TIME: Almanac 1995

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<text id=90TT3022> <title> Nov. 12, 1990: Cracking Cancer's Code </title> <history> TIME--The Weekly Newsmagazine--1990 Nov. 12, 1990 Ready For War </history> <article> <source>Time Magazine</source> <hdr> SCIENCE, Page 97 Cracking Cancer's Code </hdr> <body> 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. </body> </article> </text>