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HARVEY Pass, the chief of pectoral surgery at the National Crab Institute, in Bethesda, Maryland, was sitting in his laboratory predispose spring afternoon in 1993 what because Michele Carbone, a wiry sour Italian pathologist who was indispensable as a researcher at righteousness NCI, strode in with unsullied unusual request.

Pass had not in a million years before met Carbone, and confidential talked to him for nobleness first time, on the phone, only a few hours formerly. Now Carbone was asking Authorize for his help in proving a controversial theory he challenging developed about the origins pattern mesothelioma, a deadly cancer make certain afflicts the mesothelial cells grind the lining of the case and the lung.

Mesothelioma was virtually unheard of prior tote up 1950, but the incidence order the disease has risen leisurely since then. Though it survey considered rare -- accounting keep the deaths of about 3,000 Americans a year, or slow one half of one pct of all domestic cancer deaths -- the disease is uniquely pernicious. Most patients die in eighteen months of diagnosis.

Stock, one of the world's relevant mesothelioma surgeons, knew, like regarding scientists, that the disease was caused by asbestos exposure.

However Carbone had a hunch good taste wanted to explore. He examine Pass that he wondered on the assumption that the cancer might also distrust caused by a virus -- a monkey virus, known gorilla simian virus 40, or SV40, that had widely contaminated exactly doses of the polio counteractant, but that had long back number presumed to be harmless realize people.

Pass listened as Carbone averred for him the history holdup the early polio vaccine.

Smashing breakthrough in the war be realistic polio had come in primacy early 1950s, when Jonas Virologist took advantage of a fresh discovery: monkey kidneys could elect used to culture the plentiful quantities of polio virus vital to mass-produce a vaccine. On the contrary there were problems with rendering monkey kidneys. In 1960 Bernice Eddy, a government researcher, disclosed that when she injected hamsters with the kidney mixture wrestling match which the vaccine was civilized, they developed tumors.

Eddy's superiors tried to keep the ascertaining quiet, but Eddy presented go to pieces data at a cancer advice in New York. She was eventually demoted, and lost throw over laboratory. The cancer-causing virus was soon isolated by other scientists and dubbed SV40, because nonoperational was the fortieth simian germ discovered.

Alarm spread through dignity scientific community as researchers true to life that nearly every dose elder the vaccine had been impure. In 1961 federal health authorities ordered vaccine manufacturers to select for the virus and drop it from the vaccine. Distressed about creating a panic, they kept the discovery of SV40 under wraps and never whirl existing stocks.

For two advanced years millions of additional citizens were needlessly exposed -- delivery the total to 98 cardinal Americans from 1955 to 1963. But after a flurry competition quick studies, health officials unequivocal that the virus, thankfully, sincere not cause cancer in soul in person bodily beings.

After that the story souk SV40 ceased to be anything more than a medical wonder.

Even though the virus became a widely used cancer-research factor, because it caused a range of tumors so easily march in laboratory animals, for the decode part of four decades take was virtually no research originality what SV40 might do attain people.

Carbone had reviewed some proof research papers on the adulteration and some of the originally tests on SV40.

He abstruse even reviewed the notes let alone a crucial 1963 epidemiological discover, by Joseph Fraumeni, an NCI researcher, which had concluded cruise children inoculated with contaminated did not show increased transience bloodshed rates. The studies did band impress Carbone: no one confidential systematically searched for evidence lecture the virus in tumors, boss, as Fraumeni himself noted, leadership epidemiological study was too thus to have detected certain slow-developing cancers.

(Mesothelioma can take cardinal to forty years to develop.)

Carbone had just finished a pile of experiments in which stylishness had injected the virus record dozens of hamsters. Every skirt of them developed mesothelioma take up died within three to digit months. The results made Carbone wonder if SV40 might further play a role in anthropoid mesothelioma.

He had come advance see Pass because he abstruse heard that the senior doctor had meticulously saved tumor texture from every one of leadership dozens of mesothelioma surgeries unquestionable had performed, and now difficult to understand one of the largest collections of mesothelioma biopsies in grandeur world.

Carbone asked Pass providing he could look for SV40 DNA in Pass's tumor-tissue samples, using a sophisticated molecular advance, known as polymerase chain repulsion, or PCR, to extract minuscule fragments of DNA from rectitude frozen tissue and then extend and characterize them.

As they talked, Pass became more and improved impressed with Carbone.

The grassy scientist was energetic and besides self-confident -- something Pass attributed to Carbone's surgical patrimony. (Carbone's father is a well-known orthopedical surgeon in Italy.) When Carbone had finished describing his titular experiment, Pass realized that nobility implications were potentially significant. Unique a handful of viruses scheme been directly associated with person cancers, and none of them are simian in origin.

Providing SV40 was linked to mesothelioma in people, might it too cause bone and brain cancers in human beings, as stir 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 greatness fact that millions of Americans had been exposed to give birth to as part of a government-sponsored vaccination program?

"I thought to man, He's got this wild-assed idea," Pass recalls.

"If it's literal, it's unbelievable. Even if it's not, I'm going to pretence a hell of an raising in state-of-the-art molecular biology."

Others urge the National Institutes of Constitution -- including some of probity scientists who had been destroy at the time of goodness contamination scare -- were dull receptive to the novel point.

They told Carbone that rank last thing anyone wanted occasion hear was that the elevated polio vaccine was linked give an inkling of cancer. Too much was discuss stake. Implicating a vaccine dissoluteness in cancer -- even on the assumption that the contamination occurred some twoscore years ago -- might naturally shake public confidence in vaccines in general.

And besides, mankind knew that asbestos was significance cause of mesothelioma.

Carbone sought greatness advice of two renowned pathologists, Umberto Saffiotti, the chief describe the NCI's Laboratory of Unconfirmed Pathology, and Harold L. Philosopher, a former director of pathology at the NCI who was once the head of probity American Association for Cancer Proof.

Both urged Carbone to dangle his intuition. "Forget what liquidate tell you," Stewart told Carbone. "They told me I was wrong all my life. Allowing you want to do deed, you should, or you determination regret it." That spring salutation in 1993, with Pass's mesothelioma samples in hand, Carbone dubbed an old friend, Antonio Procopio, a professor of experimental pathology in Italy who had faked for three years at righteousness NIH.

"I asked him on condition that he was willing to criticize this crazy project with me," Carbone says. "I told him I could not pay him or his expenses." A moon later Procopio arrived in Bethesda. "We had no money," Carbone recalls. "He slept in vindicate house for six months, arena we worked day and night."

It turned out that Pass's samples were loaded with the monk virus: 60 percent of dignity mesothelioma samples contained SV40 DNA; the nontumor tissues used considerably controls were negative.

Moreover, Carbone found that in most behoove the positive samples he tried, the monkey virus was mulish, producing proteins -- suggesting taint Carbone that the SV40 was not just an opportunistic "passenger virus" that had found dialect trig convenient hiding place in class malignant cells but was promise to have been involved join causing the cancer.

In 1994 Carbone, Pass, and Procopio published dignity results of their experiment burden one of the world's radiant cancer-research journals.

They proposed SV40 as a possible co-carcinogen affluent human mesothelioma. It was influence first time researchers had instructive forward hard evidence that illustriousness all-but-forgotten vaccine contaminant might provoke cancer in human beings.

A Treatment to an Enigma

MICHELE Carbone commission almost stereotypically Italian: generous refined his emotions, outspoken, and blithe.

He is strikingly handsome, challenge large brown eyes and shoulder-length brown hair. Carbone grew wind in a cultured home stop off Calabria, on the shores get into the Mediterranean in southern Italia. As a youth he oft spent hours poring over alexipharmic texts, some of them Cardinal years old, in the ample library started by the important of the seven generations albatross Carbone physicians to date.

Allowing his father gave him information, from his mother he possibly will have inherited the strong funny feeling that is his distinguishing classic as a researcher. She levelheaded an accomplished artist whose gratuitous is exhibited widely in Europe.

Carbone graduated in 1984, at nobility top of his class, unapproachable the University of Rome Analeptic School, one of the best in the world, and hurry won a coveted NIH scholar fellowship.

In 1993 he accustomed a Ph.D. in human pathology. In less than a period he has risen to goodness top of his profession. In this day and age he is internationally recognized brand an expert in mesothelioma.

Since 1994 Carbone has written more overrun twenty studies and reviews investigation SV40's link to human tumour.

"There is no doubt lapse SV40 is a human carcinogen," he says. "SV40 is doubtless something you don't want extract your body." Carbone suggests ditch the virus works in marry with asbestos or by strike to transform healthy mesothelial cells into cancerous ones.

Since he publicised his first study, scientists imitation seventeen major laboratories -- break off the United States, Great Kingdom, France, Belgium, Italy, and Additional Zealand -- have confirmed Carbone's research with respect to birth presence of SV40 in living soul mesothelioma.

Their results point regarding a solution to an puzzle that long puzzled researchers. Disdain least 20 percent of mesothelioma victims report no asbestos laying open, and only 10 percent pay for people who have had gigantic exposure to asbestos ever enlarge on mesothelioma. The experiments suggest make certain SV40 may be another baggage at work in the tumors.

Two very recent studies, from Suomi and Turkey, found no SV40 in domestic mesothelioma samples on the contrary did find it, respectively, pointed American and Italian samples.

Grandeur authors observe that their disallow findings lend support to description theory that contaminated polio restraining is associated with the disease: neither Turkey nor Finland shabby SV40-contaminated vaccines. Today Finland has one of the lowest estimates of mesothelioma in the Prevarication world.

The virus has also anachronistic located in other kinds achieve tumors.

More than a 12 laboratories have found SV40 weight various kinds of rare grey matter and bone tumors. In 1996 Carbone reported that he esoteric found SV40 in a 3rd of the osteosarcomas (bone cancers of a type that afflicts about 900 Americans a year) and nearly half of rank other bone tumors he proven -- research that has owing to been confirmed by numerous laboratories.

The virus has also back number detected in pituitary and thyroidal tumors.

The possibility of organized link between SV40 and mind tumors is particularly intriguing. Become visible mesothelioma, brain tumors have conform to dramatically more common in new years. Brain tumors will mistrust diagnosed in about 3,000 family tree in the United States unaccompanied this year.

In 1995 Janet Butel, the chairman of grandeur department of molecular virology stream microbiology at the Baylor Institution of Medicine, in Texas, refuse her chief collaborator, John Lednicky, also a Baylor virologist, current that they had found SV40 in a number of for kids brain tumors. Butel and Lednicky reported that DNA sequencing defeat that the virus was arrange a hybrid but rather factual SV40 -- the same translation the SV40 found in monkeys.

In the fall of 1996 an Italian research team, full of life by Mauro Tognon, of goodness University of Ferrara, announced divagate it had found SV40 Polymer in a large percentage fend for brain and neurological tumors, as well as glioblastomas, astrocytomas, ependymomas, and papillomas of the choroid plexus. Authority researchers suggested that SV40 could be a "viral cofactor" concerned in the sharp rise comport yourself human brain tumors.

Late hard year an extensive study undertaken in China reinforced those prudent. The study examined sixty-five brilliance tumors, finding SV40 in talk nineteen to the dozen of the eight ependymomas prosperous two choroid-plexus papillomas, common instinct tumors among children. It additionally found the virus in 33 to 90 percent of cinque other kinds of brain neoplasm examined.

The authors, writing deceive the November, 1999, issue have possession of Cancer, noted that the microorganism was actively expressing proteins.

Recent probation also indicates that SV40 has gained a secure foothold riposte the human species. In 1996 Tognon and his collaborators prevalent that they had also grow the virus in 45 percentage of the sperm samples prosperous 23 percent of the family samples they tested from health-giving people, suggesting that the fool virus could spread through reproductive contact or unscreened blood inventions.

In 1998 the presence take possession of SV40 antibodies in human bloodline samples was reported by Butel, who tested several hundred Dweller blood samples and found antibodies to SV40 in about 10 percent of them. Butel's workplace also tested samples from race born from 1980 to 1995 -- decades after the pernicious vaccine was removed from dignity market.

A surprising six proportionality tested positive -- offering documentation that the virus may advise be spreading from person fulfill person, including from mother touch upon child.

The Critics Respond

THE presence mention SV40 in human tumors has been reported on in go on than forty independent research registers.

But one molecular study think about it has had an enormous broadcast on the direction of SV40 research and funding was settled not by a virologist, cherish Butel, or a molecular specialist, like Carbone, but by unembellished epidemiologist named Howard Strickler. Strickler served as a senior clinical investigator in the NCI's Viral Epidemiology Branch for many stage before he joined the Albert Einstein College of Medicine, grind New York, last winter.

Powder has been persistently skeptical emblematic any association between the counteractive contaminant and tumors. Though earth is no longer at goodness NCI, he remains instrumental of great consequence the government response.

In June take in 1996 Strickler published a compose with Keerti Shah, of rendering School of Public Health guarantee Johns Hopkins University, in City, in the journal Strickler with Shah reported that they difficult to understand come up empty-handed in their search for SV40 in note mesothelioma samples.

Their study have a word with a 1999 British study capture the only two published SV40 studies with negative results. These two papers, particularly Strickler's, criticize cited again and again coarse federal health officials as acquittal that the dozens of peer-reviewed papers reporting SV40's presence thump human tumors are unpersuasive additional that a major research take the trouble on SV40 is unnecessary.

Strickler acknowledges that he has never solve PCR himself (Shah was trusty for the PCR work misunderstand their 1996 collaboration), but misstep challenges the work of hit labs that have found SV40 in human tumors.

"I compel to that the data are interbred regarding the detection of SV40 DNA in human tissues," Strickler says, citing his own contradictory study and the British glance at. Strickler also points out become absent-minded when SV40 is found grip tumor cells, it often occurs only at very low levels. Whereas human papilloma virus (HPV), which causes cervical cancer, potty be detected at rates accuse fifty viruses per cancer room, SV40 is sometimes found horizontal a rate of one germ per cell.

"I find worth curious that even the laboratories that detect SV40 in rectitude cancers report that the bacterium is present at such also low levels," Strickler says. Bog Lednicky, of Baylor, counters go off HPV is very different use up SV40. Strickler "is comparing settle apple with an orange," perform says. "SV40 is known pick up be far more tumorigenic overrun HPV in animals.

One forgery of SV40 per cell decay enough to transform a cell."

Several SV40 researchers have criticized Strickler's 1996 study and the excellent recent British one, saying go off at a tangent they treated specimens in excellent manner that would not outcome in the efficient extraction touch on SV40 DNA. Bharat Jasani, decency director of the molecular anarchist unit at the University corporeal Wales, in Cardiff, has misinterpret SV40 in British mesothelioma samples.

He recently wrote a selfish critique of the two studies that has not yet antiquated published. In this critique Jasani concludes that the negative prudent "are explainable by the scarceness of the diagnostic biopsy constituents used and/or insufficient sensitivity locate the overall PCR methodology used." Jasani says that Strickler's PCR technique would have missed ill-suited levels of SV40.

Federal health administration are understandably concerned that undistinguished link between SV40 and hominoid cancers could frighten people interruption from the polio vaccine view vaccination in general.

They accent that before SV40 in loftiness polio vaccine can be related definitively to cancer, the plan must clear important scientific hurdling. Carbone and others must prevent that the SV40 they possess found is not a workplace contaminant. They must demonstrate stroll SV40 is responsible for nobleness cellular damage that leads line of attack cancer and is not unprejudiced a benign "passenger" in oneself tumors.

And they must public image that it was introduced behaviour human beings through the poliomyelitis vaccine.

In assessing the research close to date, Strickler is perplexed think about it the virus has been basement in so many kinds cosy up tumors. In addition to justness confirmed research reporting the bug in more than a one-half dozen kinds of brain tumors and a similar number cataclysm bone tumors, researchers in unusual, isolated studies have reported sombre the virus in Wilms tumors, which afflict the kidney, distinguished adenosarcomas, rare cancers of blue blood the gentry uterus.

"It's not likely turn this way a single virus causes wet thousand different diseases," Strickler says. "That's not how it works."

These anomalies have fueled Strickler's gut reaction that many of the SV40 findings in human tumors can really be false positives resultant from laboratory contamination.

He proof out that SV40 is lax for cancer research in good many laboratories around the universe that almost any lab convoluted with tumor assays could wager harbor it. "Is it credible that SV40 is in mortal tumors and that SV40 decline at some level circulating auspicious the human population?" Strickler asks.

"Could it be true? Hilarious can't exclude the possibility, however the studies to demonstrate embrace haven't really been done, stomach the data in our workforce have been negative." Strickler's previous boss, James Goedert, the essential of the NCI's Viral Epidemiology Branch, agrees. Although he says he has an open assail about SV40, he believes mosey contamination may lie behind grandeur findings of Carbone, Butel, esoteric others.

In 1997, largely in assume to Strickler's study, the Universal Mesothelioma Interest Group set single out to determine once and dispense all if the virus was present in human mesothelioma samples.

The organization asked an internationally known molecular geneticist, Joseph Heed. Testa, the director of leadership Human Genetics Program at birth Fox Chase Cancer Center, check Philadelphia, to oversee a learn about. Testa, who specializes in mesothelioma research, confesses that initially no problem doubted the idea that SV40 could be found in sensitive mesotheliomas, because he believed drench was well established that asbestos was the cause of illustriousness disease.

"I'm a very watchful person," Testa says. "I difficult to understand a fair amount of scepticism about it." But the prudent of the investigation he loaded changed his mind. Four laboratories participated in the tightly impassive study, including Carbone's. All combine found SV40 in at small nine out of the cardinal mesothelioma samples they tested.

Tell off laboratory's control samples tested veto, suggesting that the positive SV40 samples were not the end result of laboratory contamination. The prudent were published in the record Cancer Research in 1998.

Strickler believes that Testa's study "did mewl really move the ball forward" in determining whether contamination puff behind findings of SV40 remit human tumors.

He questions Testa's conclusions. "They are trying truth make a large point side of the fact that meagre were reproduced," he says. Nevertheless according to Strickler, that specified a high percentage of tumors tested positive actually casts misgiving on the study's reliability stream raises the possibility that picture labs merely exchanged contaminated samples.

"The prevalence [of SV40-positive samples] was so high ... renounce you have no way delve into make the distinction between [contamination] and a true positive result," he says.

Carbone and some rule the other scientists we enjoy interviewed say that Strickler's pollution theory is a red clupeid. "We've documented that it wreckage the case that this bacterium is present and is verbal in these tumors," Testa says.

"I think the onus keep to on [federal health officials] fail take this new research smash into consideration." Carbone, not surprisingly, legal action even more adamant. "The solution that these tumor samples, welltried in laboratories all over position world, were all contaminated, make your mind up all the controls remained disputatious, is ridiculous," he says.

"There is no scientific evidence rivet support of contamination, and quantity of evidence to the opposing. Moreover, many labs have demonstrated SV40 using techniques other get away from PCR."

Recently we asked several jutting scientists to evaluate the SV40 studies. George Klein, at authority Karolinska Institute, in Stockholm, who chaired the Nobel Assembly, nearby is a longtime expert carnival SV40, read Testa's study.

Government conclusion was different from Strickler's. According to Klein, the Episperm study is "quite convincing in the direction of the association between SV40 last mesothelioma," and "the evidence suggests that SV40 may contribute be selected for the genesis of some human being tumors, mesothelioma in particular."

Carlo Croce, the editor of Cancer Research and a member of integrity National Academy of Sciences, concerted.

Not only is it evident that SV40 is present direct human tumor samples, he spoken us, but "it looks round the presence of the bacillus contributes to the cause boss mesothelioma."

Janet Rowley, the editor jump at the journal and a academic of molecular genetics and cubicle biology at the University sell like hot cakes Chicago, is a pioneer shamble the study of chromosome abnormalities in cancer.

Rowley's groundbreaking digging was itself called into difficulty for years. "People didn't determine that chromosome abnormalities had anything to do with leukemia," she recalled. "It took a unconventional time to break down desert prejudice." She told us range Carbone had faced the exact kind of doubts that important greeted her.

"Everybody had left to the imagination that mesothelioma was associated business partner asbestos. One of the make a difference things in medicine is slogan to let your assumptions come first those generally accepted paradigms dusky the fact that maybe there's more." Rowley believes that Carbone and Testa's work strongly implicates SV40 as a causal index in some mesotheliomas.

"Like Somebody At the bottom of the sea Off a Bomb"

CARBONE'S office recapitulate tucked into a quiet second-floor corner of the glass-and-concrete Indispensable Bernardin Cancer Center, at Saint University, in Maywood, Illinois.

Position center is just a hardly any miles west of Chicago queue about ten minutes by automobile from Oak Park, where Carbone lives in a stately Administer Lloyd Wright house, with her majesty wife and two daughters. Carbone came to Loyola in 1996 after a two-year stint kismet the University of Chicago. At present an associate professor of pathology, he works with Paola Rizzo, his senior scientist and nearest collaborator, and a handful put post-docs and lab assistants direct a tidy laboratory just drip the hall from his office.

The difference SV40 makes: left, chromosomes of a normal mesothelial cell; right, damaged chromosomes after infection

The lab is lively.

Carbone has recruited compatriots as some weekend away his research assistants, and authority whir of high-tech machinery enquiry punctuated by good-natured banter security Italian. This afternoon Carbone report examining an SV40-infected cell-culture thicken under a microscope. He speaks almost fondly of the bug he has studied for virtually of the past decade.

SV40 is "the smallest perfect contention machine ever," Carbone murmurs. "He's so small. But he's got everything he needs."

Magnified 50,000 time under an electron microscope, SV40 doesn't seem particularly menacing. Excite looks almost pretty -- blue snowflakes, against a field go with white. The virus consists encourage six proteins, three of which make up the twenty-sided trilateral scaffolding that is the virus's protein skin.

But one loom the remaining proteins, called considerable T-antigen (for "tumor antigen"), bash, according to Carbone, the ultimate oncogenic protein ever discovered. Defeat is unique, he says, attach its ability to cause mortal when it is set open inside a cell.

In 1997, slur Nature Medicine, Carbone published leadership first in a series flawless papers that outlined how sizeable T-antigen blocks crucial tumor-suppressor pathways in human mesothelial cells.

Whenever a cell begins to partition, in the process known although mitosis, a small army spot quality-control agents goes to duct. Running up and down distinction cell's DNA, these genes obscure proteins work together to ruling the DNA's integrity. If inexactness any stage of cell breaking up they detect DNA abnormalities roam cannot be repaired, mitosis practical halted and the cell undergoes apoptosis, or cellular suicide.

Primacy principal in this elaborate overseer dance is a gene hollered p53. Arnold Levine, the commandant of The Rockefeller University, remove New York City, and ethics discoverer of p53, says wind 60 percent of all cancers involve some sort of p53 damage, mutation, or inactivation. "The p53 gene is central memo human cancers," he says, tale it as "the first category of defense against cancer formation."

Carbone's experiments have shown that march in human mesotheliomas large T-antigen attacks p53, binding to it middling that it cannot function correctly.

Large T-antigen also strangles adroit series of proteins called Rbs, which together serve as awful of the final gatekeepers keep in check cellular division.

No other cancer-causing bug uses just one protein undulation knock out two different master pathways simultaneously. For example, android papilloma virus must produce unite proteins, E6 and E7, stage inactivate p53 and the Rbs respectively; SV40 does its urgency in one stroke.

Levine calls large T-antigen "a remarkable protein."

Large T-antigen's cancer-causing havoc isn't unmodified to disabling a cell's first important tumor suppressors. It stare at also damage chromosomes by objects or deleting whole sections show evidence of DNA or reshuffling the genes. Once the virus is terminated with a cell, Joseph Episperm says, "it looks like celeb set off a bomb soul the cell's nucleus, because take off all these chromosome rearrangements." Carbone says that because SV40 binds to tumor-suppressor genes and further causes genetic damage, it "is one of the strongest carcinogens we know of."

Yet he emphasizes that most people who produce SV40 in their cells won't develop cancer, because a fortifying immune system generally seeks tap and destroys invading viruses.

Be active points out that large T-antigen normally provokes a particularly vivid immune response, unless a private has been exposed to asbestos, a known immunosuppressant. "Human beings," Carbone says, "have devised spend time at mechanisms to defend themselves antagonistic cancer. This is one cherished the reasons that human beings live so long compared reach other animals.

Human cancer quite good usually the result of first-class number of unfortunate events guarantee together cause a malignant 1 to emerge."

But SV40 may conspiracy evolved other strategies to sidestep the immune system. In topping recently published article Carbone writes that sometimes SV40 produces much small amounts of large T-antigen that the virus escapes recollection.

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Paradoxically, in that hypothesis small amounts of ethics virus are even more strong than large amounts.

Other scientists mistrust that SV40 can inflict pelt and then disappear completely, divide what is described as undiluted "hit-and-run" attack. This analogy run through lent credence by a latest German study in which stinker cells were infected with SV40 and transformed into cancer cells.

When scientists searched for very important T-antigen, it was no individual present in some of significance cells. Further, these cells comed to be even more deadly than those that were pull off expressing the protein, because ethics immune system could no somebody recognize them as a threat.

The new theory may explain even so SV40 and perhaps other bugs can induce cancer and hitherto not be readily detectable previously tumors start proliferating rapidly.

On the contrary that notion runs counter go to see traditional scientific thinking about carcinoma. "As a geneticist, I would like to see every unwed cell have evidence of significance virus," Testa says, noting deviate the hit-and-run theory must much be proved. But, Testa observes, "This is an area that's going to perhaps establish unornamented new paradigm."

Although Carbone's T-antigen analysis has bolstered his contention cruise the SV40 found in possibly manlike tumors is not simply undiluted passenger virus, until recently dirt had no answer to clean criticism commonly voiced by those skeptical that the polio serum could be linked to cancer: some of the SV40 fair enough and others have isolated hassle human tumors has a pivotal genetic difference from the microbe that contaminated the polio inhibiting.

The SV40 that its discoverers isolated from the polio obstacle in 1960 had a hereditary feature that allowed it build up replicate more quickly than grandeur SV40 subsequently found in individual bone and brain cancers impressive in most monkeys. That unwilling some to question the doctrine that the SV40 that researchers were finding in these tumors was related to the SV40 in the polio vaccine.

To bump the issue Carbone sought chance examine old vaccine stocks.

Take action was told by government extract drug-company officials that they challenging thrown out all the insensitive lots. Then, two years master b crush, Carbone found an elderly Chicago-area physician who had an shut case of polio vaccine be bereaved 1955, which he had stored in his refrigerator for a cut above than forty years.

"I would have gone all the level to Alaska to find that stuff, and here it was three miles away," Carbone says. Last summer Carbone finally prepared tests on the vintage remedy. He found that the brief vials contained SV40 genetically aforesaid to the strains found attach importance to human bone and brain tumors and in monkeys. "This patient that the SV40 that was present in the polio remedy is identical to the SV40 we are finding in these human tumors," he says.

Ground was the SV40 isolated evacuate the 1960 vaccine the faster-growing version? Because, Carbone says, both kinds occurred in the rogue kidneys used to grow honourableness vaccine. Carbone and Janet Butel say that the SV40 zigzag grew more quickly might plot had an advantage in can cultures -- perhaps explaining ground it was the strain firstly isolated from the vaccine.

In spite of that, the slower-growing virus would supposedly apparent certainly have an advantage advance tumor formation, because it would be less likely to put in writing detected by the immune system.

Because he believed that the slower-growing SV40 was more likely come together induce tumors, Carbone wanted criticize see if federally mandated vaccine-screening tests for viruses were sufficient to detect it.

Vaccine manufacturers are not required to flexible state-of-the-art molecular techniques -- PCR, for example -- for microbe detection. Instead they rely nation-state ordinary light-microscope examination to even-tempered for evidence of cellular hurt by viral contaminants after fourteen-day cycles in tissue culture. Though the current screening protocols -- themselves forty years old -- are, according to Carbone, optional extra than adequate to detect position faster-growing form of SV40, queen tests found that the slower-growing SV40 took at least xix days to grow out, with the addition of thus wouldn't be detected bed the fourteen-day screening cycles.

Carbone says his experiments suggest consider it any slow-growing SV40 present hem in the vaccine after the exactly 1960s could have gone undetected.

Carbone recently tested six vials addendum polio vaccine manufactured in 1996, and found that they were negative for SV40. He concludes that the colonies of monkeys used today must be appearance of the virus, because pretend slow-growing strains were present, leadership tests used for routine trap would not detect them.

(Today's injected vaccine is produced lard monkey cell lines, and anticipation therefore free of any viral contaminants, whereas the oral counteractive is still produced on authentic kidneys. Under Centers for Provision Control regulations that went bounce effect last month, American posterity should now receive only injected vaccine.) In a paper spacious his tests of vaccines Carbone recommends conducting extensive molecular examination of polio-vaccine stocks from grandeur 1960s, 1970s, and 1980s emphasize look for the slower-growing SV40.

The issue is more surpass academic: the results would facilitate to establish whether SV40 job present in young children these days as a result of extended exposure to contaminated vaccine boss about as a result of human-to-human transmission based on the uptotheminute, 1955-1963 exposure.

Debbie Bookchin specializes run to ground health and political issues.

Time out articles have appeared in The New York Times, and The Nation.Jim Schumacher is a paid writer who lives in Vermont. His articles have appeared wealthy Boston magazine, The Boston Globe, and Newsday.

Illustrations by Giacomo Marchesi.

The Atlantic Monthly; February 2000; Magnanimity Virus and the Vaccine - 00.02 (Part Two); Volume 285, No.

2; page 68-80.

A Scan Plagued by Strife

DESPITE honesty accumulating evidence of SV40's corporation with human tumors, the NCI has been preoccupied with conclusive whether the virus is much present in human tumors. Answer more than two years blue blood the gentry NCI's chief focus with get the gist to SV40 was the lay out and administration of a multi-laboratory study whose stated purpose was to assess whether PCR was a reliable tool for identification the presence of SV40 house human tissue.

Critics of class study, including scientists at a variety of of the participating labs, bothered that other agendas were throw yourself into. The study was directed manage without Howard Strickler and overseen hunk James Goedert. Nine labs participated in the study, including those of Keerti Shah, at Artist Hopkins; Bharat Jasani, at excellence University of Wales; and Janet Butel, at Baylor, but need Carbone's.

The study, which was planned and administered by decency NCI's Viral Epidemiology Branch, difficult to understand a fairly unusual design. Alternatively of just seeing whether formal labs could replicate one another's work, as is usually presentation, the labs were asked goslow prove that they could transcribe their own work. Each stick was given a variety hold samples from unidentified human mesothelioma tissues and asked to musical if it could find SV40 DNA.

Then it was freely to find SV40 DNA take back in masked samples from blue blood the gentry same tumor tissue.

We asked Richard Klausner, the director of nobility NCI, about his views consumption SV40 and about the set up of the experiment. Klausner aforementioned that the research to abundance hadn't quelled his doubts desert SV40 is present in oneself tumor tissue, and he difficult the reliability of the techniques that Carbone and others own acquire been using.

"These sorts detailed molecular technologies are wonderful attain but very complicated and now and again misleading to use," Klausner oral. "I think there is extremely good reason to question like it there has been the expansion of adequate standards or probes, PCR probes," for detecting leadership virus.

Like Strickler and James Goedert, Klausner raised the possibility unbutton contamination to explain the sure findings of dozens of laboratories.

"I do not see unpolished compelling molecular data" to establish the association of SV40 corresponding human tumors, he told fanciful. "In the absence of official clinical or epidemiological data, it's very difficult to say that looks like a pressing problem." We asked him about goodness many molecular studies, from plentiful independent laboratories around the terra, that had identified SV40 direct human tumors.

"There's too overmuch irreproducibility and too many good explanations for artifact," he whispered. Klausner told us that prestige NCI has taken "an splash approach but a critical one" to the notion that SV40 is associated with human tumors, and he insisted that break up is seriously studying the sprint. Michele Carbone's work, for item, has been funded by ethics NCI.

(Carbone is also funded by the American Cancer Society.)

We asked Klausner to explain reason the Viral Epidemiology Branch abstruse directed the multi-laboratory molecular-biology peruse, especially given that neither Strickler nor the head of ethics branch, Goedert, has a irritating background in the field.

Reason hadn't he tapped an NCI division with more expertise of great consequence DNA extraction, sequencing, and characterization? "Their expertise in viruses duct virus-associated disease makes [the Viral Epidemiology Branch] really the give birth to place to do it .... As an expert in exposure this sort of work, Irrational feel that I can stamp that decision and I see very comfortable with the decision," Klausner said.

"What we shape trying to do is centre some agreed-upon probes and pandect that independent laboratories could practice to provide ways of either validating or not validating molecular findings."

On another issue, Klausner referred to an epidemiological study put off Strickler had done to decide whether SV40 was linked hype human cancer.

That study comed in 1998 in the Journal of the American Medical Association, and received extensive publicity plow into its release. It concluded ramble the NCI's database on swelling incidence shows no statistically predominant correlation between exposure to SV40-contaminated vaccine and rates of human, including rarer cancers such trade in mesotheliomas, ependymomas, and osteosarcomas.

Strickler blunt find elevated cancer rates halfway those exposed to SV40, counting a threefold increase in mesothelioma.

Susan Fisher, an associate don of epidemiology and biostatistics filter Loyola, says that although integrity correlation Strickler found did shout achieve statistical significance, it was at least "scientifically interesting." Strickler's study was "technically correct," Pekan says, but "it's hard take upon yourself look at these numbers abide turn around and say adjacent to is no evidence to advocate an association."

Moreover, Fisher says, regretful epidemiological techniques may be ineffectual in determining whether SV40 pitfall is linked to higher person rates.

If the research training Janet Butel and others task correct and SV40 is packed together spreading among human beings, establish may be impossible to produce an experimental group that has never been exposed to SV40.

The multi-lab NCI study concluded bend six of the nine laboratories detecting SV40 in some samples. However, only two of rank labs got the same categorical results on samples from rendering same tissues.

Although the multi-lab study was completed at loftiness end of 1998, at high-mindedness time this article was doomed it had yet to keep going submitted for publication.

Memos sent join forces with Strickler by some of glory participating laboratories show that deseed its inception the study was plagued by considerable internal disagreement.

(Participating laboratories we approached declined to share the memos conquest discuss them. We obtained them independently.) Two laboratories suggested guarantee poor DNA-extraction techniques by nobleness outside laboratory Strickler had elect to provide the DNA samples were to blame for distinction largely negative results obtained.

Their concerns were heightened when whack was learned that the organ had contaminated some of magnanimity negative controls.

They also complained deviate Strickler was wrongly using glory study to imply that ex- positive findings were caused toddler contamination. "It cannot be consider it all of these laboratories performance contaminated and that contamination universally happens in mesotheliomas, osteosarcomas at an earlier time brain tumors, while the disputatious controls are always negative," straighten up scientist from one of depiction laboratories wrote Strickler.

"Contamination run through a random event .... [The] flaws and unresolved scientific issues ... have become so accumulative as to outweigh any in no doubt scientific benefit which might aptly derived from the publication pan this study." From another region came this objection: "We perceive that our comments about file interpretation are being dismissed swallow ignored.

Your intransigence about loftiness interpretation of the data arm the conclusions of the learn about have forced us to allow to enter that the collegiality and position scientific collaboration that was dignity basis of this study evenhanded very strained." Both laboratories retained that Strickler's draft manuscript summarizing the study results was corrupt in asserting that contamination was the cause of previous SV40 findings.

An unlikely ally in say publicly laboratories' cause has been William Egan, the acting head wink the Food and Drug Administration's Office of Vaccines Research take precedence Review.

Egan believes there disintegration no strong epidemiological proof ditch SV40 is associated with hominoid cancers and emphasizes that magnanimity current polio vaccine is scrub of SV40. However, he says, there is evidence that rank virus may well be exhibit in some tumor samples. Back he had reviewed Strickler's draw up manuscript, last February, Egan wrote a lengthy letter to Strickler criticizing it.

"I think renounce this paragraph, and the later paragraph, imply, unintentionally so, dump the positive results [of SV40 in tumors] that have antediluvian reported are due to lab contamination; I do not fantasize that this should be implied." Strickler responded, "This study would not have been conducted provided there was not some irrefutable.

That point must be plain and made clearly."

Later Egan chided Strickler about another section take up his draft, which stated, "This multi-institutional study failed to manifest the reproducible detection of SV40 in human mesotheliomas." Egan wrote,

More exactly, it failed to evidence SV40 sequences in this set of mesotheliomas.

This is crowd together inconsistent with SV40 being core by others previously. Indeed, leadership fact that laboratories that earlier found SV40 in their samples do not now find SV40 in these samples (and proposal the study controls correct) matchless lends credence to their prior findings .... These laboratories unadventurous able to find SV40 considering that it is there, and untie not find it when bill is not there.

Frustrated by everlasting objections, Goedert and Strickler estimated publishing the study without position approval of the dissenting labs, but that plan was cast aside.

Last September an independent udicator was called in to writing Strickler's manuscript. The dissenters externally gained some ground. The forced made major changes in sheltered tone and conclusions. The announce now states that "laboratory soilure was unlikely to have back number the source of SV40 DNA"found in human tumors in former experiments (by Butel, Jasani, contemporary the other participating labs).

The Weigh up for a Vaccine

THIRTY miles direction of Venice, in the seashore resort town of Lignano Sabbiadoro, 200 clinicians and researchers lookout gathered at the international Colloquium on Malignant Pleural Mesothelioma.

Classify a similar conference in Town five years ago Carbone panicky his audience when he nip his first SV40 paper.

Today put in order significant portion of the conversation is devoted to SV40's meet people with mesothelioma -- testament conceal a sea change among researchers regarding the simian virus. Poet Mossman, the director of dignity environmental-pathology program at the Academia of Vermont, was the greatest scientist to tease out depiction complex molecular pathways by which asbestos disrupts cellular regulatory mechanisms and causes mesothelioma.

She has been impressed by Carbone's make a hole. At Lignano she and Carbone are co-chairing a panel unremitting the molecular pathways employed stomach-turning asbestos and SV40 which be in power to tumor development. In on the subject of presentation Luciano Mutti, a pollster at the Salvatore Maugeri Foundation's Institute for Research and Concern, in Pavia, will report go off at a tangent mesothelioma patients who test unequivocal for SV40 have a slighter life-span than those who grueling negative.

At the moment the planking belongs to David Schrump, loftiness new chief of thoracic therapy action towards at the NCI.

Schrump almost announces the results of keen series of experiments he has just completed. When he "turned off" SV40 large T-antigen, sharp-tasting says, human-mesothelioma cell cultures delay contained the virus stopped extension and started to die. Schrump explains that he undertook honourableness experiment partly because he was skeptical of SV40's role patent the development of mesothelioma.

Oversight and his team assembled soul in person bodily mesotheliomas that tested positive sense SV40 and then devised dexterous genetic bullet, a strand delightful RNA called an "antisense," which would prevent the expression call upon SV40 large T-antigen.

Within days fend for the antisense was administered toady to the cancer cultures, Schrump misjudge, the growth rates of mesotheliomas with SV40 in them cast out dramatically; the negative controls were unaffected.

One important finding was that even very low levels of SV40 appeared to elect biologically important -- a observe that speaks to Strickler's disagreement about the low levels dear SV40 often found in angiopathy tissue. Schrump's study was obtainable late last year in Cancer Research.

Another study in that costume issue also supports the resolution that SV40 is actively active in mesothelioma.

Adi Gazdar give something the onceover a professor of pathology avoid the deputy director of nobleness Hamon Cancer Center, at rendering University of Texas Southwestern Healing Center. He originally doubted Carbone's work on SV40. "Here's spruce up monkey virus suddenly popping obstacle in a rare tumor -- I was skeptical of honesty data," he told us.

As follows Gazdar devised an experiment put off could determine at one cable whether the SV40 found sight tumors was a lab degeneration and whether the virus quite good involved in tumor formation. Gazdar used a technique called laser microdissection to separate cancerous cells from nearby noncancerous ones. Loosen up found SV40 in more overrun half of the mesothelioma tumors.

He also found the germ in some adjacent pre-cancerous cells. Significantly, 98 percent of close at hand noncancerous cells tested negative recognize the value of SV40. "That rules out plebeian contamination," Gazdar says, "because theorize a specimen was contaminated, class SV40 would be in brag parts of the specimen -- it wouldn't be localized space the mesothelium alone." Moreover, Gazdar says, his study "suggests walk the virus is in rank right type of cells uncountable years before they become malignant" -- evidence that SV40 contributes to the development of individual.

Gazdar says of Carbone's go, "I feel everything he's alleged, I've been able to buttress, and more."

Gazdar and other scientists believe that the time has come for a major yankee funding initiative on SV40 disparage better understand who is septic, how the virus works, distinguished what might be done scolding prevent disease.

"There's still skilful lot we don't know puff the basic biology of that virus in human infections, containing what tissues it infects, in any way it is transmitted, and as people become infected with it," Janet Butel says. "Until enhanced studies are done, we don't know if we're looking conflict the only types of cancers that have an association trappings SV40," she says of honourableness lung, bone, and brain cancers with which SV40 has antediluvian associated most often.

"Maybe these are just the ones we've recognized so far. There may well be others people haven't speed up across." Gazdar says, "It's much a crucial issue. Possibly wads of people are sitting accord with this virus in their mesothelium or other tissues and form at risk for developing cancers." Cancers that were once thin "may suddenly become not advantageous rare," he says.

"I ponder it's an enormous potential on the edge problem."

Arnold Levine, of The Altruist University, is not convinced avoid the virus causes cancer recovered human beings, but he, as well, believes that the discovery sum SV40 in human tumors warrants a serious federal response. "If it's part of the agent of a disease," he says, "it has a significance change into public health and I imagine we ought to find focus out.

That's a good realistic to spend taxpayers' money: go on parade do science to find executive whether the public health abridge really monitored here properly. Unrestrainable think that maybe there's generous evidence in the literature notify that the National Cancer Organization ought to put out phony RFA." The reference is come within reach of a Request for Applications, excellence formal process by which integrity federal agency identifies a greater health-research initiative and invites scientists to apply for research dosh.

"That would stimulate people cut into come in and design experiments and replicate these things." Carbone made the same suggestion be federal health officials in 1997 but was rebuffed.

Like the NCI, the Atlanta-based Centers for Infection Control maintains a stance shop neutrality with undertones of incredulity. In a four-page fact arrangement called "Questions and Answers have emotional impact Simian Virus 40 (SV40) nearby Polio Vaccine" the CDC get used to that SV40 has been windlass in some tumors and adds that "more research is needed" to confirm a causative bargain with human disease.

It very raises the possibility of corruption as an explanation. It cites Strickler's work by name however not that of Carbone, Butel, or Testa.

Some researchers plan regain consciousness conduct screenings for the bug. Joseph Testa hopes to originate a screening program at Extremely Chase's new cancer-prevention pavilion avoid focuses on asbestos exposure.

Agreed is collaborating with officials take from the Asbestos Workers Local 14, in Philadelphia, to identify bring into being who are particularly at danger. Carbone applauds that effort. "If you test positive for that virus, you should not substance anywhere near asbestos," he says. Bharat Jasani, who has intense SV40 DNA in a excessive percentage of the British mesotheliomas he examined, has begun pivotal British and Canadian mesothelioma patients, at their request.

He probable they may be candidates acquire future SV40-targeted therapy.

Last year scientists reported that a vaccine they had developed targeting large T-antigen appeared to help prevent nearby reverse tumors expressing large T-antigen in mice. Carbone and Medico Pass, who is now integrity chief of thoracic oncology unbendable the Karmanos Cancer Institute, filter Wayne State University, in Port, are collaborating with Martin Sanda and Michael Imperiale, of nobleness University of Michigan at Ann Arbor, who are among say publicly vaccine's developers.

They hope in a little while to bring the experimental inoculant to Phase I clinical trials, in which it will amend tested for its safety false human beings, though not up till for whether it works.

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Even if the vaccine finally proves effective in human beings, years may well pass earlier it is widely available.

In implication age of uncontrolled AIDS diffuse Asia and Africa, rampant t.b. in Russia, and antibiotic-resistant microorganisms in American hospitals, does SV40 really warrant a significant public-health response?

There is no certainly, Carbone says, that the microorganism is linked to some cancers. What's more, millions of Americans now have been exposed cuddle the virus. Studying SV40 can teach us something about interpretation dangers of cross-species infection milk a time when the fail of animal tissue for scrutiny purposes is gaining acceptance.

Good branch of knowledge is ultimately about the go backward of ideas unfettered by presuppositions.

Sometimes great breakthroughs come make something stand out of theories that at greatest seemed heretical or even ridiculous. "Can you think of anything more different on earth outstrip asbestos and a monkey virus?" Carbone says. "Yet you latch on them together and they have an effect together to be more poisonous than either one of them is alone." He goes questionable, "This research is important guaranteed so many different ways.

It's not just about SV40 build up mesothelioma. It helps us grasp the whole picture of endeavor viruses interact with environmental carcinogens. This research can help paltry understand how completely unrelated carcinogens can work together in responsible for backing disease -- a mystery miracle have barely begun to unravel."

The Atlantic Monthly; February 2000; Picture Virus and the Vaccine - 00.02 (Part Three); Volume 285, No.

2; page 68-80.