[Paleopsych] NYT: Slowly, Cancer Genes Tender Their Secrets

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Slowly, Cancer Genes Tender Their Secrets

[I usually pass over articles that merely confirm what Mr. Mencken said that 
the human body proves the truth of the Trinity, namely that man was made by a 
committee and that so much goes wrong. I am far more interested in progress 
than breakdowns. But this article is all about progress, the enormous 
conceptual progress we are getting in understanding this particular kind of 

[Read carefully.]

    Preventing Cancer

    Jay Weinstein found out that he had chronic myelogenous leukemia in
    1996, two weeks before his marriage.

    He was a New York City firefighter, and he thought his health was

    He learned that there was little hope for a cure. The one treatment
    that could save him was a bone marrow transplant, but that required a
    donor, and he did not have one. By 1999, his disease was nearing its
    final, fatal phase. He might have just weeks to live.

    Then, Mr. Weinstein had a stroke of luck. He managed to become one of
    the last patients to enroll in a preliminary study at the Oregon
    Health & Science University, testing an experimental drug.

    Mr. Weinstein is alive today and still taking the drug, now on the
    market as Gleevec. Its maker, Novartis, supplies it to him free
    because he participated in the clinical trial.

    Dr. Brian Druker, a Howard Hughes investigator at the university's
    Cancer Institute, who led the Gleevec study, sees Mr. Weinstein as a
    pioneer in a new frontier of science. His treatment was based not on
    blasting cancer cells with harsh chemotherapy or radiation but instead
    on using a sort of molecular razor to cut them out.

    That, Dr. Druker and others say, is the first fruit of a new
    understanding of cancer as a genetic disease. But if cancer is a
    genetic disease, it is like no other in medicine.

    With cancer, a person may inherit a predisposition that helps set the
    process off, but it can take decades - even a lifetime - to accumulate
    the additional mutations needed to establish a tumor. That is why,
    scientists say, cancer usually strikes older people and requires an
    element of bad luck.

    "You have to get mutations in the wrong place at the wrong time," Dr.
    Druker says.

    Other genetic diseases may involve one or two genetic changes. In
    cancer, scores of genes are mutated or duplicated and huge chunks of
    genetic material are rearranged. With cancer cells, said Dr. William
    Hahn, an assistant professor of medicine at Harvard Medical School,
    "it looks like someone has thrown a bomb in the nucleus."

    In other genetic diseases, gene alterations disable cells. In cancer,
    genetic changes give cells a sort of superpower.

    At first, as scientists grew to appreciate the complexity of cancer
    genetics, they despaired. "If there are 100 genetic abnormalities,
    that's 100 things you need to fix to cure cancer," said Dr. Todd
    Golub, the director of the Cancer Program at the Broad Institute of
    Harvard and M.I.T. in Cambridge, Mass., and an oncologist at the
    Dana-Farber Cancer Institute in Boston. "That's a horrifying thought."

    Making matters more complicated, scientists discovered that the
    genetic changes in one patient's tumor were different from those in
    another patient with the same type of cancer. That led to new
    questioning. Was every patient going to be a unique case? Would
    researchers need to discover new drugs for every single patient?

    "People said, 'It's hopelessly intractable and too complicated a
    problem to ever figure out,' " Dr. Golub recalled.

    But to their own amazement, scientists are now finding that untangling
    the genetics of cancer is not impossible. In fact, they say, what
    looked like an impenetrable shield protecting cancer cells turns out
    to be flimsy. And those seemingly impervious cancer cells, Dr. Golub
    said, "are very much poised to die."

    The story of genes and cancer, like most in science, involves many
    discoveries over many years. But in a sense, it has its roots in the
    1980's, with a bold decision by Dr. Bert Vogelstein of Johns Hopkins
    University to piece together the molecular pathways that lead to

    It was a time when the problem looked utterly complicated. Scientists
    thought that cancer cells were so abnormal that they were, as Dr.
    Vogelstein put it, "a total black box."

    But Dr. Vogelstein had an idea: what if he started with colon cancer,
    which had some unusual features that made it more approachable?

    Colon cancer progresses through recognizable phases. It changes from a
    tiny polyp, or adenoma - a benign overgrowth of cells on the wall of
    the colon - to a larger polyp, a pre-cancerous growth that, Dr.
    Vogelstein said, looks "mean," and then to a cancer that pushes
    through the wall of the colon. The final stage is metastasis, when the
    cancer travels through the body.

    "This series of changes is thought to occur in most cancers, but there
    aren't many cancers where you can get specimens that represent all
    these stages," Dr. Vogelstein said.

    With colon cancer, pathologists could get tissue by removing polyps
    and adenomas in colonoscopies and taking cancerous tumors in surgery.

    Colon cancer was even more appealing for such a study because there
    are families with strong inherited predispositions to develop the
    disease, indicating that they have cancer genes that may be

    So Dr. Vogelstein and his colleagues set out to search for genes "any
    way we could," Dr. Vogelstein said. Other labs found genes, too, and
    by the mid-1990's, scientists had a rough outline of what was going

    Although there were scores of mutations and widespread gene deletions
    and rearrangements, it turned out that the crucial changes that turned
    a colon cell cancerous involved just five pathways. There were dozens
    of ways of disabling those pathways, but they were merely multiple
    means to the same end.

    People with inherited predispositions to colon cancer started out with
    a gene mutation that put their cells on one of those pathways. A few
    more random mutations and the cells could become cancerous.

    The colon cancer story, Dr. Druker said, "is exactly the paradigm we
    need for every single cancer at every single stage."

    But scientists were stymied. Where should they go from there? How did
    what happens in colon cancer apply to other cancers? If they had to
    repeat the colon cancer story every time, discovering genetic
    alterations in each case, it would take decades to make any progress.

    The turning point came only recently, with the advent of new
    technology. Using microarrays, or gene chips - small slivers of glass
    or nylon that can be coated with all known human genes - scientists
    can now discover every gene that is active in a cancer cell and learn
    what portions of the genes are amplified or deleted.

    With another method, called RNA interference, investigators can turn
    off any gene and see what happens to a cell. And new methods of DNA
    sequencing make it feasible to start asking what changes have taken
    place in what gene.

    The National Cancer Institute and the National Human Genome Research
    Institute recently announced a three-year pilot project to map genetic
    aberrations in cancer cells.

    The project, Dr. Druker said, is "the first step to identifying all
    the Achilles' heels in cancers."

    Solving the problem of cancer will not be trivial, Dr. Golub said.
    But, he added, "For the first time, we have the tools needed to attack
    the problem, and if we as a research community come together to work
    out the genetic basis of cancer, I think it will forever change how we
    think about the disease."

    Already, the principles are in place, scientists say. What is left are
    the specifics: the gene alterations that could be targets for drugs.

    "We're close to being able to put our arms around the whole cancer
    problem," said Robert Weinberg, a biology professor at the
    Massachusetts Institute of Technology and a member of the Whitehead
    Institute. "We've completed the list of all cancer cells needed to
    create a malignancy," Dr. Weinberg said. "And I wouldn't have said
    that five years ago."

    The list includes roughly 10 pathways that cells use to become
    cancerous and that involve a variety of crucial genetic alterations.
    There are genetic changes that end up spurring cell growth and others
    that result in the jettisoning of genes that normally slow growth.
    There are changes that allow cells to keep dividing, immortalizing
    them, and ones that allow cells to live on when they are deranged;
    ordinarily, a deranged cell kills itself.

    Still other changes let cancer cells recruit normal tissue to support
    and to nourish them. And with some changes, Dr. Weinberg said, cancer
    cells block the immune system from destroying them.

    In metastasis, he added, when cancers spread, the cells activate genes
    that normally are used only in embryo development, when cells migrate,
    and in wound healing.

    But so many genetic changes give rise to a question: how does a cell
    acquire them?

    In any cell division, there is a one-in-a-million chance that a
    mutation will accidentally occur, Dr. Weinberg notes. The chance of
    two mutations is one in a million million and the chance of three is
    one in a million million million million.

    This slow mutation rate results from the fact that healthy cells
    quickly repair damage to their DNA.

    "DNA repair stands as the dike between us and the inundation of
    mutations," Dr. Weinberg said.

    But one of the first things a cell does when it starts down a road to
    cancer is to disable repair mechanisms. In fact, BRCA1 and 2, the gene
    mutations that predispose people to breast and ovarian cancer, as well
    as some other inherited cancer genes, disable these repair systems.

    Once the mutations start, there is "a kind of snowball effect, like a
    chain reaction," Dr. Vogelstein said.

    With the first mutations, cells multiply, producing clusters of cells
    with genetic changes. As some randomly acquire additional mutations,
    they grow even more.

    In the end, all those altered genes may end up being the downfall of
    cancer cells, researchers say.

    "Cancer cells have many Achilles' heels," Dr. Golub says. "It may take
    a couple of dozen mutations to cause a cancer, all of which are
    required for the maintenance and survival of the cancer cell."

    Gleevec, researchers say, was the first test of this idea. The drug
    knocks out a gene product, abl kinase, that is overly abundant in
    chronic myelogenous leukemia. The first clinical trial, which began
    seven years ago, seemed like a long shot.

    "The idea that this would lead to therapy was something you wrote in
    your grant application," said Dr. Charles Sawyers, a Howard Hughes
    investigator at the University of California, Los Angeles. "It wasn't
    anything you believed would happen soon."

    But the clinical trial of Gleevec, conducted at the Oregon Health &
    Science University, U.C.L.A. and M. D. Anderson Cancer Center in
    Houston, was a spectacular success. Patients' cancer cells were beaten
    back to such an extent that the old tests to look for them in bone
    marrow were too insensitive, Dr. Sawyers said.

    Gleevec is not perfect. It is expensive, costing about $25,000 a year.
    It is not a cure: some cancer cells remain lurking, quiescent and
    ready to spring if the drug is stopped, so patients must take it every
    day for the rest of their lives. And some patients are now developing
    resistance to Gleevec.

    Still, Dr. Sawyers says, "Seven years later, most of our patients are
    still doing well." Without Gleevec, he added, most would be dead.

    As for the future of cancer therapy, Dr. Golub and others say that
    Gleevec offers a taste of the possible.

    Dr. Golub said he expected that new drugs would strike the Achilles'
    heels of particular cancers. The treatment will not depend on where
    the cancer started - breast, colon, lung - but rather which pathway is

    "It's starting to come into focus how one might target the problem,"
    Dr. Golub said. "Individual cancers are going to fall one by one by
    targeting the molecular abnormalities that underlie them."

    And some cancer therapies may have to be taken for a lifetime, turning
    cancer into a chronic disease.

    "Seeing cancer become more like what has happened with AIDS would not
    be shocking," Dr. Golub says. "Does that mean cure? Not necessarily.
    We may see patients treated until they die of something else."

    That is what Mr. Weinstein hopes will happen with him. The cancer is
    still there: new, exquisitely sensitive tests still find a few cells
    lurking in his bone marrow. And Gleevec has caused side effects. Mr.
    Weinstein says his fingers and toes sometimes freeze for a few
    seconds, and sometimes he gets diarrhea.

    But, he said, "Certain things you put out of your mind because life is
    so good."

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