Berkeley biologist disputes current dogma that genetic mutation
is the cause of cancer
Robert Sanders, Public Affairs
-- A University of California, Berkeley, scientist is challenging
one of the central tenets of cancer research, that cancer results
from a chance series of genetic mutations that drive a cell
into wild, uncontrolled growth.
biologist Peter Duesberg, better known for his claim that the
human immunodeficiency virus is not the cause of AIDS, contends
that mutation is not the cause of cancer. Rather, he says, cancer
results from disruption of the normal number of chromosomes
in a cell, primarily duplication of one or more chromosomes.
aneuploidy, this type of chromosomal abnormality is found in
nearly every solid cancer studied to date, but has always been
considered a side effect of cancer, not the cause itself.
a peer-reviewed article in the March 28 issue of the journal
Proceedings of the National Academy of Sciences, Duesberg and
his colleagues at UC Berkeley argue instead that aneuploidy
is the primary cause of cancer and explains many aspects of
cancer that the genetic mutation theory cannot.
some 25 years, Duesberg has pointed out problems with the genetic
mutation theory of cancer. Now that the theory has become almost
dogma, he is ratcheting up his criticism and receiving support
from numerous other scientists
won't let the field stand still, which is extremely important,"
said Avery A. Sandberg, chief editor of the journal Cancer Genetics
and Cytogenetics. "Once scientists think of one theory
as being the de facto theory, we're in great trouble."
Duesberg is right, it would overthrow a theory that has dominated
thinking for the past 15 years, guiding research and dictating
how doctors detect and prevent cancer. One field that would
feel the impact is cancer screening.
than looking for mutations in biopsied cells, we should look
for aneuploidy as a sign of early cancer," said Duesberg,
a professor of molecular and cell biology.
group of physicians at UC San Francisco is now screening for
a type of skin cancer called melanoma by looking for chromosomal
anomalies in skin cells.
said that the principal problem with the mutation theory of
cancer is that no one has successfully turned a normal human
cell into a cancer cell by inserting mutated genes. Such a demonstration
would definitively prove that mutations cause cancer.
one has found, even once, a combination of genes from any cancer
that when inserted into normal cells turns them into cancer
cells," he said.
finds particular fault with a report last year in the journal
Nature by Robert Weinberg and others of MIT's Whitehead Institute,
in which the authors claimed to have accomplished just that.
They took normal human cells and inserted two cancer-causing
genes, called oncogenes, plus another gene that makes cells
grow unchecked, and generated cancerous cells. This showed,
they wrote, that these genetic mutations "suffice to create
a human tumor cell."
so, says Duesberg. He requested samples of the cancer cells
from Weinberg and found that all of them also had numerical
chromosome alterations, or aneuploidy.
cause could have been either aneuploidy or genetic mutation,"
argument against the genetic mutation hypothesis, said Duesberg,
is that nearly half of all cancer-causing chemicals appear not
to cause mutations at all. Asbestos, arsenic, some hormones,
urethane, nickel and polycyclic aromatic hydrocarbons all are
known to induce cancer in humans, but none are mutagens.
mutation hypothesis predicts that all carcinogens are mutagenic,"
he said. "Yet half of all carcinogens are not mutagenic,
so how do they cause cancer?"
Duesberg argues, if genetic mutations cause cancer, then cancer
should arise immediately after a mutation. Instead, cancers
appear decades after exposure to a carcinogen.
hallmark of carcinogens is that they have a very long latency
period," he said. "Scientists argue that this is because
cancer is a multi-step, epigenetic phenomenon, but that exactly
major argument for aneuploidy over genetic mutation, Duesberg
says, is that the cellular disruption caused by having too many
copies of an entire chromosome is much greater than that expected
from a handful of mutated genes, and is much more likely to
affect the many cellular processes known to be fouled up in
more likely to cause cancer," asked Duesberg's colleague
and coauthor David Rasnick, a visiting scientist in his laboratory,
"the tens or hundreds of genes screwed up by aneuploidy,
or the several genes screwed up by a few genetic mutations?"
evidence analyzed by Rasnick and Duesberg and reported last
year shows that cancer cells exhibit massive overproduction
and underproduction of a large number of proteins. They found
thousands of proteins whose expression was doubled in cancer
not a small number of genes that have a large increase in expression,
but a large number with a small increase in expression that
transforms a normal cell into a cancer cell," Rasnick said.
comes from a number of scientists, including Athel Cornish-Bowden,
director of research at the CNRS Institut Fédératif
de Recherche in Marseilles, France. In a July 1999 analysis
piece in the journal Nature Biotechnology he wrote, "Not
only is the association between aneuploidy and cancer so close
as to be virtually exact, but the predicted metabolic effect
of over-expressing a large and arbitrary set of genes is just
the collapse of normal regulation seen in cancer. Altering just
one enzyme activity rarely produces much effect, ... but simultaneous
alteration in many activities can overwhelm the normal controls."
1998, Nature Biotechnology science editor Harvey Bialy noted
that the only solid tumors - so-called to distinguish them from
leukemia and similar immune system cancers - whose cells contain
a normal number of chromosomes are those very rare ones caused
by retroviruses. Otherwise, some 5,000 known solid tumors have
concluded that in a new, dynamic theory of the genome, "the
oncochromosome may come to supplant the oncogene as the primary
to Sandberg, "There's a lot to be said for Peter's theory.
No one has disproved it, and since the genetic mutation theory
was proposed 15 years ago, people have found lots of exceptions.
predict that both theories will turn out to be right, because
cancer will be found to result from multiple pathways."
to Duesberg's scenario, carcinogens enter cells and disrupt
the spindle apparatus that drags chromosomes apart during cell
division. Just as unbalanced cables twist a suspension bridge
out of shape, so unbalanced spindles twist and improperly separate
chromosomes during mitosis, causing duplication and loss of
entire chromosomes. The damage such duplication can cause is
evidenced by diseases such as Down's syndrome, in which cells
have three rather than two copies of chromosome 21. That disease
is characterized by severe developmental problems and retardation,
plus many metabolic problems, a 100-fold increased risk of leukemia,
sterility and an average life span of only 30 years.
chromosome disruptions of aneuploid cells only worsen in subsequent
generations of the cells. Luckily, Duesberg said, most such
cells die, which means cancer is rare. Occasionally, however,
the chromosome abnormalities will generate a cell that survives
better than the normal cell, and it will grow into a cancer.
a scenario, not unlike the evolution of a new species, explains
the slow development of most cancers, Duesberg said. Natural
evolution of a new species also is based on chromosome number
variation, he pointed out.
and his colleagues have conducted several experiments that have
produced support for his aneuploid theory of cancer. Among these
are tests of nonmutagenic carcinogens that show that most of
them do cause aneuploidy, even though they do not create genetic
problem, he claims, is that funding agencies refuse to fund
experiments in the area. Of 13 proposals Duesberg has sent to
federal, state and local funding agencies, none has been approved.
Nevertheless, he continues to build support for the aneuploid
theory of cancer.
is an old concept that was abandoned too soon," he said,
noting that scientists 50 years ago seriously considered aneuploidy
a possible cause of cancer.
aneuploidy is not in the textbooks, it's not in the scientific
repertoire," Duesberg said. "Two years ago, even some
of my Berkeley colleagues didn't know about aneuploidy. Now