TIME: Almanac 1993/TIME Almanac 1993.iso/time/111290/1112300.000

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                                                                                SCIENCE, Page 97

Cracking Cancer's Code


Researchers are learning how genes start tumors -- or stop them

By J. MADELEINE NASH


    Just 10 days earlier, the laboratory cultures had all
contained the same number of microscopic cancer cells. Now even
an untutored eye could tell the difference. Globs of wildly
dividing cell colonies filled half the flasks, while in the
others the cells refused to multiply. Reason: a research team,
led by Johns Hopkins University oncologist Bert Vogelstein, had
endowed the quiescent cells with a protective device that the
dividing ones lacked, in this case a normal copy of a gene that
acts as a circuit breaker, shutting down growth. The scientists
had found a way, at least in theory, to stop a tumor after it
gets started.

    This discovery is so striking that even cautious scientists
are finding it difficult to rein in their excitement. It is
among the latest in a chain of discoveries that have rapidly
confirmed what for a long time scientists only suspected:
mutations in specific genes are the underlying cause of cancer.
As knowledge about these genes expands, so too does the
likelihood researchers will devise new treatments that may one
day target cancer cells as selectively as antibiotics attack
bacteria. "Cancer cells," says gene mapper David Housman of
M.I.T., "are too damn close to normal cells, and that's been
the basic problem in attacking this disease. Finally, we are
beginning to learn what makes cancer cells different."

    A decade ago, scientists puzzling over cancer cells
resembled 18th century Egyptologists in their struggle to
decipher ancient hieroglyphics. Now they have assembled a
biological Rosetta stone that has enabled them to lay out in
sharp detail the changes that cause a cell to go from normal to
malignant. "The cancer cell used to be a black box," says Dr.
Vincent T. DeVita Jr., physician in chief of New York City's
Memorial Sloan-Kettering Cancer Center. "But the lid of the
black box has been opened, and we can see the wheels turning
inside." The "wheels" are genes that regulate growth. Some,
called oncogenes, activate the process of cell division; others,
known as tumor-suppressor genes, or anti-oncogenes, turn the
process off. In their normal form, both kinds of genes, working
together, enable the body to perform the critical function of
replacing dead or defective cells. But slight alterations in the
genetic material, whether inherited or caused by environmental
insult, can provoke the rampant cell division that leads to
cancer.

    The first oncogene known to exist inside animal and human
cells was discovered in 1976 by Drs. J. Michael Bishop and
Harold Varmus of the University of California at San Francisco.
Since then, scientists have found more than 50, some of which
appear to be more important than others in human cancers.
Mutations in the RAS oncogene, for instance, are believed to
play a role in a majority of pancreatic and colon cancers, and
some lung cancers as well. Mutations in other oncogenes have
been linked to leukemia and the most lethal forms of breast and
ovarian cancer.

    But oncogenes are just one piece in this genetic jigsaw
puzzle. In 1986 scientists, including molecular biologist Robert
Weinberg of M.I.T., identified the first human tumor-suppressor
gene, dubbed the RB gene because, if it ceases to function, the
result is retinoblastoma, a rare childhood eye cancer. Problems
with the RB gene have since been tied to cancers of the lung,
breast and bladder. "What was initially thought to be involved
in one obscure tumor," observes Weinberg, "is a player in
commonly occurring cancers as well."

    Now that they recognize the importance of the genes, medical
researchers are faced with the mind-bending task of figuring out
how they work, singly and in tandem. "A damaged oncogene is like
having the accelerator pedal stuck to the floor," notes Johns
Hopkins' Vogelstein. "A damaged tumor-suppressor gene is like
losing the brakes." Increasingly, scientists think cumulative
damage to both sorts of genes must occur before full-blown
cancer results. Cells strongly resist malignant transformation,
which is the reason most cancers require 20 or more years to
develop. According to Vogelstein, colon cells must accumulate
damage in at least one oncogene and three tumor-suppressor genes
before becoming truly malignant. The earliest of these mutations
gives rise to a benign polyp; subsequent changes cause this
polyp to expand in size and become more and more irregular in
shape. At least one of the cells that make up the polyp then
undergoes an additional genetic break that transforms the tissue
into the progenitor of an aggressive tumor.

    For many of the most common forms of malignancy, including
colon cancer, the crucial damage is believed to occur in the
so-called p53 gene, the same tumor suppressor that prevented
cells from growing out of control in the Johns Hopkins
laboratory cultures. Like others of its ilk, this gene appears
to act as a master switch that regulates many important
activities, including the receipt of chemical messages
originating outside the cell. Thus, speculates M.I.T.'s
Weinberg, cells with defective tumor-suppressor genes may no
longer heed growth-control signals sent by surrounding cells.
The first hard evidence that p53 may play a key role in human
cancer came from Vogelstein's group at Johns Hopkins, which last
year identified a mutant form of the gene in colon-cancer cells.
Since then, mutant p53 has shown up in breast- , lung-, brain-
and bladder-cancer cells. Many researchers believe p53, because
it is so ubiquitous, offers an unusually promising platform from
which to launch a major assault on cancer. For instance, drugs
that mimic the action of a normal p53 gene could conceivably
cause cancers to revert to a premalignant phase. One day,
albeit in the very distant future, it may even be possible for
molecular surgeons to replace faulty p53 genes.

    In the meantime, tests that detect mutations in this
critical gene could be an invaluable diagnostic tool. At a
meeting of top cancer-gene researchers at M.I.T. last September,
Vogelstein created quite a stir when he noted, almost in
passing, that his laboratory had detected cells with abnormal
p53 genes in the urine of patients with advanced bladder cancer.
A similar scan might pick up such cells in the stools of
patients with colon cancer, the cause of more than 60,000
deaths in the U.S. each year.

    At first, these tests would be used to guide physicians in
selecting therapies. In fact, screening for oncogenes is
beginning to help clinicians identify a few particularly
aggressive forms of cancer and tailor treatments accordingly.
Eventually, scientists may be able to fashion tests sensitive
enough to detect the presence of abnormal genes in undiagnosed
patients well before the cancer has embarked on its Shermanesque
march through the body. Such tests would no doubt be lifesavers:
if caught early enough, many cancers can be cured by surgery
alone.