metabolism,
but their genetic control system and protein synthesis mechanism are more
like a eukaryotic cellour cells. They were rst called extremophiles
because they often live in unusual and extreme environments. Now we know
that theyre common and abundant in a wide variety of habitats.
Archaeans ability to cope with the most extreme environments makes them
a model organism for microbial life on an alien planet. But what are the odds
of encountering alien life? If were talking about intelligent life, the odds
may be very small. But if were talking about microbes, the odds are much,
much higher.
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Many people have since abandoned

Millers model in favor of a CO2/
neutral model. Neutral models base
their chemistry on a carbon dioxide, Some scientists argue that life on
Earth may have been seeded by
nitrogen, and water atmosphere, bacteria carried on an asteroid
which is actually a much more from Mars.
probable starting point for Earths
atmosphere, and one that relies on very heavy volcanic activity. Another
alternative hypothesis for the origins of life on earth points out that cosmic
dust clouds are vast synthetic factories for an astonishing array of organic
compounds. The early bombardment of Earth by comets, which may have
been the source of most of our planets water, would also have added large
amounts of organic material to the primordial soup.
Panspermia is the theory that life was seeded on Earth and other planets
from outer space. We think the idea originated with the Greek philosopher
Anaxagoras, although similar ideas are found all the way back in the ancient
Hindu Vedas. Francis Crick, the co-discoverer of DNA, and Leslie Orgel
proposed what they called directed panspermia, the theory that life was
intentionally seeded on Earth and other planets by an intelligent race of
aliens or their robotic probes.
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Digital Vision/Thinkstock.
In 1953, a graduate student named Stanley Miller demonstrated how

easily a random combination of chemicals can almost accidentally form
complex organic molecules. Miller mixed water with methane, ammonia,
and hydrogen, and he passed electric sparks through the mixture to imitate
lightning strikes. Within 2 days, amino acids were forming in the mixture.
The Miller-Urey experiments, as they came to be called, have since
created all 20 amino acids found in
living cells, all 5 nucleotide bases
in DNA and RNA, and fatty acids
the precursors of cell membranes.
Given that the same raw ingredients
of Earths microbes are common
throughout the universe, the MillerUrey experiments greatly increase the
chances of microbial aliens.
We already know that Earths microbes are hardy enough to survive for
long periods of time in outer space, especially if theyre embedded in a
solid object, like a rock or a piece of space equipment. If we are truly the
descendants of alien microbes, then an alien virus or bacterium might be
able to start the ultimate virgin soil
pandemic, possibly bringing about
the end of humanity.
Life on Earth could actually
have begun with the arrival of
A Martian meteorite called

ALH84001, found in Antarcticas
Allan Hills, might contain tiny
microbial fossils, or nanofossils.
Most scientists have dismissed the nanofossils as human contamination, but
NASAs closer examination of the rock in 2009 has reopened the issue. This
new study found evidence that the rock had been exposed to liquid water on
Mars. We may, in fact, be looking at fossils of a microbial life form from
another planet. The rock itself is over 4 billion years old, which raises an
interesting possibility: We might be Martians. Life on Earth could actually
have begun with the arrival of microbes from Mars.
Lecture 23: Close Encounters of the Microbial Kind
microbes from Mars.
Mars seems a dead planet today, but can we bring it back to life? The logical
way to try would be with cyanobacteria, or blue-green algae, the microbe
that invented photosynthesis some 4 billion years ago. Cyanobacteria
created Earths oxygen atmosphere as a waste product, changing the basic
chemistry of the planet to an oxidizing environment. This so-called oxygen
revolution allowed eukaryotic cells, the oxygen-using cells that we are made
from, to replace prokaryotic cells, the cells bacteria and archaeans are made
from, as the dominant organisms on Earth in terms of size and complexity.
Important Terms
archaea (sing. archaean): Primitive prokaryotic cells that share a common
ancestor with members of the domain Eukarya; when capitalized, refers to
one of the 3 taxonomic domains of living things.
cyanobacteria: Formerly called blue-green algae, a diverse group of bacteria
that evolved photosynthesis nearly 3 billion years ago.
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directed panspermia: The theory that life was intentionally seeded on Earth
by an alien race, either directly or through robotic probes.
Eukarya: One of the 3 domains of living things; Eukarya include plants,
animals, fungi, and protists (algae and protozoa).
extremophile: A microorganism (bacterium or archaean) that is adapted to
live in extreme environmental conditions.
oxygen revolution: The creation of the oxygen atmosphere by ancient
cyanobacteria and the many chemical and biological changes that resulted
from this fundamental alteration of planetary chemistry.
panspermia: The theory that life was seeded on Earth from outer space.
photosynthesis: The synthesis of glucose from water and carbon dioxide
through the use of light energy, producing atmospheric oxygen as a
byproduct.
Suggested Reading
Boss, The Crowded Universe.
Cooper, The Search for Life on Mars.
Davies, The Fifth Miracle.
Ward and Brownlee, Rare Earth.
1. What do you think of the theory of panspermia? If you think such a thing
is possible, do think accidental or directed panspermia is more likely?
2. In what ways do extremophiles serve as valuable models for life in outer

space?
95
Microbes as Friends
Lecture 24
By now, you may be thinking microbes are all bad guys. Nothing could
be further from the truth. Bacteria literally created the world we
know today; they continue to make life as we know it both possible
and pleasurable.
nly about 1400 species of the million or so microbes that we know

about are harmful. Imagine a world without good wine or beer, a
world without chocolate, a world without oxygen. We wouldnt
even exist were it not for the microscopic life that preceded us.
Lecture 24: Microbes as Friends
We carry the ghosts of distant bacterial ancestors in our genes, ancestors

who harnessed the power of the Sun, created the worlds rst ecosystem, and
even changed the chemistry of the planet. We might even use them to make
a better tomorrow.
The rst reports from 2010s Deepwater Horizon oil spill horried the
worldthe beautiful Gulf of Mexico, its coastline and islands, all soaked in
oil. Yet by the summer of 2010, much of the damage, at least to the naked
eye, had disappeared. This isnt to the credit of BP and their repeated failures
to cap the well but to hungry bacteria. Dr. Terry Hazen, a microbial ecologist
at the Lawrence Berkeley National Laboratory, found that underwater
microbes were not only gobbling up the oil but doing it much, much faster
than anybody had anticipated.
Cleaning up oil spills is just one of the many ways that bacteria can be
used in bioremediationthat is, using natural organisms to decontaminate
polluted environments. Bacteria are especially good at breaking down human
sewage, industrial toxic waste, and the chlorinated hydrocarbons from which
pesticides are made.
Bacteria can also be used in engineering and industry. For example, many
bacteria and archaeans live in and naturally extract minerals from ores,
including copper, uranium, and gold. Using microorganisms to process
96
ore is not only cheaper than traditional methods; it also does much less
environmental damage. About 25 percent of the worlds copper is currently
obtained through biomining.
When we study bacteria in the lab, we usually study them in a liquid
suspension. But in nature, bacteria more often occur in thin sheets called
biolms. Bacteria in biolms can behave very differently than bacteria in
liquid suspension. For instance, bacteria in biolms may be more resistant
to antibiotics. The study of biolms
is at the cutting edge of modern
microbiology.
Microbes also make the world
a tastier place to live in.
Biolms of cyanobacteria formed

column-like
groupings
called
stromatolites, which led to the
oxygen revolution. The oxygen revolution in turn led to a biological
revolution, because a more efcient type of cell soon evolved to take
advantage of those higher levels of oxygen in the airEukarya. All
higher organisms, including microscopic algae and protozoa, are made of
eukaryotic cells.
Bacteria can be used as targeted and environmentally friendly biological
controls in place of broad spectrum pesticides. Bacillus thuringiensis is
used against caterpillars, and the subspecies B. thuringiensis israelensis is
used to kill black ies, which carry the nematodes whose gut bacteria cause
river blindness (onchocerciasis), which currently affects 37 million people
worldwide. Bacillus popilliae and Bacillus lentimorbus have been used since
the 1940s to control Japanese beetle infestations. A virus is used to kill the
rhinoceros beetles that attack coconut palms throughout the South Pacic.
Microbes also make the world a tastier place to live in. Part of the complex
taste of chocolate is due to the bacterial fermentation of the seeds from which
chocolate is made. Bacterial fermentation also causes the stink in Limburger
cheese, courtesy of Brevibacterium linens, and Propionibacterium
freudenreichii puts the holes in Swiss cheese. Yeast, a microscopic fungus, is
responsible for the primary fermentation of wine and bacteria for malolactic
fermentation, which mellows too-acidic wines.
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Yeast is also used in beer making, and a scientist named Vladimir Baibakov
has discovered that adding Bidobacteria to beer slows down oxidation.
The bacteria absorb traces of detergents and heavy metal from the brewing
process and allow the beer to function as a probiotic. This makes bidobeer
a better-tasting and much healthier brew.
Bacteria could also be used to help protect babies from AIDS. A team at
the University of Madrid recently isolated several species of bacteria in
breast milk that can inhibit infections of HIV-1 up to 55 percent. That study
explains the puzzling fact that breastfed babies do not tend to get AIDS from
their HIV-positive mothers. It remains to be seen whether the bacteria are
effective in isolation or only work as part of breast milk.
Lecture 24: Microbes as Friends
Dr. Dorothy Matthews found that mice fed a common soil bacterium,
Mycobacterium vaccae, complete lab mazes at twice the speed of control
mice and showed signicantly less stress in the testing environment. As it
turns out, these bacteria activate a group of neurons in the brain that secrete
serotonin. Cancer patients treated with the bacteria show much lower
depression scores than the average patient.
The long road of coevolution with our constant microscopic companions has
changed our bodies, our history, and our world. Where the future of men and
microbes is concerned, were only limited by our imagination. I hope this
series of lectures has given you a new perspective on the invisible world that
surrounds us. Solving the mysteries of the microscopic world will not be
easy, but learning more about our microbial partners will make the world our
children inherit a better place to live.
Important Terms
bioremediation: The use of natural organisms to decontaminate polluted
environments.
bidobeer: Beer prepared with bidobacteria, which are a common gut
bacteria that aid in digestion.
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biolm: A thin sheet or mat of bacteria held together by a sticky substance

on their cell walls. Bacteria growing in biolms can behave differently from
those grown in suspension.
biological control: The use of natural organisms and processes instead of
chemical pesticides to control common pest species (for example, using
Thuringen bacteria against caterpillars).
biomining: Exploiting the natural reactions of microorganisms, many of
which leach metals from ores, as a tool for mineral extraction.
environments.
probiotic: A commercial preparation containing benecial bacteria as a
dietary supplement.
stromatolite: A thick, column-shaped mound formed by many layers of
cyanobacteria biolms; a dominant feature of Earth for 100 million years
and its rst true ecosystem.
Suggested Reading
Davidson, Big Fleas Have Little Fleas.
Margulis and Sagan, Microcosmos.
Sachs, Good Germs, Bad Germs.
1. Can you think of some of the ways we teach our children, by word or
action, about the microbial world that might predispose them to consider
all microbes as bad or dangerous?
2. In what 2 fundamental ways do we carry the ghosts of our bacterial

ancestors in our cells?
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Glossary
acidophile: An acid-loving extremophile; specically, bacteria and

archaeans that thrive in extremely acid environments like sulfuric pools and
geysers or acid mine drainage.
activation: The process by which helper T cells can trigger B cells to start
producing antibodies and memory cells. See also cellular immune response
and presentation.
adaptive immunity: A type of immunity evolved by higher animals that
doesnt look for general patterns of shared structure but rather for minute
differences in molecules shared by hosts and microbes. See also innate
immunity.
allele: A variant form of a gene.
allergen: Any environmental substance that provokes an allergic reaction.
allergic reaction: An inammatory response to an allergen, usually
involving itchiness, redness, swelling, hives, or runny nosesymptoms
collectively called type 1 hypersensitivity. See IgE and IgG antibodies.
allergy: Hypersensitivity to a foreign substance to which most people do not
react.
Glossary
anaphylaxis: A severe type 1 hypersensitivity reaction; it can lead to

anaphylactic shock, in which widespread leakage in ne blood vessels
results in a rapid drop in blood pressure and a critical condition.
antibiotic: Any substance that either kills microbes outright or slows down
their population growth.
antibiotic resistance: The evolutionarily acquired ability of microbes to
either neutralize or withstand an antibiotic.
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antibody: A protein that can attach to a corresponding epitope and ag a cell

or molecule for destruction by the immune system. See B cell and plasma
cell.
antigen: A fragment of a cell or protein that can be detected by the immune
system; also, a molecule or cell with an epitope in its structure.
antigen receptors: Molecular binding sites on immune system cells that
correspond to a particular antigen.
antigenic drift: A signicant alteration in the structure of the surface proteins
of a virus, effectively disguising it from the immune system. Usually refers
to inuenza, especially the structure of H spikes and N spikes.
antigenic shift: A dramatic alteration in the structure of the surface proteins
of a virus sufcient to trigger an epidemic.
antigen-presenting cell (APC): Immune system cells that act as messengers
by carrying antigens on their major histocompatability complex to the
corresponding T cells for activation. APCs include macrophages, B cells,
and dendritic cells.
arboreal: Adapted for living in and moving through trees. See also cursorial.
archaea (sing. archaean): Primitive prokaryotic cells that share a common
ancestor with members of the domain Eukarya; when capitalized, refers to
one of the 3 taxonomic domains of living things. See bacteria, domain,
Eukarya.
argument from design: The claim that the order of the natural world could
only have come into existence as a product of divine will and intelligent
design. A central tenet of the modern-day intelligent design and creation
science movements, but actually a very ancient argument.
astrobiology: The study of life beyond the Earth, also known as xenobiology
or exobiology.
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atopy: Susceptibility to allergies.

autoimmune disease: The failure of the immune system to properly
distinguish self from nonself, causing the immune system to attack the
bodys own cells and tissues. See self-tolerance.
B cell: A type of lymphocyte whose function is to produce antibodies for
specic antigens and to form memory cells to guard against any future
encounters with that same antigen. See also plasma cell and T cell.
bacteria (sing. bacterium): Primitive unicellular organisms; when
capitalized, refers to one of the 3 taxonomic domains of living things. See
archaea, domain, Eukarya.
banded iron deposits: Dark layers or stripes in ancient rocks that were
formed by oxygen from early cyanobacteria reacting with iron suspended in
water, with the heavier iron oxides settling out of solution.
benign strain: A species or subspecies of microbe that is less harmful than
competing strains of the same species.
bidobeer: Beer prepared with bidobacteria, which are a common gut
bacteria that aid in digestion. See probiotic.
biolm: A thin sheet or mat of bacteria held together by a sticky substance
on their cell walls. Bacteria growing in biolms can behave differently from
those grown in suspension.
Glossary
biological control: The use of natural organisms and processes instead of

chemical pesticides to control common pest species (for example, using
Thuringen bacteria against caterpillars).
Biological Weapons Convention (BWC): A 1975 agreement extending
from the 1925 Geneva Protocol that bans the production and stockpiling of
biological agents for use as weapons.
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biomining: Exploiting the natural reactions of microorganisms, many of

which leach metals from ores, as a tool for mineral extraction.
environments.
bioterrorism: The use of biological weapons in terrorist activities.
blood type: The presence or absence of the A and B antigens on human
blood cells.
catalyst: A chemical that takes part in or mediates a chemical reaction but
is not altered by that reaction. A small amount of catalyst can catalyze many
chemical reactions, making it invaluable in many industrial processes and in
the control of complex processes like living systems. See enzyme.
cellular immune response: The presentation and activation of T cells in
the immune system. See also humoral immune response and primary
immune response.
cellular immunity: Actions of the immune system that involve macrophages,
killer cells, and the release of cytokines but not antibodies or complement
system proteins.
codon: A series of 3 genetic nucleotides that code for a particular amino
acid. The sequence of codons determines the proper sequence of amino acids
needed to assemble a particular protein.
coevolution: An evolutionary change in one organism that leads to an
evolutionary change in another organism that interacts with it.
Columbian Exchange: The exchange of trade goods, cultures, ideas, crops,
livestock, and diseases between the Old World and the New World following
the voyage of Columbus.
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commensalism: A form of symbiosis in which one partner is helped and the

other is neither helped nor hindered, such as Spanish moss hanging on trees.
See also mutualism and parasitism.
competition: A contest for resources that affects the birth rate or the death
rate of 2 or more competing species. See also interspecic competition,
intraspecic competition, niche overlap, and realized niche.
competitive exclusion: A situation in which one species or population
outcompetes its rival to the point where the rival is locally eliminated.
complement system: A group of about 25 proteins found in blood or other
bodily uids that can build up on the surface of a microbe, starting a cascade
reaction that punctures the microbes cell wall. The complement system has
a variety of other functions, including releasing chemicals to attract other
immune cells and opsonization.
crowd disease: A disease that requires a dense population to sustain itself.
cryophile (a.k.a. psychrophile): A cold-loving extremophile; specically,
bacteria and archaeans that thrive in extremely cold environments like pack
ice and the polar seas.
cursorial: Adapted for moving rapidly over the ground. See also arboreal.
cyanobacteria: Formerly called blue-green algae, a diverse group of bacteria
that evolved photosynthesis nearly 3 billion years ago. See also biolm and
stromatolite.
Glossary
cytokine: A molecule that mediates an interaction between cells. The

immune response relies on many different types of cytokines. See also
histamine, inammatory cell, and mast cell.
cytokine storm: A cascade reaction of defensive proteins that can prove
fatalthe immune systems equivalent of a thermonuclear attack.
104
cytotoxic cell: A type of defensive cell common to all animals that effectively
stabs foreign cells to death by punching holes through their cell walls.
Darwinian medicine (a.k.a. evolutionary medicine): The consideration
of traditional medical problems from an ecological and evolutionary
perspective, focused on the coevolution of humans and pathogens.
dendritic cell: A type of lymphocyte in mammals that functions as an
antigen-presenting cell, helping to bridge the gap between the innate and
adaptive immune systems.
density-dependent limiting factor: A limiting factor whose effects are
directly proportional to the density of a population, such as predation or
disease.
density-independent limiting factor: A limiting factor whose effects are
not proportional to population density, like bad weather or natural disasters.
diffusion: The movement of atoms and molecules from an area of higher
concentration to an area of lower concentration.
directed panspermia: The theory that life was intentionally seeded on
Earth by an alien race, either directly or through robotic probes. See also
panspermia.
disturbance: Any force or factor that perturbs the normal functioning of an
ecosystem.
DNA: Two strands of complementary nucleotides attached to a molecular
backbone of sugar and phosphate molecules. The sequence of nucleotides
codes for the synthesis of proteins. See also RNA.
DNA vaccine: Plasmids that code for a critical protein in the life cycle of a
particular microbe.
domain: The highest level of biological classication. See archaea,
bacteria, and Eukarya.
105
Drake equation: An equation proposed by astrophysicist Frank Drake

that represents the number of alien civilizations in the galaxy that could
communicate with us.
durability: The microbial strategy of persistence and dormancy for the longterm possibility of infection.
ecosystem: All of the biological communities in a given area, together with
their physical habitat.
enzyme: A protein that can act as a chemical catalyst, mediating a reaction
without being changed by it. Enzymes control the rate, direction, synthesis,
and degradation of many biochemical reactions in the body. Most of what
our genes actually code for are different kinds of enzymes.
epidemic: An outbreak of disease that exceeds the expected norm, usually
applied to an infectious disease that appears suddenly and moves rapidly
through a population. See also pandemic.
epidemiologic cycle: The demographic pattern of infection or mortality over
time in a given population.
epitope: A fragment of protein from a cell or molecule that can be detected
by the immune system. See also antigen.
Eukarya: One of the 3 domains of living things; Eukarya include plants,
animals, fungi, and protists (algae and protozoa). See also archaea and
bacteria.
Glossary
eukaryote: A relatively advanced cell type characteristic of members of

the domain Eukarya, with a cell nucleus and several cellular organelles
constructed from membranes, such as mitochondria and chloroplasts. See
also prokaryote.
evolution: A change in gene frequency over time; descent with modication
from a common ancestor.
106
evolutionary arms race: The coevolution of 2 competing organisms, each

of which must constantly adapt to changes in the strategies of the other; a
kind of evolutionary one-upmanship.
extremophile: A microorganism (bacterium or archaean) that is adapted to
live in extreme environmental conditions. See also acidophile, cryophile,
halophile, and thermophile.
extrinsic limiting factor: A limiting factor that comes from outside the
individual or population, such as sunlight, water, or nutrients. See also
intrinsic limiting factor.
fermentation: An ancient metabolic pathway evolved by cells before the
formation of an oxygen atmosphere. Fermentation produces alcohol as a
byproduct. See respiration.
fundamental niche: The niche an organism occupies in the absence of
competition; also called its theoretical niche. See also realized niche.
fusion inhibitor: A type of AIDS drug that prevents HIV from fusing with
the surface of a cell to inject its contents.
germ theory: The theory that microorganisms were the cause of human
diseases, nally established in the late 19th century. See humors and miasma.
Great Famine: A famine in Europe between 1315 and 1317 that claimed
millions of lives.
halophile: A salt-loving extremophile; specically, bacteria and archaeans
that thrive in extremely saline environments like the Dead Sea.
helper T cell (a.k.a. TH or CD4+ cells): A critical immune system T cell
that, when activated, coordinates a wide range of immune processes through
the secretion of messenger molecules called cytokines. See also killer T cell.
hemoglobin: The protein that binds oxygen to transport it throughout the
circulatory system.
107
herd immunity: A complete or partial immunity in the surviving population

(the remaining herd) after an epidemic.
histamine: An inammatory cytokine produced by mast cells and cells
called basophils that causes capillaries (tiny blood vessels) to dilate, which
in turn increases blood ow and lets lymphocytes and defensive proteins get
to the site of the injury. As a result, the injured area becomes red and swollen
and feels warm to the touch. See also inammatory cell.
host manipulation: A microbial strategy in which the parasite alters host
behavior in a way that signicantly benets the parasite.
host switching: The transfer of a parasite to a new primary host.
humoral response: Part of the primary immune response; the activation of
B cells by helper T cells to make antibodies (plasma cells) and memory cells.
See also cellular immune response and plasma cell.
humors: Bodily uids whose imbalance was once thought to be the cause
of human diseases. The 4 humors were black bile, yellow bile, phlegm, and
blood. The theory of humors was inspired by the 4 elements of the ancient
Greeks (earth, air, re, and water). See also germ theory and miasma.
hunter-gatherer: A person who leads a nomadic lifestyle, living directly off
the land, with no attempt to cultivate or domesticate food organisms.
Glossary
hypermutability: The tendency of certain organisms, such as the inuenza

virus, to mutate at a relatively high rate. See RNA virus.
IgE and IgG: Two immunoglobulins (Ig) that lie at the heart of the allergic
reaction. IgG antibodies, which make up about 7580 percent of the
antibodies in circulation, are good for ghting viruses and bacteria, and IgE
antibodies, found in skin, mucous membranes, and the lungs, are best at
handling allergens like pollen, fungal spores, and parasitic worms. See also
allergic reaction.
108
immunity: Disease resistance acquired by exposure to a pathogen. The

immune system remembers the encounter by keeping some antibodies
around from each disease it defeats, in case the same pathogen returns. See
adaptive immunity and innate immunity.
incubation period: Period of time between infection and the rst symptoms
of an infection. Sometimes called the latency period, although that term
usually refers to the time between infection and becoming infectious to
others.
inammatory cell: A cell involved in the inammatory response that is
densely packed with granules loaded with potent chemical mediators like
histamine. See also cytokine and mast cell.
innate immunity: A primitive type of immune system common to a wide
variety of animals that gives certain cells the ability to identify foreign cells
by recognizing patterns of sugar molecules in their cell walls. Phaogocytes,
cytotoxic cells, and inammatory cells are components of innate immunity.
See also adaptive immunity.
inoculation: Introduction of a serum or vaccine into the body of an animal.
interstitial habitat: A habitat within and among the grains of soil in
terrestrial or aquatic habitats.
intrinsic limiting factor: A limiting factor that operates from within
the individuals of a population, affecting reproductive physiology or
reproductive behavior. See extrinsic limiting factor.
iron withholding: Adaptive response in which the human body sequesters
or binds iron so that it is not accessible to bacteria, for whom it is a limiting
nutrient.
killer T cells (TC or CD8+ cells): Cytotoxic T cells that are especially good
at killing cells that are cancerous or have been infected with a virus. See
cytotoxic cell and helper T cell.
109
Kochs postulates: A series of steps established by physician Robert Koch

to prove that a particular microbe causes a particular disease.
leukocyte (a.k.a. white blood cell): An immune system cell that helps ght
infectious diseases or foreign proteins. The presence and number of these
cells is often used in the diagnosis of disease. White blood cell types include
neutrophils, dendritic cells, lymphocytes, and macrophages.
limiting factor: Any force or factor that regulates the growth of a natural
population. See density-dependent limiting factor, density-independent
limiting factor, extrinsic limiting factor, and intrinsic limiting factor.
Little Ice Age: A 500-year climate aberration (A.D. 13501850) during
which temperatures in Europe were signicantly colder than normal; the
period was characterized by extreme and intense weather, such as oods and
droughts. See also Medieval Warm Period.
long-term nonprogressor: An HIV-positive individual who has avoided
developing the symptoms of AIDS for 10 years or more.
lymph nodes: Small spherical organs of the immune system where B cells
and T cells are concentrated in large numbers; the immune system equivalent
of a garrison fort.
lymphatic system: A major part of the immune system consisting of a
circulatory network containing a clear uid called lymph, which carries
a wide variety of cells involved in immunity, together with the structures
associated with making and moving lymphocytes.
Glossary
lymphocytes: Cells involved in adaptive immunity. See B cell, natural

killer cell, and T cell.
macrophage: An immune cell common to most animals that eats
pathogens. Macrophages can travel almost anywhere in the body, devour
pathogens, and carry them to the lymph nodes to trigger an immune response.
110
magic bullet: Term coined by the physician Sir Alexander Fleming to refer
to drugs that can target a particular type of bacteria.
mast cell: An inammatory cell that releases the cytokine histamine.
Medieval Warm Period: A climate aberration preceding the Little Ice Age,
during which average temperatures were signicantly higher than normal.
See also Little Ice Age.
memory cell: An activated B cell that is relatively long-lived and can be
rapidly cloned if the same antigen or invader returns. See also plasma cell.
messenger RNA (mRNA): A form of RNA used in the synthesis of proteins
that is assembled by matching complementary nucleotides (A/T, C/G) to
replicate the sequence of nucleotides on a strand of DNA. See also codon,
ribosomal RNA (rRNA), and transfer RNA (tRNA).
methanogens: A group of anaerobic archaeans that generate methane as a
result of their metabolic processes. Found (among other places) as symbionts
in the guts of cows and termites, where they help digest cellulose.
major histocompatability complex (MHC): A receptor site on the outside
of every vertebrate cell that can hold onto an epitope or antigen so that
immune system cells can recognize it. See also antigen-presenting cell
(APC).
miasma: A noxious vapor once believed to be the cause of human disease.
See germ theory and humors.
microbe: Any organism small enough to require a microscope to clearly see
it.
molecular mimicry: The similarity between epitopes in our cells and those
in various microbes, probably resulting from a shared genetic heritage; these
similarities may be exploited as a microbial strategy.
111
mutation: A random alteration of genetic information that can occur in RNA

or DNA.
mutualism: A form of symbiosis in which both partners are helped by
the relationship (the traditional meaning of symbiosis), such as a lichen, a
fungus cooperating with a green algae or cyanobacteria. See commensalism
and parasitism.
myelin sheath: A sheath insulating the nerves that is essential for the rapid
conduction of nervous signals in vertebrates and is attacked in multiple
sclerosis.
nave population: An isolated population that has not been systematically
exposed to an infectious disease. See virgin soil epidemic.
natural killer cell (NK cell): A cytotoxic cell that seeks out and destroys
cells invaded by microbes; NK cells specialize in attacking cancerous cells
or cells invaded by a virus.
natural killer T cell (NKT cell): A cell that acts like a regular natural killer
cell but can also mediate adaptive immune responses by releasing messenger
chemicals called cytokines.
natural theology: A school of philosophy that seeks to prove the existence
of God through observing the natural world and through the use of human
reason. Natural theologians maintained that the balance of nature and the
exquisite t between form and function were evidence of a divine plan
behind nature.
Glossary
neutrophil: A type of lymphocyte that specializes in attacking bacteria

and fungi. They account for over half of the lymphocytes circulating in our
bodies at any given time. See also pus.
niche: The functional role that an organism plays in an ecosystem; also, the
sum total of a speciess needs and the range of conditions within which it can
survive.
112
niche overlap: The degree to which the needs of 2 competing species

overlap one another, which determines the intensity of the competition
between them.
nitrogen xation: The enzymatic process by which bacteria x atmospheric
nitrogen into ammonium, a form that can be used by plants.
nonequilibrium theory: The idea that certain ecosystems are not harmed by
disturbance but rather thrive on it.
nosocomial infection: A hospital-acquired infection.
nucleotide: A biomolecule whose many important functions include carrying
the genetic code. The 4 nucleotides used in DNA are adenine, guanine,
cytosine, and thymine (abbreviated A, G, C, and T). RNA substitutes uracil
(U) for thymine (T). See codon.
oceanic conveyor belt: The pattern of global ocean currents that redistribute
equatorial heat to the poles.
opsonization: Part of the complement system; a process through which an
invading cell is coated with proteins that help phagocytes bind to them.
oxygen revolution: The creation of the oxygen atmosphere by ancient
cyanobacteria and the many chemical and biological changes that resulted
from this fundamental alteration of planetary chemistry. See photosynthesis
and stromatolite.
pandemic: An epidemic that occurs over a wide geographic area.
panspermia: The theory that life was seeded on Earth from outer space. See
also directed panspermia.
parasitism: A form of symbiosis in which one partner is helped and the
other is harmed. See also commensalism and mutualism.
113
pathogen: The umbrella term for disease-causing organisms, including

bacteria, viruses, ukes, and nematode worms, and so forth.
phagocyte: An amoeboid eating cell found in all types of animals that can
engulf and consume other microbes.
phagocytosis: The process by which cells can engulf materials, and even
other cells, by pinching off a spherical membrane-bound space called a
vesicle or (if relatively large) a vacuole.
photosynthesis: The synthesis of glucose from water and carbon dioxide
through the use of light energy, producing atmospheric oxygen as a
byproduct. See respiration.
pica: A dietary craving for nonfood items such as chalk and dirt; sometimes
a symptom of nematode infection.
plasma cell: B cell that produces large quantities of antibodies when
activated. See also memory cell.
plasmid: Tiny loops of genes freely exchanged between bacteria, often
bearing useful traits.
Pleistocene extinction: A highly selective extinction event about 10,000
12,000 years ago that claimed many species of megafauna, such as
mammoths, mastodons, and saber-toothed cats. It may have been caused by
the rst organized human hunting (the overkill hypothesis).
Glossary
prebiotic synthesis: The synthesis of complex organic compounds and

networks of biochemical reactions prior to the origin of life.
presentation: The action of a macrophage or other antigen-presenting cell
in locating and bringing a foreign antigen to the corresponding T cell for
activation. See cellular immune response.
primary immune response: The cellular (presentation and activation of T
cells) and humoral (B cell activation) immune responses. See also cellular
114
immune response, humoral immune response, and secondary immune

response.
probiotic: A commercial preparation containing benecial bacteria as a
dietary supplement.
professional APC: An antigen-presenting cell that has a special type of
major histocompatability complex called MHC II, which identies traveling
macrophages as messengers, not enemies.
prokaryote: A primitive cell type characteristic of bacteria and archaeans,
with a cell wall and no cell nucleus or cellular organelles made from
membranes (e.g., no chloroplasts or mitochondria). See archaea, bacteria,
and Eukarya.
prophylactic antibiotic: Antibiotics given without a clear indication of
disease as a preventative measure.
protein: A biomolecule constructed from a linear series of amino acids.
Proteins provide biological structure, function, and control.
protein synthesis: The assembly of proteins from amino acids using
information carried by complex forms of RNA. See codon, messenger RNA
(mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA).
pus: A mixture of dead and dying neutrophils, microbes, and body cells that
forms at the site of an infection.
pyrogen: A type of cytokine that triggers a rise in body temperature or fever.
realized niche (a.k.a. actual niche): The niche an organism occupies in the
presence of competition. See also fundamental niche.
Red Queen hypothesis: Theory of biologist Leigh Van Valen that there is an
upper limit to adaptation. The genetic resources of any species are nite, and
because the environment never stops changing, every species will eventually
exhaust its ability to adapt to those changes and will go extinct.
115
resistance: A physiological trait that helps prevent infection by pathogens.

Although often used as synonym for immunity, resistance is a physical
feature that can be directly inherited (like lacking a certain protein on the cell
wall that a virus could use to enter the cell), whereas immunity is a cellular
memory of a disease in the form of stored antibodies. See also immunity.
respiration: At the cellular level, the breakdown of glucose into water and
carbon dioxide by using oxygen that releases stored chemical energy for use
by the cell. See fermentation and photosynthesis.
retrovirus: A virus that uses an enzyme called reverse transcriptase to
convert its RNA into DNA, which is then incorporated into the hosts DNA.
reverse transcriptase: An enzyme used to turn viral RNA into DNA, which
is then stitched into a hosts DNA. This is the reverse of the normal process
of transcription, in which the genetic message contained in a strand of DNA
is copied or transcribed onto a strand of messenger RNA. The enzyme is
used by viruses like HIV and feline leukemia virus. See also retrovirus.
ribosomal RNA (rRNA): A type of RNA that reads a strip of messenger
RNA to allow transfer RNA to identify and fetch the next amino acid coded
for. This in turn allows a ribosome to create a chain from the amino acids
supplied by transfer RNA that will subsequently roll up into a functional
protein. See also codon, DNA, and protein synthesis.
RNA: A single strand of nucleotides attached to a molecular backbone of
sugar and phosphate molecules. The nucleotides code for synthesis of a
particular protein.
Glossary
RNA virus: A virus whose genetic material consists solely of RNA (not
DNA). Because such viruses lack the proofreading mechanism that
governs the reproduction of DNA, they mutate at a very high rate. See
hypermutability and retrovirus.
secondary immune response: The rapid cloning of memory cells and
production of appropriate antibodies in response to a second encounter with
116
a microbe. See activation, B cell, humoral immune response, primary

immune response, and T cell.
self-tolerance: The immune systems tolerance for the bodys own cells. See
also autoimmune disease.
self-reactive cell: An immune system cell that reacts to the bodys own cells
as if they were foreign.
stem cell: A cell produced in both embryos and adults that have the ability to
differentiate into several different types of cells.
stromatolite: A thick, column-shaped mound formed by many layers of
cyanobacteria biolms; a dominant feature of Earth for 100 million years
and its rst true ecosystem. See also oxygen revolution.
subtype: A variant within a genus of viruses.
symbiosis: Literally, life shared together; a long-term biological interaction
between 2 species. See commensalism, mutualism, and parasitism.
T cell: A lymphocyte that plays many key roles in the immune system and
has a receptor on its cell surface that lets it recognize antigens bound to the
major histocompatability complex. Types include cytotoxic T cells, helper T
cells, and natural killer T cells. See also B cell, cytotoxic cell, natural killer
cell, and thymus.
thermophile: A heat-loving extremophile; specically, bacteria and
archaeans that thrive in extremely hot environments like undersea thermal
vents.
thymus: A gland located near the base of the neck that performs several
functions in the immune system, including the ltering of mature T cells
against self-reactivity. See self-reactive cell.
transfer RNA (tRNA): A form of RNA that to transfers amino acids from
the cytoplasm to the ribosomes to be added to a chain of amino acids that
117
will form a protein. It has a binding site on one end that matches up with a
codon on messenger RNA and a binding site for the corresponding amino
acid at the other.
vaccine: A therapeutic technique that introduces foreign antigens into an
animal to help improve immune response to a particular pathogen; usually
made from dead microbes, fragments of dead microbes, or microbial toxins.
See DNA vaccine.
variant: A distinct genetic variant of a virus subtype.
variolation: Intentionally introducing smallpox into a human body to
provide immunity. See vaccine.
vector: Any organism that carries a pathogen.
virgin soil epidemic: An epidemic in a population not previously exposed to
that disease. See nave population.
virulence: The intensity of a particular infectious disease as measured by its
mortality rate.
virus: A microscopic organism consisting of a core of RNA or DNA in a
protein capsule, which can only reproduce by invading a living cell and
using its protein synthesis mechanisms to make and assemble copies of the
virus.
weaponize: To convert or prepare a biological agent for use in warfare. See
also bioterrorism.
Glossary
zoonosis: A disease that pass directly from a vertebrate animal to humans

and back, with no intermediate vector such as an insect.
118
Bibliography
Ackert, James E. Some Inuences of the American Hookworm. American

Midland Naturalist 47, no. 3 (May 1952): 749762. A detailed history of the
Rockefeller Sanitary Commissions hookworm eradication campaign and its
subsequent expansion into an international effort.
Adams, Francis V. The Asthma Sourcebook: Everything You Need to Know.
3rd ed. New York: McGraw-Hill, 2006. In a sea of patent medicine and
self-help guides, its nice to nd a clearly written and authoritative book on
the causes, symptoms, and treatments of asthma. Highly recommended for
asthma sufferers and their families.
Albert, Lori J., and Robert D. Inman. Molecular Mimicry and
Autoimmunity. New England Journal of Medicine 341, no. 27 (December
30, 1999): 20682074. After absorbing the lectures on immunity and
autoimmunity, you will nd this seminal review of molecular mimicry in
autoimmunity to be challenging but informative.
Anonymous. M. Yersin on the Prophylaxis of Plague. The British Medical
Journal 2, no. 2078 (Oct. 27, 1900): 12561257. A turn-of-the-century
interview with Yersin concerning the modern outbreak of the bubonic plague
and his ideas for combating it.
Appleby, Andrew B. Epidemics and Famine in the Little Ice Age. Journal
of Interdisciplinary History 10, no. 4 (Spring 1980): 643663. Examines the
relationship between climate, famine, and outbreaks of epidemic diseases.
Armelagos, George J. Take Two Beers and Call Me in 1,600 Years.
Natural History 109, no. 4 (May 2000): 5053. A delightful article extolling
the therapeutic powers of ancient Egyptian beer based on the discovery of
the antibiotic tetracycline in Egyptian mummies.
119
Averner, M. M., and R. D. MacElroy, eds. On the Habitability of Mars: An

Approach to Planetary Ecosynthesis. U.S. NASA SP-414, 1976. The mother
lode for modern research on terraforming: a detailed NASA study of the
practicality of turning Mars into a new Earth by using cyanobacteria and
similar microorganisms to alter planetary conditions.
Barnaby, Wendy. The Plague Makers: The Secret World of Biological
Warfare. New York: Continuum, 2000. A brief popular introduction to
germ warfare with a survey of known national programs and lots of good
information, but it suffers from sloppy editing and proofreading.
Barnett, Tony, and Alan Whiteside. AIDS in the Twenty-First Century:
Disease and Globalization. 2nd ed. New York: Palgrave Macmillan, 2006.
One of the most important books on the subject of AIDSauthoritative,
comprehensive, and sobering. Considers the social and economic effects
of the disease, especially in Africa, and what can be done to combat it. An
invaluable reference for anyone in business or public affairs.
Barry, John M. The Great Inuenza: The Epic Story of the Deadliest Plague
in History. New York: Viking, 2004. Next to Crosby, the best general
introduction to the u. Scholarly and well written, it tells the story of the
u in part through the lives of the key researchers involved in ghting the
epidemic and includes a detailed account of the origins of our modern system
of medical education.
Bibliography
Beveridge, W. I. B. Inuenza: The Last Great Plague: An Unnished Story

of Discovery. New York: Prodist, 1977. A good short survey of the epidemic,
if a bit dated. Provides a good description of how subtypes and variant forms
of the virus are formed and how they compete with one another to generate
waves of fresh infection during pandemics.
Black, Francis L. Infectious Diseases in Primitive Societies. Science 187,
no. 4176 (February 14, 1975): 515518. Based on an analysis of infectious
diseases in isolated Amazonian tribes, Black concludes that many common
infectious diseases cannot maintain themselves in small, isolated populations
and were therefore not a problem for early man.
120
Blake, John B. The Inoculation Controversy in Boston: 17211722. The

New England Quarterly 25, no. 4 (December 1952): 489506. A good
historical account of the efforts of Cotton Mather and others to inoculate the
citizens of Boston in the face of a smallpox epidemic.
Blakely, D. E. Mass Mediated Disease: A Case Study Analysis of Three Flu
Pandemics and Public Health Policy. Lanham, MD: Lexington Books, 2006.
Examines how contemporary media accounts shaped public perceptions
during the pandemics of 1918 (Spanish u), 1957 (Asian u), and 1968
(Honk Kong u).
Bongaarts, John, Franois Pelletier, and Patrick Gerland. Poverty, Gender,
and Youth: Global Trends in AIDS Mortality. Working Paper no.16,
The Population Council, 2009. One of the best sourcebooks for current
information on the extent of the AIDS pandemic and its pattern of age and
gender distribution. Includes a good current bibliography.
Boss, Alan. The Crowded Universe: The Search for Living Planets. New York:
Basic Books, 2009. Takes you to the front lines of the search for life beyond
the Earth; a well-written and thought-provoking introduction to astrobiology.
Brooks, F. G. Charles Wardell Stiles. Systematic Zoology 13, no. 4 (Dec.
1964): 220226. An excellent and sympathetic biography, with some
entertaining detail on Stiless childhood and school days.
. Charles Wardell Stiles, Intrepid Scientist. BIOS 18, no. 3
(Oct. 1947): 139169. A good portrayal of the young Stiles, showing the
early religious inuences that were to motivate him during the hookworm
campaign, such as the gift for language he acquired from translating the
Bible, which in turn allowed him to study in Germany and at the Pasteur
Institute.
Brown, E. Richard. Rockefeller Medicine Men: Medicine and Capitalism in
America. Berkeley: University of California Press, 1979. Takes the contrary
view to Ettlings thesis in The Germ of Laziness, claiming that the driving
forces behind the hookworm campaign were more political and economic
than social and philanthropic.
121
Bud, Robert. Penicillin: Triumph and Tragedy. New York: Oxford University
Press, 2007. A well-written and authoritative history of the discovery,
application, and importance of penicillin and the evolution of resistant
microbes.
Burney, D. A., and T. F. Flannery. Fifty Millennia of Catastrophic
Extinctions after Human Contact. Trends in Ecology & Evolution 20, no.
7 (July 2005): 395401. Reviews the various theories proposed to explain
the Pleistocene extinction event and concludes that we need to have a deeper
appreciation of the way humans affect ecosystems.
Bushnell, O. A. The Gifts of Civilization: Germs and Genocide in Hawaii.
Honolulu: University of Hawaii Press, 1993. Examines the effect of Captain
Cook and other European explorers and exploiters on the health and
abundance of native Hawaiians, with an excellent bibliography.
Byerly, C. R. Fever of War: The Inuenza Epidemic in the U.S. Army During
World War I. New York: New York University Press, 2005. A scholarly and
in-depth account of the effects of the u both in military camps and on the
front, as well as the conicting roles of medical doctors in wartime. Argues
that the war created the pandemic by giving the virus a new environment in
which to mutate and thrive.
Cassedy, James H. The Germ of Laziness in the South, 19001915: Charles
Wardell Stiles and the Progressive Paradox. Bulletin of the History of
Medicine 45 (1971): 159169. Discusses the contrast between economic and
evangelical motives in the Rockefeller Sanitary Commissions campaign to
eradicate hookworm disease.
Bibliography
Clark, Thomas Dionysius. The Emerging South. 2d ed. New York: Oxford
University Press, 1968. A classic study of the rise of the New South; dated
but still relevant.
Clark, William R. In Defense of Self: How the Immune System Really Works.
New York: Oxford University Press, 2008. An excellent and very readable
introduction to the bewildering complexities of the immune system. Highly
recommended.
122
Cohn, Samuel Kline. The Black Death Transformed: Disease and Culture
in Early Renaissance Europe. New York: Arnold/Oxford University Press,
2002. Takes the controversial view that the Black Death and the bubonic
plague are actually different diseases with distinct differences in their
virulence and epidemiology.
Cole, Leonard A. Clouds of Secrecy: The Armys Germ Warfare Tests over
Populated Areas. Totowa, NJ: Rowman & Littleeld, 1999. A shocking
expos of the secret germ warfare experiments conducted in San Francisco,
the New York City subway system, and elsewhere, including a detailed
account of the lawsuit by Edward Nevin over the death of his grandfather,
the rst ofcial victim of U. S. germ warfare.
Cooper, Henry S. F. The Search for Life on Mars: Evolution of an Idea. New
York: Holt, Rinehart and Winston, 1980. A good contemporary account of
NASAs quest to nd life on Mars, with much insider historical information.
Not in print, but regularly available through Amazon.
Cowdrey, Albert E. This Land, this South: An Environmental History. New
Perspectives on the South. Lexington: University Press of Kentucky, 1983.
An excellent and classic survey of the ways that Southern culture and history
have been shaped by environment.
Crawford, Dorothy. The Invisible Enemy: A Natural History of Viruses. New
York: Oxford University Press, 2000. A well-written introduction to the
world of viruses, including an extensive discussion of viruses and cancer.
Crawford, Dorothy H. Deadly Companions: How Microbes Shaped Our
History. New York: Oxford University Press, 2007. One of the best books in
print on the coevolution of humans and microbes; well-written, absorbing,
and informative, with an excellent bibliography and glossary.
Crosby, Alfred W. Americas Forgotten Pandemic: The Inuenza of 1918.
2nd ed. New York: Cambridge University Press, 2003. Crosby is one of the
most authoritative sources on the u, and his book is an excellent starting
point for further research. Previously published as Epidemic and Peace,
1918 (1976).
123
. The Columbian Exchange: Biological and Cultural Consequences of

1492. Contributions in American Studies. Vol. 2. Westport, CT.: Greenwood,
1972. One of the most signicant scholarly studies of the great exchange of
culture, trade goods, crops, livestock, and diseases from the Old World to the
New in the wake of the voyage of Columbus.
Davey, Basiro, Tim Halliday, and Mark Hirst. Human Biology and Health:
An Evolutionary Approach. Health and Disease Series. 3d ed. Philadelphia,
PA: Open University, 2001. An excellent general textbook of evolutionary
medicine, including several chapters covering basic biology and evolutionary
theory.
Davidson, Elizabeth W. Big Fleas Have Little Fleas: How Discoveries of
Invertebrate Diseases Are Advancing Modern Science. Tucson: University
of Arizona Press, 2006. Surveys the many ways in which microbes, parasitic
worms, and the biological controls derived from them are being used for our
benet.
Davies, Paul. The Fifth Miracle: The Search for the Origin and Meaning of
Life. New York: Simon and Schuster, 2000. Davies brings his usual skill at
communicating science to nonscientists to the challenging topic of where
and how life began, including extremophiles, life on Mars, and the theory of
panspermia.
Bibliography
Davis, Joel. Defending the Body: Unraveling the Mysteries of Immunology.

New York: Atheneum, 1989. A general introduction to immunity for the
nonscientist, with a particularly good section on AIDS; unusual for its
scientist-oriented journalistic style, which brings the reader into the front
lines of immunological research.
Dawson, A. Hannibal and Chemical Warfare. The Classical Journal 63,
no. 3 (Dec. 1967): 117125. Explores the possibility that Hannibal, the great
Carthaginian general and enemy of the Romans, may have used chemical
weapons.
De Kruif, Paul. Microbe Hunters. New York: Harcourt, Brace and Company,
1926. A classic, still in print after nearly 85 years, with detailed and highly
124
personal biographies of 12 great men who dedicated their lives to unraveling

the mysteries of the microscopic world. Highly recommended.
Defoe, Daniel. Journal of the Plague Year. Oxford World Classics. Oxford:
Oxford University Press, 2010. The classic contemporary account of the
Black Deaths rampage though 17th-century London.
Des Marais, D. J., and M. R. Walter. Astrobiology: Exploring the Origins,
Evolution, and Distribution of Life in the Universe. Annual Review of
Ecology and Systematics 30 (1999): 397420. An excellent literature review
of the eld of astrobiology, also called exobiology or xenobiology, with a
good assessment of primary hypotheses and discoveries on the origin of life
and the possibility of life in outer space.
Despommier, Dickson D. West Nile Story. New York: Apple Trees
Productions, 2001. Describes the search for the West Nile virus in New York
City at the turn of the century, weaving together the roles of biology, politics,
and human behavior in the spread of emergent diseases.
Diamond, Jared M. Guns, Germs, and Steel: The Fates of Human Societies.
New York: Norton, 2005. A modern classic, tracing the rise and dispersal
of the human race and the often subtle relationships between geography
and human culture and history. Includes a good account of the relationship
between livestock diseases and the great Columbian Exchange.
Dobson, Mary. Disease: The Extraordinary Stories Behind Historys
Deadliest Killers. London: Quercus, 2007. As a former college librarian,
Im always reluctant to recommend anything remotely resembling a coffeetable book, but Dobson knows her stuff, and the engaging and informative
style and superb illustrations put this one in the winners circle. Includes a
detailed timeline. A word of warning, some of you might nd the cover a bit
unsettling.
Dobyns, Henry F., and William R. Swagerty. Their Number Become Thinned.
Native American Historic Demography Series. Knoxville, TN: University of
Tennessee Press/ Newberry Library Center for the History of the American
Indian, 1983. An excellent review of the size and distribution of precolonial
125
Native American populations and the effects of diseases and other factors in
reducing them.
Duckett, Serge. Ernest Duchesne and the Concept of Fungal Antibiotic
Therapy. The Lancet 354, no. 9195 (1999): 20682071. A good biographical
sketch of Duchesne, focused on his discovery of the antibiotic properties
of penicillin and his pioneering recognition of the importance of microbial
competition.
Duncan, Kirsty. Hunting the 1918 Flu: One Scientists Search for a Killer
Virus. Toronto: University of Toronto Press, 2003. Chronicles the efforts of
amateur virologist Kirsty Duncan to recover an intact sample of the 1918
virus.
Elkin, W. B. An Inquiry into the Causes of the Decrease of the Hawaiian
People. The American Journal of Sociology 8, no. 3 (November 1902):
398411. A valuable turn-of-the-century survey of the gradual destruction
of Hawaiian native populations, including a discussion of the effects of
epidemic diseases.
Bibliography
Eppig, Christopher, Corey L. Fincher, and Randy Thornhill. Parasite

Prevalence and the Worldwide Distribution of Cognitive Ability.
Proceedings of the Royal Society B 277, no. 1701 (2010): 38013808. The
latest study of the effects of disease on regional intelligence, which nds a
very high correlation between national IQ levels and the extent of infectious
diseases.
Epstein, Helen. The Invisible Cure: Africa, the West, and the Fight against
AIDS. New York: Farrar, Straus and Giroux, 2007. An important book on the
AIDS crisis, suggesting that Western efforts to ght AIDS in Africa might
be counterproductive and that the problem might be better handled from an
African perspective. Examines the changes in sexual behavior behind sharp
declines in AIDS in Uganda and Tanzania.
Ettling, John. The Germ of Laziness: Rockefeller Philanthropy and Public
Health in the New South. Cambridge, MA: Harvard University Press,
1981. The best book available about the commissions efforts to eradicate
126
hookworm in the South. In contrast to other authorities, Ettling takes the

view that Stiless motivation was more evangelical than economic.
Ewald, Paul W. Evolution of Infectious Disease. New York: Oxford
University Press, 1994. A solid introduction to evolutionary medicine from
one of its founders; very accessible to the nonscientist, with a particular
emphasis on the evolution of virulence. Includes an extensive bibliography.
. Plague Time: The New Germ Theory of Disease. New York: Anchor
Books, 2002. A controversial book in which Ewald proposes that many
modern ailments, like heart disease and Alzheimers, may actually be due to
chronic infectious diseases.
Fagan, Brian M. The Little Ice Age: How Climate Made History, 13001850.
New York: Basic Books, 2000. A pioneering work on the effects of climate
on human history, detailing the harsh weather that led to widespread famine,
poor health, and increased vulnerability to diseases like the Black Death.
Fehervari, Zoltan, and Shimon Sakaguchi. Peacekeepers of the Immune
System. Scientic American 295, no. 4 (Oct. 2006): 5663. A readable
account of the recent discovery of a subpopulation of helper T cells called
regulatory T cells and their possible use in ghting autoimmune diseases and
cancer.
Fenn, Elizabeth A. Biological Warfare in Eighteenth-Century North
America: Beyond Jeffery Amherst. The Journal of American History 86,
no. 4 (March 2000): 15521580. Reviews the use of smallpox by colonial
ofcials against tribes of Native Americans, presenting convincing evidence
that such tactics were actually employed.
Finlay, B. B. The Art of Bacterial Warfare. Scientic American 302, no.
2 (2010): 5663. Looks at the way bacteria can hijack cellular mechanisms
and cellular communication for their own benet through bacterial behaviors
and bacterial toxins and discusses strategies used by Escherichia coli and
Salmonella.
127
Garrett, Laurie. The Coming Plague: Newly Emerging Diseases in a World

Out of Balance. New York: Farrar, Straus and Giroux, 1994. A somewhat
sensational and ominous look at the future of emergent diseases as microbes
nd ways to adapt to the new evolutionary opportunities provided by new
technology.
Gluckman, Peter, Alan Beedle, and Mark Hanson. Principles of Evolutionary
Medicine. Oxford: Oxford University Press, 2009. An excellent and
authoritative text covering the basic biology behind human diseases,
microbial and otherwise, including the fundamentals of variation, natural
selection, and life-history strategies. Challenging in parts, but accessible to
the nonscientist.
Gottfried, Robert Steven. The Black Death: Natural and Human Disaster in
Medieval Europe. New York: Free Press, 1983. A well-written survey of the
progress of the 14th century pandemic, with a good summary of its social,
political, and historical effects on the medieval world.
Gronlund, Hans, Tiiu Saarne, Guro Gafvelin, and Marianne van Hage.
The Major Cat Allergen, Fel d 1, in Diagnosis and Therapy. International
Archives of Allergy and Immunology 151, no. 4 (2010): 265274. For those
who suffer from cat allergies, some solid scientic discussion of the problem,
with an excellent bibliography. Be prepared to do a lot of skimming if youre
not an immunologist!
Bibliography
Gross, Ludwik. How the Plague Bacillus and Its Transmission through Fleas
Were Discovered: Reminiscences from My Years at the Pasteur Institute in
Paris. Proceedings of the National Academy of Sciences of the United States
of America 92, no. 17 (August 15, 1995): 76097611. An excellent account
of the pioneering work of Yersin and Simond in the third plague pandemic.
Haensch, Stephanie, Raffaella Bianucci, Michel Signoli, Minoarisoa
Rajerison, et al. Distinct Clones of Yersinia pestis Caused the Black Death.
PLOS Pathogens 6, no. 10 (October 2010): 18. DNA analysis of the remains
of medieval plague victims from mass graves across Europe conrm that the
Black Death was actually caused by Yersinia pestis.
128
Harper, David R., and Andrea S. Meyer. Of Mice, Men, and Microbes:
Hantavirus. San Diego: Academic Press, 1999. A comprehensive study of the
emergence of hantavirus among the Navajo and the evolutionary response of
microbes to natural environmental changes.
Harris, Sheldon H. Factories of Death: Japanese Biological Warfare
193245 and the American Cover-Up. New York: Routledge, 1994. An eyeopening account of the secret Japanese warfare campaign against China and
America by the maddest of mad scientists, Shiro Ishii, and the subsequent
cover-up by the Allies. Extensively researched and referenced; out of print
but regularly available through Amazon.
Henderson, Donald A. Smallpox: The Death of a Disease: The Inside Story of
Eradicating a Worldwide Killer. Amherst, NY: Prometheus Books, 2009. An
excellent and detailed review of the global campaign to eliminate smallpox
from the planet, including a good short history of the disease.
Herring, Ann, and Alan C. Swedlund. Plagues and Epidemics: Infected
Spaces Past and Present. Wenner-Gren International Symposium Series.
English ed. New York: Berg, 2010. A good collection of current scholarly
articles on several epidemic diseases, both historical and modern.
Honigsbaum, M. Living With Enza: The Forgotten Story of Britain and the
Great Flu Pandemic of 1918. London: Macmillan, 2009. A detailed and
scholarly account of the British experience during the pandemic. Later
chapters provide a good summary of more recent encounters with the u and
efforts to sequence the 1918 virus.
Hopkins, Donald R. Princes and Peasants: Smallpox in History. Chicago:
University of Chicago Press, 1983. An excellent survey of smallpox in
human history, from ancient Egypt to the modern-day campaign to eradicate
the disease. One of the best scholarly books on smallpox, with an extensive
bibliography.
Hotez, Peter J., Jeffrey M. Bethony, David J. Diemert, Mark Pearson, and
Alex Loukas. Developing Vaccines to Combat Hookworm Infection and
Intestinal Schistosomiasis. Nature Reviews: Microbiology 8 (November
129
2010): 814826. A good recent review of the global status of hookworm

and schistosomiasis, with a detailed discussion of available therapies. A bit
technical in parts, but readable, with good illustrations and a very extensive
bibliography.
Hotez, Peter J., Paul J. Brindley, Jeffrey M. Bethony, Charles H. King,
Edward J. Pearce, and Julie Jacobson. Helminth Infections: The Great
Neglected Tropical Diseases. The Journal of Clinical Investigation 118, no.
4 (April 2008): 13111321. A good review of the current state of research
on parasitic worm infections, their global extent, and our responsibility for
taking international action to control the problem.
Hoyle, Fred, and N. C. Wickramasinghe. Diseases from Space. London:
Dent, 1979. A very controversial book in which the authors extend the
theory of panspermia to propose that emerging diseases might have an
extraterrestrial origin.
. Living Comets. Cardiff, UK: University College Cardiff Press, 1985.
Proposes that interstellar microbes, trapped in cometary dust, are carried to
Earth during the passage of comets.
Jackson, Mark. Allergy: The History of a Modern Malady. London: Reaktion,
2006. A good review of the history of allergy, starting with the work of
Pirquet and continuing to the latest modern research. Highly recommended
for allergy sufferers.
Bibliography
Jeans, Roger B., Jr. Alarm in Washington: A Wartime Expos of Japans

Biological Warfare Program. The Journal of Military History 71, no. 2 (Apr.
2007): 411439. Looks at media and government reaction to a badly written
book titled Japans Secret Weapon, an early work on Japanese biowarfare,
which drew attention to a sensitive area the federal government did not want
the press or public to examine.
Jones, E. W. Inuenza 1918: Diseases, Death, and Struggle in Winnipeg.
Toronto, ON: University of Toronto Press, 2007. Uses Winnipegs encounter
with the 1918 Flu as a case study in the roles of social institutions and public
130
health policies in pandemics. Concludes that the u had a more severe impact
on the poor, the working class, and women than is generally acknowledged.
Karlen, Arno. Biography of a Germ. New York: Pantheon Books, 2000.
A good popular account of the emergence, biology, and ecology of Lyme
disease.
. Man and Microbes: Disease and Plagues in History and Modern
Times. New York: Simon & Schuster, 1996. Traces the history of our
coevolution with epidemic diseases, including the rise of crowd diseases and
the modern emergence of new diseases related to our continuing cultural and
technological development. Includes an excellent bibliography.
Kelly, John. The Great Mortality: An Intimate History of the Black Death, the
Most Devastating Plague of All Time. New York: HarperCollins Publishers,
2005. A popular and fast-paced account of the plague in the 14th century.
Kelly does a good job of bringing the medieval world alive but sometimes
takes a few historic liberties in trying to make us feel the personal impact of
the plague.
Knollenberg, Bernhard. General Amherst and Germ Warfare. The
Mississippi Valley Historical Review 41, no. 3 (Dec. 1954): 489494.
Presents contemporary letters and notes to determine whether the military
used smallpox as a biological weapon during the Pontiac Indian Rebellion,
concluding that although someone deliberately gave blankets infected with
smallpox to Indian diplomatic representatives, there is no direct evidence
that they were instructed to do so by their superiors.
Koblentz, Gregory. Pathogens as Weapons: The International Security
Implications of Biological Warfare. International Security 28, no. 3 (Winter
2003): 84122. Reviews the characteristics of pathogens used as weapons
and how to defend against them, concluding that the intense secrecy
surrounding their use is a destabilizing factor in bioweapons security.
Koenig, Robert L. The Fourth Horseman: One Mans Secret Mission to
Wage the Great War in America. New York: PublicAffairs, 2006. The tangled
tale of Anton Dilger, the son of an American war hero who grew up to run
131
a secret German biological warfare lab in the suburbs of Washington DC

during World War I.
Kolata, Gina Bari. Flu: The Story of the Great Inuenza Pandemic of 1918
and the Search for the Virus That Caused It. New York: Farrar, Straus and
Giroux, 1999. A good popular introduction to the pandemic, with a lengthy
account of the subsequent search for an intact virus.
Koplow, David A. Smallpox: The Fight to Eradicate a Global Scourge.
Berkeley: University of California Press, 2003. Traces the history of the
global campaign to eradicate smallpox, including chapters on the biology of
the virus, its use as a biological weapon, and the morality of driving it into
extinction.
Kotb, Malak, John D. Fraser, and the American Society for Microbiology.
Superantigens: Molecular Basis for Their Role in Human Diseases.
Washington, DC: ASM Press, 2007. A current collection of scientic
papers on the role of superantigens in human diseases, including stateof-the-art therapeutic techniques. Very challenging, like most primary
literature in this eld.
Krohn, Katherine E., Bob Hall, Keith Williams, and Charles Barnett III. The
1918 Flu Pandemic. Mankato, MN: Capstone Press, 2008. A graphic novel
depicting the pandemic in comic format. Valuable for educators.
Bibliography
Lagerkvist, Ulf. Pioneers of Microbiology and the Nobel Prize. River Edge,
NJ: World Scientic, 2003. Biographies of some of the great pioneers of
immunology and microbiology: Paul Ehrlich, Emil von Behring, Robert
Koch, and Elie Metchnikoff.
Lapp, Marc. Evolutionary Medicine: Rethinking the Origins of Disease.
San Francisco: Sierra Club Books, 1994. An excellent introduction to
evolutionary medicine. Concludes that considering traditional medical
problems from the standpoint of ecological and evolutionary theory may
offer new solutions to old diseases.
132
Lau, S., and P. M. Matricardi. Worms, Asthma, and the Hygiene

Hypothesis. Lancet 367, no. 9522 (May 13, 2006): 15561558. A short
but informative review of the hygiene hypothesis concerning asthma and
exposure to parasitic worms, with a good bibliography.
Leskowitz, Sidney. Immunologic Tolerance. Bioscience 18, no. 11 (Nov.
1968): 10301034, 1039. May be a little challenging for the general reader
but provides a concise review of the biology of tolerance and antigen
structure and the theoretical issues remaining to be resolved in this important
area of immunology.
Levenson, Jacob. The Secret Epidemic: The Story of AIDS and Black
America. New York: Pantheon Books, 2004. An eloquent and absorbing
account of the way AIDS affects the lives of individuals; one of the most
heartfelt and best-written books on the subject of AIDS.
Levy, Buddy. Conquistador: Hernn Corts, King Montezuma, and the
Last Stand of the Aztecs. New York: Bantam Books, 2008. A highly detailed
and scholarly study that reads like a novel, discussing the many military,
political, and biological factors (like smallpox) that led to the downfall of
the Aztecs.
Link, William A. Privies, Progressivism, and Public Schools: Health
Reform and Education in the Rural South, 19091920. The Journal of
Southern History 54, no. 4 (November 1988): 623642. Reviews the effects
of the Rockefeller Sanitary Commission hookworm program on student
health, school attendance, and academic performance, concluding that the
commission had a signicant and continuing positive effect on local and
regional education, such as regular medical examination of school children.
Macfarlane, Gwyn. Alexander Fleming, the Man and the Myth. Cambridge,
MA: Harvard University Press, 1984. Good biography of the great medical
pioneer; addresses the controversy over the shared credit between Fleming
and his less-recognized colleagues and concludes that Fleming himself was
not after personal glory for their shared discovery.
133
Mak, Tak W., and Mary E. Saunders. Primer to the Immune Response.
Boston: Academic Press/Elsevier, 2008. A good general textbook on
immunity, profusely illustrated and relatively well written. The word
primer in the title may be a misnomer, but it does make you wonder how
much more formidable an advanced textbook would be!
Mangold, Tom, and Jeff Goldberg. Plague Wars: A True Story of Biological
Warfare. New York: St. Martins Press, 2000. A highly detailed and chilling
history of biological warfare programs in Russia, Iraq, and South Africa,
with an emphasis on the Russian program.
Margulis, Lynn, and Dorion Sagan. Microcosmos: Four Billion Years
of Microbial Evolution. Berkeley: University of California Press, 1997.
Margulis is a towering gure in biodiversity and a skilled writer. The book
highlights the many contributions microbes have made to the history of life
and the evolution of the modern world.
Martin, Paul S. Twilight of the Mammoths: Ice Age Extinctions and the
Rewilding of America. Organisms and Environments. Vol. 8. Berkeley:
University of California Press, 2005. A scholarly yet readable investigation
of the role of human hunters in the Pleistocene extinction event.
Mayor, Adrienne. Greek Fire, Poison Arrows, and Scorpion Bombs:
Biological and Chemical Warfare in the Ancient World. Woodstock, NY:
Overlook Press, 2003. A well-written and absorbing history of germ warfare
in the ancient world, highly recommended. Warningthis book can be hard
to put down!
Bibliography
McNeill, William Hardy. Plagues and Peoples. Garden City, NY: Anchor
Press, 1976. One of the best books ever written on the coevolution of the
human race with its microbial adversaries, including the social, political, and
ecological context of epidemic diseases. Highly recommended.
Merrell, D. S., and S. Falkow. Frontal and Stealth Attack Strategies in
Microbial Pathogenesis. Nature 430, no. 6996 (Jul. 8, 2004): 250256. An
excellent but advanced overview of microbial strategies, both direct and
stealthy, with the focus on molecular-level immune system mechanisms.
134
Moote, A. Lloyd, and Dorothy C. Moote. The Great Plague: The Story of
Londons Most Deadly Year. Baltimore, MD: Johns Hopkins University
Press, 2004. A good detailed account of the Great Plague of London;
scholarly and thorough, yet told from the viewpoint of the people who
suffered through it.
Morens, David M., and Anthony S. Fauci. The 1918 Inuenza Pandemic:
Insights for the 21st Century. Journal of Infectious Diseases 195, no. 7 (April
1, 2007): 10181028. Considers the origins of the virus and its age-related
pattern of mortality, including a table summarizing current information on
basic questions posed by the pandemic.
Morse, Stephen S. Emerging Viruses. New York: Oxford University Press,
1993. A collection of authoritative and scholarly articles on the modern
emergence of infectious diseases like AIDS, Ebola, and Hantaan fever.
Mullen, T. The Last Town on Earth. New York: Random House, 2006. A
rare novel about the u that tells the story of a young soldier who talks his
way through a quarantine roadblock in a small mining town in Washington,
triggering a series of events that illustrates the problems faced by small
communities during the pandemic.
Nesse, Randolph M., and George C. Williams. Why We Get Sick: The New
Science of Darwinian Medicine. New York: Vintage Books, 1996. A great
introduction to the coevolution of humans with their microbial pathogens.
Includes material on the evolutionary arms race, microbial strategies, and
allergies as well as a survey of nonmicrobial disease problems related to the
nature of human evolution and lifestyles (evolutionary legacies and diseases
of civilization).
Nuland, Sherwin B. The Doctors Plague: Germs, Childbed Fever, and the
Strange Story of Ignaz Semmelweis. Great Discoveries. New York: W. W.
Norton, 2003. An engaging biography of the doctor who taught us to wash
our handsa troubled man with a noble but elusive goal.
135
Oro, J., Stanley L. Miller, and Antonio Lazcano. The Origin and Early
Evolution of Life on Earth. Annual Review of Earth and Planetary Sciences
18 (1990): 317356. An excellent, if challenging, review of experiments in
prebiotic synthesis and the origin of life, with an inside perspective from
Stanley Miller.
Patterson, Andrea. Germs and Jim Crow: The Impact of Microbiology
on Public Health Policies in Progressive Era American South. Journal of
the History of Biology 42, no. 3 (Fall 2009): 529559. Addresses the racial
attitudes that excluded African Americans from public health programs and
how these attitudes were exploited by the eugenics movement and other
racist organizations. Well written, well researched, and very disturbing.
Pettit, Dorothy Ann, and Janice Bailie. A Cruel Wind: Pandemic Flu in
America, 19181920. Murfreesboro, TN: Timberlane Books, 2008. An
excellent introduction to the pandemic; stands with Barry and Crosby as one
of the best books on the u. Scholarly and well-written, it tells the story of
the u through contemporary accounts, with an emphasis on the individuals
who struggled against it.
Pier, Gerald Bryan, Jeffrey B. Lyczak, and Lee M. Wetzler. Immunology,
Infection, and Immunity. Washington, DC: ASM Press, 2004. If textbooks
were worth their weight in gold, anyone possessing this book would be very
wealthy indeed! A good introduction to an extremely complex subject at an
advanced undergraduate or medical-school level.
Bibliography
Playfair, J. H. L. Living with Germs. New York: Oxford University Press,

2004. A good, concise introduction to the immune system for nonscientists.
Porter, K. A. Pale Horse, Pale Rider. The Collected Short Stories of
Katherine Anne Porter. Orlando: Harcourt Books, 1979. The only major
work of ction on the u. Porter and her anc both fell ill, but only she
survived the pandemic.
Preston, Richard. The Hot Zone. New York: Random House, 1994. A chilling
account of the emergence of Ebola and its near escape into Washington DC.
136
Purkitt, Helen E., and Stephen Burgess. South Africa's Chemical and
Biological Warfare Programme: A Historical and International Perspective.
Journal of Southern African Studies 28, no. 2 (Jun. 2002): 229253. A
detailed analysis of one of the planets best-kept secrets, the extensive germ
warfare program developed by South Africa.
Ramenofsky, Ann F. Vectors of Death: The Archaeology of European
Contact. Albuquerque: University of New Mexico Press, 1987. An
independent and scholarly effort to chart the size of native populations and
determine the effect of European contact in the 16th century.
Reidel, Stefan. Biological Warfare and Bioterrorism: A Historical Review.
Baylor Univeristy Medical Center Proceedings 17 (2004): 400406. Hard to
locate but worth the effort, this is a concise review of the history of biological
warfare with a lengthy bibliography.
Reisman, Robert E. Insect Stings. New England Journal of Medicine 331,
no. 8 (1994): 523527. An excellent review of allergic responses to insect
stings; an important source for those with severe bee and insect allergies.
Ripple, William J., and Blaire Van Valkenburgh. Linking Top-Down
Forces to the Pleistocene Megafaunal Extinctions. Bioscience 60, no.
7 (JulyAugust 2010): 516526. Reviews evidence that human hunting
caused the Pleistocene extinctions and concludes that the vanished species
were especially vulnerable due to their low population densities and their
susceptibility to predators.
Rockefeller Sanitary Commission for the Eradication of Hookworm Disease.
Publication. No. 19. Washington, DC: Ofce of the Commission, 1910
1915. A very thick stack of government documents detailing the long and
thorough investigation of the commission over several years and several
states.
137
Sachs, Jessica Snyder. Good Germs, Bad Germs: Health and Survival in
a Bacterial World. New York: Hill and Wang, 2007. A well written survey
of how microbes affect our lives, with a particularly useful section on the
relationship between hygiene and immunity. Includes several examples of
how microbes can be used to improve our health and welfare.
Sompayrac, Lauren. How the Immune System Works. 3rd ed. Malden, MA:
Blackwell, 2008. A popular, concise guide to the bewildering complexity
of the immune system that has saved the skin of many a medical student
cramming for exams; clearly written, well organized, and profusely
illustrated.
Sartin, Jeffrey S. Infectious Diseases during the Civil War: The Triumph of
the Third Army. Clinical Infectious Diseases 16, no. 4 (April 1993): 580
584. An informative summary of the extent of disease-related casualties,
versus combat casualties, in the American Civil War, concluding that 2/3 of
the total casualties were due to disease.
Savitt, Todd Lee, and James Harvey Young. Disease and Distinctiveness
in the American South. Knoxville: University of Tennessee Press, 1988. A
collection of papers on the effects of various epidemic diseases on Southern
health and history, including an informative essay on hookworm.
Scientic American. Infectious Disease: A Scientic American Reader.
Chicago: University of Chicago Press, 2008. A collection of 30 articles
published in Scientic American between 1993 and 2007 on viruses, bacteria,
and other microbial pathogens, including several articles on immunity.
Bibliography
Scott, Susan, and C. J. Duncan. Return of the Black Death. Hoboken, NJ:
Wiley, 2004. A good treatment of the medieval and modern outbreaks of
the plague, maintaining that the 2 pandemics were caused by 2 different
diseases, with the Black Death caused by an unknown Ebola-like virus.
Sencer, D. J., and J. D. Millar. Reections on the 1976 Swine Flu Vaccination
Program. Emerging Infectious Diseases 12, no. 1 (January 2006): 2933. A
good review of the policy decisions surrounding the swine u vaccination
program, with lessons learned for coping with future epidemics of avian u.
138
Shilts, Randy. And the Band Played On: Politics, People, and the AIDS
Epidemic. Rev. ed. New York: St. Martins Grifn, 2007. An important and
controversial work rst published in 1987 and recently revised and reprinted.
Shilts followed the rst 5 years of the AIDS epidemic as a reporter for the
San Fancisco Chronicle and deplored the inaction and grandstanding he
observed on all sides of the issue.
Silverstein, A. M. Autoimmunity versus Horror Autotoxicus: The Struggle
for Recognition. Nature Immunology 2, no. 4 (April 2001): 279281.
Studies the early history of immunology, noting the negative effects of Paul
Ehrlichs theories on the acknowledgement of the existence and prevalence
of autoimmune diseases.
. Clemens Freiherr von Pirquet: Explaining Immune Complex
Disease in 1906. Nature Immunology 1, no. 6 (December 2000): 453455.
A good sketch of von Pirquets career, including his famous research in
fungal antibiotics.
Smith, Geddes. Plague on Us. New York: The Commonwealth Fund,
1941. A classic work on the epidemiology of infectious diseases; dated but
informative and well written.
Spellberg, Brad. Rising Plague: The Global Threat from Deadly Bacteria
and Our Dwindling Arsenal to Fight Them. New York: Prometheus Books,
2009. A compelling review of the rise of antibiotic resistance and a critique
of the current state of drug research, or lack thereof, with several suggestions
for restoring the balance.
Stiles, Charles Wardell. Hookworm Disease in its Relation to the Negro.
Public Health Reports (18961970) 24, no. 31 (Jul. 30, 1909): 10831089.
Stiles acknowledges the Rockefeller Sanitary Commissions neglect of the
problem of hookworms in Southern black communities but concludes that
exposure in Africa has kept them relatively immune to its effects.
139
Suttle, C. A. Viruses in the Sea. Nature 437, no. 7057 (September

15, 2005): 356361. A detailed look at the vast diversity and staggering
abundance of viruses in the ocean that discusses aquatic viruses as a possible
source of emerging terrestrial diseases.
Taubenberger, J. K., and D. M. Morens. 1918 Inuenza: The Mother of
all Pandemics. Emerging Infectious Diseases 12, no. 1 (January 2006):
1522. Examines the origins and epidemiological patterns of the 1918 Flu,
the reasons for its high virulence, and the causes of the W-shaped agedistribution curve of u mortality.
Taubenberger, Jeffery K., Johan V. Hultin, and David M. Morens. Discovery
and Characterization of the 1918 Pandemic Inuenza Virus in Historical
Context. Antiviral Therapy 12, no. 4 (2007): 581591. A thorough review
of the history of efforts to identify the biological nature of the 1918 Flu
leading to the modern sequencing of the viral genome.
Tauber, A. I. Metchnikoff and the Phagocytosis Theory. Nature Reviews
Molecular Cell Biology 4, no. 11 (November 2003): 897901. Puts
Metchnikoffs work on immunity in the larger context of the contemporary
theoretical issues in general biology that he was interested in solving.
Bibliography
Tuchman, Barbara Wertheim. A Distant Mirror: The Calamitous 14th

Century. New York: Knopf, 1984. A classic and absorbing account of a
period the author claims was one of the worst times to be alive in human
history, an age marked by a series of unfortunate events, including the
beginning of the Little Ice Age and the onset of the Black Death.
U. S. Army Medical Department, Borden Institute. Medical Aspects of
Chemical and Biological Warfare. http://www.bordeninstitute.army.mil/
published_volumes/chemBio/chembio.html. An exhaustive and authoritative
online textbook of chemical and biological warfare, with individual chapters
devoted to plague, anthrax, smallpox and other perennial favorites. Chapters
are available in PDF format.
Waller, John. The Discovery of the Germ: Twenty Years that Transformed the
Way We Think about Disease. Revolutions in Science. New York: Columbia
140
University Press, 2002. A brief but fascinating survey of the most critical
period in the formulation of germ theory. Very highly recommended.
Walters, Mark Jerome. Six Modern Plagues and How We Are Causing Them.
Washington, DC: Island Press/Shearwater Books, 2003. A good survey
of modern diseases caused by humans impact on natural environments,
including mad cow disease, AIDS, salmonella DT-104, Lyme disease,
hantavirus, and West Nile virus.
Ward, Peter Douglas, and Donald Brownlee. Rare Earth: Why Complex Life
is Uncommon in the Universe. New York: Copernicus, 2000. Takes the view
that complex alien life forms may actually be scarcer than we think due to
a variety of geological, physical, and biological factors illustrated by the
history of our own planet. Microbial life, however, may be abundant in the
cosmos.
Watkins, Renee Neu. Petrarch and the Black Death: From Fear to
Monuments. Studies in the Renaissance 19 (1972): 196223. A scholarly
study of Petrarchs reaction to the outbreak of Black Death that claimed his
lover Laura and most of his friends, as well as its effects on his writing.
Conveys the despair of the plagues survivors.
Watkins, W. E., and E. Pollitt. Stupidity or Worms: Do Intestinal Worms
Impair Mental Performance? Psychological Bulletin 121, no. 2 (Mar. 1997):
171191. Reviews 80 years of research on the cognitive effects of parasitic
worm infection and concludes that the effect is signicant but that not all
victims recover cognitive performance after treatment.
Westing, Arthur H. The Threat of Biological Warfare. Bioscience 35, no.
10 (November 1985): 627633. A good article for the general reader on the
spread of biological weapons and the possibility of a biological arms race
with the Russians.
Wilcox, Lynne S. Worms and Germs, Drink and Dementia: US Health,
Society, and Policy in the Early 20th Century. Preventing Chronic Disease:
Public Health Research, Practice, and Policy 5, no.4 (October 2008): 112.
Examines hookworm, pellagra, alcoholism, and cholera to show how public
141
policy is often shaped by social and political forces instead of by logic and
scientic data.
Woese, Carl R., Otto Kandler, and Mark L. Wheelis. Towards a Natural
System of Organisms: Proposal for the Domains Archaea, Bacteria, and
Eucarya. Proceedings of the National Academy of Sciences of the United
States of America 87, no. 12 (Jun. 1990): 45764579. The classic paper in
which Carl Woese formally dened and named the Domain Archaea and
proposed the 3-domain system, one of the most signicant publications in
biodiversity in the last 50 years.
Wolfe, Thomas. Look Homeward Angel. New York: Scribner, 1929. Hailed by
many as the great American novel, Wolfes autobiographical masterpiece
is one of the few works of ction that mentions the u. His sad and eloquent
description of his brother Ben on his deathbed is a scene that was repeated
hundreds of thousands of times across America during the 1918 pandemic.
Wray, Matt. Not Quite White: White Trash and the Boundaries of Whiteness.
Durham, NC: Duke University Press, 2006. A fascinating scholarly study
of the phenomenon of the white trash stereotype, with extensive material
on the role of the hookworm campaign in redening the Southern white
working class.
Wright, Willard H. Charles Wardell Stiles: 18671941. The Journal of
Parasitology 27, no. 3 (June 1941): 195201. A more formal biography of
Stiles with good background on his early research on tapeworms.
Bibliography
Ziegler, Philip. The Black Death. Wolfeboro, NH: Sutton, 1991. A detailed
account of the 14th century pandemic, with an emphasis on England. Well
researched and authoritative but a bit dry.
Zinsser, Hans. Rats, Lice and History. Boston: Atlantic Monthly Press,
1935. The rst great study of epidemic and vector-borne diseases, with an
emphasis on typhus. Especially good for historical plagues.
142
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Mysteries of the

Copyright The Teaching Company, 2011

Printed in the United States of America

Bruce E. Fleury, Ph.D.

rofessor Bruce Edward Fleury is Professor

Mysteries of the Microscopic World

his course will take you on a guided tour through an invisible

diseases like Lyme, Legionnaires, toxoplasmosis, and death by chocolate.

In the fourth set of lectures, we follow Christopher Columbus and the

The Invisible Realm

Along the journey from

Lectuire 1: The Invisible Realm

The idea that nature keeps itself in

2. In what way, mathematically speaking, is small size an advantage for a

Stone Knives to Iron Plows

As humans changed the way we lived and consequently changed our

lagues were not always a problem for humankind. Epidemics

Lecture 2: Stone Knives to Iron Plows

The results of urbanization

Disease cycles can be very complex. They are affected by political,

Lecture 2: Stone Knives to Iron Plows

The Angel of Death

The Medieval Warm Period allowed for a rapid increase in European

any of the most devastating epidemics come from vector-borne

Lecture 3: The Angel of Death

There are 3 distinct forms of plague:

In septicemic plague, the bacterium enters the bloodstream, where

Weakened by generations of famine

workers in San Francisco. By that time, however, we were aware of germ

vaccine: A therapeutic technique that introduces foreign antigens into an

Lecture 3: The Angel of Death

Southwest. Why do you rarely hear of an outbreak of plague in

Before we could begin to solve the puzzle of disease, we rst had to

Girolamo Fracastoroa Renaissance

Louis Pasteur convinced the scientic

Lecture 4: Germ Theory

2. Why, according to the medical theory of humors, was there no such

Lecture 4: Germ Theory

thing as a specic disease?

The Evolutionary Arms Race

icrobes and humans are locked in a perpetual evolutionary arms

Although Sir Alexander Fleming is usually credited with discovering

Lecture 5: The Evolutionary Arms Race

coevolution: An evolutionary change in one organism that leads to an

Lecture 5: The Evolutionary Arms Race

ne of the most important microbial strategies is one of the easiest to

Lecture 6: Microbial Strategies

Skin is humans rst line

2. How is it possible to drive a parasite into extinction without actually

Lecture 6: Microbial Strategies

killing all of them?

ooperation and coexistence often prevail in nature, thanks to

Competition and coevolution can cause some diseases to gradually lose

Another important aspect of virulence is dispersal. Getting into a victim is

With vector-borne diseases, however, an immobile host is less of a problem.

Human civilization gave microbes countless new dispersal routes,

he trade routes and roads of antiquity were interstate highways for

Air conditioning gave bacteria that cause

Lecture 8: Death by Chocolate