Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century by Morton A. Meyers Page A
Authors: Morton A. Meyers
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cancers of the blood and lymph nodes. Put another way, of the ten million people diagnosed with cancer each year worldwide, about half have p53 mutations in their tumors. The gene's inactivation through mutation enables tumor cells, in a famous phrase, “to reach for immortalization.”
In 1993 Science magazine named p53 the Molecule of the Year. It has generated much enthusiasm for the development of strategies for the diagnosis, prevention, and cure of cancers.
Arnold Levine is a round-faced, high-energy, fast-thinking, fast-talking individual who commands deep affection from his laboratory team. He went on to become the president of Rockefeller University in New York. Would he consider the discovery of p53 serendipitous? “Absolutely,” he frankly responds, noting the frequency of chance discoveries and citing the observations of Richard Feynman, the Nobel laureate in physics, on how scientists commonly write their articles in such a way as to “cover their tracks” when it comes to how they stumbled upon the truth. 5
P ROBING THE G ENOME FOR THE R ENEGADE P ATHWAY
A major focus resulting from such advances in recognizing the influences of genetic mutations upon cancer is the field of targeted drug therapy. In the human cell's intricate inner circuitry are dozens of molecular chains of communication, or “signaling pathways,” among various proteins. It is now understood that there are roughly ten pathways that cells use to become cancerous and that these involve a variety of crucial genetic alterations.
Research is actively directed toward developing drugs able to interfere with the molecular mechanisms that drive the growth in a tumor and that are attributable to these mutated genes. A handful have been approved for use. The best known is Gleevec, which has a dramatic effect on an uncommon kind of leukemia called chronic myelogenous leukemia (CML) and an even more rare stomach cancer, gastrointestinal stromal tumor (GIST). CML, however, is exceptional in that it is due to a single gene mutation, and the drug is able to block its specific tumor-signaling mechanism. Unfortunately, over time, further mutations circumvent the molecular signal that Gleevec blocks, building drug resistance. Most cancers are more complex, with multiple mutations that require a multipronged attack.
Picking the right targets is critical, and the most promising new diagnostic technology is the DNA microarrary, or “gene chip.” Gene chips can identify mutations in particular genes, as well as monitor the activity of many genes at the same time. It is hoped that this precise molecular biology will lead to the design of a range of drugs that target highly specific signaling pathways of cancer.
Cancer was long thought of as one disease expressed in different parts of the body—breast, lung, brain—but researchers are now teasing apart the myriad genes and proteins that differentiate cancer cells, not just from healthy cells but also from each other. The aim is to classify cancers mainly by their genetic characteristics, by which pathway is deranged, not by where in the body they arise or how they look under a microscope. The ideal is to fine-tune the diagnosis and treatment of cancer for more “personalized medicine.”
But knowledge of how to do that is still lacking in most cases. The magic bullet has yet to be found. Many of the new cancer drugs are targeting things in cancer cells that may or may not be driving that cancer. The drugs in use by many patients in clinical trials work for only a minority. In truth, scientists cannot really identify, in most cases, the Achilles’ heel of a cancer cell or understand very well the targets at which they are shooting. And as the tumor grows, the target is ever changing. The successes claimed seem, at times, to be merely instances of drawing a bull's-eye around the spot where the arrow landed.
Even here, serendipity may be grafted upon imperfect knowledge. The story of the drug Iressa
In 1993 Science magazine named p53 the Molecule of the Year. It has generated much enthusiasm for the development of strategies for the diagnosis, prevention, and cure of cancers.
Arnold Levine is a round-faced, high-energy, fast-thinking, fast-talking individual who commands deep affection from his laboratory team. He went on to become the president of Rockefeller University in New York. Would he consider the discovery of p53 serendipitous? “Absolutely,” he frankly responds, noting the frequency of chance discoveries and citing the observations of Richard Feynman, the Nobel laureate in physics, on how scientists commonly write their articles in such a way as to “cover their tracks” when it comes to how they stumbled upon the truth. 5
P ROBING THE G ENOME FOR THE R ENEGADE P ATHWAY
A major focus resulting from such advances in recognizing the influences of genetic mutations upon cancer is the field of targeted drug therapy. In the human cell's intricate inner circuitry are dozens of molecular chains of communication, or “signaling pathways,” among various proteins. It is now understood that there are roughly ten pathways that cells use to become cancerous and that these involve a variety of crucial genetic alterations.
Research is actively directed toward developing drugs able to interfere with the molecular mechanisms that drive the growth in a tumor and that are attributable to these mutated genes. A handful have been approved for use. The best known is Gleevec, which has a dramatic effect on an uncommon kind of leukemia called chronic myelogenous leukemia (CML) and an even more rare stomach cancer, gastrointestinal stromal tumor (GIST). CML, however, is exceptional in that it is due to a single gene mutation, and the drug is able to block its specific tumor-signaling mechanism. Unfortunately, over time, further mutations circumvent the molecular signal that Gleevec blocks, building drug resistance. Most cancers are more complex, with multiple mutations that require a multipronged attack.
Picking the right targets is critical, and the most promising new diagnostic technology is the DNA microarrary, or “gene chip.” Gene chips can identify mutations in particular genes, as well as monitor the activity of many genes at the same time. It is hoped that this precise molecular biology will lead to the design of a range of drugs that target highly specific signaling pathways of cancer.
Cancer was long thought of as one disease expressed in different parts of the body—breast, lung, brain—but researchers are now teasing apart the myriad genes and proteins that differentiate cancer cells, not just from healthy cells but also from each other. The aim is to classify cancers mainly by their genetic characteristics, by which pathway is deranged, not by where in the body they arise or how they look under a microscope. The ideal is to fine-tune the diagnosis and treatment of cancer for more “personalized medicine.”
But knowledge of how to do that is still lacking in most cases. The magic bullet has yet to be found. Many of the new cancer drugs are targeting things in cancer cells that may or may not be driving that cancer. The drugs in use by many patients in clinical trials work for only a minority. In truth, scientists cannot really identify, in most cases, the Achilles’ heel of a cancer cell or understand very well the targets at which they are shooting. And as the tumor grows, the target is ever changing. The successes claimed seem, at times, to be merely instances of drawing a bull's-eye around the spot where the arrow landed.
Even here, serendipity may be grafted upon imperfect knowledge. The story of the drug Iressa
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