THE FIRST PANDEMIC
In early July 2002 in Franklin County, Tennessee, a thirteen-year-old boy named
Jeremy Watkins picked up a sickly bat on his way home from a day of fishing. None
of the other family members handled it, and his stepfather wisely made him release
the animal soon after Jeremy revealed his find.
Events like this happen all over the world with thousands of wild animals every
day, largely without ill consequences. But Jeremy’s encounter with this particular
bat would be quite different.
In the CDC report that would document Jeremy’s case, the next events were de-
scribed with clinical efficiency. On August 21 Jeremy complained of headache and
neck pain. Then a day or so later his right arm became numb and he developed a
slight fever. Perhaps of greater concern, he also developed diplopia, or double vi-
sion, and a constant, queasy confusion. Three days later he was taken to the local
hospital’s emergency room but was discharged with the incorrect diagnosis of
“muscle strain.” The next day he was back in the emergency room, this time with a
fever of 102°F. He had the same symptoms, but now his speech was slurred, he
had a stiff neck, and difficulty swallowing.
At this point, Jeremy was transferred to a local children’s hospital. By August 26
he could no longer breathe or think normally. He was also producing copious
amounts of saliva. Highly agitated to the point of being combative, Jeremy was se-
dated and put on life support. His mental status deteriorated rapidly and by the
next morning he was completely unresponsive. On August 31 Jeremy was pro-
nounced brain-dead and, following the withdrawal of life support, he died of bat-
borne rabies.
Jeremy’s family did not know that bats could carry rabies, much less transmit it
to humans. They did not remember him complaining of a bite, although that’s ex-
actly what must have happened while he carried the bat home from his fishing
excursion. They probably did not know that the incubation period for rabies is
generally three to seven weeks, well within the range of the time between his expo-
sure to the bat and the first symptoms he experienced. Detailed studies of the virus
that killed Jeremy revealed evidence of a variety of rabies found in silver-haired and
eastern pipistrelle bats common in Tennessee.
Rabies is a terrible way to die. It’s a disease that devastates the families of its
victims, with patients becoming virtual zombies in the days before death. It is
among the small number of viruses that kill virtually all of the individuals they in-
fect. But as tragic as it is that the doctors at the local Franklin County emergency
room sent Jeremy home with a diagnosis of muscle strain, the reality is that it was
already too late to help the boy at that point. Without rapid postexposure prophy-
laxis after infection, the boy was destined to die.
If we take a different view, the virus that causes rabies is not only a deadly menace
but also a truly amazing feat of nature. This virus, shaped like a bullet, is a meager
180 nanometers long and 75 nanometers across. If you stacked rabies viruses one
on top of the next, you would need more than a thousand of them to reach the
thickness of a single human hair. Rabies has an almost trivial genome, with only
twelve thousand bits of genetic information for a meager five proteins. It’s simple,
tiny, and incredibly powerful.
While diminutive, the virus accomplishes remarkably sophisticated tasks. In
addition to the standard viral work of invading cells, releasing genes, making new
viruses, and spreading, it has some unique tricks. From the point of entry, the virus
travels preferentially along neural pathways, making its way into the central nervous
system. It accumulates selectively in the saliva. The virus particles that infect the
central nervous system modify the host’s behavior, increasing aggression, inter-
fering with swallowing, and creating a profound fear of water. When put together, a
rabies infection leads to an aggressive host literally foaming at the mouth with
virus. A host that lacks the capacity to drink or swallow further increases the proba-
bility of delivering a successful bite—a bite that gives this particular virus the abil-
ity to advance from one individual to the next.
As frightening and deadly as rabies is, as a global community we need not fear
it. That a virus is exceedingly and dramatically deadly does not mean it will become
a pandemic. Rabies kills more than fifty-five thousand people a year worldwide. It is
a cause for serious public health measures, but it does not present a global pan-
demic threat. In all of the years that the CDC and other public health organizations
have followed rabies, it has never once gone from person to person. Every one of
those deaths, like the death of Jeremy Watkins, resulted from an independent ani-
mal infection. From a pandemic perspective, it doesn’t have the right stuff.
So, what is a pandemic? Defining them creates some trouble. The word itself
comes from the Greek pan, meaning “all,” and demos, meaning “people.” Yet, in
reality, it is almost impossible to imagine an infectious agent that infects the entire
human population, a high bar to set for a virus. In humans or any hosts, different
individuals will have different genetic susceptibility, so at least a few individuals
will likely be incapable of sustaining an infection because of some kind of genetic
immunity. Also, the simple logistics of spreading to every single individual in any
population makes such a feat nearly impossible.
Among the most common viruses infecting humans that we are aware of is the
human papilloma virus,¹ and it doesn’t afflict 100 percent of people. HPV currently
infects 30 percent of women between the ages of fourteen and sixty in the United
States, a whopping high rate for a virus. Rates are likely even higher in some parts
of the world. Amazingly, the majority of sexually active humans on our planet,
whether male or female, will get HPV at some point in their lives. The virus is made
up of over two hundred different strains, all of which infect either skin or genital
mucosa. Once the virus enters an individual, it generally stays active for years or
even decades. Fortunately, the vast majority of HPV strains cause no problems for
us. The few strains that do cause disease generally do so by causing cancer, the
most important example being cervical cancer.² Luckily, most HPV simply spreads
from individual to individual with little harm.
We’re still aware of only a small percentage of all viruses that call humans their
home. There may be viruses out there that infect even more people than HPV does;
the work to identify all of the viruses that infect us has only just begun. Research
over the last ten years has identified multiple previously unknown viruses circu-
lating in humans that infect many individuals yet do not appear to cause any ill-
ness. The TT virus was named after the first individual to be infected, a Japanese
man with the initials T.T. Very little research has been done yet on TTV, but it may
be quite common in some locations. A report by one of my collaborators, Peter
Simmonds, an excellent Scottish virologist, found prevalence rates ranging from
1.9 percent among Scottish blood donors to 83 percent among residents of The
Gambia in Africa, a startlingly high range. Fortunately, TTV does not appear to be
harmful.
GB virus is another recently identified and still largely unstudied virus present in
many people. The virus got its name from a surgeon, G. Barker; at the time, his
hepatitis was mistakenly attributed to the virus.³ I know from my own work how
common both TTV and GBV are. Using very sensitive approaches to viral dis-
covery, we frequently see these two—largely to our dismay, since they interfere with
our ability to catch the dangerous culprits we’re really looking for.
However common TTV and GBV are, they do not infect 100 percent of humans.
So the literal Greek-derived definition of pandemic is probably an impossibility. The
World Health Organization (WHO) has devised a six-stage classification of pan-
demics beginning with a class-one virus that infects just a few people and going on
to a class-six pandemic, which occurs when infections have spread worldwide.
The WHO faced widespread criticism for labeling H1N1 a pandemic in 2009,
but that’s exactly what it was. H1N1 went from infecting only a few individuals in
early 2009 to infecting people in every region of the world by the end of the same year. If that’s not a pandemic, then I don’t know what is. Whether or not we label a
microbe that’s spreading as a pandemic is unrelated to its deadliness. It’s just a
marker of its ability to spread. And as we discussed in chapter 1, the fact that H1N1
doesn’t kill 50 percent of the people it infects (or even 1 percent for that matter)
doesn’t mean it won’t kill millions of people or represent a massive threat.
In fact, from my perspective, it’s possible that we could have a pandemic and
not even notice it. If, for example, a symptomless virus like TTV or GBV were to
enter into humans today and spread around the world, we probably wouldn’t be
able to tell. Most conventional systems to detect diseases only catch things that
cause clear symptoms. A virus that didn’t cause any immediate harm would likely
be missed.
Of course, “immediate” isn’t the same thing as “never.” If a virus like HIV were
to enter into humans today and spread globally, it wouldn’t be detected for years,
since major disease would occur sometime after initial infection. HIV causes only a
relatively minor set of syndromes immediately, even though it starts to spread right
away. AIDS, the major disease of HIV, doesn’t emerge until years later. Since con-
ventional methods for detecting new pandemics rely primarily on seeing
symptoms, a virus that spreads silently would likely miss our radar, spreading to
devastating levels before an alarm could be triggered.
Missing the next HIV would obviously be a catastrophic public health failure.
Yet new viruses, even if likely to be completely harmless, like TTV and GBV, need
to be monitored if they are moving quickly through the human population. As we
saw in chapter 1, viruses can change. They can mutate. They can recombine with
other viruses, mixing genetic material to create something new and deadly. If
there’s a new virus in humans and it’s spreading globally, we need to know about
it. The dividing line from spreading and benign to spreading and deadly is a poten-
tially narrow one.
For our purposes, we’ll define a pandemic as a new infectious agent that has
spread to individuals on all continents (with the exception, of course, of Antarc-
tica). One may counter that it would theoretically take only a dozen or so infected
people to accomplish this—a few infected people per continent. That may be true,
but it would be exceptionally rare for a microbe to spread so widely and infect so
few individuals. And if it did manage to occur, even with twelve people, it would
still represent a potent risk to all of us.
Defining precisely when a new spreading agent actually becomes a pandemic is
less important for our objective here than understanding how pandemics are born.
What I wanted to know when I began my research on pandemics was how some-
thing goes from being a strictly nonhuman infection to one spreading to humans
on every continent.
In 2007 I worked with the aforementioned polymath biologist and geographer
Jared Diamond and the tropical medicine expert Claire Panosian to develop a five-
step classification system for understanding how an infectious agent living exclu-
sively in animals can become an agent that spreads globally in humans. The sys-
tem moves stepwise from agents that infect only animals (Category One) to agents
that exclusively infect humans (Category Five).
Jared and I spent many afternoons pondering this process over extended writing
sessions at his home in Los Angeles. During our lunch breaks, we’d stop writing to
brainstorm, using thought experiments, how a virus might make this jump. We
came up with one fairly elaborate idea centered around the Diamonds’ geriatric but
much beloved pet rabbit, Baxter, and his invented disease—the dreaded Baxterpox.
Even in our imaginary world, most human diseases have their start in animals.
Few of us now live on or near farms; fewer still live as hunter-gatherers sur-
viving on wild plants and animals. We live in worlds filled with buildings and
streets, where the dominant and notable forms of life are basically ourselves. De-
spite living on every continent with a population of seven billion individuals, we
still represent a very restricted segment of the biological diversity on our planet.
As discussed in chapter 1, most of the diversity of life on our planet resides in
the unseen world; in bacteria, archaea, and viruses. Despite our massive numbers
and global reach, our human diversity pales in comparison. This is true even for
our microbes. Most of the diversity in mammalian microbes resides in other ani-
mals, not humans. Some animals house greater microbial repertoires than others.
For example, fruit bats are a notorious reservoir species. They often live in large
colonies and are highly mobile “travelers” connecting multiple regions with high
levels of biodiversity. On average a species of colonial fruit bat will have a greater
diversity of microbes than, say, a two-toed sloth living a largely solitary life.
However you cut it, there are estimated to be over five thousand species of
mammals on the planet and only one species of human. The diversity of microbes
that can infect us from other mammals has and will always be substantially greater
than the diversity of microbes that already does infect us. That’s why we concep-
tualize the process as a pyramid, with the greatest diversity of microbes falling into
Category One.
We’ve seen that most of the microbes with the potential to cause new human
pandemics live in animals. Domestic animals certainly represent a threat, but as
discussed earlier, most of what they had to contribute to the human microbial
repertoire has already jumped over. Right now, the threat from domestic animals
comes more from them acting as bridges to allow the movement of wild animal
microbes into the human population. Moreover, while the actual number of living
domestic animals is quite high, they represent a small percentage of the diversity of
mammals since we’ve only domesticated a small percentage of all animals. Clearly,
when it comes to new pandemics, wild animals are where the action is.
When I lived in Malaysia during the 1990s conducting my doctoral research, I
spent time working with the accomplished parasitologists Janet Cox and Balbir
Singh. Janet and Bal devised creative ways to detect malaria in blood that had been
dried on small pieces of laboratory filter paper (it looks like plain but thick white
paper). This technique made it easier to do field screening or specimen collection
in remote locations. Since blood could be dried easily and stored at room temper-
ature, this method did away with the logistics of having to keep a specimen cold in
regions without electricity. Janet and Bal taught me how to use these lab tech-
niques, and, with their sweet kids, Jas and Serena (now both college students!),
introduced me to the amazing Malaysian state of Kelantan.
Kelantan is a small state on the border of Thailand that still adheres to
Malaysian traditions that have disappeared in much of the now modern and
economically booming country. Many of the people in Kelantan wear traditional
Malaysian clothing, the official weekend is on Thursday and Friday, and there’s not
a drop of alcohol to drink (at least officially) in the majority of the state. The pace
of life in Kelantan is more relaxed than almost anywhere I’ve visited in the now
bustling, dynamic countries of Southeast Asia.
Among the fascinating sights to see in Kelantan was one that held particular
scientific interest to Bal, Jan, and me—coconut-picking macaques. In a unique
practice, some coconut farmers in northern Malaysia and southern Thailand work
with pig-tailed macaques, a species of Southeast Asian monkey, trained to climb
palms and harvest coconuts. A well-trained animal can pick up to fifty coconuts an
hour—quite an efficient farmhand.
One evening after dinner at their house, Bal told us of a report he’d heard of a
man with a particularly devastating neurological disease, the symptoms of which
suggested it was caused by a virus or other infectious agent. This man worked with
the curious coconut-picking macaques.
The close and long-term relationship between macaques and their human han-
dlers presented an ideal chance to study the first and second stages of the classi-
fication system I’d developed with Jared and Claire. We could study the microbes
present in the animals and monitor them for any cross-species jumps into hu-
mans. Among the more interesting targets of our investigation would be the deadly
herpes B virus.
Herpes B may not sound as if it should be particularly dreaded, but it’s among
the deadliest viruses a human can contract. Amazingly, the virus is almost com-
pletely benign among the macaques that sustain it. For the coconut-picking
macaques, herpes B virus is just like herpes simplex is for a human, creating minor
lesions that spread the virus through intimate contact like a bite or sex. Incon-
venient for these monkeys, perhaps, but certainly not deadly. Yet when the virus
crosses into humans, it causes severe neurological symptoms and invariably re-
sults in death. Transmission of the virus has been documented in a number of pri-
mate handlers in the West, including a sad case of a young woman working at the
Yerkes Regional Primate Research Center in Atlanta who became infected after a
captive macaque spit in her eye. At the time, no one had documented the infection
occurring among the Kelantan coconut harvesters, despite the fact that they work
with these animals daily and with far fewer protective measures in place.
For Bal, Janet, and me, studying the Kelantanese macaques and their handlers
provided an interesting way to monitor the entry of these viruses into human pop-
ulations and to witness the first step in the process of how potential pandemics are
born. Yet, as with the case of rabies in young Jeremy Watkins, we did not expect to
see these herpes B viruses go anywhere outside Category Two. They would remain
as infections that had made the leap but didn’t have the potential to spread in hu-
mans. While the victims might die from infection, the people infected by these
monkeys would never go on to spread the virus to their families or others. Thus,
no pandemic for herpes B. For that, we’d need a different kind of virus.
The interface we have with the animals in our world leads to a constant flow of mi-
crobes. Every day, millions of people are exposed to animal microbes. Some rare
infections lead to death. Much more frequently, they are transient and benign infec-
tions, such as a bacteria from a pet dog or cat. The vast majority of these Category
Two viral jumps represent dead ends from the perspective of a microbe: they infect
a single individual, and that’s that.
Sometimes, though, something unusual happens that is potentially pivotal for
our species: a microbe that jumps over may have the capacity to move from one
human to another human. If a microbe accomplishes this, it moves to a Category
Three and toward becoming a pandemic.
In late August, 2007 information began to trickle in to health authorities on an
unidentified illness in a remote area of the Kasai-Occidental Providence in the
Democratic Republic of Congo. The outbreak was centered around Luebo, a town
of some historical importance as the last point that early twentieth-century
steamers could navigate to on the Lua Lua River. The case reports listed a number
of bad symptoms—fever, severe headache, vomiting, major abdominal pain,
bloody diarrhea, and severe dehydration. The first recognized cases were on June 8,
following the funerals of two village chiefs. Tellingly, the entire first group of indi-
viduals infected had assisted with the burials.
The symptoms and the connection to burials led the Congolese health author-
ities to consider the possibility of Ebola, a virus that spreads through direct contact
with blood and body fluids, and they responded accordingly. The head of the Con-
golese team was Jean-Jacques Muyembe. Jean-Jacques is a professor and the direc-
tor of the national biomedical research institute, the INRB. His bright laugh and
mild-mannered demeanor belie the fact that he’s had more experience dealing with
viral hemorrhagic fevers⁴ than perhaps any other single person in the world. I have
fond memories of working with Jean-Jacques in a remote location in central DRC
and watching him break into hysterics as he watched me devour a meal of pan-
fried grub worms for dinner.
Jean-Jacques and his team called in long-standing collaborators, including Eric
Leroy, a crack virologist who runs the only high containment bio-safety level four
laboratory in central Africa that is capable of studying the world’s deadliest viruses.
Leroy, Muyembe, and colleagues at the CDC and from other groups like Médecines
Sans Frontières (MSF) worked to contain the Luebo outbreak. They sequenced a
small portion of the virus’s genetic information and discovered that it was, in fact,
the Ebola virus.
Ebola hemorrhagic fever strikes fear in the hearts of people in the DRC and
throughout the world. The Ebola virus kills quickly and dramatically. It also
spreads. While the exact number of cases will never be known, the Luebo outbreak
of 2007 probably infected around four hundred people. All of them were infected
from a single virus that jumped from an animal into the first human victim and
then subsequently spread. Around two-thirds of them died.
Part of the public fascination with Ebola relates to how little we know about
something so deadly. The truth is that it largely remains a devastating and un-
solved mystery.
What we do know about the Ebola virus is that it appears occasionally in hu-
mans. We know that it can enter into humans from multiple animal species. Leroy
and his colleagues have identified the Ebola virus in a few species of bats, helping
to pinpoint them as the likely reservoir. A range of studies also documents how
Ebola affects gorillas, chimpanzees, and some species of forest antelope. We know
that for now it’s a Category Three microbe on the route to pandemics: it can infect
and spread in humans, although not to the point of sustained transmission. Effec-
tively, it’s a virus with potential for localized outbreaks.
Together with Leroy and his colleagues, we looked in detail at the virus that
caused the Luebo outbreak of 2007, as well as a smaller outbreak that occurred
about a year later in December 2008 in exactly the same region of DRC. We found
that the viruses that caused the two outbreaks were nearly identical and formed an
entirely new type in the deadliest group of the Ebola viruses: the Zaire group.
That the Luebo outbreaks came from a new variant virus was significant. It
meant that the depth of the genetic pool of viruses that could jump to us from ani-
mals was greater than we’d imagined. Now we understood that new versions of the
Ebola virus had the potential to enter into humans, perhaps someone who hunted
or butchered the meat of wild fruit bats. This meant that we probably haven’t seen
everything that the Ebola virus can serve up. For now, we classify Ebola as a Cate-
gory Three agent, but our finding suggests that there are more undiscovered
variants of Ebola out there that can cross into us. It’s possible that a distinct and
as yet unknown Ebola virus circulating in animals might have the potential to
spread more broadly than any Ebola in the past.
Does the Ebola virus have the right stuff? Could it move higher in our pyramid
classification system? From the perspective of a pandemic, all of the Ebola hemor-
rhagic fever outbreaks to date have been stillborn. They spread, but lucky for us,
that spread remains limited.
Unlike the casual contact or airborne transmission of influenza, the majority of
cases in the Ebola hemorrhagic fever outbreaks that have been studied resulted
from intimate contact with the blood and body fluids of a very sick person. Gener-
ally, people become infected when preparing a previous victim for burial or when
caring for the sick. Limited transmission makes broader, sustained spread less
likely.
There are other disadvantages that the Ebola virus has in the microbial race to
become a pandemic. The incredibly nasty symptoms of Ebola are both very specific
and also coincide with its capacity to spread. Since few other viruses cause the dra-
matic symptoms of Ebola, it can be identified relatively quickly and the sick
individuals can be isolated. Since it’s the very sick people who spread the virus,
isolation works to stop it. This is the approach that organizations like the CDC and
MSF use to quell Ebola outbreaks: get in, isolate victims, stop contact with blood
and body fluids. For the Ebola viruses that have emerged to date, it’s a strategy that
works. This kind of strategy often fails with more nimble viruses.
In 1996 and 1997 quite another sort of outbreak occurred in the DRC. This out-
break lasted over a year, and while estimates vary, it likely hit over five hundred
people. Like Ebola hemorrhagic fever, the cases began with fever, aches, and
malaise. After a few days, rather than the bleeding characteristic of Ebola, patients
developed a severe rash consisting of pustules all over the body, often first appear-
ing on the face. The symptoms looked quite a bit like smallpox, perhaps the great-
est scourge of human history. But that was impossible. Smallpox had been eradi-
cated nearly twenty years earlier.
The cause of this outbreak was not smallpox, but it was a virus in the same
group of viruses (the Orthopoxvirus genus) called monkeypox. Monkeypox has
probably affected humans for ages, but it was only first recognized in 1970 during
the smallpox eradication effort. Prior to that, any monkeypox cases were likely
misdiagnosed as smallpox. While the ultimate animal reservoir for monkeypox re-
mains unknown, it’s almost certainly not a monkey, but rather a squirrel or other
rodent. Because the virus can infect species of nonhuman primate, occasional
human cases can result following contact with an infected monkey, hence the mis-
nomer.
I’ve been working on monkeypox since 2005 with Anne Rimoin, an epidemi-
ologist from UCLA, and her colleagues in the DRC, including Jean-Jacques Muyem-
be. Annie’s spent much of the last ten years pushing deeper into the logistical
nightmare of conducting high-quality surveillance for novel diseases like mon-
keypox in some of the most rural regions in the world. She manages to do it with
flare. I’ve seen her touch up her eyeliner in the mirror of an off-road motorbike in a
rural town in central DRC.
In 2007 we reported that monkeypox does not simply appear in outbreaks. The
long-term work Annie and her colleagues did showed us that the virus should
probably be considered endemic among humans—it is a permanent part of our
world. Rather than follow the traditional method for investigating monkeypox out-
breaks, Annie and her team set up shop in regions that had known infections.
Through constant monitoring, it became clear that there were monkeypox cases all
year long. And the number of cases was growing.
In the final analysis it was just a matter of how hard you looked. During my vis-
its to these sites, I’ve always seen cases of monkeypox. Some of these cases were
the result of exposure to infected animals, but a number of them were the result of
person-to-person transmission, the hallmark of a virus that’s beginning to fully
transition to a new host species.
You might wonder how such frightening cases of monkeypox could exist
without the world being aware of them. The answer is that the region where we
conducted this work is among the most remote in the world. Just to get to this area
requires a chartered flight on a small plane or a three-week boat trip on tributaries
of the Congo River that are only navigable during the rainy season. The setting is
austere and beautiful, with very few roads. Most villages are linked together by sim-
ple footpaths. The research uses rugged off-road motorbikes traveling sometimes
for as long as ten hours to get to the site of a case. Just dodging the chickens and
pigs represents a major challenge.
Despite the incredible dedication and skill of our Congolese colleagues, the idea
that the current meager resources devoted to health in the DRC could permit full
coverage of a country four times the size of France is crazy. Yet this is one of the
most important places in the world for the emergence of new viruses. Without a
doubt, an interconnected world that doesn’t invest in the infrastructure needed to
monitor these viruses is doomed to fall victim to more epidemics.
Whether or not monkeypox has the potential to join the pantheon of our Category
Four agents remains to be seen. Microbes that reach Category Four can live exclu-
sively in humans while simultaneously continuing to live in animal reservoirs. Mi-
crobes in Category Four include dengue, discussed in chapter 4. Dengue maintains
itself in human populations but also persists in a forest cycle spread by mosquitos
among nonhuman primates.
Category Four agents represent the final step on the journey to become a
human-specific microbe. They also present particular problems for public health.
When scientists finally succeed at generating a vaccine for dengue, it will help
countless people. But vaccination alone does not mean that we can eradicate
dengue. Even if every single human were vaccinated, the fact that the virus can per-
sist among monkeys in forests in Asia and Africa means that it will always have the
potential to reenter human populations.
Monkeypox still ranks as a Category Three agent, but that could certainly
change. Since our work in 2007, we’ve shown that the cases of monkeypox con-
tinue to grow in the DRC. Part of the explanation for this is that after smallpox was
eradicated in 1979 the smallpox immunization program was stopped. As more and
more nonimmunized, and therefore susceptible, children have been born into the
population, the number of cases has steadily risen. And each additional case repre-
sents an opportunity for a unique monkeypox virus to jump or mutate. One of
these may have the potential to spread and push monkeypox to the next level,
which is why we keep tabs on this particular virus.
Only a handful of the microbes that have started on the path toward becoming
exclusive human microbes have succeeded. The examples that have made it repre-
sent the mainstay of contemporary disease control. Viruses like HIV are generally
considered to be present exclusively in humans, as are bacterial microbes like
tuberculosis and parasites like malaria.⁵ Yet it’s often difficult to make the human-
exclusivity call. Unless we have comprehensive data about the diseases of wildlife,
it’s hard to know if there may be a hidden reservoir of a supposedly exclusive
human agent that could reenter human populations. And our understanding of the
diversity of microbes in wild animals is still in its infancy. We know very little about
what’s out there.
Agents like human papilloma virus and herpes simplex virus almost certainly
reside exclusively in humans, but they have likely been with us for millions of
years. With an agent like HIV, we get into a gray area. Could the virus that seeded
HIV a hundred or so years ago continue to live on in chimpanzees? Viruses very
close to HIV have been found in chimpanzees, but we haven’t sampled every chim-
panzee in nature, so even closer relatives might still be out there. Similarly, given
the diversity of malaria parasites we’ve seen in some of the African apes during re-
cent studies, the possibility remains that some population of ape in some forest
shares “human” malaria.
The question of reservoirs is an important one. We celebrated with great fanfare
the eradication of smallpox in 1979. Eliminating that scourge from the human
population was probably the greatest feat in public health history. Yet much re-
mains unknown about how smallpox originated.
Smallpox appears to have first emerged during the domestication revolution.
Evidence points to an origin in camels, which are infected with the closest known
viral relative to smallpox, camelpox. Yet camels may very well have been a bridge
host permitting the virus to jump from rodents, where most of the viruses like
smallpox reside. If so, could there be a virus out there living in some North
African, Middle Eastern, or central Asian rodent that’s too close for comfort? A
virus close enough to smallpox to reemerge and spread in humans? If so it might
look a lot like monkeypox, and, like monkeypox, it might be largely missed.
For our purposes we should certainly consider smallpox to be one of our Category
Five agents—a virus that made it to the point where it could live and survive exclu-
sively in humans. And we should be proud of the herculean and successful effort
to wipe it out.
Smallpox certainly had the right stuff. It probably killed more humans than any
virus that has ever infected our species. Following the domestication revolution,
the growing human populations and domestic animal populations (like camels)
set the stage for the virus to gain a true foothold in our species.
We’ll probably never know definitively what the first real pandemic was, but
smallpox is a good candidate. It spread throughout the Old World after its likely
camel origins but never made it to indigenous human populations in the New
World on its own. When the Old World and New World collided at the onset of
global travel some five hundred years ago, smallpox had the chance to make the
jump, killing millions of the completely susceptible inhabitants of the Americas.
That jump across continents positions it as the most likely candidate for the first
real pandemic.
By the middle of the eighteenth century, smallpox had not only spread to every
part of the world but had established itself just about everywhere, save for some is-
land nations. And it killed. During the eighteenth century, it’s estimated that small-
pox killed around four hundred thousand people a year in Europe. The death rates
elsewhere may have been even higher.
The human tendency to travel, to explore, and to conquer would accelerate dramat-
ically over the five hundred years that would follow the discovery of the New
World—and the coinciding smallpox pandemic. Global transportation networks
would tie humans and animals together in a way that would accelerate the emer-
gence of new viruses. These connections would result in a single, interconnected
world—a world vulnerable to plague.
