Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century by Morton A. Meyers
Authors: Morton A. Meyers
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seem unfortunate, but what happened next is another example of how serendipity works its magic. Thorough testing uncovered the surprising finding that the first monkey species harbored a previously undetectable virus that was harmless to them but capable of killing and replicating in the cells of the second species. The conclusion was both startling and distressing: the Salk polio vaccine, in use since 1953, was badly contaminated with a virus. Had itnot been for the chance measles infection and the subsequent switch to African green monkeys, the virus would not have been detected.
Alarm spread when both Merck and NIH researchers showed that the virus caused cancer when injected into newborn hamsters. The shocking reality could not be dismissed: The polio vaccine, which acted to reduce or eliminate poliovirus epidemics all over the world, was contaminated with a virus that initiated cancer in hamsters. Mass immunizations with injections of three doses of vaccine were so popular that about 450 million doses had been administered in the years 1955–59. The United States Bureau of Biologics acted swiftly to eliminate the virus from poliovirus seed stocks and grow poliovirus solely in the African green monkey cells.
Meanwhile, amid the intellectual ferment in molecular biology of this era in cancer research, Arnold Levine, a molecular biologist at Princeton University, was intrigued by this newly discovered virus shown to transform normal cells into cancer cells. Levine started by thinking that the virus's protein shell might induce an antibody in the blood. The antibody could be detected as a biomarker to indicate the presence and severity of the infection and even the results of treatment.
Levine's search led him in 1979 to unexpectedly discover a new protein in the blood. He named it simply p53 because the protein has the molecular weight of 53,000 hydrogen atoms. 2 For ten years after its discovery, Levine followed the p53 gene and its protein down a false trail, believing it to be an oncogene, a cancer-accelerating gene. He found that putting the gene into normal cells (using rat embryos) made them cancerous. In 1983 he cloned the gene for the first time and demonstrated what appeared to be its tendency to induce tumors. But Levine was wrong about the actual nature of p53.
Finally, in 1989, the real breakthrough occurred. While pursuing the genetic causes of colorectal cancer in humans, Bert Vogelstein at Johns Hopkins University found a mutation in the p53 gene. 3 As Levine reviewed the data, he experienced what can only be described as a “Eureka!” moment. In a conceptual leap, he realized that p53 was not a gene that stimulates cancer but a gene that suppresses tumors. 4 He had been led astray because the clones he had used in the early experimentswere unwittingly composed of mutants. It was as though he was struck by lightning when he came to understand that the p53 gene had to be mutated in order to foster cancer transformation within a cell—that is, its normal function is to inhibit division and growth of tumor cells.
The normal p53 protein acts as an emergency brake to arrest any runaway growth of cells that may have acquired cancerous tendencies and as a damage-control specialist to induce cell death under specific circumstances, such as in the presence of DNA damage. It has been dubbed the “guardian of the genome” because of its vital biological functions. After ten years of dedicated research, “suddenly,” Levine ruefully noted, “p53 became a hot ticket in cancer research.” A single mutation in the 135th position of its 393 amino acids can eliminate the surveillance capability of the protein and allow a cancer to grow. In its mutated form, it is found in more than 50 percent of human cancers, including most major ones. Among the common tumors, about 70 percent of colorectal cancers, 50 percent of lung cancers, and 40 percent of breast cancers carry p53 mutations. The p53 gene is also linked to
Alarm spread when both Merck and NIH researchers showed that the virus caused cancer when injected into newborn hamsters. The shocking reality could not be dismissed: The polio vaccine, which acted to reduce or eliminate poliovirus epidemics all over the world, was contaminated with a virus that initiated cancer in hamsters. Mass immunizations with injections of three doses of vaccine were so popular that about 450 million doses had been administered in the years 1955–59. The United States Bureau of Biologics acted swiftly to eliminate the virus from poliovirus seed stocks and grow poliovirus solely in the African green monkey cells.
Meanwhile, amid the intellectual ferment in molecular biology of this era in cancer research, Arnold Levine, a molecular biologist at Princeton University, was intrigued by this newly discovered virus shown to transform normal cells into cancer cells. Levine started by thinking that the virus's protein shell might induce an antibody in the blood. The antibody could be detected as a biomarker to indicate the presence and severity of the infection and even the results of treatment.
Levine's search led him in 1979 to unexpectedly discover a new protein in the blood. He named it simply p53 because the protein has the molecular weight of 53,000 hydrogen atoms. 2 For ten years after its discovery, Levine followed the p53 gene and its protein down a false trail, believing it to be an oncogene, a cancer-accelerating gene. He found that putting the gene into normal cells (using rat embryos) made them cancerous. In 1983 he cloned the gene for the first time and demonstrated what appeared to be its tendency to induce tumors. But Levine was wrong about the actual nature of p53.
Finally, in 1989, the real breakthrough occurred. While pursuing the genetic causes of colorectal cancer in humans, Bert Vogelstein at Johns Hopkins University found a mutation in the p53 gene. 3 As Levine reviewed the data, he experienced what can only be described as a “Eureka!” moment. In a conceptual leap, he realized that p53 was not a gene that stimulates cancer but a gene that suppresses tumors. 4 He had been led astray because the clones he had used in the early experimentswere unwittingly composed of mutants. It was as though he was struck by lightning when he came to understand that the p53 gene had to be mutated in order to foster cancer transformation within a cell—that is, its normal function is to inhibit division and growth of tumor cells.
The normal p53 protein acts as an emergency brake to arrest any runaway growth of cells that may have acquired cancerous tendencies and as a damage-control specialist to induce cell death under specific circumstances, such as in the presence of DNA damage. It has been dubbed the “guardian of the genome” because of its vital biological functions. After ten years of dedicated research, “suddenly,” Levine ruefully noted, “p53 became a hot ticket in cancer research.” A single mutation in the 135th position of its 393 amino acids can eliminate the surveillance capability of the protein and allow a cancer to grow. In its mutated form, it is found in more than 50 percent of human cancers, including most major ones. Among the common tumors, about 70 percent of colorectal cancers, 50 percent of lung cancers, and 40 percent of breast cancers carry p53 mutations. The p53 gene is also linked to
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