[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
http://chronicle.com/prm/daily/2005/07/2005072201j.htm

    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
    alternative research.

    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
    cancerous cells.

    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."

    --Devin Varsalona

--------------------------

   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 
research.i

   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 
clinically.i

   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 
answer.

   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 
received any.)

   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 
mutation theory.

   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.