December 2012

The field of (Nobel) dreams

receptor figure

Every year in the first week of October, when the Nobel Prize winners are announced, the world is much more focused on science than usual. This year, the fields of biochemistry and molecular biology were well represented in the awards. The Nobel Prize in chemistry was awarded to longtime American Society for Biochemistry and Molecuar Biology member Bob Lefkowitz and 2013 ASBMB Earl and Thressa Stadtman Distinguished Scientist awardee Brian Kobilka for “studies of G-protein-coupled receptors” (1, 2). These investigators integrated biochemical approaches to purify the receptors for key substances such as adrenaline, molecular biological techniques to clone cDNAs and genes that encode these receptors, and crystallographic methods to determine their three-dimensional structures. The Nobel Prize in physiology or medicine was awarded to Sir John Gurdon and Shinya Yamanaka “for the discovery that mature cells can be reprogrammed to become pluripotent” (3). Yamanaka was recognized for discovering that introducing four genes into differentiated cells through the use of molecular biological methods could induce the cells to dedifferentiate into pluripotent stem cell-like cells, while Gurdon used cell and developmental biological methods many years earlier.

The Nobel Prizes were established in Alfred Nobel’s will (4), where he wrote:


Of course, biochemistry and molecular biology were not mentioned, as biochemistry was just emerging as a field in 1895 and the concept of molecular biology was still more than half a century away. Nonetheless, biochemistry and molecular biology have been quite well represented in both the chemistry and physiology or medicine prizes over the years. By my count, 67 of the 104 chemistry prizes and 56 of the 103 physiology or medicine prizes have included major components of biochemistry or molecular biology.

The inclusion of biochemistry goes back to the beginning of the Nobel Prize program. In 1902, the second Nobel Prize in chemistry was awarded to Emil Fischer “in recognition of the extraordinary services he had rendered by his work on sugar and purine syntheses. ”Fischer was a chemist’s chemist (recall, for example, Fischer projections from organic chemistry) (5), and he also proposed the lock-and-key model for enzyme specificity in addition to his syntheses of many important biochemicals, including glucose and caffeine. The first biochemical physiology or medicine prize was awarded to Albrecht Kossel in 1910 “in recognition of the contributions to our knowledge of cell chemistry through his work on proteins, including nucleic substances.” Kossel discovered the nucleobases and made major contributions to understanding the chemical nature of proteins and their amino acid constituents (6).

Despite the long inclusion of biochemistry as a subject for recognition by the chemistry Nobel Prize, concerns are occasionally heard (including this year) regarding whether the science that is being recognized “is really chemistry.” The initial question that Lefkowitz and Kobilka were addressing was certainly a medical and physiological one, namely, “What is the mechanism by which hormones such as adrenaline induce their biological effects?” Lefkowitz’s laboratory (including Kobilka, then as a postdoctoral fellow) purified a receptor protein to homogeneity, determined its partial amino acid sequence, and used this sequence to clone the cDNA and the gene for the receptor. Analysis of the complete deduced amino acid sequence revealed this protein to be homologous to the visual protein rhodopsin, with seven characteristic presumed transmembrane helical regions. These proteins turned out to be members of a vast protein family (the G-protein–coupled receptors) that are central to many biological processes and are estimated to be the targets of approximately half of all drugs in use today.

Consideration of the mechanism of action of these receptors led to a fundamentally chemical question: How does the information that a hormone has bound to a receptor from one side of a lipid bilayer get transmitted to proteins on the other side of the bilayer? Considerable progress had been made on this question, but the most definitive answer came with the determination of the structure of a receptor caught in the act of activating a G protein.

This structure revealed key aspects of the conformational changes that couple hormone binding to structural features of the opposite side of the membrane that result in changes in the interacting G protein at a nearly atomic level. In addition, the crystallization of this membrane-protein complex required the use of specialized, synthesized detergents and a deep understanding of the physical chemistry of lipid solutions. Thus, while medicine and biology supplied the questions, chemistry provided the answers. I commend the current president of the American Chemical Society, Bassam Shakhashiri, for his appreciation of this accomplishment in the context of chemistry (7).

This October also included another important event for American science, the DeWitt Stetten Jr. Symposium (8) held in the Ruth Kirschstein Auditorium at the National Institutes of Health in honor of the 50th anniversary of the National Institute of General Medical Sciences. In his introductory remarks at this symposium, NIH Director Francis S. Collins noted that NIGMS had supported 75 Nobel Prize winners over its 50-year history (9). This represents 55 percent of the 137 total Nobel Prize awardees the NIH has supported. Yet NIGMS distributes only about 8 percent of the NIH budget.

Recalling that Nobel Prizes are issued to recognize contributions of “the greatest benefit to mankind,” this puts the tremendous return on the investment in basic research in quantitative terms.

Biochemistry and molecular biology reflect the combination of scientific fields that were once considered distinct. Of course, such fusion and recombination applies to other fields. This year’s Lasker Award in Basic Medical Research was awarded to Mike Sheetz, Jim Spudich and Ron Vale “for discoveries concerning cytoskeletal motor proteins, machines that move cargoes within cells, contract muscles, and enable cell movements” (10). Key to these discoveries were techniques adapted from physics for examining single molecular motor proteins in action. Indeed, some of the key studies were performed in collaboration with Nobel laureate Steven Chu, who was recognized in 1997 for developing laser-based methods for trapping and controlling single atoms.

My own training was in chemistry, and my dissertation project, although motivated by biological questions, was solidly in the mainstream of chemistry. First while a postdoctoral fellow and then while an assistant professor, my approaches moved into biochemistry and molecular biology, driven by the questions in which I was most interested. These changes were quite exhilarating scientifically but occasionally ran into some cultural barriers. At a scientific meeting, a chemist colleague of my Ph.D. adviser came up to me and said, “I understand that you have become a biologist.” I was involved in another discussion, and I responded without thinking, “No, just a modern chemist.” I do not believe he attended my talk. Many key scientific questions will continue to come into sharper focus only through the continued blurring of traditional scientific boundaries. We should all be careful to avoid being too ensconced in our own traditional fields.

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