THEY SOUND LIKE traffickers in contraband. They talk of connections and spot markets, suppliers and harvests. One once rode shotgun along the Mexican border looking for a supply, and another time tracked down a frozen shipment that had been misplaced in transit from Peru. These traffickers, however, are scientists, students of a banal affliction: warts. They believe that some strains of the virus responsible for unsightly bumps may be shown to cause cancer, in this case cervical cancer, a leading killer of women worldwide. Their belief has turned the unraveling of the mysteries of warts into one of the hottest chases in science.
Medical scientists observed long ago that cervical cancer seemed in many ways like an infectious disease. Nuns almost neer get it. Women who start having sexual intercourse at an early age and have many sexual partners are more likely victims. So for decades researchers have been trying to isolate an infectious agent.
In the politics of contemporary cancer research, the money and glamor is focused on viruses. Now scientists at Georgetown's Vincent T. Lombardi Cancer Center are closing in on a virus they strongly believe is the culprit in cervical cancer. It is a type of the human papilloma virus, the virus responsible for warts.
'Virtually all cervical cancer is caused by this virus," says Georgetown gynecologist and pathologist Dr. Robert Kurman.
"People were shocked with AIDS. They were shocked with herpes. When you tell them warts are dangerous, they're going to laugh like hell," says Dr. Wayne Lancaster, a microbiologist at Georgetown who has extracted, dissected and fractionated warts for 11 years.
The potential payoff of successfully identi- fying a cancer-causing virus is enormous: the identification would supply scientists with a switch to shut off cancer before it begins. If vaccines for cancer viruses can be developed, inoculations will ensure that the cancers they cause do not occur. "You need a series of changes in order for (cervical) malignancy to develop. One link is papilloma virus," Kurman says. "So if we cut that link we can help prevent the development of cancer."
ALL WARTS are caused by the papilloma virus, but most warts are harmless.
"Skin warts are absolutely nothing to worry about," Lancaster says of the horny excrescences that commonly erupt on the hands and feet. But Lancaster and other scientists are accumulating evidence that one type of wart may be dangerous -- conmitted disease that more people probably have than have heard of.
At Adrian College in Michigan, he majored in biology, he says, because it was the path of least resistance. After graduation he was accepted to medical school at Wayne State University, but decided not to go. "I don't like people," he says. "When you have patients come to you, they're sick, they're complaining, and I don't like to hear that." Instead he turned to research. After getting his PhD in microbiology from Wayne State in 1973, he went to Scripps Clinic and Research Foundation in La Jolla, Calif., as a postdoctoral fellow, still unsure about what to do with his education.
At Scripps, Lancaster was told he could have his choice of investigating one of three viruses: mouse polyoma virus, which causes tumors in mice; herpes simplex 2, which causes genital herpes; or papilloma virus, which causes warts. He knew that polyoma and herpes simplex 2 were being dissected by hordes of researchers, so Lancaster went to the scientific literature to see what investigators before him had turned up about papilloma virus. He found practically nothing, and he liked that.
"By the process of elimination and lack of competition, I chose that virus," he says.
There was something else about papilloma virus that made it attractive to a young, ambitious researcher -- Lancaster's suspicion that it was linked to cancer. Humans aren't the only species susceptible to warts. Papilloma virus pervades the animal kingdom: cows get warts the size of bowling balls, horses have papilloma infections of the muzzle. Deer, sheep, rabbits, dogs and birds also are susceptible to warts. And in some animals, papilloma virus is known to cause cancers.
There is also a rare, inherited human disorder, known as epidermodysplasia verruciformis, which has been extensively studied by papilloma virus researcher Dr. Gerard Orth of the Pasteur Institute in Paris. People with this disorder can have warts covering their entire body. About 30 percent of the victims develop skin cancer on those areas exposed to sunlight.
These links of papilloma to cancer "indicated that the virus may be a causal agent in some human cancers," Lancaster says.
But his hunch was difficult to test. Unlike most viruses, human papilloma cannot be grown in tissue culture. "It's like starting a car to see how fast it will go. If you can't get the motor started, you don't know," Lancaster says. The car, so to speak, is easier to start with animal papilloma viruses, some of which are active in tissue culture. But in order to work on an animal papilloma virus, a scientist needs an animal with warts. "Probably one of the reasons there are so few people working in the field (is) the availability of the lesions," Lancaster says. At the beginning of his career at Scripps, Lancaster was so short of supply that he traded in his microscope for a shotgun.
"I was so desperate to get warts that for a week I jacklighted rabbits on the Tijuana border in California," he recalls. "We went to a truck farm, he had a rabbit problem you wouldn't believe. We actually drove up and down the rows of vegetables, one guy sitting on the front of the truck.
"I shot about 500 of the buggers, and not one of them had a wart."
Wart-infested cottontails, Lancaster subsequently learned, live east of the Mississippi. He's had better luck with cows.
"I paid someone to inoculate some animals and grow them: Buy a heifer, grow the warts, harvest the warts, sell the heifer as a full-grown animal, get your money back and you have the warts. It's kind of like a spot market."
He has also spent a day at National Airport waiting for a shipment of cervical cancer and associated cancerous lymph nodes from Peru that had missed their plane from Miami. They were of an advanced stage of the disease, difficult to obtain in this country, and were crucial in experiments he had planned. If the samples hadn't arrived when they did, "the tissue would have thawed out and been like hamburger," he says.
Lancaster and his associate, Dr. Dennis Groff, have worked so closely with papilloma viruses that they imagine them as having personalities.
"I get the sense that they're extremely private. They won't reveal their secrets . . . You have to seduce them, basically . . . I get the impression that deer virus is a lot more difficult to understand and get your hands on than bovine. Bovine type 1, whatever you want to do, you can do. Deer, you try the same thing and it sits there going, 'Not today, no way.'
Lancaster says, "If you're exposed to it long enough, you have a feeling for it. You get a certain gut feeling things are going to work."
YOU COULD CALL papilloma virus researchers the herpes apostates. Their apostasy has had its payoff, for the rise in the fortunes of genital warts research has meant a decline in the fortunes of genital herpes research.
Views widely held in the scientific community tend to have the power of religious dogma. And scientists, who can spend decades trying to unravel a single virus, often become evangelists for their particular bug. "That's how you get grants. You've got to have faith in it," Lancaster says. For the past 15 years or so, some of the most vocal promoters of the malignancy of their virus have been the genital herpes researchers.
While genital herpes is nasty enough in its own right, and being able to understand and arrest it would be a medical coup, its purported association with cervical cancer has attracted to it over the years many hundreds of researchers and millions of dollars.
"One of the reasons papilloma virus research has been retarded is because of the almost conclusive feeling that herpes virus causes cervical cancer," Lancaster says. However, "there is absolutely no direct evidence. There never has been."
Dr. William C. Summers, a molecular biologist at Yale Medical School and a herpes investigator, says one of the major reasons the university began experimenting with the virus was because of the long-held assumption that herpes simplex 2 was carcinogenic.
"Everyone wanted to believe. It's such a nice hypothesis. People wanted very much to find a virus that causes human cancer. When anyone stood up and said the emperor has no clothes, he was vilified."
What started the herpes bandwagon were epidemiological studies in the 1960s and '70s that indicated that women with genital herpes antibodies in their blood -- meaning they'd been exposed to the virus -- had a higher incidence of cervical cancer than women without the anti- bodies. But for 15 years the link never got beyond statistics. In the laboratory, researchers could not find the herpes virus DNA in cervical malignancies. Still, armed with statistics, the researchers shouldered on, and the grant money kept coming.
Last year, however, a Czechoslavakian study involving 10,000 women showed that there was no difference in the incidence of herpes among healthy women and those with cervical cancer -- thus calling into doubt even the statistical link.
Some genital herpes researchers now concede that if they were looking for a cause of cancer, they chose the wrong virus. "The predominant opinion in the field is that the data were overinterpreted and there is no good epidemiological or statistical evidence to say there's an association with herpes and cervical cancer," says Summers, with what sounds like a hint of resignation.
A link between herpes and cervical cancer, however, has not yet been entirely ruled out. Some investigators now hypothesize a connection through an as yet unknown mechanism.
During the reign of herpes as the suspected cause of cervical cancer, the country's few papilloma researchers were, Lancaster recalls, "sneered at."
Dr. Robert Kurman admits he was at first reluctant to join the papilloma heretics and renounce herpes. "When I first began, I was skeptical that papilloma virus was important. So much of your teaching, what you read, the dogma is all herpes, it takes a little bit of convincing that it's not . . . "
Georgetown pathologist Dr. Alfred Bennett Jenson remembers what happened when he and Lancaster sent an article to the British scientific journal Nature several years ago. The article linked papilloma virus infection to premalignant cervical disease. It was rejected with "a one-sentence written response saying we were crazy."
And Dr. Gregorio Delgado, a Georgetown gynecologist specializing in cancers of the female reproductive system, says that while the scientific community is beginning to accept papilloma virus research, the word hasn't spread far enough. "The public has not understood the problem. Papilloma is a bigger threat than herpes by far," he says.
The reason for the change in fortunes of the two viruses is in the laboratory. While the genital herpes researchers have been running into dead ends, papilloma virus researchers are turning up the right clues on the trail of the cancer virus.
For example, using molecular biology's new techniques of cloning and DNA hybridization, Dr. Harald zur Hausen, scientific director of the German Cancer Institute in Heidelberg and one of the world's leading papilloma virus researchers, found the DNA of human papilloma virus in cervical cancer tissue.
Building on zur Hause work, working with the tissue they received from Peru, the Georgetown group found human papilloma virus DNA in the cancerous lymph nodes of cervical cancer patients as well. This means that as the cancer traveled through the body, the papilloma virus traveled with it. The scientists say this suggests that the virus has a close tie to tumor development.
"The cells that migrated contained (papilloma) viral sequences, and those are the cells that kill," says Lancaster.
Not every scientist in papilloma research is willing to make the claims for the virus the Georgetown group makes. Some fear papilloma virus may be the next herpes: a venereal disease that doesn't finally live up to the extravagant claims of its malignancy, but that does cause a lot of hysteria.
The man who heads papilloma virus research at the National Cancer Institute, Dr. Peter Howley, 38, is a prematurely gray Harvard Medical School graduate who decided to pursue a research career when he realized that viruses were more interesting to him than their human hosts.
In one of the small rooms that make up the complex of his laboratories is a hanging intravenous bottle that has been stoppered and filled with goldfish. A door is decorated with a picture of a cow with Brobding has written, "Where's the beef?"
Howley is as soft-spoken, understated and precise as the Georgetown team is voluble. "The field has been cautious and has some credibility," he says of papilloma virus research. "The herpes thing got blown all out of proportion, especially the possible association with cervical cancer. It may have involved misinterpretations by the press, or it may have involved misstatements by investigators in the field." Of the human papilloma virus-cervical cancer connection, Howley says, "The association is real enough that it has to be looked at seriously. It is a wise thing to invest significant amounts of money, i fact the National Cancer Institute is doing that . . . (But) you don't know yet what kind of a risk it is, or if it's a risk at all."
Lancaster concedes scientists cannot prove categorically that papilloma virus is the essential factor in a chain of events that lead to cervical cancer. "We can't do the experiment," he explains. "We can't infect someone with the virus and wait for cancer to develop." He says the best proof would be to vaccinate a high- risk population and see the cervical cancer rate plunge. WHILE the scientists in the laboratory are injecting papilloma virus into mouse cells, women are dying of cervical cancer. This year 15,000 American women will be diagnosed as having the disease, and about 7,000 will die from it.
Researchers believe that papilloma virus infections are far more widespread than the incidence of genital warts would indicate. They believe that most precancerous cervical abnormalities detected by Pap smears (named not for papilloma but for the test's developer, Dr. George Papanicolaou), are caused by papilloma virus infections, and that the abnormalities themselves are a form of microscopic genital wart. Because of wide spread Pap-smear screening in this country, which allows women to be treated before they develop malignancies, the number of deaths from cervical cancer in this country has been cut by 46 percent in the past 30 years.
But in many Third World countries, where screening is not standard, cervical cancer is rampant. "Cervical cancer is the leading cause of cancer mortality in women in Latin America. It's a cancer of poverty," says Dr. Santiago Pavlovsky of the Pan American Health Organization.
cancer is the leading cause of "cancer mortality in women in Latin America. It's a cancer of poverty," says Dr. Santiago Pavlovsky of the Pan American Health Organization.
Even so, only a small percentage of women with genital warts ever develop cancer. The Georgetown scientists and other papilloma virus researchers believe that it is a few of strains of papilloma virus found in genital warts which may be responsible for helping to turning normal cells cancerous. To date, 31 types of human papilloma virus have been identified. And research shows that different types of the virus infect different parts of the body. Types 1 and 4 are found in plantar warts, for example. Type 2 is the strain found in "common warts" -- the kind children get on their hands. Types 6, 11, 16 and 18 are found in genital warts. Scientists suspect that 16, 18 and some as yet unidentified types may be those will malignant potential.
In collaboration with Bethesda Research Laboratories, a molecular biology supply company, the Georgetown team is developing a diagnostic test that would detect the presence of papilloma virus in women, as well as the type of the virus, so women infected with more potentially dangerous strains can be identified.
In cooperation with Bethesda Research Laboratories, a molecular biology supply company, the Georgetown team is developing a diagnostic test that would detect the presence of papilloma virus in women, as well as the type of the virus, so women infected with more potentially dangerous strains can be identified early.
They are also working on the development, under a grant from the Centers for Disease Control, of a serum antibody test for papilloma virus -- a test that will detect the presence of papilloma antibodies in the blood, and thus give the first accurate estimate of how widely infected the population is. "It's like sampling presidential precincts," pathogist Jenson says. "By doing 1 percent of the population, you see how the rest of the country will go. So you sample 1 percent of the population and see how prevalent (papilloma virus infection) is." IN THE PARABLE of the vineyard laborers, the workers who harvested all day in the hot sun were showed up for only the last hour of the day. When the all-day workers complained, they were told, "Thus the last will be first, and the first, last." Now that the virus he has championed all these years is finally getting the recognition he feels it deserves, Wayne Lancaster is afraid that he may end up like one of the laborers who spent the day out in the hot sun. He is worried that scientists are now abandoning herpes and other viruses and taking up papilloma just in time to reap the glory of clinching the cancer connection.
"I've got to compete now with individuals who for one reason or another stayed away from papilloma virus and are very intelligent, clever people. I have been fortunate to get around that because I took a subject no one else was interested in and I had enough faith in it to think that it was really going to go into something. And it has, or is starting to.
"But the latecomers, the guys that have a little bit more going for them, are going to dominate the market so to speak . . . There's going to be a big rush. There's going to be a lot of people getting into the field."
Dr. Richard Adamson of the National Cancer Institute agrees that many scientists hear papilloma's siren song. "A lot of DNA virus people are now switching from work on other DNA viruses," he says. And the federal government is getting into the act in a big way. The National Cancer Institute is spending $1.5 million to convert a building into the Laboratory of Tumor Virus Biology to investigate papilloma virus. This fiscal year NCI will spent an additional $3.5 million on papil- loma virus research, and next year funding will reach about $4.5 million. Five years ago NCI spent $1 million on papilloma research.
As the money follows what's hot, it leaves what's not.
"Over the past three years genital herpes has been dropping a bit concerning cervical cancer," Adamson says. "It's not thought likely to be the major player now. It's probably papilloma virus."
So NCI funding for genital herpes research is dropping, too -- $5.5 million this fiscal year, $4.5 million next year. NCI's 1980 herpes 2 funding was $2.5 million.
But Lancaster sees even the government's new commitment to papilloma virus research as a threat. Now that the NCI is heavily funding its own papilloma scientists he feels there will be much stiffer competition for the small amount of money left, and upon which he depends, that is earmarked for outside investigators. He says being a research scientist at a university is "like running your own business . . . I support 10 salaries including my own, that's technical people, PhDs. And if those grants don't come in, then I lose personnel.
"You have to be a rather elite individual to maintain your funding," he says.
His concerns carry echoes of the story of scientist Rosalind Franklin. Franklin toiled years in obscurity on the question of the structure of DNA, eventually making an X-ray picture of a DNA molecule that revealed for the first time the form now known as the double helix. Her picture was obtained by scientists Francis Crick, James Watson and Maurice H. F. Wilkins, who in 1962 won the Nobel prize. In an epilogue to later editions of his book on the discovery, The Double Helix, Watson paid belated tribute to his colleague Franklin, who had received cursory notice in the book's text, despite her crucial contribution, and went unmentioned in the Nobel citation. She died of cancer at age 37 in 1958.