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Holley, Robert William

HOLLEY, ROBERT WILLIAM

(b. Urbana, Illinois, 28 January 1922; d. Los Gatos, California, 11 February 1993),

organic chemistry, biochemistry, molecular biology, cell biology.

Holley was the first to provide the full sequence of an RNA molecule, alanine transfer RNA, and therefore, indirectly, of a gene. He shared the Nobel Prize in Physiology or Medicine with Marshall Warren Nirenberg and Har Gobind Khorana in 1968 for the characterization of the mechanisms by which the genetic code controls the synthesis of proteins.

Early Life and Training . Robert Holley was one of the four sons of Charles and Viola Holley, both educators. He graduated from Urbana High School in 1938, studied chemistry at the University of Illinois, and received his BA degree in 1942. He studied for his PhD in organic chemistry at Cornell University with Professor Alfred T. Blomquist from 1942 to 1947. His graduate work was interrupted for two years during the war (1944–1946) when he participated with Professor Vincent du Vigneaud at Cornell University Medical College in the first chemical synthesis of penicillin. He married Ann Dworkin in 1945, and they had one son, Frederick.

After two years spent as an American Chemical Society Postdoctoral Fellow at Washington State University, he returned as assistant professor of organic chemistry to the Geneva Experiment Station of Cornell University. He was associate professor there from 1950 to 1957.

The work done during this period differed greatly from the subsequent work that would make Holley famous: characterization of the metabolic transformations of 2,4-dichlorophenoxyacetic acid in bean plants, and identification of the plant hormones, auxins, present in cabbage. From his work on penicillin, Holley established a correlation between the chemical reactivity of amides and their spatial structures, and from these observations he proposed in an article published in Science a general mechanism of action for enzymes that hydrolyze amides, such as proteases, a mechanism which is no longer tenable. This model was inspired by the model of enzymatic catalysis proposed some years before by Linus Pauling—the stabilization of the transition state of the reaction by the enzyme.

These early studies were not without influence on the future activities of Holley, even if they did not point to one particular line of research. They already demonstrate the attention paid by Holley to the contributions that organic chemists can make to biochemistry. Most of all, they familiarized him with the purification procedures that would be of a major importance for his future work—in particular, countercurrent distribution.

Sabbatical Year at Caltech . Holley discovered the world of RNA and protein synthesis during a sabbatical year spent studying with James F. Bonner at the California Institute of Technology. It was increasingly obvious at that time that the characterization of the mechanisms of protein synthesis would come from a full description of the components present in the in vitro protein synthesis systems that had been recently developed in various laboratories, in particular by the group of Paul Zamecnik at the Massachusetts General Hospital. The studies had shown that, before being incorporated into proteins, the amino acids were activated as amino acyl-adenylates by a family of enzymes. More recently, the group of Zamecnik and Mahlon Hoagland had made a puzzling observation: the next step was the attachment of amino acids to RNAs; not the RNAs present in the microsomes and considered for that reason as playing a major role in protein synthesis, but to a new family of small RNAs present in another of the subcellular fractions used for the in vitro synthesis system. Because they were present in a supernatant of ultra-centrifugation, these RNAs were named soluble RNAs. They were shown to be one hundred nucleotides long, but their precise role in protein synthesis remained unknown.

Holley reached the same conclusion by a different approach—the study of the sensitivity to RNAse, the enzyme which degrades RNAs, of the opposite reaction to that of activation of amino acids. At least as far as the amino acid alanine was concerned, soluble RNAs were involved in amino acid activation and incorporation into proteins.

A relation was progressively established between these soluble RNAs and the adapter nucleic acids, which Francis Crick had hypothesized three years before to make the link between the genetic information contained in the nucleic acids and the amino acids constituting the proteins. It pushed the soluble RNAs to the forefront of research. Their characterization increasingly appeared as a sort of Rosetta stone able to reveal the mechanisms of protein synthesis and, for those who were convinced of its existence, to allow the decipherment of the genetic code.

Purification of Alanine tRNA . When Holley returned to Cornell at the Plant, Soil and Nutrition Laboratory of the U.S. Department of Agriculture, he soon undertook the

purification and characterization of tRNA— t for transfer, the new name given to soluble RNA to make its function explicit.

The first step in this seven-year study, which occupied most of Holley’s time, was the purification of this tRNA from yeast. One hundred fifty kilograms of yeast were necessary to yield two hundred grams of mixed tRNAs and one gram of pure alanine tRNA. Two other tRNAs were purified in parallel, tyrosine tRNA and valine tRNA. The technique that proved essential for this purification was countercurrent distribution, a method based on the differential solubility of a molecule between two solvents, which had been designed at the Rockefeller Institute in the 1940s by Lyman C. Craig and David Craig, with whom Holley had worked, and which he had already used to purify auxins.

It was essential to prepare a pure alanine-tRNA fraction in order to proceed to the second part of the work, the sequencing of tRNA. Holley took a gamble on the purity of the fraction that he had obtained in devoting the next four years to this task. Fortunately for him, the gamble paid off.

To determine the sequence of the 77-nucleotide molecule, Holley used the same strategy as the one adopted by Fred Sanger for the protein insulin a few years before: to cut the molecule into different fragments by using enzymes acting at different places, and assemble the different fragments thus obtained, like a puzzle, from the overlapping of the fragments. The work on RNA was made more difficult by the fact that there are only four different nucleotides, compared with twenty amino acids, and this created a lot of ambiguities in the relative positioning of the different fragments. Another unexpected difficulty was the existence of bases with a modified structure and unusual properties, such as the lack of absorption of ultra-violet light, the structure of which had to be characterized. These modifications occur after the synthesis of the tRNA from DNA, at a posttranscriptional stage.

Holley used two different nucleases, pancreatic ribonuclease and takadiastase ribonuclease T1, recently characterized by a Japanese group, which cut at different positions in the sequence, and separated the fragments by chromatography on DEAE-cellulose, a recently designed ion-exchange chromatographic technique which Holley adapted to his purpose. It was not sufficient to determine the full sequence, and a lot of additional tricks had to be used to complete it: progressive degradation of the fragments by an exonuclease, snake venom phosphodiesterase, starting at one extremity of these fragments; a limited and preferential cutting of the tRNA molecule into two fragments obtained by working at low temperature; use of the different characteristics of the two extremities of the tRNA molecule and of the modified bases as markers of unique positions, and so forth.

With the help of “platoons” of graduate students, the full sequence was described in 1965. The position of the anticodon, the site of interaction, by base-pairing, with the messenger RNA, and a model for the secondary structure of the molecule were simultaneously proposed.

A Major Discovery . The value of this experimental achievement was immediately recognized. It was the result of intensive work headed by Holley, from his participation in the discovery of soluble RNA to the final characterization of its structure. The race was intense—a half-dozen structures of tRNA were determined in the next two years, and Holley had won it. The importance of the discovery was rapidly acknowledged: Tracy Sonneborn called it a “marvelous achievement” in Science; Maxine Singer described it as a “formidable job.” Named professor of biochemistry at Cornell University in 1962, Holley became a full professor of biochemistry and molecular biology in 1964 and chairman of the department from 1965 to 1966. He received the Albert Lasker Award in Basic Medical Research in 1965, a first step to the Nobel Prize in 1968, won in conjunction with Marshall Warren Nirenberg and Har Gobind Khorana. He was elected member of the National Academy of Sciences.

The importance of the work was multiple, and the perception of it evolved from its beginnings to its completion. As stated above, tRNAs were first considered as the Rosetta stone leading to the decipherment of the genetic code. But the genetic code was cracked by the use of artificial polynucleotides with a well-determined base composition and sequence from the initial observation made with polyU by Nirenberg. And the anticodon was identified in the tRNA from this previous knowledge. One cause of the degeneracy of the genetic code was explained by the wobble hypothesis proposed by Francis Crick, that is, the imperfect pairing of the third base of the codon with the corresponding one of the anticodon. This hypothesis was proposed from data collected by the use of synthetic polynucleotides, even though it was further supported by observations made on the sequences of tRNAs.

One important result obtained through the sequence of tRNA was the first sequence of a gene. The discovery of Holley was seen as a first step toward knowledge of the full genome. The discourses on what could be expected from this knowledge were not so different from those heard at the end of the twentieth century, when the human genome was sequenced. However, the perception of it as a first step was an illusion: the methodology used for this first study could not provide access to the regulatory sequences that control the expression of genes. In addition, the strategy adopted by Holley could not be easily extended to large RNAs such as messenger RNAs. The technologies for sequencing genes would be invented later, in the mid-1970s, and are of a different nature.

Some of the observations made as Holley’s work progressed—such as the abundance of modified bases— are somehow anecdotal: their physiological meaning is still dubious. The cloverleaf secondary structure proposed by Elizabeth Betty Keller and John Penswick and rapidly adopted by Holley was shown to be true for all tRNAs. It was unduly considered by some researchers as a three-dimensional structure until the characterization of crystallized tRNAs by x-ray diffraction studies done by the group of Aaron Klug showed that this was not the case.

This explains why Holley now occupies both an important and a circumscribed place in the historiography of molecular biology. Retrospectively, while the technological exploit is still worthy of acknowledgment, the consequences of this work for later developments in molecular biology are less important than was initially anticipated. Holley’s discovery was a milestone for his contemporaries, not for his followers.

Control of Cell Division and Cancer . In 1968, there were still many questions pending in the field of protein synthesis: the precise three-dimensional structure of tRNAs and ribosomes was ignored, and the different steps in protein synthesis were still fuzzy. Holley followed the same direction for some years, characterizing the structure of other tRNAs, using indirect chemical techniques to try to elucidate the three-dimensional structure of tRNAs, and turning his efforts to the enzymes involved in the modification of the tRNA bases. But he rapidly abandoned tRNAs, and devoted his efforts to the control of cell division in mammalian cells until the end of his academic career.

In 1966–1967, he spent two years at the recently created Salk Institute for Biological Studies as a National Foundation Postdoctoral Fellow. In 1968 he joined the permanent staff of the Salk Institute as a professor in molecular biology. He was also an adjunct professor at the University of California at San Diego.

Holley was not alone in his movement toward complex biological issues. Many of the founders and heroes of molecular biology made a similar move—Francis Crick, Seymour Benzer, and Gunther Stent toward the study of behavior and the brain, François Jacob and Sydney Brenner toward embryogenesis. Holley preferred to focus on the control of cell division in established mammalian cell lines, probably considering it the best system to characterize and isolate the factors involved in this control.

After some experiments on the extensively studied 3T3 cells, Holley focused his work on an epithelial cell line BSC-1, for the reason that most human cancers are of epithelial origin. He demonstrated that the cells secrete a growth inhibitor, the sequence of which he finally characterized in 1988 after more than ten years of effort.

These twenty years of research on the control of cell division and the characterization of growth inhibitors did not consist simply of data generation. A Nobel Prize winner cannot enter a new field of research without expressing new and general views that strongly oppose previous models. Such was Holley’s attitude. He never accepted the idea that cell division can be limited by “contact inhibition,” signals originating from the physical contact between adjacent cells. For Holley, contact inhibition was only a consequence of a reduced supply of nutrients, due to the fact that their diffusion was limited by the surrounding cells. In a similar way, he was initially reluctant to attribute a major role to growth factors in the control of cell division. In contrast, he emphasized the role of low molecular weight nutrients. In a review article published in 1975 in Nature, he admitted the role of polypeptide hormonelike materials, but once again emphasized the importance of the most common molecules, such as metabolites.

Holley was not interested in the internal, intracellular mechanisms controlling cell division. His only attempt in this direction was the characterization of membrane proteins controlling ion exchange. In 1972 he published in the Proceedings of the National Academy of Sciences a unifying hypothesis concerning the nature of malignant growth. He believed that the crucial alteration leading to malignancy was an alteration in the cell membrane that resulted in an increased internal concentration of nutrients. Over the following years, with the characterization of oncogenes and tumor suppressor genes, the emphasis in cancer research shifted to transformations occurring inside cells and affecting intracellular signaling pathways and gene regulation, and not to membranes as Holley had anticipated. Because of his well-established opinions on the control of cell division and the origin of tumors, Holley was at odds with mainstream research. This prevented him from making a major breakthrough in his new field of research.

BIBLIOGRAPHY

The Salk Institute has decided to create an archival center at the University of California, San Diego.

WORKS BY HOLLEY

With F. P. Boyle, H. K. Durfee, and A. D. Holley. “A Study of the Auxins in Cabbage Using Countercurrent Distribution.” Archives of Biochemistry and Biophysics 32 (1951): 192–199.

“Steric Inhibition of Amide Resonance and Its Possible Significance in Enzyme Action.” Science 117 (1953): 23–25.

“An Alanine-Dependent, Ribonuclease-Inhibited, Conversion of AMP to ATP, and Its Possible Relationship to Protein Synthesis.” Journal of the American Chemical Society 79 (1957): 658–662.

With Jack Goldstein. “An Alanine-Dependent, Ribonuclease-Inhibited Conversion of Adenosine 5'-Phosphate to Adenosine Triphosphate. II. Reconstruction of the System from Purified Components.” Journal of Biological Chemistry 234 (1959): 1765–1768.

With John Robert Penswick. “Specific Cleavage of the Yeast Alanine RNA into Two Large Fragments.” Proceedings of the National Academy of Sciences of the United States of America 53 (1965): 543–546.

With Jean Apgar, George A. Everett, James T. Madison, et al. “Structure of a Ribonucleic Acid.” Science 147 (1965): 1462–1465.

“The Nucleotide Sequence of a Nucleic Acid.” Scientific American 214 (February 1966): 30–39.

“Alanine Transfer RNA.” Nobel Lecture, 12 December 1968. Available from http://nobelprize.org/nobel_prizes/medicine/laureates/1968/holley-lecture.html.

With Josephine A. Kiernan. “‘Contact Inhibition’ of Cell Division in 3T3 Cells.” Proceedings of the National Academy of Sciences of the United States of America 60 (1968): 300–304.

“A Unifying Hypothesis concerning the Nature of Malignant Growth.” Proceedings of the National Academy of Sciences of the United States of America 69 (1972): 2840–2841.

“Control of Growth of Mammalian Cells in Cell Culture.” Nature 258 (1975): 487–490.

With Rosemary Armour, Julia H. Baldwin, et al. “Density-Dependent Regulation of Growth of BSC-1 Cells in Cell Culture: Control of Growth by Serum Factors.” Proceedings of the National Academy of Sciences of the United States of America 74 (1977): 5046–5050.

With Peter Böhlen, Roy Fava, Julia H. Baldwin, et al. “Purification of Kidney Epithelial Cell Growth Inhibitors.” Proceedings of the National Academy of Sciences of the United States of America 77 (1980): 5989–5992.

With Ronald F. Tucker, Gary D. Shipley, and Harold L. Moses. “Growth Inhibitor from BSC-1 Cells Closely Related to Platelet Type Beta Transforming Growth Factor.” Science 226 (1984): 705–707.

With Steven K. Hanks, Rosemary Armour, Julia H. Baldwin, et al. “Amino Acid Sequence of the BSC-1 Cell Growth Inhibitor (Polyergin) Deduced from the Nucleotide Sequence of the cDNA.” Proceedings of the National Academy of Sciences of the United States of Amerca 85 (1988): 79–82.

OTHER SOURCES

Crick, Francis. “Codon-Anticodon Pairing: The Wobble Hypothesis.” Journal of Molecular Biology 19 (1966): 548–555.

Hoagland, Mahlon. Toward the Habit of Truth: A Life in Science. New York: Norton, 1990.

Judson, Horace Freeland. The Eighth Day of Creation: Makers of the Revolution in Biology. Plainview, NY: Cold Spring Harbor Laboratory Press, 1996.

Kay, Lily E. Who Wrote the Book of Life?: A History of the Genetic Code. Stanford, CA: Stanford University Press, 2000. The most complete historical work on the way that led to the “cracking” of the genetic code.

Portugal, Franklin H., and Jack S. Cohen. A Century of DNA: A History of the Discovery of the Structure and Function of the Genetic Substance. Cambridge, MA: MIT Press, 1977.

Rheinberger, Hans-Jörg. Toward a History of Epistemic Things: Synthesizing Proteins in the Test Tube. Stanford, CA: Stanford University Press, 1997.

“Robert W. Holley: The Nobel Prize in Physiology or Medicine 1968.” Available from http://nobelprize.org/nobel_prizes/medicine/laureates/1968/holley-bio.html.

Singer, Maxine F. “1968 Nobel Laureate in Medicine or Physiology.” Science 162 (1968): 433–436.

Sonneborn, Tracy M. “Nucleotide Sequence of a Gene: First Complete Specification.” Science 148 (1965): 1410.

Michel Morange

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Holley, Robert William

Robert William Holley, 1922–93, American biochemist, b. Urbana, Ill., Ph.D. Cornell, 1947. He was a professor at Cornell (1948–68) before he joined (1968) the Salk Institute, and he continued an association with Cornell after 1968. Holley received the 1968 Nobel Prize in physiology or medicine jointly with Har Gobind Khorana and Marshall W. Nirenberg for their interpretation of the genetic code and its function in protein synthesis. Holley is credited with isolating transfer RNA (tRNA) and then determining the sequence and structure of alanine tRNA, which incorporates the amino acid alanine into proteins. Knowledge of the structure of tRNA was key to explaining how proteins are synthesized from messenger RNA.

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Holley, Robert William

Holley, Robert William

(b. 28 January 1922 in Urbana, Illinois; d. 11 February 1993 in Los Gatos, California), biologist, biochemist, and Nobel laureate in physiology or medicine (1968) for his research into the genetic code and its function in protein synthesis.

Holley was one of four sons of Charles Holley and Viola Wolfe, who were both educators. He attended public schools in Illinois, California, and Idaho and graduated from Urbana High School in 1938. He studied chemistry at the University of Illinois and received his B.A. degree in 1942. His graduate work at Cornell University led to a Ph.D. in organic chemistry in 1947. A few years earlier he participated in the first chemical synthesis of penicillin. Various appointments eventually led to a professorship of biochemistry and molecular biology in 1964 at Cornell. It was then on to the Salk Institute for Biological Studies in La Jolla, California, as a resident fellow from 1966 to 1993 and the American Society Professor of Molecular Biology.

Because of Holley’s biochemical training and his basic interest in living things, one could have anticipated further painstaking research into the molecular structure of the cell. Work on amino acids and peptides led to the biosynthesis of proteins. Thus the alanine transfer ribonucleic acid (tRNA) was discovered. There followed a period of a few years that were spent working with RNA, first concentrating on the isolation of RNA, and then working on the determination of the structure of RNA. The nucleotide sequence was completed at the end of 1964. His classic paper on the subject, “Sequences in yeast alanine transfer ribonucleic acid,” appeared in the Journal of Biological Chemistry in 1965. Because of this achievement Holley was awarded the Nobel Prize in physiology or medicine in 1968.

The process by which every individual—black, white, blonde, brunette, dull, or smart—acquires countless inherited characteristics depends on a complex chemical code— the genetic code stored in the cell’s DNA, which dictates the synthesis of proteins. Many of these proteins are enzymes that control the biochemical reactions that regulate inherited characteristics (including eye color, skin color, and intelligence) that make every individual different. Our genes (DNA) form messenger RNA, which in turn forms proteins. Proteins are then used as building blocks. Holley was largely responsible for deciphering the genetic code.

At the Nobel presentation ceremony, Professor Peter Reichard, a member of the Nobel Committee for Physiology or Medicine of the Royal Caroline Institute, remarked on that year’s prize for medicine, which was shared by Dr. Robert Holley, Dr. Har Khorana, and Dr. Marshall Nirenberg. In the past, no connection between genes and nucleic acid could be seen. Previously, nucleic acid research was considered dull, exclusive, and of interest to only a few scientists. But nucleic acid research came of age in 1944 with the American scientist Oswald T. Avery transferring a hereditary property from one bacterium to another with the aid of pure nucleic acid, signifying that genes are made up of nucleic acids. Avery’s discovery launched the new science of molecular biology. To emphasize the importance of this new area, Professor Reichard stated that the 1968 prize to Holley and his corecipients was the fifth prize in medicine since 1958 to be awarded to molecular biologists.

What is the mechanism for the translation of the code within the cell? This question was successfully challenged by Holley, who was one of the discoverers of a special type of nucleic acid that was called transfer-RNA. This nucleic acid has the capacity to read off the genetic code and to transform it to the protein alphabet. In 1965 Holley wrote its chemical structure. His work represented the first determination of the complete chemical structure of a biologically active nucleic acid. This was an awesome piece of research and from this was built piece by piece the puzzle of what is now the human genome. Humans could finally begin to understand the causes of numerous diseases and possibly treat them.

Holley married Ann Dworkin, a mathematics teacher, on 3 March 1945. They had one son. The family enjoyed the outdoors, especially the mountains and the ocean. Holley died of lung cancer in 1993 at the age of seventy-one.

At the end of his Nobel lecture in 1958 Edward Tatum mused that in some of the future developments in molecular biology there would be a solution of the genetic code, and that it would occur in the lifetime of some of his audience. Little did he realize that this was to be achieved less than three years before the first letters of the code were deciphered. Because of Holley and his co—Nobel recipients, the nature of the code and much of its function in protein synthesis were known within less than eight years. At that moment, they had written the most exciting chapter in modern biology.

The Robert Holley Papers, covering the years from 1942 to 1989, are kept in the Division of Rare and Manuscript Collections, Cornell University Library. See also entries in Current Biography Yearbook (1967) and in several editions of standard bibliographical works, including American Men and Women of Science and Who’s Who. Obituaries are in the New York Times (14 Feb. 1993) and The Scientist 7, no. 6 (22 Mar. 1993).

John E. Fisher

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Holley, Robert William

HOLLEY, Robert William

(b. 28 January 1922 in Urbana, Illinois; d. 11 February 1993 in Los Gatos, California), biochemist who in 1965 completed the sequencing of the first transfer RNA molecule and in 1968 was a co-winner of the Nobel Prize in physiology or medicine.

Holley was one of four sons born to Charles Elmer and Viola Esther (Wolfe) Holley. Both of his parents were teachers. In 1942 Holley received a B.A. in chemistry from the University of Illinois in Urbana. Five years later he earned a Ph.D. in organic chemistry from Cornell University in Ithaca, New York. During World War II, Holley participated as a civilian in war research conducted at the United States Office of Research and Development. Between 1944 and 1946 he was part of the research team at Cornell that was the first to produce synthetic penicillin. Holley married Ann Lenore Dworkin, a math teacher, on 3 March 1945; they had one son.

In 1948, after a year of postdoctoral work at Washington State College (later Washington State University) in Pullman, Holley returned to Cornell and became an assistant professor at the New York State Agricultural Experiment Station in Geneva. From 1950 to 1957 Holley was an associate professor at the same facility. In 1955 he took a sabbatical as a Guggenheim Memorial Fellow at the California Institute of Technology in Pasadena. While there, Holley began studying protein synthesis and became interested in how the information in nucleic acids is translated into proteins.

The scientific community's interest in nucleic acids intensified in the 1950s following Alfred Hershey's 1952 experiment confirming deoxyribonucleic acid (DNA) as the hereditary material. The following year, James Watson and Francis Crick solved the mystery of the DNA molecule's structure, and the era of genetics truly began. At the end of his sabbatical, Holley began researching receptors for amino acids, the building blocks of proteins. He discovered that the amino acid alanine binds to what at the time was known as low-molecular-weight soluble ribonucleic acid (RNA). This molecule was later called transfer RNA (tRNA).

Intrigued by this discovery, Holley continued his research upon his return to Cornell in 1957; at that time he worked for the U.S. Plant, Soil, and Nutrition Laboratory, a U.S. Department of Agriculture laboratory at Cornell. The first challenge for Holley and his colleagues was to try to isolate pure tRNA that was amino acid specific. Proteins are a combination of any of twenty amino acids, and there are twenty different tRNA molecules, each specific to one of these amino acids. Holley used yeast RNA, because it was easy to obtain in large quantities. Four years after they started, Holley and his colleagues were satisfied that they had a method good enough to isolate individual tRNAs for alanine, tyrosine, and valine. Of these, the alanine tRNA was the purest, and the decision was made to use it for structural analysis. Interestingly, with so little knowledge of the molecule, Holley and his team could not be sure that the material was indeed as pure as they thought. In his 1968 Nobel lecture, Holley recounted, "There seemed no alternative but to gamble a few years of work on the problem hoping that the material was sufficiently pure for structural analysis." Fortunately, Holley's gamble paid off.

Since both molecular biology and genetics were in their infancy in the early 1960s, Holley's task was momentous. The technique he perfected in his lab for obtaining pure alanine tRNA gave very low yields of the material. Over the next three years, Holley and his team used 140 kilograms (308.65 pounds) of commercial baker's yeast to obtain 1 gram (0.0035 ounce) of pure alanine tRNA. The experiments they carried out to sequence the molecule were described by Holley as being "equivalent to breaking a sentence into words, identifying the words, and reconstructing the sequence of the letters in the sentence by determining the order of the words." By the end of 1964 Holley's team had completed the sequencing of alanine tRNA, having dedicated roughly nine years to this project from start to finish. Through the sequencing analysis, Holley also was able to show how alanine attached to its tRNA molecule.

After the confirmation that DNA was the hereditary material, scientists struggled to understand how the information coded in DNA was translated into proteins—the complex molecules that make up all living things and differentiate between various living organisms. Crick suggested that "adaptor molecules" were responsible for translating DNA into proteins. In 1961 Sydney Brenner, François Jacob, and Matthew Meselson discovered that messenger RNA (mRNA) is the molecule that takes DNA's code outside the cell nucleus into the cytoplasm, where protein synthesis can occur.

Holley's discovery of tRNA's specificity and its sequence was the next step in a rapid deciphering of the genetics of protein synthesis. Holley's colleague Elizabeth Keller used the sequence to figure out the cloverleaf structure of tRNA, a model she sent to Holley in a Christmas card, according to Cornell legend. For this contribution to his efforts Holley shared his Nobel Prize money with her. By 1968, when Holley received his Nobel Prize in physiology or medicine with Marshall Warren Nirenberg, and Har Gobind Khorana, the genetic code had been deciphered completely. Scientists knew which amino acids were coded by which three-base combination on the DNA molecule. They knew how the DNA was translated to RNA and how RNA facilitated the assembly of proteins. Holley's contribution was a large piece of that puzzle, made all the more impressive because he tackled the problem from scratch, creating the tools for his discovery as he went along.

In 1966 Holley spent another sabbatical in California, this time at the Salk Institute for Biological Studies and the Scripps Clinic and Research Foundation in La Jolla. While there, he moved on to the next phase of his career and began looking into mechanisms that control cell growth and division. Holley sequenced several compounds that controlled or inhibited cell growth. His work provided insights that proved useful in the understanding of cancer, and pharmaceutical companies were able to use his results to create better cancer treatments. In 1968 Holley joined the Salk Institute as a resident fellow, also becoming an adjunct professor at the University of California, San Diego. He remained at the Salk Institute until his death in 1993. Holley was the recipient of many awards, including the prestigious Albert Lasker Award in basic medical research, which he won in 1965. He died of lung cancer at his home in Los Gatos.

The 1960s saw an explosion of knowledge and discovery in genetics. In an amazingly short time scientists moved to learning not only how the DNA code was translated into actual proteins but also how to read the code. Holley's discovery was a huge contribution to our ever increasing knowledge of genetics in the 1960s. That alone would have been enough, but not satisfied, Holley moved on (in the late 1960s) to studying cell growth and increased our understanding and knowledge in the area of cancer medicine and pharmacology. In both areas Holley's influence extended from the 1960s to the present day.

Biographical essays on Holley are in Encyclopedia Britannica (1997) and Notable Scientists: From 1900 to the Present (2001). Obituaries are in the New York Times (14 Feb. 1993) and the Times (London) (16 Feb. 1993).

Adi R. Ferrara

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