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Nobelist Nirenberg Honored at NHLBI Symposium at Natcher

By Miriam Sander

Photos by Bill Branson

It is often said that scientific discoveries are made by a collective process that moves forward in many small incremental steps. But it is also said that the exception proves the rule. At a recent symposium honoring Nobel Prize-winning NIH scientist Dr. Marshall Nirenberg, NIH director Dr. Elias Zerhouni pointed out that some scientific discoveries are more important than others. He was referring to Nirenberg's discovery of the universal genetic code, which was described by symposium cochair Dr. Samuel Wilson of NIEHS as "a monumental step forward which is now an essential part of the intellectual framework of modern medical investigation and practice."

Dr. Marshall Nirenberg National Academy of Sciences president Dr. Bruce Alberts said the impact and implications of Nirenberg's discovery were so immediately obvious that he remembers to this day exactly where he was and what he was doing when he learned of Nirenberg's seminal result. Nirenberg's prize-winning work began in the early 1960s when he was a newly appointed research biochemist at the National Institute of Arthritis, Metabolic and Digestive Diseases (NIAMDD, later NIDDK). His laboratory was working on one of the major scientific problems of the time: how does DNA and/or possibly RNA direct the synthesis of proteins? How can a polynucleotide composed of the four deoxyribo- or ribonucleotide bases (G, C, A and T or U) be decoded by the cellular protein synthesis machinery to produce a protein composed of up to 20 different amino acids? Unlike other scientists who were trying to understand protein coding, Nirenberg took a biochemical approach. According to Dr. Thomas Caskey, now with Cogene, Inc., Nirenberg "saw the opportunity to take biochemistry to an extremely elite level" by breaking the genetic code. Nirenberg told the symposium audience that one of his colleagues cautioned him that his experimental approach to this question "was suicidal." Despite this warning, he "went ahead and did it anyway!"

Fellow NIH Nobel laureates Nirenberg and Dr. Julius Axelrod, scientist emeritus at NIMH, share a moment at the Dec. 16 symposium.

In collaboration with postdoctoral scientist J. Heinrich Matthaei, Nirenberg set up an in vitro protein synthesis system using synthetic polynucleotides as templates and a mixture of the 20 amino acids, one of which was radioactively labeled. The now famous "poly U experiment" led to the momentous discovery in 1961 that runs of U direct the synthesis of polyphenylalanine. From 1962 to 1966, Nirenberg and his colleagues at the National Heart Institute deciphered the code for all 20 amino acids. This work led to many insights about the genetic code, demonstrated that the genetic code is degenerate and universal, and earned him the 1968 Nobel Prize in Physiology or Medicine, which he shared with Robert W. Holley and Har Gobind Khorana. Symposium cochair Judith Levin of NICHD described the atmosphere in Nirenberg's laboratory at the heart institute as "exhilarating and intense."

Dr. Thomas Caskey Nirenberg's discovery was a major step in the path from classical genetics to molecular genetics, from biology to molecular biology and into the age of genomics and functional genomics. The sequencing of the human genome, which will reach completion in 2003, has also played a huge role in the recent transformation of biological science. NAS's Alberts described the conceptualization of the Human Genome Project (HGP) in the late 1980s. He chaired an NAS committee whose charge was to reach consensus on the value of pursuing such a project. Consensus was reached with great difficulty; but in the end, Alberts said that the committee "got it right" when they recommended that the entire human genome, including both gene and intergenic regions, should be sequenced. The committee also made a remarkably accurate prediction of how long it would take to complete the human genome sequence, estimating in 1988 that it would take approximately 15 years.

Dr. Francis Collins, NHGRI director, pointed out that the genome era has just begun and that there is still much to discover about the human genome. Ongoing projects at his institute include comparative genomics, the HAPmap project, analysis of the mammalian gene collection and continuing study of the ethical, legal and social implications associated with genomics information and technology; projected initiatives include characterization of the proteome, identification of environmental risk factors for human disease and development of animal models of human disease.

Dr. J. Craig Venter of the Center for the Advancement of Genomics emphasized the importance of technology development to the success of the HGP and many other sequencing efforts. He and his colleagues developed EST mapping and shotgun DNA sequencing, two critical technologies that have enhanced the rate of DNA sequencing and analysis considerably.

Dr. Eric Lander of the Whitehead Institute at MIT addresses the gathering.

The universal genetic code deciphered by Nirenberg and his colleagues is the best known code in biological systems. However, Dr. Eric Lander of the Whitehead Institute at MIT suggested that the genetic code is one of several important biological codes. He proposed that genes, gene regulation, genetic variation and biological function all have their own distinct codes. Lander also thinks one of the key challenges facing researchers in genomics is to understand the significance of the large number of non-coding DNA sequences conserved between the human and mouse genomes. When the functions of these sequences are understood, the code of gene regulation and gene regulatory networks may begin to unravel.

Dr. Leroy Hood of the Institute for Systems Biology also emphasized the importance of higher levels of biological organization including gene regulatory networks. He contrasted traditional hypothesis-driven biological research with discovery-based approaches, which produce large datasets that can be used to describe an entire biological system. Systems biology, a method he promotes, interrogates an entire biological system and "ascertains the relationships between all its parts." Hood said systems biology is only possible now that genomic sequences are available, and that the development of systems biology depended on discoveries such as the genetic code, which allow us to decipher the information contained in DNA sequences.

Dr. Elias Zerhouni The scope of the NHLBI-sponsored symposium (formally titled "The Genetic Code Revisited: The Impact of Functional Genomics in Medical Research," also cochaired by NCI's Dr. Dolph Hatfield) was broadened by the remaining five speakers, who, with the exception of Dr. Susan Taylor of the University of California, San Diego, were former Nirenberg lab members. Taylor, an expert on protein kinase A and related kinases, discussed structure, function and regulation of this protein kinase family. She emphasized that protein covalent modifications are a non-linear function that is critical to cell signaling. She also pointed out the importance of understanding protein kinases as structurally dynamic proteins.

Dr. Philip Leder of Harvard Medical School pioneered the study of cancer-susceptible strains of mice, in part based on the concept that an oncogene is "necessary but not sufficient" to produce cancer. He used cancer-susceptible mouse strains and an assay based on functional genomics to identify a range of cancer protagonists.

Dr. Edward Scolnick of Merck Research Laboratories discussed the emerging role of functional genomics in drug discovery. He said the challenge of the genomic era is to facilitate identification of therapeutic targets. Several hundred validated therapeutic targets have been identified in the past two decades, but many putative targets fail during clinical validation; functional genomics has the potential to reduce the rate of failure significantly. Recent drug success stories that depended on genomic information include statins, antidepressants, Gleevec, Herceptin and Cox-2 inhibitors.

Nobel laureate Dr. Joseph Goldstein of the University of Texas Southwestern Medical Center demonstrated that sterol regulatory binding proteins (SREBPs) play a key role in controlling the fluidity of the plasma membrane. SREBPs monitor and control production of cholesterol and fatty acids by salvage and de novo synthesis pathways. Dysregulation of these cellular functions plays a role in important human diseases including heart disease, diabetes and obesity.

Nobel laureate Dr. Joseph Goldstein (r) of the University of Texas Southwestern Medical Center pauses to chat with NHLBI scientist Dr. Earl Stadtman, head of the enzyme section in the Laboratory of Biochemistry.

The last speaker was Dr. Sidney Pestka of the University of Medicine and Dentistry of New Jersey, who demonstrated that fluorescence resonance energy transfer (FRET) enables scientists to look inside living cells. FRET can be used to demonstrate protein-protein interactions and to measure intermolecular distances. Pestka emphasized that FRET can be used for high-throughput screening and has the advantage that it works with a single cell.

All of the speakers at the symposium strongly asserted that Nirenberg's discovery of the genetic code is a seminal scientific achievement that has had enormous impact on modern science. In addition, Nirenberg's colleagues and former postdoctoral fellows uniformly acknowledged that he is an excellent mentor with extraordinary scientific vision as well as a wonderful friend. NICHD's Levin added that Nirenberg inspired his fellow scientists because he "taught, by example, how to be a true scientist." By the end of the gathering, it was clear that NHLBI director Dr. Claude Lenfant was correct in stating that "people like Marshall Nirenberg make the NIH the great institution it is today."