Francesca Tomasi received her B.A. from the University of Chicago and currently does tuberculosis research.
If you are familiar with ancient mythology – or even the Harry Potter books – animal hybrids are nothing new. From centaurs to hippogriffs, these eclectic organisms have long been a part of fantastical artwork and literature. And while most creatures are solely the product of mental conjuring (as far as we know), there is one popular hybrid whose roots are very real.
The infamous jackalope is a cunning and dangerous creature. It is a rabbit with antlers (hence the portmanteau) known to gore the legs of unsuspecting hunters. The jackalope has an official Latin name, Lepus antilocapra, and it is extremely rare (because it sheds its antlers in the summer and therefore becomes indistinguishable from regular rabbits). At night, it mimics human voices to reel in prey. Its favorite drink is whiskey.
Tales like these date back centuries. The first known appearance of the jackalope in popular culture dates back to thirteenth-century Persian art. The horned rabbit made many additional appearances throughout the Middle Ages and Renaissance; by the end of the eighteenth century, the jackalope was extremely popular in society – and its legitimacy totally rejected by scientists.
Where did the idea of a horned rabbit come from? Wouldn’t something like a horned lion be a little more menacing than a bunny-rabbit? There are many theories that seek to explain the conception of the jackalope. My favorite, of course, is the one that brings viruses into the picture. It also happens to be the most realistic explanation, especially after you see this photo.
Richard E. Shope was a physician in the late 20th century who took a special interest in the peculiar disease plaguing rabbits. Hunters in northwestern Iowa had been complaining about cottontail rabbits with “numerous, horn-like protuberances…over various parts of their bodies.” Dr. Shope obtained a large collection of these mutant rabbits and removed their “warts,” crushing them into a fine paste while mixing them in a saline solution. A liquefied concoction of rabbit horns sounds like a bizarre healing potion produced by a medieval healer, but Shope quickly learned that inoculating this solution in healthy rabbits caused them to develop horns of their own.
Viruses are an interesting entity. They are tiny sequences of genetic material, sometimes packaged and sometimes naked. Compared to a single bacterium, a virus can be more than 50 times smaller. This size discrepancy is actually what led to the discovery of viruses in the first place. In 1892, a Russian scientist named Dmitri Ivanovski used a porcelain filter (also known as the Chamberland-Pasteur filter after its inventors. This filter had 0.1-1 micron-wide pores, small enough to completely remove all bacterial cells from a liquid) to pass a liquid extract from tobacco plants plagued with a mysterious disease. If the disease was caused by bacteria, filtering the extract and inoculating plants with it would have no effect on their health. However, to Ivanovski’s surprise, his experiment led to disease in tobacco plants. Ivanovski thus concluded that these plants were afflicted by a hitherto unknown soluble toxin. Six years later, a Dutch scientist named Martinue Beijerinck performed similar experiments using filtered (bacteria-free) extracts and concluded that tobacco plants were infected with some “contagious living fluid.” The infectious substances, it turned out, were not fluids. Instead, Ivanovski and Beijerinck had just extracted viruses for the first time. The world’s first virus ever to be isolated is now known as Tobacco Mosaic Virus, or TMV.
Richard Shope subjected his saline solution of jackrabbit warts to this historic and beautifully simple filter test. Upon passing his extract through tiny porcelain pores to keep out any bacteria, he inoculated rabbits with the supposedly-sterile fluid. Sure enough, the fluid was not sterile: the rabbits developed similar horn-like warts to their diseased counterparts. Shope thus concluded that the wart-causing agent was a “filterable virus.” The disease that gave rise to the “jackalope” is now known as Shope papillomavirus. Papillomaviridae is the name of an ancient family of DNA viruses. More commonly known as papillomaviruses, these entities can infect an impressive variety of mammals, reptiles, and birds (i.e. the so-called amniotes). Each affected animal species has its own unique papillomaviruses – a rabbit virus, for instance, cannot infect a human, and vice versa. The remarkable ubiquity and specificity of papillomaviruses has led evolutionary virologists to posit that this is an extremely ancient pathogen dating back to some early common ancestor of modern animals (even dinosaurs had it). To date, there are over 150 human papillomaviruses alone. To what does this family owe its success?
An important concept to define here is the “successful virus.” While one might speculate that the most prosperous virus is the deadliest one that ravages populations and sends society into a downward spiral of death and disaster, it is imperative to understand that the overarching “life” purpose of a virus is not to kill its hosts. A virus is just like any other living organism (with the caveat that a virus itself is not alive) – it really just wants to reproduce.
Viruses work by infecting a host in a particular type of cell (or, in some cases, types of cells). There are more viruses around than any other entity on Earth, so it should come as no surprise that specific viruses exist for pretty much any type of cell. Once a virus is in its host, it hijacks cellular machinery – the specific machinery it uses and how it goes about doing this varies between different species – to make more copies of itself. These copies are then expelled from their host (usually by lysing open the cell) and spread to more cells to make even more copies. When we cough or sneeze, we send viral particles flying onto our unsuspecting (and now probably extremely annoyed) neighbors, essentially doing the dirty work for the virus.
With the advent of germ theory and the discovery of infectious diseases, humans have begun to outsmart many viruses: when we are sick, we stay away from others and cover our coughs. So when we die of a viral infection, doesn’t it seem even more difficult for a virus to spread? And it has to spread to a new host if it wants to survive, because dead cells no longer have functional machinery for viruses to hijack. Thus, the most successful virus is actually the seemingly innocuous one that goes unnoticed in its host. A host does not change his or her behavior to limit this virus’s spread, allowing the virus to hop from one person to another. Untouched. Such a delicate balance between a virus and its host’s immune system reflects an incredible amount of host/virus co-evolution; papillomaviruses had billions of years to figure it out.
Papillomaviruses are immensely successful viruses. While the intricacies of their life cycles vary by genus, papillomaviruses are very well-adapted to their hosts: in humans, infection itself rarely causes noticeable disease. Papillomaviruses infect epithelial (skin) cells, which is why human papillomaviruses (HPV) spread easily during sex. HPV can only infect undifferentiated (nonspecific) epidermal stem cells, which are found below epithelial cells. As such, microabrasions induced by friction allow the virus to enter the body. As a host’s cells undergo differentiation, the process by which stem cells become tough skin cells and migrate to the dermis (our outer layer of skin), HPV proceeds through its own life cycle. It does so by hijacking the cellular machinery currently working to differentiate host cells. When its host cells mature and no longer actively replicate, HPV assembles so-called virions, the core viruses that may cause genital warts or other lesions through which HPV then spreads.
HPV infection is generally harmless. In fact, our immune system usually does a pretty good job holding it at bay, calming it into a latent state. Sometimes, however, unchecked virus can wreak havoc on its host, and this occurs more often in immunocompromised patients.
Life may be a miraculous feat of chemistry and evolution, but it is by no means perfect. As organisms became more and more complex, evolving from a fledgling cell to genetically intricate plants and animals, the cells making up these organisms developed many different checkpoints to make sure their DNA was being properly replicated and expressed – the more complex the organism, the more important it became to make sure everything was running smoothly.
HPV expresses eight proteins to carry out its life cycle in human cells. Two of these genes – called E6 and E7 (“E” because they are expressed “early” in the HPV cycle, while the host epidermal stem cells are still differentiating) – are the proteins most commonly associated with mayhem. E6 and E7 work by inhibiting normal cell cycle function. This means that these proteins keep host cell checkpoints from being able to proofread DNA before allowing replication to continue. Just as a book editor is bound to miss the occasional typo, so do our cells. But just as a book editor reading through a manuscript is bound to miss even more typos if he is being tickled, our cells let a dangerous amount of mutations accrue if HPV proteins are interfering with their editing skills. More mutations mean more chances for a cancer-causing abnormality to arise and go unchecked.
That’s exactly what happens with HPV when it becomes oncogenic. When infected cells go unchecked long enough, they accumulate mutations that may trigger them to replicate uncontrollably. Simply put, these cells turn into cancer. A couple of strains of HPV have been linked to this. In fact, today nearly all cases of cervical cancer are caused by papillomavirus. Similarly, about 95 percent of anal cancers and 70 percent of throat cancers are caused by HPV. You can check out the CDC’s table listing different HPV-associated cancers and cancer rates here.
Current estimates are that as many as 80 percent of sexually active people have been infected with HPV. While the vast majority of these cases are asymptomatic, there are approximately 40,000 new cases of HPV-associated cancers each year in the US alone and over 500,000 globally – accounting for about 1% of all HPV infections. Each year, nearly 270,000 women with cervical cancer alone die.
“Half a million cancer cases” is on its way to becoming “zero” thanks to Gardasil and Cervarix. These vaccines, released in 2006, provide very strong protection against certain high-risk strains of HPV. In fact, in the last ten years, they have been administered in over 65 countries and have nearly halved cervical cancer rates. Experts think all HPV-associated cancers can be wiped out in the next few decades, as long as we reach 80% global immunization rates.
Here’s what we know: HPV infects the majority of reproductive-age people. Several strains of this virus have been linked to multiple aggressive cancers. There is a safe, effective vaccine against two major oncogenic strains – that is, the possibility to eradicate most cervical, anal, vaginal, and throat cancers. Here’s what else we know: barely 1% of women have received the full immunization course (3 doses administered 2 and 6 months apart at around 12 years old) in developing regions, and about one-third of women have in developed countries. There are many factors that play into the socioeconomic discrepancy in vaccination rates – differences in public health infrastructure that lead to varying vaccine availability; Gardasil is one of the most expensive immunizations on the market; the 3-dose, multi-month course raises logistical issues. Furthermore, the data above only consider women, and absolute numbers for all people worldwide are probably even lower. HPV does not discriminate between sexes, yet vaccination rates are significantly higher in women than men likely because the vaccine is most associated with preventing cervical cancers. These factors all contribute to low vaccination rates, but given the massive impact Gardasil and similar immunizations can have on cutting cancer cases worldwide, why are the baseline rates so low? After all, according to the WHO, viruses like measles (1 dose) and hepatitis B (3 doses) have over 80 percent global coverage.
A major factor boils down to sex and stigma. Because HPV is transmitted sexually, parents often refuse to have their teenagers vaccinated because they see it as implicit approval of sexual activity. Doctors often hear “my child is not sexually active, so there is no need to give them Gardasil.” The truth, however, is that nearly half of adolescents are sexually active by the age of 16, regardless of whether their parents know or not. Furthermore, someone does not need to be having sex in order to get vaccinated against HPV. The point is to build immunity over time to the virus so that when the time comes and someone is exposed, they do not get infected. An even more significant barrier, according to the National Cancer Institute, is that “[h]ealth care providers recommend the vaccine late, half heartedly, or not at all.” This, too, mostly boils down to uncomfortable conversations about sex, especially to parents of 12 to 13-year-olds. Last January, researchers from the National Cancer Institute published a consensus calling “low rates of HPV vaccination…a serious public health threat.” HPV vaccination has given us the rare prospect of preventing a variety of cancers in a safe and effective way. Stigma on the part of parents and providers, however, has tragically put forth major barriers to achieving global vaccination rates as high as other common viruses. When vaccines for other sexually transmitted pathogens, such as HIV or gonorrhea, eventually hit the market, will we see similarly low immunization rates?