The Viral Storm

by Nathan Wolfe

  Braconid wasp eggs on a caterpillar larva. (James H. Robinson / Photo Researchers, Inc.)

  In their battle to win this evolutionary arms race, the female braconids and ichneumonids 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 caterpillar. 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 caterpillar. 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 caterpillar’s immune system and causing severe disease and even death to the caterpillar, 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, neither substantively harming nor benefiting the organisms they must at least temporarily 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 diseases. The goal of public health should not be to eradicate all viral agents; the goal should be to control the deadly ones.

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  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 findings 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 eradication campaign. D. A. had kindly lent me one of his largely unused offices at Hopkins 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 itself 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.

  Parchment signed at Geneva on December 9, 1979, by the members of the Global Commission for Certification of Smallpox Eradication. (World Health Organization)

  Because cowpox is close enough to smallpox that it leads to immunity but distinct enough that it does not cause disease, it becomes the ultimate weapon to fight the plague. It leads to immunity without causing death. Those first infected with cowpox are safely protected against the related smallpox. That is what a vaccine does.

  Rather than think about vaccines as creative constructs of humans, another way of viewing them is as partnerships. Just as the wasp forms a mutualism with the polydnavirus to help protect its eggs, Jenner discovered that we could use cowpox to protect our children.

  Although we think of vaccines as sophisticated examples of human-developed technology, the vast majority of vaccines in current use are viruses or parts of viruses. Some, like the smallpox vaccine, are simply live viral vaccines. In other 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 hepatitis 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.

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  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 intercourse and promiscuity seemed related to the frequency of the cancer. He concluded 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.2

  Dr. Francis Peyton Rous, ca. 1966. (New York Public Library / Photo Researchers, Inc.)

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  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 papillomaviruses, 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.r />
  Zur Hausen, like his predecessor Rous, received the Nobel Prize for his breakthrough. 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 papillomavirus 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 Gardasil, 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 cancer.

  Chronic diseases are notoriously difficult to treat. Whether for cancer, heart disease, or mental illness, treatments rarely return people to their pre-disease condition, and in many cases there are no treatment options at all. When a chronic disease is found to be caused by a microbe, the potential for cure and prevention improves 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. Researchers 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 culprit 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 identified. 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.

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  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 suggest that wintertime illnesses such as influenza, infecting either the pregnant mother or infant, may predispose an individual toward schizophrenia, although the results 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 definitive 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 experience 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 parasite is not likely to be involved in all cases of schizophrenia, a disease that also has important genetic determinants.

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  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 fatigue, 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, recent 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 finding has offered hope to many.

  Dr. Robert Yolken with one of his subjects. (McClatchy-Tribune / Getty Images)

  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 papilloma 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 discovery 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 microbes 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 handful 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 randomly. 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 cancerous 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 livin
g 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 Pennsylvania’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 virotherapy researchers use and adapt a range of viruses, including herpes virus, adenovirus (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.

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  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.