Marshall Nirenberg 1927–2010

On January 15, 2010, the world lost one of the true giants in the history of science. Marshall Nirenberg, the man who deciphered the genetic code, was taken from us by a rare neuroendocrine cancer. He was 82 years old.I was one of the many scientists who had the good fortune to be trained in Marshall's lab, to be exposed to his brilliance, to be instilled with his values, and to be inspired by his enthusiasm for the discovery of important new truths in science. An incredible cornucopia of scientists were trained and profoundly influenced by him: Phil Leder, Sid Pestka, Thomas Caskey, Art Beaudet, Sam Barondes, Al Gilman, Joe Goldstein, John Minna, Dolph Hatfield, Fritz Rottman, and many others. What drew us to him? What did we learn from him? What is his ultimate legacy to mankind?I met Marshall for the first time in July 1966, when I interviewed for a fellowship in the National Heart Institute. I had followed his work during my medical training and was in awe of his discoveries. With great trepidation, I sat down and began to chat with him about his work on the genetic code and the work he was now doing. He put me at ease immediately. Marshall had no pretense. He had no need for pretense. His self-confidence, based upon accomplishment, and his self-effacing persona drew me in as we talked for over an hour.As we discussed the potential for my joining his lab, I asked him a question that I had been grappling with for some time: How did he handle the intense competitive environment surrounding the work on the genetic code? He smiled and said, “Ed, science is hard work. 99% of what you try fails. If you go into science, work on something that really matters. So if you discover something, it will be important.” I agreed to join his lab. It was the pivotal decision in my scientific career.The world of science knows the substance of his work: He opened up the mystery of the genetic code with the poly-U-polyphenylalanine experiment, then with the triplet binding assay with Phil Leder, and finally with the triplet termination assay with Tom Caskey. From UUU to all 64 triplets: the “periodic table” for molecular biology.But how many have read the poly-U paper—I mean, really read it? Marshall's approach to science comes through, loud and clear. Every possible control is tested. Every method is described so that anyone else can reproduce it. Every piece of data, even imperfect data, is included in the tables and figures. The incorporation of phenylalanine into the product is more than a thousand-fold over background without the poly-U template, and the incorporation of this amino acid is selective for this homopolymer. How many of us would take the care to characterize the actual product to be sure it had the characteristics of polyphenylalanine?Marshall NirenbergPhoto courtesy of National Heart, Lung, and Blood Institute.View Large Image | View Hi-Res Image | Download PowerPoint SlideMarshall believed deeply in being meticulous and in being certain that one's data were true, that the results were due to the variables one had manipulated and were not caused by some vagary that had not been thought of or controlled for. He believed that the methods in one's paper should be so clearly described that any investigator trying to reproduce the results could do so on the very first attempt. Supplementary sections could never be a part of a Nirenberg paper.The even more amazing part of this man's legacy is that he could teach his students how to investigate the scientific world: How to design exploratory experiments so you have an optimal chance of making the discovery if it is there to be made. How to design the intellectual part of an experiment and then execute it with technical precision so your results are always reproducible. Protocol design, reagent tracking, data keeping—if you followed Marshall's system, you simply could never do an experiment that you could not reproduce. His system, his intellectual dissection of how experimental science should be performed, prevented you from ever experiencing that agony.Marshall was not only analytically and deductively brilliant, he was also equally creative. He understood the scientific process so well that he could formalize it and teach it to any student who came through his laboratory. In my scientific career, whenever I have been faced with a thorny problem, with results that don't make sense, I have always fallen back on Marshall's teachings—and clarity has always emerged. It has been like having a guardian angel looking over my shoulder.But even more than teaching care and approach, he instilled confidence in his students. Never be afraid to try a new technique, he counseled; anyone can do a technique that someone else has already done. Don't be bounded by what techniques you know, and don't try to make it perfect the first time. Ask an important biological question and search for or invent a method to approach the answer to the question experimentally. How many study sections think this way when a new investigator's grant appears for review? How many young careers never get such a chance?What was Marshall like personally? He was a warm and modest individual. He was always accessible to his students. He lived for science and the thrill of discovery. I once called him at 10:30 p.m. on a Friday night with news about the termination factors that Tom Caskey and I had just discovered. We talked for over an hour. I, not he, had to end the conversation. He participated actively in the journal clubs in his lab; he bounced around the labs all the time thinking out loud about something new and potentially exciting.If you wanted to engage him in a discussion about the work you were doing, or the results of your experiments, he was always there to help. But he always began those conversations with, “Don't tell me the data, tell me how you did the experiment.” He taught us how to break down a problem into each of its pieces so we could master them all and work through to the correct answer. In my life as a scientist, I have never met anyone else like him. He could think about the highest intellectual content of the project as well as the most detailed nitty-gritty about how to unravel its mysteries. He was always ready to accept another budding student into his lab. When I asked him if my fellow Massachusetts General Hospital house officer Joe Goldstein could join us after Joe's original designated NIH lab no longer existed, he willingly agreed. “As long as you can squeeze him into your space, he can come. It sounds as if he is a very good person.” Prophetic indeed.He was devoted to his first wife, Perola, and was deeply upset when she passed away. They had no children. He was equally devoted to his second wife, Myrna Weissman, and to her family. When they got married, Marshall bought a huge house in Potomac, Maryland so that Myrna's children and grandchildren and his nieces and nephews could visit. Each year at least two of them would spend the summer with Marshall and Myrna, doing some kind of internship in Washington, DC. The children and grandchildren loved visiting, and they came from all over to be with Marshall during the last weeks of his life. His nieces and nephews made a modern-day pilgrimage, flocking from San Francisco, Chicago, Dallas, New Haven, Tampa, and Jackson, Mississippi to comfort him in his last days.It is also worth reflecting for a moment on the context of his life's work. It is well known that he was a young, unknown scientist in 1957 when he was taken in by his brilliant mentor, Gordon Tompkins at NIH. After the breakthrough poly-U experiment was conducted, being at NIH was key to what Marshall was able to accomplish subsequently and the depth to which he could elaborate on the protein synthesis system and define the whole code. Many NIH scientists, across institutes, gladly collaborated with him for years because of the importance of the work. These were halcyon days at NIH, and the deciphering of the genetic code was a galvanizing event. It is a great testimony to the NIH and to its collaborative environment, then largely unencumbered by bureaucracy. It was a proud moment in its history, one that would be hard to recreate in the complex world in which we now live.Members of Congress—guardians of taxpayer dollars and decision-makers for NIH funding—often ask themselves whether the funding for science provided to NIH really matters to the health of the nation. We should tell them to think for a moment about the impact of the cracking of the genetic code. If it were not for Marshall Nirenberg's work, there would be no recombinant DNA technology, which changed life science and medicine. The sequence of the human genome and the era of modern genomics could not have come into being. Protein therapeutics for cancer and autoimmune diseases, drugs for HIV, statins for atherosclerosis, and modern vaccines all ultimately owe their origin to the knowledge of the code. The genetic code is the periodic table for biological science.How can we honor Marshall Nirenberg's memory? We can remember all the things he stood for: complete truth in science, meticulous attention to detail, passionate love for discovery, thorough training of students, deep values about how science should be carried out. Marshall will never be dead, because what he stood for in science is timeless—bridging generations of scientists, and bridging millennia.All of us extend our deepest sympathies to his family and especially to Myrna, his beloved and devoted wife. I will forever cherish my time with him, and I am deeply saddened by his death. My sadness will linger. My guardian angel is no longer with me, but his legacy of values and teachings will never fade. Few humans have the impact he had on humanity. Marshall, we all miss you but we keep in our hearts your memory and in our minds what you have taught us. This will be timeless.