Fw: Growing Medical Fear Over Possible Carcinogenic Virus

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Sent: Tuesday, July 17, 2001 12:07 PM

Subject: Growing Medical Fear Over Possible Carcinogenic Virus

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> ------------------------------------------------------------------------

> Growing Medical Fear Over Possible Carcinogenic Virus

> July 16, 2001

>

> SAN FRANCISCO (San Francisco Chronicle) -- A growing number of medical

> researchers fear that a monkey virus that contaminated polio vaccine given

> to tens of millions of Americans in the 1950s and '60s may be causing rare

> human cancers.

>

> For four decades, government officials have insisted that there is no

> evidence the simian virus called SV40 is harmful to humans. But in recent

> years, dozens of scientific studies have found the virus in a steadily

> increasing number of rare brain, bone and lung-related tumors - the same

> malignant cancer SV40 causes in lab animals.

>

> Even more troubling, the virus has been detected in tumors removed from

> people never inoculated with the contaminated vaccine, leading some to

> worry that those infected by the vaccine might be spreading SV40.

>

> The discovery of SV40 in human tumors has generated intense debate,

> pitting government health officials, who are convinced that the virus is

> harmless, against researchers from Boston to China who now suspect SV40

> may be a human carcinogen. At stake are millions of research dollars and

> potential medical treatments for those afflicted with the cancers SV40 may

> be causing.

>

> In April, more than 60 scientists met in Chicago to discuss the

> controversial virus and how it works to defeat certain cells' natural

> defenses against cancer.

>

> " I believe that SV40 is carcinogenic (in humans), " said Dr. Michele

> Carbone of Loyola University Medical Center in Maywood, Ill. " We need to

> be creating therapies for people who have these cancers, and now we may be

> able to because we have a target - SV40. "

>

> But scientists at the National Cancer Institute say their studies show

> almost no SV40 in human tumors and no cancer increase in people who

> received the contaminated vaccine.

>

> " No one would dispute there's been a widespread, very scary exposure to

> the population of potentially cancer-causing virus, " said Dr.

> Strickler, NCI's chief investigator. " But none of our studies and other

> major analyses have shown an inkling of an effect on the population. "

>

> Critics charge, however, that the few studies done by the government are

> scientifically flawed and that health officials have downplayed the

> potential risks posed by SV40 ever since they learned in 1961 that the

> virus contaminated the polio vaccine and caused tumors in rodents.

>

> " How long can the government ignore this? " asked Dr. Adi Gazdar, a

> University of Texas Southwestern Medical Center cancer researcher. " The

> government has not sponsored any real research. Here's something possibly

> affecting millions of Americans, and they're indifferent. "

>

> " Maybe they don't want to find out. " The recent SV40 discoveries come at a

> time of growing concern over the dangers posed by a range of animal

> viruses that have crossed the species barrier to humans, including HIV,

> which scientists now believe came from chimpanzees and ultimately caused

> the AIDS epidemic.

>

> Based on dozens of interviews and a review of the medical research, this

> is the story of how the campaign to eradicate polio may have inadvertently

> permitted another potentially deadly monkey virus to infect millions of

> people - and why the government for years discounted the accumulating

> evidence suggesting that SV40 may be a health risk for humans.

>

> During the first half of the 20th century, polio struck down hundreds of

> thousands of people, leaving many paralyzed - some in iron lung machines -

> and killing others. The worst year was 1952, when more than 57,000 polio

> cases were reported in the United States. Three thousand died.

>

> Then on April 12, 1955, Dr. Jonas Salk, a slightly built, soft-spoken

> researcher from Pittsburgh, mounted the podium at the University of

> Michigan and announced that he had developed a vaccine. That afternoon,

> the government licensed the vaccine for distribution.

>

> Salk's vaccine was made by growing live polio virus on kidney tissue from

> Asian rhesus monkeys. The virus was then killed with formaldehyde. When

> the vaccine was injected in humans, the dead virus generated antibodies

> capable of fending off live polio.

>

> Dr. Dwight Murray, then chairman of the American Medical Association,

> called Salk's announcement " one of the greatest events in the history of

> medicine. "

>

> Within weeks, the vaccine was being injected into the arms of millions of

> people worldwide.

>

> Four years later, Bernice Eddy, a researcher at the National Institutes of

> Health, noticed something strange while looking through her microscope.

> Monkey kidney cells - the same kind used to make the vaccine - were dying

> without apparent cause.

>

> So she tried an experiment. She prepared kidney extracts from eight to 10

> rhesus monkeys and injected tiny amounts under the skin of 23 newborn

> hamsters. Within nine months, " large, malignant, subcutaneous tumors "

> appeared on 20 of the animals.

>

> On July 6, 1960, concerned that a monkey virus might be contaminating the

> polio vaccine, Eddy took her findings to Dr. ph Smadel, chief of the

> NIH's biologics division. Smadel dismissed the tumors as harmless " lumps. "

>

>

> The following year, however, at a Merck laboratory in Pennsylvania, Dr.

> Maurice Hilleman and Dr. Ben Sweet isolated the virus. They called it

> simian virus 40, or SV40, because it was the 40th virus found in rhesus

> kidney tissue.

>

> By then, the nation was winning the war against polio. Nearly 98 million

> Americans - more than 60 percent of the population - had received at least

> one injection of the Salk vaccine, and the number of cases was plummeting.

>

>

> At the same time, an oral polio vaccine developed by virologist Albert

> Sabin was in final trials in Russia and Eastern Europe, where tens of

> millions had been inoculated, and it was about to be licensed in the

> United States. Unlike the Salk vaccine, the oral version contained a live

> but weakened form of polio virus and promised lifelong immunity.

>

> But U.S. Public Health Service officials were worried. Tests had found

> SV40 in both the Sabin and Salk vaccines - it was later estimated that as

> much as a third of the Salk vaccine was tainted - and that SV40 was

> causing cancer in lab animals.

>

> In the spring of 1961, they quietly met with the agency's top vaccine

> advisers. The agency found no evidence that the virus had been harmful to

> humans, but in May, the officials ordered manufacturers to eliminate SV40

> from all future vaccine.

>

> New procedures were adopted to neutralize the tainted polio virus seed

> stock and SV40-free African green monkeys were used to produce the bulk

> vaccine instead of rhesus monkeys.

>

> But officials did not recall contaminated Salk vaccine - more than a

> year's supply - still in the hands of the nation's doctors.

>

> And they did not notify the public of the contamination and SV40's

> carcinogenic effect on newborn hamsters.

>

> Hilleman would later explain that government officials were worried that

> any potentially negative information could ignite a panic and jeopardize

> the vaccination campaign.

>

> The first public disclosure that the Salk vaccine was contaminated came in

> the New York Times on July 26, 1961. A story on Page 33 reported that

> Merck and other manufacturers had halted production until they could get a

> monkey virus out of the vaccine.

>

> When asked to comment, the U.S. Public Health Service " stressed " there was

> no evidence the virus was dangerous.

>

> The next year, a young Harvard-trained epidemiologist named Dr. ph

> Fraumeni joined the National Cancer Institute and was assigned one of the

> agency's most important projects: to determine if there was any cancer

> increase among those injected with the Salk vaccine.

>

> His research would form the basis of the government's position for

decades.

>

> Working with two colleagues, Fraumeni tested stored vaccine samples from

> May and June of 1955, the first months of the national immunization

> campaign, then ranked the samples according to how much SV40 they

> contained - no, low or high amounts.

>

> It would be the only time U.S. health officials measured the level of SV40

> in the 1955-1962 vaccine. Stored samples from that period were later

> discarded.

>

> Fraumeni identified the states where the SV40-contaminated vaccines had

> been distributed during those two months. California, for example,

> received vaccine with a low level of the virus.

>

> The study looked at cancer mortality rates for 6- to 8-year-old children

> vaccinated during that narrow time frame, tracking the group for four

> years.

>

> The findings, which were published in the Journal of the American Medical

> Association, showed no significant difference in cancer deaths in states

> with high or low levels of SV40 in the vaccine when compared with cancer

> deaths in states with no SV40 in the vaccine.

>

> Fourteen years later, following isolated reports linking the virus and

> human cancers, Fraumeni decided to look at another group that had received

> contaminated vaccine.

>

> The group had been the subject of experiments conducted in the early 1960s

> at Cleveland Metropolitan General Hospital. To determine the effect of

> different amounts of the vaccines, researchers at the hospital inoculated

> newborns from mostly lower-income black families with doses ranging up to

> more than 100 times the dose recommended for adults.

>

> The experiments took place over three years and involved 1,073 infants.

> Most were given Sabin oral vaccine later determined to contain SV40.

>

> From 1976 to 1979, Fraumeni and his associates sent letters to the

> children - now aged 17 to 19 - but fewer than half responded. The

> researchers found no SV40- related health problems from exposure to

> contaminated vaccine.

>

> However, their 1982 report published in the New England Journal of

> Medicine acknowledged the study's limitations: A majority of the children

> had not responded; SV40-related cancers might take longer than 17 to 19

> years to develop and SV40 appears less likely to infect humans through the

> oral vaccine.

>

> Nevertheless, they called their findings " reassuring and consistent with

> the prevailing view that SV40 is not carcinogenic in human beings. "

>

> Then they decided to end the study, citing " the mounting complexities and

> obstacles in tracing this particular group and the negative results to

> date. "

>

> The study's closure appeared to end the government's research into the

> virus. But a few years later there would be a tectonic shift in SV40

> research.

>

> In Boston, two researchers stumbled on something disturbing. Dr.

> Garcea and his assistant, Dr. Bergsagel, were using a powerful new

> tool called polymerase chain reaction, or PCR, to look for a pair of

> common human viruses in children's brain tumors.

>

> But a different DNA footprint kept popping up in more than half the

> tumors. They finally realized they were seeing SV40.

>

> For more than a decade, scientists had reported sporadic findings of

> SV40-like proteins in human tumors. But the earlier tests were primitive

> and the results suspect. PCR, however, is capable of amplifying

> infinitesimal fragments of DNA, which makes detections far more credible.

>

> The findings were troubling. The researchers noted in their published

> report that the children were too young to have received the contaminated

> vaccine. But somehow the virus had infected them and embedded itself in

> their tumors.

>

> That same year, Michele Carbone was surprised to find a milky, rindlike

> tumor in a laboratory hamster at the National Institutes of Health in

> Bethesda, Md.

>

> The animal was one of a group given an SV40 injection directly into their

> hearts. Sixty percent of those hamsters developed the fatal cancer called

> mesothelioma.

>

> Carbone, a postdoctoral fellow at the institute, knew that SV40 caused

> tumors in hamsters but only in specific locations where large doses of

> virus were injected. Here the mesothelial membrane lining the lungs

> apparently became cancerous from minuscule amounts of SV40 shed by the tip

> of the needle on the way to the hamsters' hearts.

>

> So he tried another experiment, this time injecting SV40 directly into the

> thin mesothelial walls of another group of hamsters. Within six months,

> every animal developed mesothelioma.

>

> Carbone was puzzled. Mesothelioma is a rare cancer. Few human cases were

> reported before the 1950s, but its incidence had been increasing steadily,

> reaching several thousand cases a year in the United States by 1988.

>

> Studies had linked mesothelioma to asbestos exposure - with tumors usually

> appearing many decades later. Yet 20 percent of victims had no asbestos

> exposure.

>

> Carbone decided to use PCR to test 48 human mesotheliomas stored at the

> NIH. He was stunned: 28 of them contained SV40.

>

> PCR unleashed a wave of SV40 discoveries. By the end of 1996, dozens of

> scientists reported finding SV40 in a variety of bone cancers and a wide

> range of brain cancers, which had risen 30 percent over the previous 20

> years.

>

> Then, Italian researchers reported finding SV40 in 45 percent of the

> seminal fluid and 23 percent of the blood samples they had taken from

> healthy donors.

>

> That meant SV40 could have been spreading through sexual activity, from

> mother to child, or by other means, which could explain how those never

> inoculated with the contaminated vaccine, such as the Boston children,

> were being infected.

>

> At the National Cancer Institute in Bethesda, officials were growing

> increasingly concerned about the SV40 discoveries.

>

> The findings were of particular interest to Fraumeni, who had been

> promoted to director of NCI's Division on Cancer Epidemiology and

> Genetics. His earlier studies concluding that SV40 posed little or no

> health risk were now under challenge.

>

> But the scientific community was skeptical of the recent SV40 discoveries.

> As a potent carcinogen in lab animals, SV40 had been used for years as a

> tool to study cancer. Therefore, the powerful PCR test was suspected of

> finding stray SV40 fragments that might have contaminated laboratories.

>

> So Dr. Strickler, one of Fraumeni's epidemiologists, led a study

> using PCR on 50 mesotheliomas from Armed Forces hospitals across the

> country. And he found no SV40.

>

> Although the findings bolstered the government's long- standing position

> that SV40 did not appear to be a health risk, federal officials decided to

> convene a conference on the virus.

>

> In January 1997, 30 scientists gathered at the National Institutes of

> Health in land. Garcea, Carbone and others presented their evidence

> showing SV40 in tumors and pleaded for research funding.

>

> Strickler presented his mesothelioma study, as well as new research he had

> just completed, this time working with Fraumeni.

>

> Their new study compared 20 years of cancer rates of people born between

> 1947 and 1963, and therefore likely to have been exposed to the

> contaminated polio vaccine, with people born after 1963, whom they

> believed weren't exposed.

>

> Their study found no significant difference between the two groups.

>

> But when 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.

>

> 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 stock grown on the rhesus monkeys

> tissue to start the bulk vaccine process.

>

> Manufacturers checked 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.

>

> 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. ph 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 land prepared mesothelioma samples for

> nine participants.

>

> When tests revealed almost no SV40 in the tumor samples, some participants

> questioned the preparation methods used by the land 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 land lab to recover viral DNA - like the

> genetic sequences of SV40 - from the mesothelial tissue to create the test

> samples.

>

> The land 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.

> In laboratories around the world, researchers continued to find SV40 in a

> widening range of tumors that now included pulmonary, pituitary and

> thyroid cancers and some lymphomas.

>

> Meanwhile, an NCI investigator named Dr. 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.

>

> 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. 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

> own transformation: " Nonbeliever (arrow) Believer (arrow) 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's 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 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.

>

> 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 that is shared by the broader scientific community.

>

> But a recent NCI statement acknowledges that there is evidence to suggest

> that SV40 " may be associated with human cancer. " The 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. 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.

>

>

>