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FULFILLMENT AND FRUSTRATION: THE CONFESSIONS OF A BEHAVIORAL BIOCHEMIST LOUIS NEAL IRWIN* Both the behavior oforganisms and the chemistry of cells fascinate us today as they did the first day scientists began to probe the mysteries of each. Those of us who chose, mostly in the 1960s, to launch a concerted effort at defining the relationship between the two felt particularly fortunate to take on such an intriguing problem amid what we perceived to be the more mundane research around us. We felt that with hard work, intelligence, and creativity we had a reasonably good chance of describing learning, memory, and the mind in biochemical terms within a few decades. That ambitious objective did not seem as naive 15 years ago as it does today. We were basking in the success of molecular biology, which had recently elucidated the biochemical basis of hereditary information, historically one of the most intractable problems of biology. We were beginning to understand the chemical nature of nerve impulse conduction and synaptic transmission in some detail. And Hebb [1] had provided us with a theory of higher-brain function which seemed not only to bridge the stale standoff between connectionistic and cognitive ideologies in psychology, but also to suggest a model for plasticity among brain cells concrete enough to be tested in biochemical terms. We invested a vast amount of time and effort in our search for the biochemical basis of behavior. In time we learned a lot about the complexities ofboth behavior and brain metabolism, and in general enjoyed our mission and found our work fulfilling. But over the years the frustrations have mounted, as our initial hopes have gradually given way to a»Eunice Kennedy Shriver Center for Mental Retardation, and the Neurosciences Research Program, Massachusetts Institute of Technology, Boston, Massachusetts 02130. I thank George Adelman, Key Dismukes, Carol Irwin, and Frederic Worden for their thoughtful comments and criticisms ofa preliminary draft ofthis essay. My research at the Shriver Center is supported by the National Science Foundation. The Neurosciences Research Program is supported by grants from the National Institute of Mental Health, National Institute of Neurological and Communicative Diseases and Stroke, National Science Foundation, and private foundations.© 1978 by The University of Chicago. 0031-5982/78/2104-0046$01.00 476 I Louis NealIrwin ¦ Fulfillment andFrustration more realistic appraisal ofthe depth and breadth ofthe problem and an increasing respect for the fundamental research that we once regarded as mundane. Increasingly, those of us who entered the field with great expectations have found our methods and concepts inadequate to our ambitious task and have quietly begun to settle for more limited but achievable goals. To many of our colleagues, this outcome has seemed inevitable from the beginning—indeed, some counseled us not to invest our careers in such a high-risk enterprise. Perhaps they were right; but the case can be made (and will) that not to have made the effort would have left us even further from bridging the gap between behavior and biochemistry than we now appear to be and would have deprived us of both a great deal of knowledge and the touch of wisdom which should make our future research more incisive and effective. For the future, however, we must increasingly ask whether the strategies of the past continue to be useful in the light of what we now know. Perhaps we should examine the point we have reached with respect to several of our major objectives—to reflect on where we have been and where we are going. The Elusive Connection Few areas of neurobehavioral research seemed more promising in the early sixties than the synthesis of proteins with respect to learning. Our conceptual framework derived direcdy and without imaginative elaboration from molecular biology, which had shown that genetic information is stored in nucleic acids and expressed in proteins. Why not acquired information as well? The first step toward establishing a connection between protein synthesis and learning seemed to be to block memory (cause amnesia) by interrupting the production of proteins. We were fortunate, it first appeared , in finding that puromycin, a purine-containing nucleoside, could thoroughly inhibit brain protein synthesis as well as reliably produce amnesia at doses...


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