Synergy And Serendipity, Rather Than Planning, Often Spur Medical Breakthroughs

Government-funded research runs the gamut from investigations of the most basic physical and biological processes to applied research on more immediate needs. But in a zero-sum game, choosing among individual competing proposals can be difficult, so how can we compare their “significance” and “impact,” two criteria that must be addressed in grant applications to the National Institutes of Health?

As Harvard Medical School Professor Marc Kirschner has argued, although we may be able to recognize plausible, well-designed scientific proposals, attempting to assess their potential significance and impact can be “misleading and dangerous,” and can “invite exaggerated claims of the importance of predictable outcomes—which are unlikely to be the most important ones.” In other words, he concluded, “Significant science can only be viewed in the rearview mirror.”

The lag-time may be long between the completion of an experiment and an appreciation of its importance. After he received the 1969 Nobel Prize in Medicine or Physiology, my college microbiology professor, Salvador Luria, made a joke of the difficulty of perceiving the significance of research findings at the time they are first obtained. To all who had congratulated him on the award, Luria sent a cartoon which showed an elderly couple at the breakfast table. The husband, reading the morning newspaper, exclaims, “Great Scott! I’ve been awarded the Nobel Prize for something I seem to have said, or done, or thought, in 1934!” (Luria was probably influenced by the well-known example of Francis Peyton Rous, whose research in 1911 found that supposedly spontaneous malignant tumors in chickens were actually caused by and transmitted by a retrovirus. It took 55 years for Rous’s discovery to be recognized with a Nobel Prize in Physiology or Medicine, which he received in 1966.)

That scientific advances are often serendipitous was conveyed eloquently in a 2011 Science editorial by French biologist François Jacob in which he described the research that led to his 1965 Nobel Prize in Physiology or Medicine. His lab was working on the mechanism that under certain circumstances causes the bacterium E. coli to suddenly produce bacterial viruses (which had been dormant), while at the same time another research group was analyzing, also in E. coli, how the synthesis of a certain enzyme is induced in the presence of a specific sugar. As Jacob wrote, “The two systems appeared mechanistically miles apart. But their juxtaposition would produce a critical breakthrough for our understanding of life”–namely, the concept of an “operon,” a cluster of genes whose expression is regulated by an adjacent regulatory gene.

Another quintessential example of both the synergy and serendipity of basic research was the origin  in the early 1970’s of recombinant DNA technology (also known as “genetic modification,” or “GM”), the prototypical technique of modern genetic engineering. It resulted from the synergy among several esoteric, largely unrelated areas of basic research: enzymology and nucleic acid chemistry that led to techniques for cutting and rejoining segments of DNA; advances in fractionation procedures that permitted the rapid detection, identification and separation of DNA and proteins; and the accumulated knowledge of microbial physiology and genetics, so that “foreign” DNA could be introduced into a cell’s DNA and made to function there. The result putting these phenomena together was the ability to move functional genes from one organism to another virtually at will–the birth of modern biotechnology.

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