[Paleopsych] AmSpectator: Tom Bethell: Challenging Conventional Wisdom: Is cancer caused by genes?
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Subject: AmSpectator: Tom Bethell: Challenging Conventional Wisdom: Is cancer
caused by genes?
Tom Bethell: Challenging Conventional Wisdom: Is cancer caused by genes?
The American Spectator, 5.7-8
First, the summary from the "Magazine and Journal Reader" feature of the daily
bulletin from the Chronicle of Higher Education, 5.7.25
A glance at the July/August issue of The American Spectator: The
problem with conventional cancer theory
Researchers are pursuing the wrong cancer theory and are making one of
the "great medical errors of the 20th century," says Tom Bethell, a
senior editor at the magazine. But scientists are not solely to blame,
he says. It is the National Institutes of Health that's curtailing
Mr. Bethell bashes the dominant hypothesis that cancer is caused by
gene mutations in single cells. That theory, known as the
"multiple-hit theory," is not supported by evidence showing that
mutated genes cause cancerous cells that continually divide and
spread, he says. The truth, he argues, lies in the forgotten theory
that the disease is caused by an incorrect number of chromosomes in
The correct theory, the "aneuploid theory," is not accepted by most
mainstream researchers or the NIH, writes Mr. Bethell. For a century
scientists have known that cancer cells do not have the right number
of chromosomes, he says. Such "aneuploid" cells have as many as 80
chromosomes instead of the customary 46.
The cells occur when normal cells divide into "daughter" cells but
errors in the division result in irregular segregation of the
chromosomes. Most aneuploid cells die off immediately, but those that
survive create extra DNA in each new-generation cell. The DNA hijacks
the cell's control mechanisms, and begins multiplying. The result is a
lump of abnormal cells -- a tumor.
The NIH maintains its pursuit of gene-mutation research, though, and
has not given credit or grants to aneuploid research, although it
should, says Mr. Bethell. In the end, he says, funds from the NIH may
never go toward research that creates a "real breakthrough."
"If so," he says, "we will all have learned a very expensive lesson."
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 ibreakthroughi 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 iGenetic Test Is Predictor of Breast Cancer Relapse.i The test imarks
one of the first tangible benefits of the massive effort to harness genetics to
fight cancer,i 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 idiscovered a collection of
normal genes that can cause cancer when they go awry,i Gina Kolata later
reported in the New York Times. About 40 such genes had been discovered.
Normally harmless, ithey would spring into action and cause cancer if they were
twitched by carcinogens.i When mutated, in other words. This was ia new era in
The following week, on October 20, 1989, Science magazine also reported the
award. The article claimed: iOthe 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.i Their work was ialready paying off
And so it went. Researchers began to find more and more of these oncogenes;
then itumor suppressor genesi were added. Now, in the Washington Post article,
we read that iresearchers sifted through 250 genes that had been identified as
playing a role in breast cancer.i
So, up to 250 genes are iplaying a role.i The Sanger Institute, which was
also involved in the human genome project, claimed recently that icurrently
more than one percent of all human genes are cancer genes.i The latest figure
is 25,000 genes in total for humans, so that is surely where the 250 icancer
genesi 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 iplaying a role.i This imultiplication of entitiesi -- genes -- is
the hallmark of a theory that is not working. Itis what philosophers call a
ideteriorating paradigm.i 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 itis one-sixth that number. How long before they find that all the
genes iplay a rolei 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 imultiple hiti 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 cellis DNA. But those cells do not turn into
cancer cells, and if injected into experimental animals, they donit cause
tumors. Thatis 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 couldnit get through. He
will respond to the New York Times, surely. But maybe not with a straight
The desire to start over with a icancer genome projecti 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 icompletely change how we approach cancer.i
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 donit mean to
single out the New York Times. Science journalists donit 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 nationis 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 ipublicis
right to knowi trumped inational security.i 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 iAmes was preaching a great and simple lessoni about
carcinogens: iCarcinogens 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 donit 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 iimmortal,i 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 idiploid,i 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 iploidyi 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
isegregatei 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 didnit 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 letis think of an automobile plant. A cancer cell is the
equivalent of a monster car with (letis say) five wheels, two engines, and no
brakes. Start it running and you canit stop the damned thing. Itis hazardous to
the community. The CEO wants to know whatis 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 todayis gene mutation theorist is someone who says: iThatis 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!i 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. Thatis 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
A researcher at the University of Washington who became controversial at NIH
in an unrelated field warned Duesberg that iin the present system of NIH
grants, there is no way to succeed.i No matter how much they prate in public
about thinking outside the box and rewarding ihigh-riski proposals, ithe
reviewers are the same and their self-interest is the same.i In the cancer
field, grant proposals are reviewed by, and won by, proponents of the gene
Wayt Gibbs published a good article about Duesbergis cancer findings in the
Scientific American (July 2003). And this response is beginning to emerge in
journals like Science: Er, well, thereis nothing new here.O 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 ipoliticali compromise: Canit we say that both gene mutation and
aneuploidy iplay a rolei in the genetics of cancer?
A leading cancer researcher, Bert Vogelstein of Johns Hopkins, told me some
time back that iat least 90 percent of human cancers are aneuploid.i More
recently, his lab reported that aneuploidy iis consistently shown in virtually
all cancers.i A few years ago, Varmus from Sloan-Kettering did answer my e-mail
query, writing: iAneuploidy, and other manifestations of chromosomal
instability are major manifestations of many cancers and many labs have been
working on them.i But, he added: iAny role they play will not diminish the
crucial roles of mutant proto-oncogenes and tumor suppressor genes.i
But why not? Maybe aneuploidy is sufficient.
At the end of May, Duesberg was invited to speak at NIH. His topic:
iAneuploidy and Cancer: From Correlation to Causation.i 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 ieliminating
the suffering and death from cancer by 2015.i
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 -- ia bit of both theories.i
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,
itis important not to be funded by the NIH. If so, we will all have learned a
very expensive lesson.
Tom Bethell is a senior editor of The American Spectator.
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