THE VIRAL PLANET
Martinus Beijerinck was a serious man. In one of the few images that remain of
him, he sits in his Delft laboratory in the Netherlands, circa 1921, just a few days
before his reluctant retirement. Bespectacled and in a suit, he’s presumably as he’d
like to be remembered—among his microscopes, filters, and bottles of laboratory
reagents. Beijerinck had some peculiar beliefs, including the idea that marriage and
science were incompatible. According to at least one account, he was verbally abu-
sive to his students. While rarely remembered in the history of biology, this strange
and serious man conducted the pivotal studies that first uncovered the most di-
verse forms of life on Earth.
Among the things that fascinated Beijerinck in the late nineteenth century was a
disease that stunted the growth of tobacco plants. Beijerinck was the youngest
child of Derk Beijerinck, a tobacco dealer who went bankrupt due to crop losses
caused by this blight. Tobacco mosaic disease causes discoloration in young to-
bacco plants, leading to a unique mosaic pattern on leaves and radically slowing
the growth of the adult plants. As a microbiologist, Beijerinck must have been frus-
trated by the unclear etiology of the disease that had wiped out his father’s busi-
ness. Despite the fact that it spread like other infections, microscopic analysis did
not reveal a bacterial cause of disease. Curious, Beijerinck subjected the fluids of
one of the diseased plants to intense filtration using a fine-grained porcelain filter.
He then demonstrated that even after such filtration the fluids retained their capac-
ity to infect healthy plants. The tiny size of the filter meant that bacteria, the usual
suspects for transmissible disease at the time, would be too large to pass through.
Something else must have caused the infection—something unknown and consid-
erably smaller than everything else recognized to be alive in his time.
Unlike his colleagues, many of whom believed a bacteria would emerge as the
cause, Beijerinck concluded that a new form of life must cause tobacco mosaic
disease.¹ He named this new organism the virus, a Latin word referring to poison.
The word virus had been around since the fourteenth century, but his use was the
first to link it to the microbes to which it refers today.² Interestingly, Beijerinck re-
ferred to viruses as “contagium vivium fluidum,” or “soluble living agent,” and felt
they were likely fluid in nature. That is why he used the term virus—or poison—to
denote its “fluidity.” It wasn’t until later work with the polio and foot-and-
mouth-dis-ease viruses that the particulate nature of viruses was confirmed.
In Beijerinck’s time a new microscopic perspective began revealing itself to
scientists. Looking through microscopes and applying gradually smaller filters,
these microbiologists realized something that continues to amaze us today: shield-
ed from our human-scaled senses is a wide, teeming, startlingly diverse, unseen
world of microbial life.
I teach a seminar at Stanford called Viral Lifestyles. The title was meant to evoke
curiosity among prospective students but also describe one of the course’s objec-
tives: to learn to envision the world from the perspective of a virus. In order to
understand viruses and other microbes, including how they cause pandemics, we
need to first understand them on their own terms.
The thought experiment that I give my students on the first day is this: imagine
that you have powerful glasses allowing you to perceive any and all microbes. If
you were to put on such magical bug-vision specs, you would instantly see a whole
new, and very active, world. The floor would seethe, the walls would throb, and
everything would swarm with formerly invisible life. Tiny bugs would blanket every
surface—your coffee cup, the pages of the book on your lap, your actual lap. The
larger bacteria would themselves teem with still smaller bugs.
This alien army is everywhere, and some of its most powerful soldiers are its
smallest. These smallest of bugs have integrated themselves, quite literally, into
every stitch of the fabric of earthly life. They are everywhere, unavoidable, infecting
every species of bacterium, every plant, fungus, and animal that makes up our
world. They are the same form of life that Beijerinck found in the late days of the
nineteenth century, and they are among the most important of the microbial world.
They are viruses.
Viruses consist of two basic components, their genetic material—either RNA or
DNA—and a protein coat that protects their genes. Because viruses don’t have the
mechanisms to grow or reproduce on their own, they are dependent on the cells
they infect. In fact, viruses must infect cell-based life forms in order to survive.
Viruses infect their host cells, whether they are bacterial or human, through the use
of a biological lock-and-key system. The protein coat of each virus includes molec-
ular “keys” that match a molecular “lock” (actually called a receptor) on the wall of
a targeted host cell. Once the virus’s key finds a matching cellular lock, the door to
that cell’s machinery is opened. The virus then hijacks the machinery of that host
cell to grow and propagate itself.
Viruses are also the smallest known microbes. If a human were blown up to the
size of a stadium, a typical bacterium would be the size of a soccer ball on the
field. A typical virus would be the size of one of the soccer ball’s hexagonal patch-
es. Though humans have always felt virus’s effects, it’s no wonder it took us so
long to find them.
Viruses, the most diverse forms of life, remained completely opaque to humans
until a meager one hundred years ago with Beijerinck’s discovery. Our very first
glimpses of bacteria came a little under four hundred years ago when Antonie van
Leeuwenhoek adapted the looking glasses of textile merchants to create the first
microscope. With it, he saw bacteria for the first time. This finding represented
such an incredible paradigm shift that it took the British Royal Society another four
years before it would accept that the unseen life forms were not merely artifacts of
his unique apparatus.
Our scientific understanding of unseen life has proceeded pitifully slowly. Com-
pared to some of the other major scientific breakthroughs over the last few thou-
sand years, our understanding of the dominance of unseen life occurred only re-
cently. By the time of Jesus, for example, we already understood critical elements of
how the Earth rotated, its rough size, and its approximate distance to the sun and
moon—all fairly advanced elements in understanding our place in the universe. By
1610 Galileo had already made his first observations using a telescope. Van
Leeuwenhoek’s microscope came fifty years after that.
L: Replica of van Leeuwenhoek’s microscope, 17th century; R: van Leeuwenhoek’s
microscope in use. (L: Dave King / Getty Images; R: Yale Joel / Getty Images)
It is hard to overstate the paradigm shift that van Leeuwenhoek’s discovery
represents. For thousands of years humans had recognized the existence of plan-
ets and stars. Yet our understanding of unseen life and its ubiquity began only a
few hundred years ago with the invention of the microscope. The discovery of
novel life forms continues to this day. The most recent novel life form to be uncov-
ered is the unusual prion, whose discovery was acknowledged with a Nobel Prize
in 1997. Prions are an odd microscopic breed that lack not only cells but also DNA
or RNA, the genetic material that all other known forms of life on Earth use as their
blueprint. Yet prions persist and can be spread, causing, among other things, mad
cow disease. We would be arrogant to assume that there are no other life forms re-
maining to be discovered here on Earth, and they are most likely to be members of
the unseen world.³
We can roughly divide known life on Earth into two groups: noncellular life and cel-
lular life. The major known players in the noncellular game are viruses. The domi-
nant cellular life forms on Earth are the prokaryotes, which include bacteria and
their cousins, the archaea. These life forms have lived for at least 3.5 billion years.
They have striking diversity and together make up a much larger percentage of the
planet’s biomass than the other more recognizable cellular forms of life, the eukaryotes, which include the familiar fungi, plants, and animals.
Another way of categorizing life is this: seen and unseen. Because our senses
detect only the relatively large things on Earth, we are parochial in the way that we
think about the richness of life. In fact, unseen life—which combines the worlds of
bacteria, archaea, and viruses as well as a number of microscopic eukaryotes—is
the truly dominant life on our planet. If some highly advanced extraterrestrial
species were to land on Earth and put together an encyclopedia of life based on
which things made up most of Earth’s diversity and biomass, the majority of it
would be devoted to the unseen world. Only a few slender volumes would be dedi-
cated to the things we normally equate with life: fungi, plants, and animals. For bet-
ter or worse, humans would make up no more than a footnote in the animal vol-
ume—an interesting footnote but a footnote at best.
Global exploration to chart the diversity of microbes on the planet remains in its
infancy. Considering viruses alone gives some sense of the scale of what’s un-
known. It’s thought that every form of cellular life hosts at least one type of virus.
Essentially—if it has cells, it can have viruses. Every alga, bacterium, plant, insect,
mammal. Everything. Viruses inhabit an entire microscopic universe.
Even if every species of cellular life harbored only one unique virus, that would
by definition make viruses the most diverse known life forms on the planet. And
many cellular life forms, including humans, harbor a range of distinct viruses. They
are found everywhere—in our oceans, on land, deep underground.
The dominant forms of life on our planet, when measured in terms of diversity,
are unambiguously microscopic.
The largest virus to be discovered is the still microscopic six-hundred-
nanome-ter Mimivirus—viruses are by nature tiny. But the sheer number of viruses
in our world leaves a significant biological impression. A groundbreaking paper
published in 1989 by Oivind Bergh and his colleagues at the University of Bergen
in Norway found up to 250 million virus particles per milliliter of seawater, using
electron microscopy to count the viruses. Alternate, more comprehensive measure-
ments of the biomass of viruses on Earth are even more unimaginably outsized.
One estimate suggests that if all the viruses on Earth were lined up head to tail the
resulting chain would extend 200 million light years, far beyond the edge of the
Milky Way. Though often thought of as a pesky irritant or blight, viruses actually
serve a role that goes far beyond, and has a much greater impact than, what was previously understood—a role that scientists are only just beginning to compre-
hend.
It’s true that in order to complete their life cycle, viruses have to infect cellular
forms of life, but their role is not necessarily destructive or harmful. Like any major
component of the global ecosystem, viruses play a vital role in maintaining global
equilibrium. The 20 to 40 percent of bacteria in marine ecosystems that viruses kill
every day, for example, serves a vital function in the resulting release of organic
matter, in the form of amino acids, carbon, and nitrogen. And though studies in
this area are few, it is largely believed that viruses, in any given ecosystem, play the
role of “trust busters”—helping to ensure that no one bacterial species becomes
too dominant—thereby facilitating diversity.
Given the ubiquity of viruses, it would be surprising indeed if they were rele-
gated to a destructive role. Further studies will likely reveal the profound ecological
importance of these organisms not just in destroying but also in benefiting many
of the life forms they infect. Since Beijerinck’s discovery, the vast majority of
research conducted on viruses has understandably focused on the deadly ones. In
the same way, we know much more about venomous snakes, despite the fact that
they represent a startlingly small percentage of snake diversity. As we consider the
frontiers of virology in part III, we will explore the potential benefits of viruses in
detail.
Viruses infect all known groups of cellular life. Whether a bacterium living in the
high-pressure depths of the planet’s upper crust or a cell in a human liver, for a
virus, each is just a place to live and produce offspring. From the perspective of
viruses and other microbes, our bodies are habitats. Just as a forest provides a
habitat for birds and squirrels, our bodies provide the local environment in which
these beings live. And survival in these environments presents a range of chal-
lenges. Like all forms of life, viruses compete with each other for access to re-
sources.
Viruses face constant pressure from our immune systems, which have multiple
tactics to block their entrance into the body or disarm and kill them when they manage to get in. They face constant life choices: should they spread, which risks
capture by our immune systems, or remain in latency, a form of viral hibernation,
which can provide protection but sacrifices offspring.
The common cold sore, caused by the herpes simplex virus, illustrates some of
the challenges that viruses face in negotiating the complex habitats of our bodies.
These viruses find refuge in nerve cells, which because of their privileged and pro-
tected positions in our bodies do not receive the same level of immune attention
as the cells in our skin, mouth, or digestive tract. Yet a herpes virus that main-
tained itself within a nerve cell without spreading would hit a dead end. So herpes
viruses sometimes spread down through the nerve cell ganglions to the face to cre-
ate virus-loaded cold sores that provide them a route to spread from one person to
the next.
How viruses choose when to launch themselves remains largely unknown, but
they almost certainly monitor the environmental variables of their world when mak-
ing these decisions. Many of the adult humans who are infected with herpes sim-
plex virus know that stress can bring on cold sores. Some also have noted anecdo-
tally that pregnancy seems to bring on active infections. While still speculation, it
would not be surprising if viruses responded to environmental cues indicating se-
vere stress or pregnancy by activating. Since severe stress can indicate the possi-
bility of death, it may be their last opportunity to spread—a dead host is also a
dead virus. A pregnancy, on the other hand, presents the opportunity for spread ei-
ther through genital contact with the baby during childbirth or during the kissing
that inevitably follows the birth of a baby.
Transmission from host to host is such a fundamental need for infectious
agents that some take it a step further. The incredible malaria parasite Plasmodium
vivax hibernans goes so far as to keep a calendar of sorts. Many times larger than
herpes simplex virus, parasites like malaria are infectious agents like viruses and
bacteria but are in the eukaryotes class, and so are more closely related to animals
than they are to the others. Spread by mosquitoes, P. vivax hibernans persists in arc-
tic climates. In these cold locations, it can only infect mosquitoes seasonally dur-
ing the brief period each summer when the insects hatch. Rather than wasting en-
ergy producing offspring all year, the malaria parasite lies dormant for most of the
year in the human liver but, during summer, bursts to life, generating its spawn of
malaria offspring that spread through an infected person’s blood. While it’s still unclear exactly what triggers the relapse, recent studies suggest that it might be the
bites of mosquitoes themselves that provide an indication that the season for
spreading has begun.
The careful timing that viruses and other microbes use when choosing to
spread does not differ from the choices that other organisms make. Whether the
timing of fruiting in a tropical fruit tree or the timing of mating in water buffalo, liv-
ing things that time their reproduction appropriately have more successful off-
spring. This means the traits for accurately timing reproduction will persist and
diversify. And how microbes time their growth within our bodies also has a major
impact on illness.
The majority of microbes that cause infection in humans are relatively harmless,
but some have a striking capacity to make us sick. This can sometimes be ex-
pressed in the form of, say, a common cold (caused by a rhinovirus or adenovirus)
but can also manifest itself in life-threating illnesses such as smallpox.
Deadly microbes are a consistent challenge to evolutionary biologists because
of their paradoxical habit of eviscerating habitats upon which they depend for their
own survival. It’s analogous to a bird destroying the forest in which it and its de-
scendants live. Yet the process of evolution occurs largely at the level of the indi-
vidual or even the gene. Evolution does not proceed with forethought, and there’s
nothing to stop a virus from spreading in such a way that leads to a dead end.
Such virally induced extinction events have undoubtedly occurred throughout the
history of interactions with microbes, no matter the ultimate cost for virus or host.
More central from the perspective of a virus is the impact of disease on trans-
mission. As we learned in the introduction, on average, each germ must infect at
least one new victim for every old one who either dies or recovers and purges him-
self of the microbe in order to avoid extinction. This is the rule of the basic repro-
ductive number, or R0. If the average number of new victims per old victims drops
to less than one, then the spread of the microbe is doomed. Since microbes gener-
ally can’t walk or fly from one host to the next they often strategically alter their
host to help in their spread. From the perspective of a bug, a symptom can be an
all-important means of enlisting our help in moving itself around. Microbes often
make us cough or sneeze, which can permit them to spread through our exhaled breath, suffer from diarrhea, which can spread microbes through local water sup-
plies, or cause open sores to appear on our skin, which can spread through skin-
to-skin contact. In these cases it’s obvious why a microbe would trigger these
generally unpleasant symptoms. Unpleasant symptoms are one thing, but killer mi-
crobes are quite another.
Keeping its host alive and pumping out new microbes would seem to be an
ideal plan for a bug. And some bugs do certainly employ such a strategy. Human
papillomavirus, or HPV, infects around 50 percent of sexually active adults at some
point during their lifetimes. It currently infects around 10 percent of people on the
planet, a staggering 650 million people. And while a few strains of HPV cause cer-
vical cancer, most do not. Those strains that do kill their hosts infect them for
many years before showing any symptoms at all. Even if the current vaccines that
protect against the cancer-causing HPV variants were deployed universally, harm-
less HPV strains would continue to circulate at huge levels with an impact no
greater than occasional if unsightly warts. These viruses can spread effectively
without killing. Yet other bugs kill with startling efficiency.
Bacillus anthracis, a bacterial pathogen of grazing animals like sheep and cattle
that occasionally infects humans, causes anthrax infection, which kills quickly and
effectively. Following ingestion of anthrax spores during grazing, anthrax reacti-
vates and spreads rapidly throughout the animal, often killing it in short order. But
this dead host is by no means a dead end. After using the energetic resources of its
dying host to replicate in massive numbers, anthrax simply goes back into spore
form. Wind, a common feature of the grassy plains of the grazing hosts, then
spreads the spores throughout the environment, where they can wait for new
prospective victims to arrive. In the case of anthrax, creating hardy spores frees the
bug from any negative consequences of its destruction.
Such situations are not limited to spore-forming bacteria. The cholera bac-
terium, which gives us diarrhea, and the smallpox virus, which causes severe viral
disease, both kill in only days or weeks. But before the deaths take place, the deadly
symptoms spread trillions of microbes to potential new victims. Human deaths,
while unfortunate to us, represent a mere consequence of the conditions the bugs
need to get to their next hosts.
From the perspective of a bug the impact on its host is only measured in its
ability to survive and reproduce. And altering our physical bodies is just the beginning. Some microbes also influence our behavior, effectively making us zom-
bies acting in their benefit. One of the most striking examples comes from a feline
parasite, Toxoplasma gondii. While toxo, as parasitologists refer to it, can infect a
range of mammals from humans to rodents, its life cycle cannot be completed
until it lands in a cat. This parasite has found a frighteningly effective way to get
home when it ends up in the wrong mammal. Careful studies have documented
how the parasite spreads to the nervous system of infected, unsuspecting rodents
and hijacks their brains. Sometime after infection, having spent much of their life
steering clear of cats, mice begin to see them as positively enticing. This fatal at-
traction leads to a dead mouse, but also a toxo cyst that has the potential to com-
plete its life cycle in the newly infected, not to mention, satiated, cat.
Truly deadly diseases must strike a balance between the likelihood of causing
death in its victim once the victim is infected and their efficacy in terms of allowing
the victim to spread the disease to others. You can’t generally have your cake and
eat it, too—producing many microbes in a host increases the chance that they’ll
spread but also harms the host. Consequently, microbes sometimes use very dif-
ferent methods to cause devastation. They can keep the carrier alive for a long
time, which carries the potential to infect multiple victims over many months or
years, as in the case of the HPV virus. Or they can kill and spread quickly, infecting
dozens of new victims in the course of a day, as in the case of smallpox and
cholera.
That a tiny microbe has the potential to alter the body and behavior of its host
represents an enormous logistical feat. As scientists sequence the genomes of dif-
ferent species, they provide information on the relative size of the genetic blue-
prints that permit these organisms to function and give us a sense of how enor-
mous the feat is. The numerical genome sizes of many cellular forms of life can
range into the billions—humans, for example, have around three billion base pairs
(i.e., bits of genetic information); corn has around two billion. Certain viruses like
HIV and the Ebola virus, which use RNA rather than DNA for their genetic infor-
mation, manage to live with an average of only ten thousand base pairs of genetic
information, an incredible level of biological minimalism. How they manage to
replicate with such a small amount of genetic information, let alone do something remarkably complicated, like altering the behavior of their hosts, is truly amazing.
Viruses manage to function with such few genes through a variety of tricks that
allow them to maximize the impact of their diminutive genomes. Among the most
elegant is a phenomenon called overlapping reading frames. As an analogy, take a
poem of around thirteen thousand letters—say, T. S. Eliot’s poem The Waste Land.
It has roughly the same number of letters as the Ebola virus has base pairs. When
you read The Waste Land, it has meaning, tempo, reference—all of the charac-
teristics we normally expect from literature. In the same way, the genome of the
Ebola virus has meaning, with base pair letters making up genes that get translated
into the proteins that provide the virus with its capacity to function. If you take the
first stanza of The Waste Land, around a thousand letters, and begin to read it start-
ing with the second letter instead and move the first letters of the other words, it’s
a disaster. “April is the cruelest month” becomes “Prili sthec rueles tmonth.” Non-
sense.
Now imagine that embedded within the stanza was a second poem so that both
readings, the one that starts with the first letter and the one that starts with the sec-
ond letter, lead to fluent comprehensible verses. Now imagine that you took the
same stanza and read it backward and that a third hidden stanza emerged from the
same letters. This is precisely what viruses can do. A good challenge to poets (or
perhaps computer scientists) would be to create such a stanza to see if they could
be as creative as natural selection has been with viruses. Viruses with overlapping
reading frames use the same string of base pairs to code up to three different pro-
teins, an incredible genomic efficiency, which makes their small genomes pack a
much larger punch.
Overlapping reading frames represent just one of a range of adaptations that
viruses have to negotiate their worlds. Perhaps even more important for viruses is
their capacity to generate genetic novelty. Viruses have a diverse toolbox for alter-
ing themselves. Among the most fundamental is simple mutation. No organisms
have perfect fidelity. Any time a cell in our body or a bacterium divides to create
daughter cells or a virus replicates in a host cell, errors creep in. This means that
even in the absence of sexual mixing, offspring are never the same as their parents.
Yet viruses have taken mutation to a completely new level.
Viruses have some of the highest mutation rates of any known organisms.
Some groups of viruses, such as RNA viruses, have such high error rates that they
approach a threshold where any higher level of mutation would make them effec-
tively crash due to the loss of essential function from the resulting errors. While
many of the mutations harm the new viruses, the high number of offspring that
viruses produce increases the chances that some mutants survive and occasionally
outperform their parents. This raises the chances that they will successfully evade
the immune systems of their host, get the upper hand against a new drug, or gain
the capacity to jump to a completely new host species.
Middle-school biology teaches us that life is made up of sexual or asexual
organisms. Yet viruses and other microbes exchange genetic information in ways
that should make us question our early textbooks. When two different varieties of
virus infect the same host, from time to time they infect the same cell, setting the
stage for such exchange. In these cases, viruses sometimes create mosaic daugh-
ter viruses, which include some genetic parts from one of the viruses and com-
pletely different elements from another. In the case of reassortment, entire gene
segments are swapped between certain kinds of viruses. In recombination, genetic
material from one virus is swapped into a second virus. Genetic mixing of both
sorts provides viruses with a rapid and radical way to create novelty. As with
mutation, the novel daughter viruses have new blueprints that occasionally help
them survive and spread.
Our knowledge of microbes is still young. This vast unseen world is critical to our
planet and our species, yet we understand very little about it. We’ve already discov-
ered most of the plant and animal life on our planet, but we regularly discover
brand-new microbes. Ongoing studies of the diversity of microbes in animals,
plants, soils, and aquatic systems represent the tip of a very large iceberg. The mil-
lions of specimens that will result from these studies will catalyze our under-
standing of life. Among other things, the knowledge will help spark the devel-
opment of new antibiotics. It will also help us forecast the next pandemic. The
microbial world is the “new world,” the last frontier of undiscovered life on our
planet.
