THE GENTLE VIRUS
All living organisms focus huge amounts of energy on having successful offspring.
In humans, this means breastfeeding and constant care of babies for the first few
years of their lives. In other organisms, like sea tortoises, the energy is spent not
on care for existing offspring but in creating the conditions necessary to success-
fully launch hundreds of instantly self-sufficient infants—accumulating nutrients to
place in eggs, traveling to the right place to lay eggs, and burying eggs in sand to
protect them from predators. Whatever they may look like, parents want their kids
to succeed, and they deploy a range of techniques to aid them in that objective.
Among the concerned parents out there are wasps. Two families of wasps go to
an extraordinary measure to protect their offspring. These wasps, of the braconid
and ichneumonid families, lay their eggs on the backs of caterpillar larvae. The
eggs then eat the flesh of the caterpillar as they grow. This is actually a fairly
common setup on our planet, with thousands of such relationships in existence.
There is an evolutionary tension between the caterpillar and the wasp. The cater-
pillar’s defenses change over time to thwart the wasp eggs, and the wasp eggs de-
velop the capacity to counteract or skirt the caterpillar’s defenses, and so on.
In their battle to win this evolutionary arms race, the female braconids and ich-
neumonids do something not known among other wasps that live in this way: they
coat their eggs in a special substance before they lay them on the back of a cater-
pillar. Slowly, this potent substance kills the caterpillar, leaving the eggs to grow
unrestricted on the bounty that remains.
The wasp mothers’ truly amazing substance is not a plant toxin or a venom. It’s
a concentrated dose of virus. This virus, a member of the polydnavirus family,
harmlessly infects the wasp but unleashes a range of consequences in the cater-
pillar. It replicates in the wasp’s ovaries and is injected, together with the wasp’s
eggs, into the caterpillar. The virus returns the favor by suppressing the host cater-
pillar’s immune system and causing severe disease and even death to the cater-
pillar, thereby protecting the eggs. The wasp helps the virus, and the virus helps
the wasp.
Viruses operate along a continuum with their hosts: some harm their hosts,
some benefit their hosts, and some—perhaps most—live in relative neutrality, nei-
ther substantively harming nor benefiting the organisms they must at least tempo-
rarily inhabit for their own survival.
In this chapter we’ll shift gears. Rather than discuss the harm viruses can cause,
we’ll focus on how they can assist us in the battle against infectious and other dis-
eases. The goal of public health should not be to eradicate all viral agents; the goal
should be to control the deadly ones.
Perhaps the most profound way that viruses have assisted us in the fight against
pandemics has been in the case of vaccines. And there is no better example of this
partnership than our relationship with the cowpox virus.
In the late eighteenth century, the noted English scientist Edward Jenner became
fascinated with the observation that milkmaids somehow seemed to avoid
becoming infected with smallpox. On May 14, 1796, taking a bit of a leap, Jenner
inoculated James Phipps, the eight-year-old son of his gardener, with cowpox that
he’d scraped from the hand of a young milkmaid named Sarah Nelmes. She had
acquired the virus from a cow named Blossom, whose hide you can apparently still
see if you visit St. George’s medical school in London.
Young James Phipps got mildly sick, a bit of fever and some discomfort but that
was all. After James recovered, Jenner went on to inoculate the boy with a small
amount of the actual smallpox virus.¹ The smallpox did nothing. The effect, which
Jenner then replicated in others, would go on to be one of the most profound find-
ings in human history. He had developed a vaccine to prevent smallpox, one of the
worst scourges of humankind. The discovery is credited by some as saving more
lives than any other discovery in history.
The vaccines that were created as a result of Jenner’s work eventually led to the
eradication of smallpox from the planet. I remember seeing one of the original
documents certifying that smallpox had been eliminated. It was in the Johns
Hopkins office of D. A. Henderson, who had led the WHO’s global smallpox eradi-
cation campaign. D. A. had kindly lent me one of his largely unused offices at Hop-
kins as a staging ground to accumulate the supplies I’d need to start our work
monitoring outbreaks in central Africa. I remember thinking to myself about how
important eradication was and how it had been accomplished.
We credit the eradication of smallpox to a vaccine. But it’s worth examining this
further. The vaccine that allowed us this triumph was actually an unadulterated
virus that we harnessed and used for our benefit. In fact, even the word vaccine it-
self derives from the Latin term for cowpox, or variolae vaccinae, where variolae
means “pox” and vaccinae means “of cows.” In other words, at its very heart, the
concept of a vaccine is the productive use of one virus to fight another.
becoming infected with smallpox. On May 14, 1796, taking a bit of a leap, Jenner
inoculated James Phipps, the eight-year-old son of his gardener, with cowpox that
he’d scraped from the hand of a young milkmaid named Sarah Nelmes. She had
acquired the virus from a cow named Blossom, whose hide you can apparently still
see if you visit St. George’s medical school in London.
Young James Phipps got mildly sick, a bit of fever and some discomfort but that
was all. After James recovered, Jenner went on to inoculate the boy with a small
amount of the actual smallpox virus.¹ The smallpox did nothing. The effect, which
Jenner then replicated in others, would go on to be one of the most profound find-
ings in human history. He had developed a vaccine to prevent smallpox, one of the
worst scourges of humankind. The discovery is credited by some as saving more
lives than any other discovery in history.
The vaccines that were created as a result of Jenner’s work eventually led to the
eradication of smallpox from the planet. I remember seeing one of the original
documents certifying that smallpox had been eliminated. It was in the Johns
Hopkins office of D. A. Henderson, who had led the WHO’s global smallpox eradi-
cation campaign. D. A. had kindly lent me one of his largely unused offices at Hop-
kins as a staging ground to accumulate the supplies I’d need to start our work
monitoring outbreaks in central Africa. I remember thinking to myself about how
important eradication was and how it had been accomplished.
We credit the eradication of smallpox to a vaccine. But it’s worth examining this
further. The vaccine that allowed us this triumph was actually an unadulterated
virus that we harnessed and used for our benefit. In fact, even the word vaccine it-
self derives from the Latin term for cowpox, or variolae vaccinae, where variolae
means “pox” and vaccinae means “of cows.” In other words, at its very heart, the
concept of a vaccine is the productive use of one virus to fight another.
words, they’re just viruses we inject into people (or animals) to create an immune
response that will protect against another more deadly virus. Others, like the oral
polio vaccine and the measles, mumps, rubella (MMR) vaccine, are attenuated
virus vaccines—live viruses that we have bred in the lab to make less deadly and
used in effectively the same way. Some, like the influenza vaccines, are inactivated
virus vaccines—viruses we have made incapable of reproducing themselves yet can
elicit an appropriate immune response. They are still viruses. Others, like the hep-
atitis B vaccine and human papillomavirus (HPV) vaccine, use selected parts of the
virus. The point is that pretty much the entire contemporary science of vaccinology
uses viruses themselves to protect against other viruses. Safe viruses are some of
the best friends we have in fighting the deadly ones.
The utility of using microbes to protect us against infectious diseases seems clear
enough. But can microbes help us to control chronic diseases? The answer
increasingly is yes.
Introductory courses in public health make firm distinctions between infectious
and chronic diseases. They place infectious diseases like HIV, influenza, and
malaria on one side of the aisle and chronic diseases like cancer, heart disease,
and mental illness on the other. Yet these distinctions do not always hold up to
greater scrutiny.
In 1842 Domenico Rigoni-Stern, an Italian physician, looked at the patterns of
disease in his hometown of Verona. Among the things Rigoni-Stern noticed was
that the rate of cervical cancer appeared to be substantially lower among nuns than
married women. He also noted that behavioral factors like age at first sexual inter-
course and promiscuity seemed related to the frequency of the cancer. He con-
cluded that the cancer was caused by sex.
While sex itself did not end up being the cause of cervical cancer, Rigoni-Stern
was on exactly the right track. In 1911 the young scientist F. Peyton Rous injected
tissue from a chicken tumor into healthy chickens, while he was working at the
Rockefeller Institute for Medical Research (now the Rockefeller University). Rous
found that the injected tissue caused precisely the same type of cancer in the
healthy chicken recipient. The cancer was transmissible! The virus that causes that
chicken cancer—now called Rous sarcoma virus after its discoverer—was the first
virus demonstrated to cause any cancer, and it won Rous the Nobel Prize. It would
not be the last virus found to have a connection to cancer
In the 1970s the German physician-scientist Harald zur Hausen had a hunch about
the cause of cervical cancer. Following the work of Rigoni-Stern and Rous, zur
Hausen suspected it was caused by an infectious agent. Unlike the scientists of his
time who thought that the cause was herpes simplex virus, zur Hausen believed
that the virus that caused genital warts, the papilloma virus, was the culprit. Zur
Hausen and his colleagues spent much of the late 1970s characterizing different
human papillomaviruses from warts of various sorts and looking to see if they
could be found in tissue samples that came from biopsies of women with cervical
cancer. In the early 1980s they finally hit pay dirt. They discovered two papillo-
maviruses, HPV-16 and HPV-18, in a high percentage of biopsy specimens. Today,
these two viruses alone are considered to account for up to 70 percent of cervical
cancer.
Zur Hausen, like his predecessor Rous, received the Nobel Prize for his break-
through. And the research they conducted went on to form the foundation for a
vaccine against cervical cancer. In June 2006, Merck received approval from the US
Food and Drug Administration (FDA) to market Gardasil, an HPV vaccine. Like the
other vaccines discussed earlier, Gardasil uses elements of the human papillo-
mavirus itself to elicit an immune response that prevents those inoculated from
being infected if they later have contact with the actual virus. In the case of Gar-
dasil, the vaccine utilizes virus-like particles (VLPs) that look like the actual viruses
but have no actual genetic material so they cannot replicate themselves. And the
vaccine works. By preventing infection from the types of human papilloma virus
that cause cervical cancer, the vaccine effectively prevents most of the deadly can-
cer.
Chronic diseases are notoriously difficult to treat. Whether for cancer, heart dis-
ease, or mental illness, treatments rarely return people to their pre-disease condi-
tion, and in many cases there are no treatment options at all. When a chronic dis-
ease is found to be caused by a microbe, the potential for cure and prevention im-
proves dramatically. Cervical cancer, for example, which once required invasive,
damaging, and only sporadically effective treatment, can suddenly be prevented by
the deployment of a vaccine. Microbes make for low-hanging fruit when it comes
to preventing and possibly curing chronic disease.
Cervical cancer is not the only chronic disease that is caused by a microbe.
Liver cancer can be caused by both hepatitis B virus and hepatitis C virus. Re-
searchers are currently exploring the possibility that prostate cancer, one of the
leading causes of cancer death in American men, can be caused by xenotropic MLV
related virus (XMRV). Stomach ulcers can be caused by the bacteria Helicobacter
pylori. At least some types of lymphotropic virus, a virus family we discussed in
chapter 9 and that we’ve discovered among the hunters we worked with in central
Africa, are known to cause leukemia. It’s even possible that heart disease, the cul-
prit in one-third of US deaths and countless deaths worldwide, has an infectious
component. The innovative American evolutionary biologist Paul Ewald, who has
written on the connection between infectious agents and chronic disease, suggests
that the interplay between Chlamydia pneumoniae and environmental factors may
be to blame for heart attacks, strokes, and other cardiovascular illness.
In some cases viral causes are suspected but have not yet been confirmed—
perfect fodder for eager scientists. The distribution of type I diabetes cases suggest
a possible connection with an infectious agent, but none to date has been iden-
tified. My own research team and our collaborators recently began work on a grant
from the National Cancer Institute to screen tumor specimens from multiple types
of cancer in search of viruses. It’s exploratory research, but the potential benefits
as we find them could be monumental.
Even some mental illnesses may result from infections with microbes. As we’ve
seen, microbes can have an impact on behavior. Toxoplasma alters very specific
neural circuits in rodent brains to decrease their fear of cats and thereby increase
the chances that the parasite can complete its life cycle by ending up in a hungry
cat. Rabies causes fear of water and increases aggressiveness in those infected
with it, which helps accumulate virus in saliva and deliver it through a potentially
fatal bite.
With these prominent examples of behavioral manipulation, it’s an obvious leap
to suspect that microbes could play a contributing role in mental illness, a subject
that has been the focus of a researcher at Johns Hopkins Medical School for some
years. Robert Yolken studies a range of disorders, including bipolar disorder,
autism, and schizophrenia, examining them closely to see if microbes might play a
role. His primary focus is schizophrenia.
Schizophrenia certainly seems to invite discussion on links with infectious
agents. For years, researchers have noted a relationship between seasonality of
birth and schizophrenia: children born in winter months are more likely to develop
schizophrenia than those who are not. This finding has long been thought to sug-
gest that wintertime illnesses such as influenza, infecting either the pregnant moth-
er or infant, may predispose an individual toward schizophrenia, although the re-
sults remain unclear for now.
Yolken’s most recent focus has been Toxoplasma gondii, or simply toxoplasma.
He and others in the field have put together a plausible if perhaps not fully defin-
itive case for the parasite’s role in this devastating mental illness.³ Multiple studies
have found a correlation between schizophrenia and the presence of antibodies to
toxoplasma. Some adults who experience the onset of toxoplasma disease expe-
rience psychological side effects. And antipsychotic drugs used to treat
schizophrenia have also been seen to have an effect on toxoplasma in laboratory
cell cultures. In a sign of the intense research that has surrounded the subject of
schizophrenia, studies have documented that individuals with schizophrenia have
had more exposure to cats than unaffected controls. Together these and other
studies point to a connection. This connection still faces challenges since the para-
site is not likely to be involved in all cases of schizophrenia, a disease that also has
important genetic determinants.
A virus may also be the cause of a complex, controversial, and somewhat
mysterious disorder. Chronic fatigue syndrome (CFS) is a debilitating illness with
no known origins and a variety of nonspecific symptoms: weakness, extreme fa-
tigue, muscle pain, headaches, and difficulty concentrating, among others. Most
people who have stayed up all night studying for a final or pushed themselves too
hard at the gym will recognize these symptoms as familiar and common. They are
also common symptoms for many other medical conditions, making it difficult to
eliminate other possible root causes. As a result, medical experts and members of
the public have debated the authenticity of CFS as a unique disorder. However, re-
cent studies support those who argue that CFS is a genuine disease. Following
several studies with contradicting results, a study published in August 2010 found
a correlation between CFS and a virus in the murine leukemia virus family. More
research is necessary to establish a causal link between MLV and CFS, but the find-
ing has offered hope to many.
As with cancer, a microbial cause of schizophrenia or CFS would invite quick
and possibly important new diagnostics, therapies, and vaccines for these chronic
disorders, which cause great pain and discomfort to victims and families. In the
case of cervical cancer, the vast majority of the illness is ascribable to human papil-
loma virus, so a vaccine preventing it could be developed. This is not always the
case. If only a percentage of people who suffer from schizophrenia or CFS do so
because of a virus, it will make the associations more complicated and the dis-
covery of links more challenging. Yet it’s worth the effort. Many chronic diseases
lack good treatment options, and our ability to create vaccines and drugs for mi-
crobes is legendary. Wouldn’t you want to vaccinate yourself or your children for
schizophrenia or heart disease? Even if it only protected them from one of a hand-
ful of causes of the illnesses? One day, we hope, you will be able to do just that.
Using one microbe to prevent another microbe from causing disease is pretty
amazing. But how about using a microbe to actually address the disease directly?
This is something that’s increasingly explored in the nascent field of virotherapy.
All viruses infect cells as part of their life cycle, and they don’t infect cells ran-
domly. As we’ve discussed, viruses infect cells in a lock-and-key manner: they enter
into those cells that have particular proteins, or cell receptors, on their cell surfaces
that the virus recognizes. If a virus existed that recognized and infected only can-
cerous cells, for example, then the virus could theoretically burn through those
cells, killing the cancers along the way. The hope, of course, would be that when
they were done with the cancer cells, they’d have nothing to infect and would die
off.
Just such a virus exists. The Seneca Valley virus is a naturally occurring virus
that appears to specifically target tumor cells living at the interface of the nervous
and endocrine systems. It reproduces in the tumor cells, causing lysis, or rupturing
and death of the cells. When released, it spreads to new tumor cells to continue its
work. Now that’s a gentle virus!
Seneca Valley virus was discovered in a biotech company laboratory in Pennsyl-
vania’s Seneca Valley. The virus had likely contaminated cell cultures from cattle or
pig products commonly used in the laboratory. It was isolated and found to be a
new virus in the picornavirus family, which includes polio. Testing showed that the
virus had amazing selectivity to cancerous cells in the neuroendocrine system yet
failed to infect healthy cells. This is a good reminder that not all viruses that cross
the species barrier do harm.
The Seneca Valley virus is not alone. The small but growing group of virother-
apy researchers use and adapt a range of viruses, including herpes virus, aden-
ovirus (one of the viruses that causes colds), and the measles virus—to create
viral therapies that can knock down cancer. Probably the most advanced among
them is a herpes virus therapy developed by a biotech firm called BioVex, which is
in the last stage of trials to determine its ability to control head and neck cancer.
While the results of the trial have not yet been released, Amgen, a Fortune 500
biotech company, recently entered into the final stages of a deal to acquire the
smaller BioVex as well as its herpes virus therapy.
What about viruses that interfere with other viruses?
One brilliant example is a wonderful little virus called GB virus C, which
appeared in chapter 5 and is found in a high percentage of people. This odd-
sounding virus is in the same family as hepatitis C virus, but it certainly doesn’t kill
us. In fact, it can save us.
In an incredible study published in the top medical journal the New England
Journal of Medicine in 2004, researchers showed that infection with the GB virus C
could help prolong the lives of men who were infected with HIV. When examined
five to six years after infection with HIV, men without detectable GB virus C were
nearly three times more likely to die than those who had active GB virus C infec-
tions. How GB virus C acts to save AIDS patients is still unclear, but it appears that
it might interfere directly with HIV. Whatever the mechanism, this tiny organism
has likely prolonged millions of lives during the course of the current pandemic.
Viruses can also interfere with other kinds of microbes—bacteria can get sick too.
Viruses infect all forms of cellular life, whether bacteria, parasite, or mammal. As
we discussed in chapter 1, while nonspecialists tend to see microbes as a homoge-
nous bunch, nothing could be further from the truth. All of the cell-based life
forms (bacteria, parasites, fungi, animals, plants, and so forth) are thought to be
more closely related to each other than they are to viruses.⁴ Furthermore, parasites
fall into the class of life called eukaryotes and are more closely related to us than
either they or we are to bacteria.
A fascinating Harvard virologist now at the Texas Biomedical Research Institute,
Jean Patterson became interested in just this phenomenon in the mid-1980s. While
her main focus had been viruses, she wanted to look closer at a group of parasites
called protozoa, which includes malaria and leishmania, a harmful protozoan para-
site transmitted to humans by the bite of the sand fly. Patterson was interested in
how the parasites translated their genetic information into action, and she became
fixated on discovering a virus that could infect this interesting parasite.
In 1988 Patterson and her colleagues discovered a small virus that naturally in-
fects leishmania parasites; they were the first to characterize a virus from this
group of parasites. Viruses that infect parasites could provide natural systems for
parasite virotherapy. And as with the cancer-killing viruses, parasite viruses could
potentially be adapted for efficiency and safety.
I’ve personally spent a reasonable portion of my professional life studying pro-
tozoa parasites. First, as a doctoral student working in Malaysian Borneo with my
veterinary colleagues Billy Karesh, Annelisa Kilbourn, and Edwin Bosi, we tried to
understand malaria in wild and captive orangutans.⁵ More recently, my colleagues
and I searched for the origin of malaria in central Africa, a subject discussed in de-
tail in chapter 3. Could it be possible that in some of our vials holding an ape
malaria parasite resides a new malaria-infecting virus? One that could potentially
kill our own deadly malaria, Plasmodium falciparum?
When most people think about microbes, they frame it as a battle of people versus
bugs. Perhaps if they’re being a bit more creative, they’ll consider the battles
among the microbes themselves. But the reality is even more interesting than that.
We’re part of an incredibly rich community of interacting microbes—with hugely
complicated collaborations, battles, and wars of attrition with each other and our-
selves.
Consider the human body. Only about one out of every ten cells between your
hat and shoes is human—the other nine belong to the masses of bacteria that coat
our skin, live in our guts, and thrive in our mouths. When we consider the diversity
of genetic information on board, only one out of every thousand bits of genetic
information on and in us can properly be called human. The bacteria and viruses
represented by thousands of species will outnumber the human genes every time.
The sum total of bacteria, viruses, and other microbes present in our body is
called the microbiota, and the sum total of their genetic information is called the
microbiome. A new science has developed in the past five years to characterize the
human microbiome. Empowered by new molecular techniques that bypass the
nearly impossible task of individually culturing each of the thousands of microbes,
scientists are rapidly figuring out exactly what the overall community of human and
microbial cells in our bodies consists of.
The findings coming out are fascinating. Our guts are teeming with a complex
assemblage of microbes, many of whom are long-term residents. They are not sim-
ply free riders. A great deal of the plant material we consume requires bacteria and
their enzymes for digestion; human enzymes alone would not do the trick. And
how the community of microbes is structured makes a big difference.
In a pivotal series of studies, Jeff Gordon and his students and postdocs (many
of whom are now successful professors themselves) showed just how important
the communities of bugs in our guts actually are. They have demonstrated that
obesity is associated with a decreased relative abundance of one particular group
of bacteria—the Bacteroidetes.
In another elegant study, Gordon and his team showed that the obese micro-
biota increases the amount of energy that can be obtained from food. In the final
coup de grâce, they showed that altering the gut microbiota of normal mice with
the obese microbiota results in significant weight gain. Very simply, bacteria in our
guts play a role in obesity. Just as we saw with cervical cancer, a microbial cause of
a chronic disease may point to an easier method to solve it. One day we may very
well use a combination of probiotics and antibiotics to subtly alter our gut micro-
biota and to help us maintain a healthy weight.
Perhaps not surprisingly, the teeming masses of microbes in our guts also play
a role in how we’re affected by deadly microbes. In the case of salmonella, a deadly
bacteria and one of the leading causes of food-borne illness, it’s been known for
some time that the biggest risk factors for the disease are eating eggs away from
home and using antibiotics. Eating eggs is a risk factor since chickens infected
with the bacteria can contaminate them. The antibiotic use, however, has long pre-
sented a mystery.
Recent research on gut microbiomes may shed some light. Justin Sonnenburg,
a Stanford professor, is conducting important work to do just this. He uses an in-
credible system for maintaining germfree mice in a laboratory. The rodents live in
completely sterile conditions—even to the point where their food is autoclaved be-
fore they eat it, eliminating any potential microbial contaminants. The germfree ro-
dents provide a perfect model for picking through the exact determinants of dif-
ferent gut microbiota on the conditions of their hosts.
While it’s long been suspected that antibiotic use kills helpful microbes, thus
damaging the natural shield that our gut microbes provide against new and inva-
sive bugs like salmonella, it’s still not clear exactly how this happens. In the future,
the work done in Sonnenburg’s lab should tell us.
There are gentle microbes out there—bugs that help us, defend us, and live qui-
etly within us doing no harm at all. If we could accurately determine which of the
microbes on our bodies and in the environment were beneficial to us and which
were rogue, we’d find something pleasantly surprising: the harmful ones are cer-
tainly in the minority. The goal of public health should not be to have a completely
sterile world but to find the rogue elements and control them. A key part of ad-
dressing the nasty microbes will be to cultivate the microbes that help us. One day
soon, the way we protect ourselves may be by propping up the bugs that live within
us rather than knocking them down.
