\u201cThe posters are to cover the holes in the walls,\u201d jokes William Bonnez<\/a>, an associate professor of medicine and a veteran researcher who says not much has changed inside the room in a quarter century.<\/p>\n But this is no ordinary workspace, and some day it may merit a plaque. Here, starting more than two decades ago, Bonnez and University colleagues Richard Reichman<\/a>, a professor of medicine, and Robert Rose<\/a> \u201994M (PhD), an associate professor of medicine, developed the key technology behind two vaccines that may eliminate cervical cancer, a disease that each year kills 250,000 women internationally, including 4,500 Americans.<\/p>\n One vaccine using the Rochester technology is Gardasil, developed by pharmaceutical giant Merck, that\u2019s expected to be on the market some time this year.<\/p>\n Another candidate is Cervarix, developed by GlaxoSmithKline, that could be ready by 2008.<\/p>\n Gardasil \u201cis a phenomenal breakthrough,\u201d Gloria A. Bachmann told Newsday<\/em> last fall when results of the final trial for the vaccine were released. She\u2019s director of the Women\u2019s Health Institute at the Robert Wood Johnson Medical School in New Jersey and was not involved with the Rochester research. Such a vaccine, Bachmann adds, \u201cpromises to take this entire chapter (of cervical cancer) out of women\u2019s lives.\u201d<\/p>\n Last fall, Merck announced that in a final large trial Gardasil was nearly 100 percent effective in prompting immunity against the most troublesome forms of the human papillomavirus (HPV), a family of sexually transmitted viruses associated with diseases of the reproductive system and skin. Two of the types (HPV16 and HPV18) cause 70 percent of the cervical cancers diagnosed worldwide.<\/p>\n The study of more than 12,000 sexually active women ages 16 to 26 worldwide, the company reported, showed that after two years, those who had received the vaccine remained free of the four troublesome strains of HPV. Based on its results, Merck has applied for FDA approval to begin selling Gardasil this year.<\/p>\n While the vaccine is not the first to thwart a known cancer\u2014the vaccine for hepatitis B seems to prevent some forms of liver cancer\u2014it is the first designed to protect humans against an identified cancer-causing agent.<\/p>\n The announcement prompted headlines around the world, but largely unreported was the remarkable story of the Rochester virologists whose innovation, dedication, and perseverance resulted in the key breakthrough that lies at the heart of the vaccine.<\/p>\n Reichman, a native of Utah who still has the skiing habit he acquired in the West, moved to Rochester in 1982 from the University of Vermont. A mentor in New England had told him that HPV and genital tract cancers included uncharted territory, and were worth exploring as a life\u2019s work.<\/p>\n Bonnez, whose father and grandfather were both Resistance fighters in France during the Nazi occupation, grew up in the 1950s working-class suburbs of Paris and took his medical degree at a military college. He gave up an early dream to be a colonial physician in Africa to move to the United States to study viruses, the smallest infectious agents known.<\/p>\n \u201cThe pure biology of viruses is fascinating,\u201d says Bonnez, whose adolescent reading was seasoned with tales of Louis Pasteur and other medical adventurers interested in saving lives by studying infectious agents. What also drew him into virology was the idea that advances in the basic science of viruses could segue into the practical realm and have real meaning in clinical settings.<\/p>\n Rose took an intriguingly crooked path to the study of viruses. His first job was as a railroad brakeman, the start of a steady climb up the ladder at the Erie Lackawanna Railroad. But frustration derailed his first career.<\/p>\n \u201cOne day I said: \u2018I don\u2019t like this,\u2019\u201d Rose recounts. \u201c\u2018I\u2019m going to go to college.\u2019\u201d He enrolled as a freshman at the State University College of New York at Geneseo, and emerged in 1984 as a magna cum laude biology and chemistry graduate. That year, he started as a laboratory technician at Rochester and before long took his seat at the bench in Room 3-5135.<\/p>\n The three didn\u2019t set out to find a cancer vaccine. Instead, they were looking for a simple blood test that would allow doctors to see whether a woman was infected with a strain of HPV and whether that strain was linked to cancer.<\/p>\n Almost immediately, they hit a major roadblock. Such tests hinge on finding an \u201cantigen,\u201d the foreign protein in an invading virus that triggers an immune response. Faced with the antigen of an invading microorganism, the bloodstream floods with antibodies, the custom-made proteins that kill or neutralize the invaders.<\/p>\n To find the right antigen, the team needed plenty of virus to work with. But HPV doesn\u2019t grow in standard tissue cultures, and it\u2019s hard to extract in useful amounts from genital warts and other tissue. Says Bonnez: \u201cWe had to find a substitute.\u201d<\/p>\n Like other researchers at the time, the team turned to papillomaviruses from cows. The French researcher set out to find bovine warts, in quantity\u2014surely one of science\u2019s oddest shopping trips. Bonnez phoned veterinarians for help and visited slaughterhouses and dairy farms (\u201cI ruined one pair of pants,\u201d he says). Once in the lab, the cow warts were painstakingly minced and purified with a mix of enzymes.<\/p>\n To find out if the purified virus from cow warts would work as an antigen, it had to be tested on human blood, which was easy enough to get. Three out of every four sexually active humans\u20145.5 million adult Americans\u2014every year get an HPV infection from a partner sometime in their lives.<\/p>\n But a control was needed\u2014blood from humans who professed never to have had any sexual contact, the chief route of infection from HPV viruses. Uninfected adults were hard to find.<\/p>\n So an unusual cohort of people came to the rescue\u2014a group of Rochester-area nuns and priests. Bonnez polled the volunteers on their sex lives and asked them to give blood samples. \u201cI did it myself\u2014I was not embarrassed,\u201d he says of his unorthodox hunt. \u201cIt was really the key to finding a (blood test) that worked.\u201d<\/p>\n By 1986, the University researchers were becoming convinced that the antigen they developed from the bovine papillomavirus was not the right one, since it had no relationship to human disease. \u201cIt was a lot of work,\u201d sums up Reichman, \u201cfor not very much.\u201d To complicate matters, says Bonnez, the scientific literature of that time was full of \u201cfalse leads\u201d still pointing to cows as the key to an antigen for HPV. \u201cIt slowed things up,\u201d he says.<\/p>\n The team turned to E. coli, a type of bacteria that looked promising as a source for the kinds of proteins that would be crucial to detecting antibodies in infected blood. But to be useful, proteins\u00a0have to fold in just the right way, and the E. coli proteins proved problematic.<\/p>\n The team turned in another direction: moths and \u201cnude\u201d mice.<\/p>\n Manipulating the cellular system of moths, the team was able to make proteins that would masquerade as infectious viruses. Relying on baculovirus, a cigar-shaped insect virus roughly 300 nanometers long, the team used the moth system to make recombinant proteins that tended to fold properly.<\/p>\n Rose made the baculovirus the subject of his 1990 master\u2019s thesis. To this day, he has an electron microscope image of one on his office wall, right next to photos of his wife and children.<\/p>\n The hairless nude mice (called \u201cnude\u201d because the animals have \u201cnaked\u201d immune systems that, by design, are severely compromised) were used to grow HPV11, a virus that causes genital warts in humans.<\/p>\n By 1990, it was breakthrough time. Using a purified form of the viral particles, the researchers immunized rabbits, two of which developed antibodies to HPV11. It was the first hint that the work might go beyond a blood test and be the basis for a lifesaving vaccine.<\/p>\n After six years of tedium, false starts, hard work, and a dearth of written research, says Bonnez, \u201cfor the first time, I saw we had something good.\u201d<\/p>\n An antibody response in the rabbits meant that it was possible to block infection from a single type of the HPV virus. \u201cThis was perfect,\u201d says Rose. \u201cThis was beautiful, because it meant that a vaccine was possible.\u201d<\/p>\n But a scientific challenge remained. A working human vaccine would require a noninfectious form of the HPV virus\u2014one that would replicate the shape of the harmful virus without replicating its danger to humans. The researchers needed to make lots of these shapes, called noninfectious capsids. Resembling a soccer ball, the shape of the virus is built from 360 copies of the protein that forms HPV\u2019s outer coat. (The icosahedral shape is the favored form of many viruses.)<\/p>\n At this point, salvation took another turn. In 1990, Rose attended a virology conference in Salt Lake City, Utah, where some HIV researchers talked about \u201cvirus-like particles,\u201d or VLPs. The noninfectious particles \u201cself-assemble\u201d within infected cells and can elicit immune responses\u2014in the form of antibodies\u2014without causing disease.<\/p>\n At Rochester, Rose inserted the gene for the HPV coat, or capsid, into the baculovirus. The sought-after noninfectious particles, which took on the shape of their infectious cousins, were formed. The particles provoked the same immune response as an infectious virus but caused no disease.<\/p>\n Making the \u201cempty capsids\u201d was the subject of Rose\u2019s 1994 Ph.D. dissertation. By the time he got the degree, he had helped write three papers on the breakthrough and had applied for a patent.<\/p>\n Rose\u2019s dissertation work didn\u2019t just sit on a shelf, noted David Guzick, dean of the School of Medicine and Dentistry in a 2005 \u201cDean\u2019s Newsletter.\u201d Rose is more modest, calling his accomplishment \u201ca reduction to practice.\u201d That\u2019s when research, to use a popular phrase among scientists, goes from \u201cbench to bedside\u201d\u2014from the realm of the theoretical into the realm of the practical.<\/p>\n But the vaccine\u2019s journey from bench to bedside included some legal pitfalls. The technology was licensed in 1993 to Praxis, then a small pharmaceutical company in Rochester. But the company was bought out by American Home Products, which declined to pursue the vaccine work. In 1994, the patent was returned to the University.<\/p>\n \u201cThen we were really high and dry,\u201d says Reichman. \u201cWe had no one to help us.\u201d<\/p>\n Getting a patent returned \u201cis always a hard situation for universities,\u201d with its implication that the technology is not worthy, says Robert Goodwin, president of LygoCyte Pharmaceuticals in Montana. During the 1990s, while a technology transfer specialist at Rochester, he helped secure critical funding for developing the vaccine. \u201cA vaccine against cervical cancer,\u201d he says, \u201cwas an untested market.\u201d<\/p>\n Especially needed is an outside partner. Even in the best of situations, says Goodwin, universities are not prepared to go beyond research to manufacture and test something like a vaccine.<\/p>\n Reichman credits Goodwin (\u201cHe was a dream\u201d) with rescuing the idea of an HPV vaccine. He came across MedImmune, a small company in Maryland that would take on the project and assume the patent rights. The company made a test vaccine in sufficient amounts for Rochester to conduct the first human trial, a near-perfect Phase 1 that looked at 64 people. It proved that the harmless virus-like particles were safe and could induce antibodies that block an HPV infection.<\/p>\n MedImmune then sublicensed the technology to GlaxoSmithKline, a transfer that delayed further testing on humans.<\/p>\n Michael Goldman, a patent attorney with the Rochester law firm of Nixon Peabody, helped shop for a partner in the pharmaceutical world for Rochester\u2019s vaccine work, including Merck\u2019s eventual interest. \u201cWithout him, we\u2019d be lost,\u201d says Reichman.<\/p>\n A chemical engineer by training and a one-time U.S. Patent Office worker, Goldman had earlier been hired to help fight the legal \u201cinterference\u201d battle with other institutions working on the VLP concept.<\/p>\n \u201cPart of the challenge was getting the companies to believe we were a horse worth putting money on,\u201d Goldman says. \u201cIt was a race.\u201d<\/p>\n That race involves three other institutions: the National Institutes of Health, Georgetown University, and the University of Queensland in Australia. And it\u2019s worth running, says Goldman.<\/p>\n An HPV vaccine could represent a new global market worth $2 billion a year. \u201cThis is high-stakes patenting and litigation,\u201d he says.<\/p>\n In 2005, Merck and GSK signed a revenue-sharing agreement on future HPV vaccines. Royalties will get distributed to the University and its institutional rivals.<\/p>\n Georgetown eventually won the U.S. patent fight over the HPV\/VLP technology because its technical papers were published first. But last May the Rochester team won a European patent for the HPV16 vaccine and has since won a parallel patent in Australia.<\/p>\n In the patent fights, says Goldman, the University\u2019s key argument comes down to a single word: \u201cworkable.\u201d The Rochester technology, in contrast to the three competitors\u2019, involves a vaccine that\u2019s based on solid preclinical evidence and that has proven itself in a human trial.<\/p>\n Rochester\u2019s share is difficult to estimate without disclosing the confidential royalty rate in the 2005 agreement, says Marjorie Hunter, a former federal and corporate patent attorney and now director of the Medical Center\u2019s Office of Technology Transfer. But royalties will likely be \u201cseveral millions\u201d of dollars a year over 10 years, she says, which would put the HPV vaccine in the University\u2019s top three for earnings.<\/p>\n \u201cIt\u2019s not all about the money,\u201d says Hunter, who for six years was technology transfer director for the federal Centers for Disease Control and Prevention. \u201cThings like the HPV technology point out the real purpose\u2014seeing results at the patient\u2019s bedside, seeing lives saved.\u201d<\/p>\n Saving lives is \u201cthe net good\u201d for technology transfer, says Hunter. \u201cThat\u2019s how it fits best into a University\u2019s mission.\u201d<\/p>\n For their part, the researchers are modest about their achievement. But occasionally they reflect on affecting the health of so many.<\/p>\n \u201cIt\u2019s been an amazing life experience,\u201d says Rose. \u201cIt\u2019s been thrilling\u2014that what we\u2019ve done could affect the world.\u201d<\/p>\n This story appeared in the spring 2006 issue of <\/em>Rochester Review<\/a>, the magazine of the\u00a0University of Rochester<\/a>.<\/em><\/p>\n","protected":false},"excerpt":{"rendered":" The announcement in fall 2005 of a vaccine against cervical cancer came as a stunning breakthrough in medical science, but it was only the latest chapter in a pioneering, Rochester-born…<\/p>\n","protected":false},"author":86,"featured_media":683302,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[41112],"tags":[],"class_list":["post-683292","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-from-the-magazine"],"acf":[],"yoast_head":"\n![\"Doctors](\"https:\/\/www.rochester.edu\/newscenter\/wp-content\/uploads\/2006\/05\/2006-01-13_Cervical_Cancer_Vac_HPV_doctors_169-1590x2048.jpg\")
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