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by William Carlsen

Letter of Protest, 1998

But when Susan Fisher read Strickler and Fraumeni's study in the Journal of the American Medical Association, she fired off a letter of protest to the publication.

An epidemiologist at Loyola University Medical Center in Maywood, Ill., Fisher challenged the study's methodology, calling it "an error in judgment" and misleading.

Using the same 20-year national cancer database for the two groups, Fisher compared people of the same age - "because these cancers are highly correlated with age" - and she came up with very different results.

Studying 18- to 26-year-olds who probably had been exposed to the contaminated vaccine, Fisher found a 19.6 percent greater incidence of the two major brain cancers linked to SV40 when compared with the incidence in people the same age who were not exposed. She also found 16.6 percent more bone cancers and 178 percent more mesotheliomas among those exposed to the vaccine.

But Fisher cautioned against comparing the two groups. She argued that if SV40 is being transmitted and circulating in the population, then many people in the "unexposed" group would also be carrying the virus and that would undermine the comparison.

Two Types of SV40, 1999

For years, researchers had believed that all SV40-contaminated Salk vaccine made between 1955 and 1963 had been used or discarded.

Then in 1999, Carbone was contacted by a former public health director in Oak Park, Ill., who said he had seven sealed vials of vaccine dated October 1955 in a refrigerator in his basement.

Carbone, who had left the NIH and joined the faculty at Loyola University Medical Center, ran tests on the vaccine and made a startling discovery: Not only was the vaccine contaminated, it contained a second form of the virus - an "archetypal" SV40 strain.

Although manufacturers switched from rhesus monkeys to SV40-free green African monkeys to grow the bulk vaccine in 1961, they have continued to use potentially contaminated polio seed strains originally grown on the rhesus monkey tissue to start the bulk vaccine process.

Manufacturers check the purity of their vaccine with a series of 14-day tests to detect whether any SV40 slipped through.

But when Carbone replicated the tests, he found that the second, slower- growing "archetypal" strain took 19 days to emerge.

It was possible, Carbone noted in a published report, that this second strain of SV40 had been evading manufacturers' screening procedures for years - and infecting vaccine recipients after 1962.

Controversial Study, 2000

Meanwhile, a new study led by Strickler had bogged down in bitter internal conflict.

After the NIH's 1997 conference, nine laboratories were recruited to participate in a government-sponsored study to determine if tests were really finding SV40 in tumors or whether earlier detections were the result of laboratory contamination.

Carbone and other researchers considered the study unnecessary. A similar multilab study led by Dr. Joseph Testa of Philadelphia had just been completed, and it virtually eliminated the contamination theory. The prestigious journal Cancer Research published Testa's findings in 1998.

But Strickler pressed on.

An independent laboratory in Maryland prepared mesothelioma samples for the nine labs.

When tests revealed almost no SV40 in the tumor samples, some participants questioned the preparation methods used by the Maryland lab. They also challenged Strickler's written conclusion implying that contamination had caused the earlier findings of SV40 in tumors.

If Strickler was right, the earlier SV40 detections were probably the result of stray SV40 in the labs. But critics argued that the study was scientifically flawed and should be scrapped.

The dispute became so contentious that FDA officials were forced to intervene and a neutral arbitrator assigned to mediate.

Finally, in early 2000, more than two years after the study was initiated, a carefully rewritten report emerged for publication.

It concluded that contamination was an unlikely explanation for earlier SV40 findings. Then it struggled to explain the discrepancy between earlier detections of SV40 in about half of all mesotheliomas tested and the fact that the nine labs found the virus in only slightly more than 1 percent of the study's tumor specimens.

The report noted that discrepancy might be because of the inefficiency of the method used by the Maryland lab to recover DNA - like the genetic sequences of SV40 - from the mesothelial tissue to create the test samples.

The Maryland lab also had inadvertently contaminated some of the laboratory controls and "theoretically" could have contaminated others.

The report concluded by calling for further research.

Despite the study's ambivalent conclusions and technical problems, the NCI submitted it to Cancer Research, the journal that had published Testa's study.

It was rejected.

Further Discoveries, 2000

In laboratories around the world, researchers continued to find SV40 in a widening range of tumors that now included pituitary and thyroid cancers and some lymphomas.

Meanwhile, an NCI investigator named Dr. David Schrump was able to gut a common respiratory virus and use it to deliver genetic material called "antisense" into SV40-infected mesothelial cells and stop the cells' malignant growth.

His discovery, which was patented by the government, strongly suggested that SV40 contributed to mesothelioma and that a treatment might be possible.

Then in August, Carbone and several colleagues published a major study providing a "mechanistic" explanation of how SV40 contributes to the uncontrolled growth of mesothelial cells. The key, they found, was the large number of "tumor suppressor" proteins found in the mesothelial cells that makes them unusually susceptible to SV40.

In most human cells, they said, the virus reproduces itself and kills the infected cell in the process. But in mesothelial cells, SV40 is especially attracted to the "tumor suppressor" proteins and binds to them, knocking them out of action. The virus then lives on in the cell.

The result, they said, is a rate of malignant cell transformation in tissue cultures 1,000 times higher than has ever been observed.

In a paper published in the Proceedings of the National Academy of Science, Carbone further explained that asbestos fibers appear to act as a co- carcinogen in mesothelioma by somehow suppressing the immune system's response, which is designed to kill the infected cells.

Chicago Conference, 2001

Carbone and others believed that the time had come for another conference on the virus he calls "a perfect little war machine."

In April, more than 60 scientists gathered on a warm weekend at the University of Chicago's downtown conference center. Despite numerous faxes and certified letters inviting him, Strickler declined to attend.

Carbone opened the conference by confronting the question of whether SV40 is present in humans.

"Sixty-two papers from 30 laboratories from around the world have reported SV40 in human tissues and tumors," he said. "It is very difficult to believe that all of these papers, all of the techniques used and all of the people around the world are wrong."

For two days, scientists from as far away as China and New Zealand presented the results of their studies, with almost every speaker concluding that SV40 was present in the tissues they examined.

One of the newest discoveries came from Dr. Jeffrey Kopp, an NIH scientist who reported finding SV40 in a high percentage of patients with kidney disease. The virus was also present, he said, in 60 percent of a new "collapsing" type of renal disease that was unknown before 1980 but has since increased rapidly in incidence.

There were also reports on efforts to develop a vaccine, recently funded by the NCI, that would allow the immune system to target and eliminate SV40.

At times, the meeting took on almost revivalist overtones as scientist after scientist said he or she was initially very skeptical of SV40's presence in human tumors but was now a believer.

"I was a hard sell," said Testa, the Philadelphia geneticist who conducted the first multilaboratory tests, noting that the study had convinced him.

Gazdar, the cancer researcher from Texas, showed a slide describing his transformation: "Nonbeliever -- Believer - Zealot."

The conference concluded with a consensus among the leading scientists that SV40's presence in human tumors was no longer in question. They were more circumspect about the virus' possible role in causing cancer.

If SV40 is a human carcinogen, they said, the virus probably requires interaction with other cancer-causing substances like asbestos.

Dr. Janet Butel from Baylor Medical College in Houston said that it simply might be too soon to make a determination, citing the many years it has taken to establish that other viruses cause cancer.

But even renowned tumor biologist George Klein from Sweden said he was impressed by Carbone and Schrump's work.

"This strongly suggests that the virus plays a role (in causing tumors)," said Klein, a former chairman of the Nobel Assembly.

Low Priority, 2001

In May, shortly after the conference, Strickler's multilab study was published in a small journal called Cancer Epidemiology, Biomarkers & Prevention.

Carbone and other SV40 experts dismissed the study.

"A garbage paper in a garbage journal," said Garcea, now on the faculty at the University of Colorado School of Medicine.

But Strickler strongly defends the study. He said it was the first to use strict controls not used in other studies. He acknowledged, however, that the study "doesn't prove that SV40 is not out there."

Strickler, who now teaches at Albert Einstein School of Medicine in New York, said he remains skeptical about whether SV40 has infected humans, a suspicion he says is shared by the broader scientific community.

But the NCI recently acknowledged that there is evidence to suggest that SV40 "may be associated with human cancer." The NCI statement, released last month, also said that SV40's interaction with "tumor suppressor proteins" indicates "possible mechanisms that could contribute to the development of cancer."

Top NCI officials declined to be interviewed on the record for this report. Fraumeni also declined several requests for an interview.

Dr. James Goedert, the chief of the NCI's Viral Epidemiology Branch who supervised Strickler's work, said that if SV40 is in human tumors, it must be at extremely low levels. To critics who claim the government has downplayed SV40's potential health risks, Goedert responded: "Absolutely not."

He acknowledged that research is needed to resolve the question of whether SV40 is prevalent in the human population and, if so, how it might be spreading. But Goedert said he has no plans for such studies.

"It's not our highest priority," he said.

Key Figures In Developing Vaccines And Tracing SV40

Dr. Jonas Salk Developed the first polio vaccine using killed virus in 1955.

Virologist Albert Sabin Developed an oral vaccine using weakened live virus.

Dr. Robert Garcea Used new technology to trace SV40 in children's brain tumors.

Q&A On Polio Vaccine Contaminated With SV40

Q: How widespread is the SV40 infection?

A: Scientists and government health officials don't know because no comprehensive studies have addressed the question.

What is known: During the 1950s and '60s, more than 100 million people worldwide were given SV40-contaminated polio vaccine. The virus also has been found in people who did not receive contaminated vaccine, as well as laboratory workers and monkey handlers.

No studies, however, have examined how SV40 might be transmitted between people, or if somehow humans might have become infected with SV40 before the introduction of the tainted vaccines.

Q: Can I be tested for SV40?

A: An accurate blood test does not exist. Current antibody blood tests can be inaccurate, scientists say, because they may also detect the presence of other closely related viruses, and SV40 may be present at such a low level that no antibodies are produced. Researchers are working to create an effective test.

Q: Is the current polio vaccine safe?

A: Vaccine producers, health officials and most scientists believe that it is safe. Manufacturers say they take elaborate steps to test their vaccine for SV40, and the government says it recently tested vaccine samples back to 1972 and found no trace of SV40.

Some scientists, including Dr. Michele Carbone, have raised questions about whether manufacturers' testing techniques have been adequate. Carbone, however, tested vaccine from 1996 and found no SV40. He has had his children inoculated.

Q: In which kinds of cancers has SV40 been found?

A: The virus has been detected in rare cancers:

• Mesothelioma, a fatal tumor of the membrane surrounding the lungs. Few cases were reported prior to 1950, but the incidence has grown in the United States to 2,000 to 4,000 cases a year, with greater incidence in Europe.

• Brain cancers: Primarily ependymoma and choroid plexus tumors, but also astrocytoma, glioblastoma, medulloblastoma and meningioma. These make up a total of less than 1,000 U.S. cases each year.

• Bone cancers: Primarily osteosarcoma but also chondrosarcoma and giant cell tumors. These also make up less than 1,000 cases annually.

• Other cancers: A few detections in pituitary and thyroid tumors and lymphomas.

Report Sources

The sources for this report include the books "The Saga of Jonas Salk" by Richard Carter and "The Health Century" by Edward Shorter; articles in Atlantic Monthly and New York magazine; newspaper archives at The Chronicle and the New York Times; transcript of the 1997 National Institutes of Health Conference in Bethesda; a review of dozens of scientific journal articles and scores of interviews.

How SV40 Contaminated Polio Vaccine

When Dr. Jonas Salk introduced the first polio vaccine in 1955, it was hailed as "one of the greatest events in medicine." Within 10 years, U.S. polio cases plummeted from 30,000 to less than 1,000. But in 1960, a monkey virus called SV40 was found in the Salk vaccine.

As much as one-third of the vaccine was contaminated. SV40 was also found in earlier versions of an oral vaccine developed by Dr. Albert Sabin that replaced the Salk vaccine in the 1960s.

When it was discovered that SV40 caused cancer in lab animals, U.S. health officials ordered vaccine manufacturers in 1961 to eliminate the virus from all future vaccine, although questions remain about whether they succeeded with the Sabin vaccine. .

Making the Sabin vaccine: 1955-1961

Starting in the mid-1950s, both Sabin and Salk vaccines are made by growing polio virus on kidney tissue from Asian rhesus monkeys, which are natural hosts for the simian virus known as SV40. Special weakened seed strain of polio virus developed by Sabin is grown on rhesus kidney tissue to make large bulk amounts of vaccine. SV40 from the kidney tissue contaminates the vaccine. .

Making the vaccine safe: 1961

In 1961, after SV40 is discovered in the vaccines, U.S. health officials order manufacturers to eliminate SV40. Antiserum is used to neutralize SV40 in seed stock, and SV40-free African green monkeys are used to grow bulk vaccine. But some researchers believe small amounts of SV40 may have survived. .

San Francisco Chronicle July 15, 2001