Between Hope and Fear

by Michael Kinch

  This extraordinary efficiency, which was utilized by d’Herelle to treat bacterial infections, reflects the viral trick of appropriating the machinery of the host rather than bringing along most of its own equipment. Using this strategy of utilizing the host cell to do most of the work required for reproduction, the virus gains an extraordinary efficiency, as it only needs to encode for a small number of genes, often restricted to those that compose the viral particle structure, key enzymes needed to replicate the viral genetic material, and, of course, the machinery needed to facilitate the hijacking process. From the standpoint of genetics, one might think of viruses as the most highly evolved creatures on earth as they exploit the intense labor and machinery of their hosts for their survival and reproduction.

  We will conclude our interlude with bacteriophage by relating a story that sounds apocryphal but was verified by me and during my years as a predoctoral student. This experience verifies that viruses truly dominate the planet, including even our most hygienic environments. This story also relates to the practice of scientific transparency and reproducibility, key features of the modern research endeavor. For those unaccustomed to the academic research process, the general practice is that once a scientific manuscript has been published, it is incumbent upon the authors to share their unique tools with the wider scientific community so that the work can be reproduced and thus (presumably) verified by others. Obviously, such actions might not be palatable to investigators prone to secrecy, as this practice might surrender their “edge” to the competition.

  The apocryphal story is set in the early 1980s, when scientists often communicated by a system known at the time as “letters” (translating this for younger readers, this approach is more commonly referred to as “snail mail”). As was the custom, the source for this story, a professor researching bacteriophage at Duke University, sent a letter to a colleague at a prestigious East Coast institution, requesting a sample of the material that had been published by the colleague in a recent scientific paper. The colleague, who had a reputation for secrecy, responded politely a few weeks later with a letter indicating that he would not be able to honor the request. However, the bait had been taken, as the bacteriophage was at Duke and already in the hands of the professor. The reason for this is that the ubiquitous nature of bacteriophage, which waft along with the wind (often aboard the bacteria they are ingesting), meant that the letter and the envelope used to decline the request for the phage were coated with phage (and bacteria). The Duke investigator simply extracted the desired phage (along with others used by the colleague, as well as those that naturally floated around Boston and Durham), and with a little effort, purified the phage and began using it for his studies, all within a week. Such opportunities have been all but lost today due to e-mail. The only types of viruses that might be isolated in the more modern form of messaging are made by man and not nature.

  Common but Not Trivial

  This process of taking over the host and rewiring its programming was first discovered with viruses that infect bacteria (phage) primarily because bacteria are readily studied and less complex than eukaryotic cells. Similar processes of hijacking and replication haves been repeated by many other virus types, and it is safe to conjecture that every species on earth has a unique array of viruses that feed upon them. It may also be defensible to conjecture that virtually every type of cell in the body might be host to its own set of viruses. For example, the array of viruses that infect a hair follicle are distinct from those that infect the liver or circulating cells. Worse still, many viruses can exploit to their advantage the fundamental immune systems that have coevolved to prevent or limit viruses. For example, HIV tends to feast upon a subset of T lymphocytes that happen to control the immune system. This clever strategy undermines the ability of the host to reject the infection but ultimately dooms the larger host to succumb to other infections. As snails, insects, and other animals shed or molt to cast off unneeded or worn-out body parts, the virus constantly seeks to spread itself beyond a first host and propagate within subsequent victims.

  This chapter opened with a statement that many of the most contagious and deadly diseases arise from viruses. Among the most contagious are an array of what we refer to as “childhood” diseases (measles, German measles, mumps, and chicken pox). The next chapter will deal with these maladies as a demonstration of the extraordinary successes vaccines developed in the latter half of the 20th century. For now, we will focus our attention upon the common cold, one of the most contagious viruses known to science.

  According to the Centers for Disease Control and Prevention (CDC), the average adult suffers from two to three colds per year. Worse still, the infectiousness of the common cold is relatively high, with each infected person in turn passing the disease on to six other people.36 Each cold lasts a week or longer, and many adults absent themselves from work during this time to avoid infecting others. Thus, while mortality is rarely threatened, the economic impact of the common cold can entail billions of dollars in reduced productivity alone. Given the incidence, impact, and contagiousness, much early effort was focused upon identifying the cause of the common cold.

  Early works revealed that the causative agent was not captured by Chamberland filters, so it was accurately suspected to be some sort of virus. In 1956, word emerged from Johns Hopkins University of the discovery of the causative agent.37 The discoverer was a Baltimore scientist by the name of Winston Harvey Price, who had high aspirations for fame.38 A native New Yorker and son of a wealthy physician, Price had become inspired by Sinclair Lewis’s Arrowsmith (based on Felix d’Herelle’s life). He started his career working with several prominent scientists and institutions, including Princeton University and the Rockefeller Institute, before landing a position at Johns Hopkins. Whether consciously or not, Price had begun down a path that aped both the real-life d’Herelle and the fictional Arrowsmith. For example, Price’s early scientific work followed upon the bacteriophage discoveries pioneered by d’Herelle, but Price’s notoriously short attention span meant that he did not contribute substantially to the field during its development in the late 1940s.

  On the personal front, Price also emulated his literary hero. Like Arrowsmith, Price married first an unexceptional woman but later sought out the company of a more elite partner.39 (In real life, Price and his wife divorced, whereas Arrowsmith’s wife suffered a gruesome death from poisoning.) The second wife was the result of his passion for abstract art. Price was an avid collector and paid a substantial sum for a painting by the New York artist Grace Hartigan. Hartigan was a leading talent in the second-generation American abstract expressionist community and ran in the same circles as Jackson Pollock, Willem and Elaine de Kooning, and Mark Rothko. The newly married Hartigan invited Price to visit her gallery in 1959. Unexpectedly, the two initiated a torrid affair, and both divorced their current spouses and remarried within months.

  By 1960, Price was making quite a name for himself, both in the scientific and artistic communities. Within the former group, Price advocated a belief that infectious agents were normally present in most people and the diseases caused by them were triggered by environmental factors such as getting a chill. In studies reportedly conducted on thousands of volunteers, he advocated that physiological stressors were sufficient to trigger a collapse of the immune system (as evidenced by decreasing amounts of antibodies circulating in the blood), thereby liberating latent viruses and rendering individuals susceptible to infection. Such ideas were recognized as groundbreaking by some and made for great headlines, being touted as evidence by the Science News Letter of January 8, 1955 as evidence that “Grandma seems to have been right. You may be able to catch cold by getting your feet wet and sitting in a draft.”40 Indeed, the article goes on to relate that Price had received prestigious and lucrative rewards such as the Theobald Smith award from Eli Lilly & Company.

  Although Price was the subject of much attention, his own colleagues at Johns Hopkins felt he was superficia
l in his ideas and liberal with the interpretation of the data.41 Such charges had plagued Price from his earliest school days. While Price was receiving acclaim for linking cold feet with susceptibility to getting sick, he was working to discover the cause of the common cold. Using nasal washings from patients with a cold, Price reported the isolation of a new virus, which he called the JH virus (for Johns Hopkins).42 Like most of his studies, the results were a bit superficial and open to questioning. The discovery of the JH virus (whose name was later changed to rhinovirus—rhino being the Latin word for ‘nose’) meant that greater notoriety would be accompanied by greater scrutiny of Price’s methods and interpretations. For example, a widely reported 1957 study reporting the discovery of a vaccine for the JH virus (and thus an end to suffering from the common cold) lacked substance. Indeed his claims were refuted both by his supervisor at Johns Hopkins and by the preeminent vaccine aficionado Maurice Hilleman (whom we will meet later in our story), who claimed Price’s work to be “a complete fraud.”43 Price quietly left the field and went on to study other areas of medicine. The discovery of what we now know as the rhinovirus would ultimately represent a high-water point in terms of Price’s scientific contributions.

  Challenges of Treating Viral Infections

  As a young academic embarking on a career of teaching, I was asked to deliver a lecture on the first day of my inaugural academic year as a professor. The lecture was on antiviral medicines for a medical school course on pharmacology. Excited by the prospect, I did a lot of research. While more than a handful of antiviral therapeutics had been developed in the years before the lecture, the first sentence of my first lecture remains committed to memory: “The number of viral infections that can be definitively cured by modern medicines can be estimated to be exactly zero.”

  Our introduction to the common cold virus provides a jumping-off point to understanding some challenges associated with the treatment of viral infections. A prominent hurdle entails the timing during which one can successfully intervene against a viral infection. With a bacterial infection, the clinical signs (fever, chills, and malaise) often reflect the body’s attempt to attack and clear the infection while it remains relatively benign (to avoid more lasting damage or death). As we saw in the last chapter, the human immune response has evolved to recognize and vigorously react to certain triggers, such as the “superantigens” associated with the cell walls of many bacteria. Consequently, even a trace amount of residue from a bacterial pathogen might be sufficient to fully alert the immune system to begin taking corrective actions. The malaise associated with a bacterial infection, including redness, swelling, and fever, is often attributable as much to the defensive counterattack as to any damage caused by the pathogen itself. Such strategies evolved because, as we have seen, the toxins produced by some bacteria are among the most lethal poisons known to man. Over time, the balance between allowing a bacteria to gain a foothold and overreacting, thereby causing potential collateral damage to normal cells, tends to favor long-term survival over short-term disquiet.

  The situation with viruses can be very different. In general, the early warning signs that trigger the host defenses against bacteria are not applicable to viruses. The symptoms of a viral infection occur later during infection and often reflect pathogen-mediated damage to the body rather than a vigorously responding immune response. Thus, the earliest symptoms of a viral infection often arise after the infection is already well entrenched. If the viral infection is particularly aggressive or acute, it may be too late to intervene successfully. In recent years, the public has gained greater understanding of this limitation through the marketing of products such as Zicam® and Cold-Eeze®, which are zinc-based products that can lessen the severity or duration of symptoms from the common cold. Such medicines are effective in decreasing the duration or severity of infection only if taken within hours after the first noticeable symptoms. Likewise, the treatment of shingles (a subject to which we will return) is effective if treatment with drugs such as acyclovir is initiated within the first forty-eight hours after the first signs of the blistering characteristic of the disease. One obvious problem compounding this limitation is that most people tend not to realize they are infected or respond accordingly until after the tight window in which intervention might be useful has already closed.

  Therapeutic intervention with antivirals assumes that one has access to effective medicines. For most viruses, this is not the case. This raises a key question. Given the impact of antibacterial medicines such as penicillin, why are there comparatively few antivirals? The answer in part lies in the fact that the proteins of the virus-hijacked cell are recruited, or more accurately enslaved, by the virus to build new viruses. Therefore, if one targets these proteins with a drug, the consequences likely will include intolerable collateral damage to normal human cells. In contrast, most of the molecules needed to facilitate the growth of bacteria are quite foreign, due to extensive evolutionary changes that distinguish our prokaryote cousins from ourselves. These differences provide targets for new medicines. Thus, a key (and limitation) to developing safe and effective antivirals is to identify and distinguish the small number of molecules that are unique to the virus.

  The Love Bug

  The idea of successfully targeting a molecule that is unique to a virus is perhaps best exemplified by one of the most maligned (though not malignant) viral diseases. Attending high school in the early 1980s, I was subject to the requisite health education courses, the highlight of which was the discussion of sexually transmitted diseases. “The big three” killers were consistently portrayed as herpes, syphilis, and gonorrhea. All else paled in comparison. (Reports of a “gay cancer,” later given the less derogatory moniker Acquired Immunodeficiency Syndrome, or AIDS, were sparsely heard on the media in the Midwest.) Even after the revelation of the magnitude of risk from AIDS, the perceived risk of acquiring herpes elicited the greatest fear among most peers in the late 1980s. Such fears were propelled by frequent mention of herpes, particularly in comedies (after all, the word herpes bounds off the lips with a droller sound than the more ominous undertones of gonorrhea or syphilis).

  Despite its notorious reputation, genital herpes is mostly a benign disease. The family of viruses that cause herpes are broadly known as the Herpesviridae. The family members include HSV-1, the primary cause of small ulcerations in or near the mouth such as cold sores and aphthae (or canker sores, as they are known in North America). Individuals are infected with HSV-1 after contact with an infected person, who is actively shedding virus. The virus tends to infect the skin and nerve cells of the mouth. During an active infection, the virus will hijack and take over the cell it has infected, subverting the normal function of the cell machinery to redirect it to produce more viruses. As described at the top of the chapter, viruses have played a biological version of the old television show Name That Tune, where contestants would challenge one another to name a song with the fewest notes possible. Likewise, viruses seek to minimize the amount of nucleic acids and genes they convey as one means to remain efficient. For some of the most effective viruses, the genes are generally limited to some of the structural materials that compose their capsules and key enzymes needed to reproduce their genetic material. For the more mundane jobs, many viruses simply subvert the cell’s native machinery to do their bidding.

  Once a host cell has been successfully infected by HSV-1, it can choose from among three options. First, the virus can remain latent and simply “hang out” in the infected cell, remaining largely hidden (latent) from the immune system and not causing overt symptoms. Second, the virus can take over the cell, reproducing itself at a dawdling rate and budding out of the infected cells in a manner analogous to a slow-dripping faucet. In this case, the cell may remain alive but spew forth a constant low level of infectious particles that in turn can persistently spread infection to new cells and new hosts (if, for example, the mouths of two individuals happen to come in intimate contact). When feeling particul
arly aggressive, HSV-1 will completely take over a cell; after it has fully engorged the infected cell with new viral progeny, these burst open the cell in a process known as a lytic cycle. If the new progeny infect nearby cells and continue this aggressive approach, the damage will accumulate and become sufficient to destroy enough of the skin surface to form a painful ulcer, known as a canker or cold sore (depending on the location of the ulcer). How a virus chooses which of the three paths to take remains largely unknown to researchers, although preference for the lytic cycle is associated with certain stimuli, such as particular acidic foods, psychological stress, and immune suppression. Fortunately, the damage caused by HSV-1 tends to be rather uncomfortable but generally limited to ulcerations that heal within a week or two.