Marshall Nirenberg (1927–2010) Adenine Triplet — but Not a Doublet — Made a Humble, Gentle and Visionary Giant of Molecular Biology

NEWS & VIEWS NATURE|Vol 464|4 March 2010

OBITUARY the 20 amino acids. Nirenberg’s laboratory synthesized the codons biochemically using an enzyme-based approach, and showed that an Marshall Nirenberg (1927–2010) adenine triplet — but not a doublet — made A humble, gentle and visionary giant of molecular biology. only the tRNA for lysine and bound to the ribosome. The translation assay was also a key Marshall Warren Nirenberg was only 34 years analytical tool for subsequent achievements NIH old when, in August 1961, he reported his by other researchers in the field (including studies on the genetic code at the International myself); these included the chemical, rather Congress of Biochemistry in Moscow. For than enzyme-based, synthesis of codons this and subsequent work he was awarded the by Gobind Khorana, which led to the rapid 1968 Nobel Prize in Physiology or Medicine, assignment of codons by both his and together with Gobind Khorana and Robert Nirenberg’s laboratories, the finding that a Holley, “for their interpretation of the genetic single tRNA molecule could recognize more code and its function in protein synthesis.” than one codon (the wobble concept), and He was the National Institutes of Health’s the demonstration that the genetic code first Nobel laureate, and achieved these is universal across species — the topic of discoveries by a series of brilliant biochemical Nirenberg’s address at a Vatican-sponsored approaches — thereby disproving Ed Tatem’s meeting in 2008. Moreover, deciphering the 1958 prediction that it would take a lifetime to genetic code made possible the spectacular break the code. era of DNA sequencing, recombinant His fascination with biology began DNA technology and genome projects that early in his life. Following a family move followed. in his youth from New York City to a After his seminal work in molecular Florida dairy farm, he became an expert biology, Nirenberg redirected his research naturalist — studying birds, catching and to neuroscience, investigating, among other releasing snakes, and collecting spiders. One questions, the cellular and biochemical basis previously unrecognized spider species from of opiate addiction, and developing cellular his collection was named “Marshall” by the uracil, cytosine, adenine and guanine bases models for the formation of the synaptic American Museum of Natural History in — as the ‘messenger’ RNA intermediate. junctions between neurons. Throughout New York City. His fascination with nature And an outcome of this extraordinarily his career, Nirenberg put great emphasis on endured for a lifetime. successful approach was the observation nurturing young scientists, and many of the Nirenberg graduated in 1948 from the that polyuracil directed the synthesis of only researchers he trained are award-winning University of Florida in Gainesville, and polyphenylalanine. leaders in their own fields. One example is obtained a PhD in carbohydrate biochemistry On hearing of this breakthrough — DNA to the American Chemical Society’s recognition from the University of Michigan in Ann mRNA to protein — described by Nirenberg a few months back of his ‘code team’, Arbor. He first came to the National Institutes in a small session of the 1961 Moscow nominated by Nirenberg himself. of Health in 1957, joining the laboratory congress, Francis Crick asked him to repeat Nirenberg’s character created the of Gordon Tomkins there three years later. his presentation to the entire congress in a environment I remember while working as Although Nirenberg’s bold plan to decipher special session. Nobel-prizewinning biologist a research associate in his lab. He combined the genetic code was considered “suicidal” by Harold Varmus, at the time an aspiring an engaging, but retiring, personality with one senior scientist, Tomkins was a supporter student of English who was travelling in scientific focus. His laboratory, although small of the endeavour. On reflection, Nirenberg Moscow, remembers the presentation as being (112 square metres), fostered collaborative himself commented that the “goal was worth instrumental in changing the direction of his and successful ideas. His unusual circadian the risk”. career from literature to science. At a more rhythm meant late-night planning of Indeed it was. His research answered general level, the public announcement of experiments, and excitement in the laboratory the central question of how the hereditary this simple in vitro assay for protein synthesis about implementing them the following information stored in DNA is translated into triggered the race to match the base content of afternoon. He strove to develop several cellular proteins. He developed a succession the genetic code to each of the 20 amino acids approaches to a single question, while always of in vitro biochemical assays that led to the that constitute proteins. seeking simplicity and accuracy. Our papers, determination of the nucleic-acid content Two technologies were, however, required for example, seldom had fewer than ten drafts of the cell, the finding that trinucleotide to prove that the code was triplet and to in the pursuit of precision and clarity. sequences (codons) define a protein’s determine the sequence order: an in vitro assay Nirenberg died from cancer on 15 January. amino-acid sequence, and the discovery of for molecules that interact with ribosomes For 41 years, Nirenberg’s partner in life and ‘punctuation signals’ — codons that mark the (cellular factories for protein synthesis); and science was, until her death, his first wife beginning and end of a peptide — and of the a method for generating synthetic codons to Perola Zaltzman. His second wife, Myrna universality of the genetic code. Each approach artificially recreate the process of translation. Weissman, also shared his love of science, was simple in execution but elegant in concept. Nirenberg and Philip Leder developed a and her extensive family brought youth and The first assay Nirenberg developed was a simple translation assay in which they used excitement to Nirenberg’s final years. bacterium-based in vitro protein-synthesis radioactively labelled aminoacyl transfer C. Thomas Caskey method. Together with Heinrich Matthaei, RNA, partially purified ribosomes and C. Thomas Caskey is at the Brown Foundation he made the crucial discovery that RNA, RNA codons to detect the stable translation Institute of Molecular Medicine for the rather than DNA, programmed the synthesis complex. This elegant assay nonetheless Prevention of Human Diseases, University of proteins. This finding led to a bold shift required synthesis of all 64 possible codon of Texas Health Science Center at Houston, to studying synthetic RNA polymers — triplets from the four bases to determine Houston, Texas 77030, USA. composed of single, or random mixtures of, exactly which codons translate into each of e-mail: [email protected]