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ARVEY Pass, the chief of thoracic surgery at the National Cancer Institute, in Bethesda, Maryland, was sitting in his laboratory one spring afternoon in 1993 when Michele Carbone, a wiry young Italian pathologist who was working as a researcher at the NCI, strode in with an unusual request. Pass had never before met Carbone, and had talked to him for the first time, on the telephone, only a few hours before. Now Carbone was asking Pass for his help in proving a controversial theory he had developed about the origins of mesothelioma, a deadly cancer that afflicts the mesothelial cells in the lining of the chest and the lung. Mesothelioma was virtually unheard of prior to 1950, but the incidence of the disease has risen steadily since then. Though it is considered rare -- accounting for the deaths of about 3,000 Americans a year, or about one half of one percent of all domestic cancer deaths -- the disease is particularly pernicious. Most patients die within eighteen months of diagnosis.

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One of SV40's constituent   proteins, large T-antigen: "the most   oncogenic protein ever discovered"

Pass listened as Carbone described for him the history of the early polio vaccine. A breakthrough in the war against polio had come in the early 1950s, when Jonas Salk took advantage of a new discovery: monkey kidneys could be used to culture the abundant quantities of polio virus necessary to mass-produce a vaccine. But there were problems with the monkey kidneys. In 1960 Bernice Eddy, a government researcher, discovered that when she injected hamsters with the kidney mixture on which the vaccine was cultured, they developed tumors. Eddy's superiors tried to keep the discovery quiet, but Eddy presented her data at a cancer conference in New York. She was eventually demoted, and lost her laboratory. The cancer-causing virus was soon isolated by other scientists and dubbed SV40, because it was the fortieth simian virus discovered. Alarm spread through the scientific community as researchers realized that nearly every dose of the vaccine had been contaminated. In 1961 federal health officials ordered vaccine manufacturers to screen for the virus and eliminate it from the vaccine. Worried about creating a panic, they kept the discovery of SV40 under wraps and never recalled existing stocks. For two more years millions of additional people were needlessly exposed -- bringing the total to 98 million Americans from 1955 to 1963. But after a flurry of quick studies, health officials decided that the virus, thankfully, did not cause cancer in human beings.

After that the story of SV40 ceased to be anything more than a medical curiosity. Even though the virus became a widely used cancer-research tool, because it caused a variety of tumors so easily in laboratory animals, for the better part of four decades there was virtually no research on what SV40 might do to people.

Carbone had reviewed some old research papers on the contamination and some of the early tests on SV40. He had even reviewed the notes from a crucial 1963 epidemiological study, by Joseph Fraumeni, an NCI researcher, which had concluded that children inoculated with contaminated vaccine did not show increased mortality rates. The studies did not impress Carbone: no one had systematically searched for evidence of the virus in tumors, and, as Fraumeni himself noted, the epidemiological study was too short to have detected certain slow-developing cancers. (Mesothelioma can take twenty to forty years to develop.)

Carbone had just finished a series of experiments in which he had injected the virus into dozens of hamsters. Every one of them developed mesothelioma and died within three to seven months. The results made Carbone wonder if SV40 might also play a role in human mesothelioma. He had come to see Pass because he had heard that the senior surgeon had meticulously saved tumor tissue from every one of the dozens of mesothelioma surgeries he had performed, and now had one of the largest collections of mesothelioma biopsies in the world. Carbone asked Pass if he could look for SV40 DNA in Pass's tumor-tissue samples, using a sophisticated molecular technique, known as polymerase chain reaction, or PCR, to extract tiny fragments of DNA from the frozen tissue and then amplify and characterize them.

As they talked, Pass became more and more impressed with Carbone. The young scientist was energetic and extremely self-confident -- something Pass attributed to Carbone's surgical patrimony. (Carbone's father is a well-known orthopedic surgeon in Italy.) When Carbone had finished describing his proposed experiment, Pass realized that the implications were potentially significant. Only a handful of viruses have been directly associated with human cancers, and none of them are simian in origin. If SV40 was linked to mesothelioma in people, might it also cause bone and brain cancers in human beings, as it had done in hamsters? What if the monkey virus could spread from person to person? And if the virus was cancer-causing, or oncogenic, what was one to make of the fact that millions of Americans had been exposed to it as part of a government-sponsored vaccination program?

"I thought to myself, He's got this wild-assed idea," Pass recalls. "If it's true, it's unbelievable. Even if it's not, I'm going to get a hell of an education in state-of-the-art molecular biology."

Others at the National Institutes of Health -- including some of the scientists who had been around at the time of the contamination scare -- were less receptive to the novel theory. They told Carbone that the last thing anyone wanted to hear was that the exalted polio vaccine was linked to cancer. Too much was at stake. Implicating a vaccine contaminant in cancer -- even if the contamination occurred some forty years ago -- might easily shake public confidence in vaccines in general. And besides, everyone knew that asbestos was the cause of mesothelioma.

Carbone sought the advice of two renowned pathologists, Umberto Saffiotti, the chief of the NCI's Laboratory of Experimental Pathology, and Harold L. Stewart, a former director of pathology at the NCI who was once the head of the American Association for Cancer Research. Both urged Carbone to follow his intuition. "Forget what people tell you," Stewart told Carbone. "They told me I was wrong all my life. If you want to do it, you should, or you will regret it." That spring afternoon in 1993, with Pass's mesothelioma samples in hand, Carbone called an old friend, Antonio Procopio, a professor of experimental pathology in Italy who had worked for three years at the NIH. "I asked him if he was willing to do this crazy project with me," Carbone says. "I told him I could not pay him or his expenses." A month later Procopio arrived in Bethesda. "We had no money," Carbone recalls. "He slept in my house for six months, and we worked day and night."

It turned out that Pass's samples were loaded with the monkey virus: 60 percent of the mesothelioma samples contained SV40 DNA; the nontumor tissues used as controls were negative. Moreover, Carbone found that in most of the positive samples he tested, the monkey virus was active, producing proteins -- suggesting to Carbone that the SV40 was not just an opportunistic "passenger virus" that had found a convenient hiding place in the malignant cells but was likely to have been involved in causing the cancer.

In 1994 Carbone, Pass, and Procopio published the results of their experiment in Oncogene, one of the world's leading cancer-research journals. They proposed SV40 as a possible co-carcinogen in human mesothelioma. It was the first time researchers had put forward hard evidence that the all-but-forgotten vaccine contaminant might cause cancer in human beings.

ICHELE Carbone is almost stereotypically Italian: generous with his emotions, outspoken, and jovial. He is strikingly handsome, with large brown eyes and shoulder-length brown hair. Carbone grew up in a cultured home in Calabria, on the shores of the Mediterranean in southern Italy. As a youth he often spent hours poring over medical texts, some of them 300 years old, in the voluminous library started by the first of the seven generations of Carbone physicians to date. If his father gave him science, from his mother he may have inherited the strong intuition that is his distinguishing characteristic as a researcher. She is an accomplished artist whose work is exhibited widely in Europe.

Carbone graduated in 1984, at the top of his class, from the University of Rome Medical School, one of the largest in the world, and quickly won a coveted NIH doctoral fellowship. In 1993 he received a Ph.D. in human pathology. In less than a decade he has risen to the top of his profession. Today he is internationally recognized as an expert in mesothelioma.

Since 1994 Carbone has written more than twenty studies and reviews investigating SV40's link to human cancer. "There is no doubt that SV40 is a human carcinogen," he says. "SV40 is definitely something you don't want in your body." Carbone suggests that the virus works in tandem with asbestos or by itself to transform healthy mesothelial cells into cancerous ones.

Since he published his first study, scientists at seventeen major laboratories -- in the United States, Great Britain, France, Belgium, Italy, and New Zealand -- have confirmed Carbone's research with respect to the presence of SV40 in human mesothelioma. Their results point to a solution to an enigma that long puzzled researchers. At least 20 percent of mesothelioma victims report no asbestos exposure, and only 10 percent of people who have had heavy exposure to asbestos ever develop mesothelioma. The experiments suggest that SV40 may be another factor at work in the tumors.

Two very recent studies, from Finland and Turkey, found no SV40 in domestic mesothelioma samples but did find it, respectively, in American and Italian samples. The authors observe that their negative findings lend support to the theory that contaminated polio vaccine is associated with the disease: neither Turkey nor Finland used SV40-contaminated vaccines. Today Finland has one of the lowest rates of mesothelioma in the Western world.

The virus has also been located in other kinds of tumors. More than a dozen laboratories have found SV40 in various kinds of rare brain and bone tumors. In 1996 Carbone reported that he had found SV40 in a third of the osteosarcomas (bone cancers of a type that afflicts about 900 Americans a year) and nearly half of the other bone tumors he tested -- research that has since been confirmed by numerous laboratories. The virus has also been detected in pituitary and thyroid tumors.

The possibility of a link between SV40 and brain tumors is particularly intriguing. Like mesothelioma, brain tumors have become dramatically more common in recent years. Brain tumors will be diagnosed in about 3,000 children in the United States alone this year. In 1995 Janet Butel, the chairman of the department of molecular virology and microbiology at the Baylor College of Medicine, in Texas, and her chief collaborator, John Lednicky, also a Baylor virologist, reported that they had found SV40 in a number of children's brain tumors. Butel and Lednicky reported that DNA sequencing revealed that the virus was not a hybrid but rather authentic SV40 -- the same as the SV40 found in monkeys. In the fall of 1996 an Italian research team, led by Mauro Tognon, of the University of Ferrara, announced that it had found SV40 DNA in a large percentage of brain and neurological tumors, including glioblastomas, astrocytomas, ependymomas, and papillomas of the choroid plexus. The researchers suggested that SV40 may be a "viral cofactor" involved in the sharp rise in human brain tumors. Late last year an extensive study undertaken in China reinforced those results. The study examined sixty-five brain tumors, finding SV40 in each of the eight ependymomas and two choroid-plexus papillomas, common brain tumors among children. It also found the virus in 33 to 90 percent of five other kinds of brain tumor examined. The authors, writing in the November, 1999, issue of Cancer, noted that the virus was actively expressing proteins.

Recent research also indicates that SV40 has gained a secure foothold in the human species. In 1996 Tognon and his collaborators reported that they had also found the virus in 45 percent of the sperm samples and 23 percent of the blood samples they tested from healthy people, suggesting that the monkey virus could spread through sexual contact or unscreened blood products. In 1998 the presence of SV40 antibodies in human blood samples was reported by Butel, who tested several hundred American blood samples and found antibodies to SV40 in about 10 percent of them. Butel's laboratory also tested samples from children born from 1980 to 1995 -- decades after the contaminated vaccine was removed from the market. A surprising six percent tested positive -- offering evidence that the virus may now be spreading from person to person, including from mother to child.