Rabbits with Horns: Meet the Human Papillomavirus

The stories about rabbits with horns circulated for centuries. Eventually they crystallized into the myth of the jackalope. If you go to Wyoming and twirl a rack of postcards, chances are you'll find a picture of a jackalope bounding across the prairie. It looks like a rabbit sprouting a pair of antlers. You may even see jackalopes in the flesh-or at least the head of one mounted on a diner wall.

On one level, it's all bunk. Most jackalopes are nothing but taxidermic trickery-rabbits with pieces of antelope antler glued to their heads. But like many myths, the tale of the jackalope has a grain of truth buried at its core. Some real rabbits do indeed sprout horn-shaped growths from their heads.

In the early 1930s, Richard Shope, a scientist at Rockefeller University, heard about horned rabbits while on a hunting trip. He had a friend catch one and send him some of the tissue so that he could figure out what it was made of. Shope's colleague, Francis Rous, had done experiments with chickens that suggested viruses could cause tumors. Many scientists at the time were skeptical, but Shope wondered if rabbit "horns" were also tumors, somehow triggered by an unknown virus. To test his hypothesis, Shope ground up the horns, mixed them in a solution, and then filtered the liquid through porcelain. The fine pores of the porcelain would only let viruses through. Shope then rubbed the filtered solution onto the heads of healthy rabbits. They grew horns as well.

Shope's experiment did more than show that the horns contained viruses. He also demonstrated that the viruses created the horns, crafting them out of infected cells. After this discovery, Shope passed on his rabbit tissue collection to Rous, who continued to work on it for decades. Rous injected virus-loaded liquid deep inside rabbits and found that it didn't produce harmless horns. Instead, the rabbits developed aggressive cancers that killed them. For his research linking viruses and cancer, Rous won the Nobel Prize in Medicine in 1966.

The discoveries of Shope and Rous led scientists to look at growths on other animals. Cows sometimes develop monstrous lumps of deformed skin as big as grapefruits. Warts grow on mammals, from dolphins to tigers to humans. And on rare occasions, warts can turn people into human jackalopes. In the 1980s, a teenage boy in Indonesia named Dede began to develop warts on his body, and soon they had completely overgrown his hands and feet. Eventually he could no longer work at a regular job and ended up as an exhibit in a freak show, earning the nickname "Tree Man." Reports of Dede began to appear in the news, and in 2007 doctors removed thirteen pounds of warts from Dede's body. They've had to continue to perform surgeries to remove new growths from his body since then. Dede's growths, along with all the others on humans and mammals, turned out to be caused by a single virus-the same one that puts horns on rabbits. It's known as the papillomavirus, named for the papilla (buds in Latin) that cells form when they become infected.

In the 1970s, the German researcher Harald zur Hausen speculated that papillomaviruses might be a far bigger threat to human health than the occasional wart. He wondered whether they might also cause tumors in the cervixes of women. Previous studies on cases of cervical cancer revealed patterns that were similar to sexually transmitted diseases. Nuns, for example, get cervical cancer much less often than other women. Some scientists had speculated cervical cancer was caused by a virus spread during sex. Zur Hausen wondered if cancer-causing papillomaviruses were the culprit.

Zur Hausen reasoned that if this were true, he ought to find virus DNA in cervical tumors. He gathered biopsies to study, and slowly sorted through their DNA for years. In 1983 he discovered genetic material from papillomaviruses in the samples. As he continued to study the biopsies, he found more strains of papillomaviruses. Since zur Hausen first published his discoveries, scientists have identified one hundred different strains of human papillomavirus (or HPV for short). For his efforts, zur Hausen shared the Nobel Prize for Physiology or Medicine in 2008.

Zur Hausen's research put human papillomaviruses in medicine's spotlight, thanks to the huge toll that cervical cancer takes on the women of the world. The tumors caused by HPV grow so large that they sometimes rip the uterus or intestines apart. The bleeding can be fatal. Cervical cancer kills over 270,000 women every year, making it the third leading cause of death in women, surpassed only by breast cancer and lung cancer.

All of those cases got their start when a woman acquired an infection of HPV. The infection begins when the virus injects its DNA into a host cell. HPV specializes in infecting epithelial cells, which make up much of the skin and the body's mucous membranes. The virus's genes ends up inside the nucleus of its host cell, the home of the cell's own DNA. The cell then reads the HPV genes and makes the virus's proteins. Those proteins begin to alter the cell.

Many other viruses, such as rhinoviruses and influenza viruses, reproduce violently. They make new viruses as fast as possible, until the host cell brims with viral offspring. Ultimately, the cell rips open and dies. HPV uses a radically different strategy. Instead of killing its host cell, it causes the cell to make more copies of itself. The more host cells there are, the more viruses there are.

Speeding up a cell's division is no small feat, especially for a virus with just eight genes. The normal process of cell division is maddeningly complex. A cell "decides" to divide in response to signals both from the outside and the inside, mobilizing an army of molecules to reorganize its contents. Its internal skeleton of filaments reassembles itself, pulling apart the cell's contents to two ends. At the same time, the cell makes a new copy of its DNA-3.5 billion "letters" all told, organized into 46 clumps called chromosomes. The cell must drag those chromosomes to either end of the cell and build a wall through its center. During this buzz of activity, supervising molecules monitor the progress. If they sense that the division is going awry-if the cell acquires a defect that might make it cancerous, for example-the monitor molecules trigger the cell to commit suicide. HPV can manipulate this complex dance by producing just a few proteins that intervene at crucial points in the cell cycle, accelerating it without killing the cell.

Many types of cells grow quickly in childhood and then slow down or stop altogether. Epithelial cells, the cells that HPV infects, continue to grow through our whole life. They start out in a layer buried below the skin's surface. As they divide, they produce a layer of new cells that pushes up on the cells above them. As the cells divide and rise, they become different than their progenitors. They begin to make more of a hard protein called keratin (the same stuff that makes up fingernails and horse hooves). Loaded with keratin, the top layer of skin can better withstand the damage from the sun, chemicals, and extreme temperatures. But eventually the top layer of epithelial cells dies off, and the next rising layers of epithelial cells take its place.

This arrangement means that HPV has to try to live on a conveyor belt. As HPV-infected cells reproduce, they move upward, closer and closer to their death. The viruses sense when their host cells are getting close to the surface and shift their strategy. Instead of speeding up cell division, it issues commands to for its host cell to make many new viruses. When the cell reaches the surface, it burst open with a big supply of HPV that can seek out new hosts to infect.

For most people infected with HPV, a peaceful balance emerges between virus and host. Fast-growing infected cells don't cause people harm, because they get sloughed off. The virus, meanwhile, gets to use epithelial cells as factories for new viruses, which can then infect new hosts through skin-to-skin contact and sex. The immune system helps maintain the balance by clearing away some of the infected cells. (Dede's tree-like growths were the result of a genetic defect that left his body unable to rein in the virus.)

This balance between host and virus has existed for hundreds of millions of years. To reconstruct the history of papillomaviruses, scientists compare the genetic sequence of different strains and note which animals they infect. It turns out that papillomaviruses infect not just mammals, such as humans, rabbits, and cows, but other vertebrates as well, such as birds and reptiles. Each strain of virus typically only infects one or a few related species. Based on their relationships, Marc Gottschling of the University of Munich has argued that the first egg-laying land vertebrates-the ancestor of mammals, reptiles, and birds-was already a host to papillomaviruses three hundred million years ago.

As the descendants of that ancient animal evolved into different lineages, their papillomaviruses evolved as well. Some research suggests that these viruses began to specialize on different kinds of lining in their hosts. The viruses that cause warts, for example, adapted to infect skin cells. Another lineage adapted to the mucosal linings of the mouth and other orifices. For the most part, these new papillomaviruses coexisted peacefully with their hosts. Two-thirds of healthy horses carry strains of papillomavirus called BPV1 and BPV2. Some strains evolved to be more prone to turn cancerous than others, but researchers can't say why.

For thousands of generations, papillomaviruses would specialize on certain hosts, but from time to time, they've leaped to new species. A number of human papillomaviruses are most closely related to papillomaviruses that infect distantly related animals, like horses, instead of our closest ape relatives. Nothing more than skin contact may have been enough to allow viruses to make the jump.

When our own species first evolved in Africa about two hundred thousand years ago, our ancestors probably carried several different strains of papillomaviruses. Representatives of those strains can be found all over the world. But as humans expanded across the planet-leaving Africa about fifty thousand years ago and reaching the New World by about fifteen thousand years ago-their papillomaviruses were continuing to evolve. We know this because the genealogy of some HPV strains reflect the genealogy of our species. The viruses that infect living Africans belong to the oldest lineages of HPV, for example, while Europeans, Asians, and Native Americans carry their own distinct strains.

Each time a new species has split off from an old one, its papillomaviruses have diverged as well. The closest relatives of human papillomaviruses are the papillomaviruses that infect chimpanzees, our closest living relatives. And the next closest relatives of human papillomaviruses infect our next closest relatives, the gorillas. It is therefore likely that the common ancestor of humans, chimpanzees, and gorillas-an ape that lived some eight million years ago-carried its own strain of papillomavirus. Neanderthals probably had a strain of papillomavirus very much like our own.

The oldest fossils belonging to our own species, found in Ethiopia, date back about two hundred thousand years. Comparisons of DNA from people around the world indicate that Homo sapiens first evolved in East Africa and then spread out across the continent. Only about fifty thousand years ago did a wave of migrants successfully expand out of Africa and populate the rest of the planet. And as they migrated, they took HPV with them. We know this because the genealogy of HPV reflects the genealogy of our species. The oldest lineage of the virus is most common in living Africans, for example. Native Americans descend from East Asians, and their viruses share the same kinship.

For about 199,950 of the past 200,000 years, our species had no idea that we were carrying HPV. That's not because HPV was a rare virus-far from it: a 2008 study on 1,797 men and women found 60 percent of them had antibodies to HPV, indicating they had been infected with the virus at some point in their life. For the overwhelming majority of those people, the experience was harmless. Of the estimated 30 million American women who carry HPV, only 13,000 a year develop cervical cancer.

In this cancer-stricken minority, the peaceful balance between host and virus is thrown off. Each time an infected cell divides, there's a small chance it will mutate one of the genes that helps regulate the cell cycle. In an uninfected cell, the mutation would not do much harm. But a cell that's already being pushed by HPV to grow faster is in a precarious state. What might otherwise be a harmless mutation transforms an infected cell into a precancerous one. The cell multiplies much faster than before. Its descendants grow so fast that the shedding of the top layer of epithelial cells is not enough to get rid of them. They form a tumor, which pushes out and down into the surrounding tissue.

The best way to prevent most cancers is to reduce the odds that our cells will pick up dangerous mutations: quitting smoking, avoiding cancer-promoting chemicals, and eating well. But cervical cancer can be blocked another way: with a vaccine. In 2006, the first HPV vaccines were approved for use in the United States and Europe. They all contain proteins from the outer shell of HPV, which the immune system can learn to recognize. If people are later infected with HPV, their immune system can mount a rapid attack and wipe it out.

The introduction of the vaccines has brought controversies of many flavors. The developers recommend the vaccines for girls in their early teens. Some parents have protested that such a policy promotes sex before marriage. In 2008, medical experts raised a different set of concerns in editorials in the New England Journal of Medicine. It takes many years for HPV to give rise to cancers, they pointed out, and so we don't yet know how effective the vaccines will prove to be.

Another potential problem is the fact that current HPV vaccines only target two strains of the virus. The choice makes a certain amount of sense for vaccine makers who have to balance costs and benefits, since those two strains cause about 70 percent of all cases of cervical cancer. But we humans are host to over a hundred different strains of HPV, which are constantly acquiring new mutations and swapping genes between one another. If vaccines decimate the two most successful strains, natural selection might well favor the evolution of other strains to take their place. Never underestimate the evolutionary creativity of a virus that can transform rabbits into jackalopes or men into trees.

This is an excerpt from award-winning science journalist Carl Zimmer's new book, A Planet of Viruses (University of Chicago Press). You can get the whole book, in e-book or hardback, via University of Chicago Press or Amazon.