Id be interested in hearing what others think about this. If this
has merit, what implications does this have for treating/preventing cancer?

           Challenging Conventional Wisdom on Cancer

           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.