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SCIENTISTS THESE DAYS TEND TO BELIEVE that almost any trait can be attributed to a gene. The gene obsession, showing up in science journals and on the front page of the New York Times, culminated in the Human Genome Project. The human genome was sequenced, then that of the fruit fly, the rat, the mouse, the chimpanzee, the roundworm, yeast, and rice. Computers cranked out their mindless data. It has been a bonanza for techies and the computer industry but the medical benefits have remained elusive.
Now they are talking about a Cancer Genome Project. It would determine the DNA sequence in 12,500 tumor samples and is supposed to reveal cancer-causing mutations by comparing the order of the letters of the genetic code in tumor cells with sequences in healthy tissue. But there is no single cancer genome, and the project will not improve our understanding of cancer.
Cancer has proved resistant to every "breakthrough" and treatment hype, and the new approach will only sustain the error that has dominated cancer research for 30 years. Since the mid-1970s, leading researchers have doggedly pursued the fixed idea that cancer is caused by gene mutations. I believe it will prove to have been one of the great medical errors of the 20th century.
WHERE TO BEGIN? One place is a story in the Washington Post, a few months back, headlined "Genetic Test Is Predictor of Breast Cancer Relapse." The test "marks one of the first tangible benefits of the massive effort to harness genetics to fight cancer," Rob Stein wrote. No real benefits yet? I think that is correct. Two well-publicized genes supposedly predispose women for breast cancer, but in over 90 percent of cases these genes have shown no defect.
Genes that (allegedly) cause cancer when they are mutated are called oncogenes. They were reported in 1976 by J. Michael Bishop and Harold Varmus, who were rewarded with the Nobel Prize. Varmus became director of the National Institutes of Health (NIH) under President Clinton; Bishop, chancellor of the University of California in San Francisco, one of the largest medical-research institutions in the country. The two scientists had "discovered a collection of normal genes that can cause cancer when they go awry," Gina Kolata later reported in the New York Times. About 40 such genes had been discovered. Normally harmless, "they would spring into action and cause cancer if they were twitched by carcinogens." When mutated, in other words. This was "a new era in research."
The following week, on October 20, 1989, Science magazine also reported the award. The article claimed: "â€¦the work of the Bishop-Varmus group has had a major impact on efforts to understand the genetic basis of cancer. Since their 1976 discovery, researchers have identified nearly 50 cellular genes with the potential of becoming oncogenes." Their work was "already paying off clinically."
And so it went. Researchers began to find more and more of these oncogenes; then "tumor suppressor genes" were added. Now, in the Washington Post article, we read that "researchers sifted through 250 genes that had been identified as playing a role in breast cancer."
So, up to 250 genes are "playing a role." The Sanger Institute, which was also involved in the human genome project, claimed recently that "currently more than one percent of all human genes are cancer genes." The latest figure is 25,000 genes in total for humans, so that is surely where the 250 "cancer genes" came from.
At the beginning, the oncogene theory posited that a single gene, when mutated, turned a normal cell into a cancer cell. We have gone from 1 to 250, the latter "playing a role." This "multiplication of entities" -- genes -- is the hallmark of a theory that is not working. It's what philosophers call a "deteriorating paradigm." The theory gets more and more complex to account for its lack of success. The number of oncogenes keeps going up, even as the total number of genes goes down. Six years ago some thought humans had 150,000 genes in all. Now it's one-sixth that number. How long before they find that all the genes "play a role" in cancer?
IT ALWAYS WAS unlikely that a single mutated gene would turn a cell into a cancer cell. Mutations occur at a predictable rate in the body. As the cells of the body number perhaps trillions we would all have cancer if a single hit was sufficient. Then came the "multiple hit" theory. Three or four, maybe six or seven genes would all have to mutate in the same cell during its lifetime. Then, bingo, your unlucky number had come up. That cell became a cancer cell. When it divided it just kept on and on dividing.
Meanwhile, the underlying theory never changed. The research establishment remains in thrall to the idea that cancer is caused by gene mutations. It was and is unable to lay its hands on the genes responsible, but it believes they are in there somewhere.
There are several problems with the theory, but the most basic is this. Researchers have never been able to show that a mutated gene, taken from a cancer cell, will transform normal cells in the petri dish. They are unable to show that the allegedly guilty party is capable of committing the crime. They can transport these mutated genes into test cells. And the supposed deadly genes are integrated into the cell's DNA. But those cells do not turn into cancer cells, and if injected into experimental animals, they don't cause tumors. That's when the experts said, well, there must be four or five genes all acting at once in the cell. But they have never been able to say which ones, nor show that in any combination they do the foul deed.
There is even a genetically engineered strain of mice called OncoMouse. They have some of these oncogenes in every cell of their small bodies. You would have thought they would die of cancer immediately. But they leave the womb, gobble up food, and live long enough to reproduce and pass on their deadly genes to the next generation.
I have a suggestion for Gina Kolata, who still works on these issues for the New York Times. Why not try asking Varmus or Bishop exactly which genes, either individually or in combination, cause cancer in humans or anything else? I tried calling Bishop at UCSF a few months back but couldn't get through. He will respond to the New York Times, surely. But maybe not with a straight answer.
The desire to start over with a "cancer genome project" tells you they know they are not even at first base. Dr. Harold Varmus, now president of the Memorial Sloan-Kettering Cancer Center in New York, told the Times in March that the new project could "completely change how we approach cancer."
Completely change? Maybe we do need a complete change. What about his decades-old Nobel work? Was that a waste? In a way I think it was worse than that, because when an erroneous theory is rewarded with the top prize in science, abandoning that theory is difficult. The backtracking required is an embarrassment to all.
JOURNALISM PLAYS A CRUCIAL ROLE. Especially in the field of medical science, there is a big problem. It exists at all major newspapers and I don't mean to single out the New York Times. Science journalists don't see themselves as qualified to challenge the experts. If a reporter were to do so, quoting non-approved scientists, top-echelon NIH officials would surely complain to editors, and the reporter would be reassigned. The nation's health would be said to be endangered.
All this contrasts with the far greater freedom that journalists enjoy in the political arena, including defense and foreign policy. About 35 years ago, leading newspaper editors decided to chart their own course and form their own judgments. The context was the Vietnam War, more specifically the Pentagon Papers. A big report critical of U.S. policy was leaked to the press, and the Nixon administration went to great pains to suppress it. National security was invoked, judicial restraining orders were issued, but eventually the "public's right to know" trumped "national security." The material was published.
That was the background from which Woodward and Bernstein and the Watergate investigation emerged a year later. And we were the better off for it. The real danger, then and now, was that of unchecked government power. And we are seeing that exercised in the realm of medical science, where we do not have a press that dares to think independently.
HOW DID THE IDEA TAKE ROOT that gene mutations cause cancer? Well, in the 1920s researchers bombarded fruit flies with X-rays and mutant flies resulted. Humans exposed to large X-ray doses a hundred years ago proved to be at high risk for skin cancer and leukemia. It was convincingly shown that X-rays produced both mutations and cancers.
Working at the NIH in the 1960s, the biochemist Bruce Ames used bacteria to detect the mutagenic properties of various substances. Some carcinogens proved to be mutagenic, hence the gene-mutation theory of cancer. Robert A. Weinberg, who directs a cancer research lab at MIT, says that by the 1970s he and others had come to believe that "Ames was preaching a great and simple lesson" about carcinogens: "Carcinogens are mutagens."
Some are, but some of the best known are not. Neither asbestos nor coal tar, found in cigarettes, are mutagenic. They are carcinogens but they don't affect the DNA -- the genes. But there was one more crucial discovery still to be made. Or rather, rediscovery.
Robert Weinberg later claimed that a mutation in a single gene indeed had transformed a cell in vitro. But it turned out that the cell-line, one that had been provided by the NIH, was already "immortal," or cancerous. It did not have the right number of chromosomes.
Normal cells have 46 chromosomes -- 23 each from mother and father. Such cells are "diploid," because their complement of chromosomes is doubled. In case you never took biology, genes are segments of DNA strung along the chromosomes. The largest chromosomes, such as Chromosome 1 or 2, include several thousand genes each. Sometimes babies are born with one extra copy of the smallest chromosome, and because it is in the germ line this defect is in every cell of the body. Such babies have Down syndrome. Having an extra chromosome is serious business.
Here is the key point: cancer cells do not have the correct complement of chromosomes. Their "ploidy" is not good, so they are said to be aneuploid. Cancer cells are aneuploid. This defect arises not in the germ line, but in the grown body. Cells divide in the course of life, by a process called mitosis, and sometimes there is an error in the division. The chromosomes do not "segregate" properly (do not end up equally in the two daughter cells) and an extra chromosome may be hauled off into one of the new cells. Such over-burdened cells will usually die, but sometimes the error repeats and magnifies and increases. The cell just keeps on dividing, its control mechanisms overridden by the abundance of extra DNA in the cell. A tumor forms in that part of the body, and that is cancer. Some cancer cells may have as many as 80 chromosomes instead of 46. They may actually have double the right number of genes.
The aneuploid character of cancer cells is the first thing that Theodor Boveri and others noticed when they began to look at cancer under the microscope, 100 years ago. Leaving unresolved the question of what causes aneuploidy, early researchers thought that this was surely the genetic cause of cancer. Mutation didn't enter into it. But gradually the early research was buried. In the last generation, textbooks on the cell and even textbooks on cancer have failed to mention aneuploidy or its bizarre chromosomal combinations. Weinberg wrote two books on cancer without mentioning aneuploidy. Overlooking what was plainly visible in the microscope, researchers worked for years with those defective, immortalized cell lines, assuming that their extra chromosomes were unimportant.
An analogy suggests the magnitude of the error. Cells today are compared to factories, so let's think of an automobile plant. A cancer cell is the equivalent of a monster car with (let's say) five wheels, two engines, and no brakes. Start it running and you can't stop the damned thing. It's hazardous to the community. The CEO wants to know what's gone wrong so he sends underlings into the factory. There they find that instead of the anticipated 46 assembly lines, there are as many as 80. At the end of the process this weird machine gets bolted together and ploughs its way out the factory door.
But today's gene mutation theorist is someone who says: "That's not it. The extra assembly lines are irrelevant. What is happening is that three or four of the tens of thousands of workers along the assembly lines are not working right!" In the analogy, genes along the chromosomes correspond to workers along the assembly lines.
Any CEO would fire the lunatic who thought a few errant workers, and not the bizarre factory layout, had caused the mayhem. But in the realm of cancer research, those who do say that are rewarded with fat grants, top posts, and awards. That's a measure of what has happened to cancer research.
I HAVE LEFT THE MOST DRAMATIC PART to the end. The man who rediscovered the old work on chromosomes and cancer and has drawn attention to it ever since, supported by investigations of his own, is none other than Peter Duesberg of U.C. Berkeley. He was already in the dog house at NIH for saying that AIDS is not an infectious disease and that HIV is harmless. All his grants were cut off in retribution. But as a member of the National Academy of Sciences he could still publish in respectable journals. So for the last seven years he has been drawing attention to the cancer matter. The NIH is pursuing the wrong theory, he says. Talk about persona non grata! No more grants for him! (And he has not received any.)
A researcher at the University of Washington who became controversial at NIH in an unrelated field warned Duesberg that "in the present system of NIH grants, there is no way to succeed." No matter how much they prate in public about thinking outside the box and rewarding "high-risk" proposals, "the reviewers are the same and their self-interest is the same." In the cancer field, grant proposals are reviewed by, and won by, proponents of the gene mutation theory.
Wayt Gibbs published a good article about Duesberg's cancer findings in the Scientific American (July 2003). And this response is beginning to emerge in journals like Science: Er, well, there's nothing new here.â€¦ We have always known that aneuploidy is important in cancer. (Yes, but it was forgotten and then buried beneath the paper mountains of new research.) There is a quiet search for a "political" compromise: Can't we say that both gene mutation and aneuploidy "play a role" in the genetics of cancer?
A leading cancer researcher, Bert Vogelstein of Johns Hopkins, told me some time back that "at least 90 percent of human cancers are aneuploid." More recently, his lab reported that aneuploidy "is consistently shown in virtually all cancers." A few years ago, Varmus from Sloan-Kettering did answer my e-mail query, writing: "Aneuploidy, and other manifestations of chromosomal instability are major manifestations of many cancers and many labs have been working on them." But, he added: "Any role they play will not diminish the crucial roles of mutant proto-oncogenes and tumor suppressor genes."
But why not? Maybe aneuploidy is sufficient.
At the end of May, Duesberg was invited to speak at NIH. His topic: "Aneuploidy and Cancer: From Correlation to Causation." About 100 people showed up at Building 10. The Genetics branch of the National Cancer Institute (NCI) is interested in aneuploidy, and well aware of the political sensitivities. But I am told that the director of the NCI, Andrew von Eschenbach, a political appointee, is not particularly interested in aneuploidy. He should be, though, because he is a cancer survivor himself and in speeches calls for "eliminating the suffering and death from cancer by 2015."
Duesberg challenged the audience to prove him wrong. He is looking for diploid cancer: a solid tumor with the correct complement of chromosomes. He is not much interested in the compromise solutions -- "a bit of both theories." Prove me wrong, he says. A woman in the audience did suggest cases of tumors that looked diploid, but Duesberg knew the literature here and immediately referred her to a more recent study showing that these tumors, on closer microscopic inspection, proved to be aneuploid.
Maybe in the end he will show that in order to achieve a real breakthrough, it's important not to be funded by the NIH. If so, we will all have learned a very expensive lesson.
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