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 effort begun two decades earlier.
Room 3-5135 at the looks like a hundred other cubbyholes of basic science. A gray metal door decorated with the obligatory cartoon leads into a space the size of a motel room. White lab coats drape on wire hangers. Plain shelves, a desk, and a computer surround a breast-high bench arrayed with instrumentation. The paint scheme: early dorm room.
糖心传媒淭he posters are to cover the holes in the walls,糖心传媒� jokes , an associate professor of medicine and a veteran researcher who says not much has changed inside the room in a quarter century.
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 , a professor of medicine, and 糖心传媒�94M (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.
One vaccine using the Rochester technology is Gardasil, developed by pharmaceutical giant Merck, that糖心传媒檚 expected to be on the market some time this year.
Another candidate is Cervarix, developed by GlaxoSmithKline, that could be ready by 2008.
Gardasil 糖心传媒渋s a phenomenal breakthrough,糖心传媒� Gloria A. Bachmann told Newsday last fall when results of the final trial for the vaccine were released. She糖心传媒檚 director of the Women糖心传媒檚 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, 糖心传媒減romises to take this entire chapter (of cervical cancer) out of women糖心传媒檚 lives.糖心传媒�
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.
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.
While the vaccine is not the first to thwart a known cancer糖心传媒攖he vaccine for hepatitis B seems to prevent some forms of liver cancer糖心传媒攊t is the first designed to protect humans against an identified cancer-causing agent.
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.
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糖心传媒檚 work.
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.
糖心传媒淭he pure biology of viruses is fascinating,糖心传媒� 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.
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.
糖心传媒淥ne day I said: 糖心传媒業 don糖心传媒檛 like this,糖心传媒櫶切拇綕 Rose recounts. 糖心传媒溙切拇綐I糖心传媒檓 going to go to college.糖心传媒櫶切拇綕 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.
The three didn糖心传媒檛 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.
Almost immediately, they hit a major roadblock. Such tests hinge on finding an 糖心传媒渁ntigen,糖心传媒� 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.
To find the right antigen, the team needed plenty of virus to work with. But HPV doesn糖心传媒檛 grow in standard tissue cultures, and it糖心传媒檚 hard to extract in useful amounts from genital warts and other tissue. Says Bonnez: 糖心传媒淲e had to find a substitute.糖心传媒�
Like other researchers at the time, the team turned to papillomaviruses from cows. The French researcher set out to find bovine warts, in quantity糖心传媒攕urely one of science糖心传媒檚 oddest shopping trips. Bonnez phoned veterinarians for help and visited slaughterhouses and dairy farms (糖心传媒淚 ruined one pair of pants,糖心传媒� he says). Once in the lab, the cow warts were painstakingly minced and purified with a mix of enzymes.
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糖心传媒�5.5 million adult Americans糖心传媒攅very year get an HPV infection from a partner sometime in their lives.
But a control was needed糖心传媒攂lood 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.
So an unusual cohort of people came to the rescue糖心传媒攁 group of Rochester-area nuns and priests. Bonnez polled the volunteers on their sex lives and asked them to give blood samples. 糖心传媒淚 did it myself糖心传媒擨 was not embarrassed,糖心传媒� he says of his unorthodox hunt. 糖心传媒淚t was really the key to finding a (blood test) that worked.糖心传媒�
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. 糖心传媒淚t was a lot of work,糖心传媒� sums up Reichman, 糖心传媒渇or not very much.糖心传媒� To complicate matters, says Bonnez, the scientific literature of that time was full of 糖心传媒渇alse leads糖心传媒� still pointing to cows as the key to an antigen for HPV. 糖心传媒淚t slowed things up,糖心传媒� he says.
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聽have to fold in just the right way, and the E. coli proteins proved problematic.
The team turned in another direction: moths and 糖心传媒渘ude糖心传媒� mice.
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.
Rose made the baculovirus the subject of his 1990 master糖心传媒檚 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.
The hairless nude mice (called 糖心传媒渘ude糖心传媒� because the animals have 糖心传媒渘aked糖心传媒� immune systems that, by design, are severely compromised) were used to grow HPV11, a virus that causes genital warts in humans.
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.
After six years of tedium, false starts, hard work, and a dearth of written research, says Bonnez, 糖心传媒渇or the first time, I saw we had something good.糖心传媒�
An antibody response in the rabbits meant that it was possible to block infection from a single type of the HPV virus. 糖心传媒淭his was perfect,糖心传媒� says Rose. 糖心传媒淭his was beautiful, because it meant that a vaccine was possible.糖心传媒�
But a scientific challenge remained. A working human vaccine would require a noninfectious form of the HPV virus糖心传媒攐ne 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糖心传媒檚 outer coat. (The icosahedral shape is the favored form of many viruses.)
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 糖心传媒渧irus-like particles,糖心传媒� or VLPs. The noninfectious particles 糖心传媒渟elf-assemble糖心传媒� within infected cells and can elicit immune responses糖心传媒攊n the form of antibodies糖心传媒攚ithout causing disease.
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.
Making the 糖心传媒渆mpty capsids糖心传媒� was the subject of Rose糖心传媒檚 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.
Rose糖心传媒檚 dissertation work didn糖心传媒檛 just sit on a shelf, noted David Guzick, dean of the School of Medicine and Dentistry in a 2005 糖心传媒淒ean糖心传媒檚 Newsletter.糖心传媒� Rose is more modest, calling his accomplishment 糖心传媒渁 reduction to practice.糖心传媒� That糖心传媒檚 when research, to use a popular phrase among scientists, goes from 糖心传媒渂ench to bedside糖心传媒澨切拇綌from the realm of the theoretical into the realm of the practical.
But the vaccine糖心传媒檚 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.
糖心传媒淭hen we were really high and dry,糖心传媒� says Reichman. 糖心传媒淲e had no one to help us.糖心传媒�
Getting a patent returned 糖心传媒渋s always a hard situation for universities,糖心传媒� 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. 糖心传媒淎 vaccine against cervical cancer,糖心传媒� he says, 糖心传媒渨as an untested market.糖心传媒�
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.
Reichman credits Goodwin (糖心传媒淗e was a dream糖心传媒�) 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.
MedImmune then sublicensed the technology to GlaxoSmithKline, a transfer that delayed further testing on humans.
Michael Goldman, a patent attorney with the Rochester law firm of Nixon Peabody, helped shop for a partner in the pharmaceutical world for Rochester糖心传媒檚 vaccine work, including Merck糖心传媒檚 eventual interest. 糖心传媒淲ithout him, we糖心传媒檇 be lost,糖心传媒� says Reichman.
A chemical engineer by training and a one-time U.S. Patent Office worker, Goldman had earlier been hired to help fight the legal 糖心传媒渋nterference糖心传媒� battle with other institutions working on the VLP concept.
糖心传媒淧art of the challenge was getting the companies to believe we were a horse worth putting money on,糖心传媒� Goldman says. 糖心传媒淚t was a race.糖心传媒�
That race involves three other institutions: the National Institutes of Health, Georgetown University, and the University of Queensland in Australia. And it糖心传媒檚 worth running, says Goldman.
An HPV vaccine could represent a new global market worth $2 billion a year. 糖心传媒淭his is high-stakes patenting and litigation,糖心传媒� he says.
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.
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.
In the patent fights, says Goldman, the University糖心传媒檚 key argument comes down to a single word: 糖心传媒渨orkable.糖心传媒� The Rochester technology, in contrast to the three competitors糖心传媒�, involves a vaccine that糖心传媒檚 based on solid preclinical evidence and that has proven itself in a human trial.
Rochester糖心传媒檚 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糖心传媒檚 Office of Technology Transfer. But royalties will likely be 糖心传媒渟everal millions糖心传媒� of dollars a year over 10 years, she says, which would put the HPV vaccine in the University糖心传媒檚 top three for earnings.
糖心传媒淚t糖心传媒檚 not all about the money,糖心传媒� says Hunter, who for six years was technology transfer director for the federal Centers for Disease Control and Prevention. 糖心传媒淭hings like the HPV technology point out the real purpose糖心传媒攕eeing results at the patient糖心传媒檚 bedside, seeing lives saved.糖心传媒�
Saving lives is 糖心传媒渢he net good糖心传媒� for technology transfer, says Hunter. 糖心传媒淭hat糖心传媒檚 how it fits best into a University糖心传媒檚 mission.糖心传媒�
For their part, the researchers are modest about their achievement. But occasionally they reflect on affecting the health of so many.
糖心传媒淚t糖心传媒檚 been an amazing life experience,糖心传媒� says Rose. 糖心传媒淚t糖心传媒檚 been thrilling糖心传媒攖hat what we糖心传媒檝e done could affect the world.糖心传媒�
This story appeared in the spring 2006 issue of Rochester Review, the magazine of the聽糖心传媒.
