The 2000 Genetics Society of America Medal Jack W. Szostak

JACK W. SZOSTAK was awarded the 2000 Genetics Society of America Medal in recognition of his fundamental contributions to the understanding and uses of genetic recombination, to the field of artificial chromosomes, and to the creation of in vitro genetics. Jack Szostak is one of the world's most original, path-breaking geneticists. He was the codiscoverer of double-strand breakage as an initiating event in recombination, was the codiscoverer with Elizabeth Blackburn of the portable nature and functional activity of telomeres, created the first artificial linear chromosomes, and more recently has become a leader in the field of directed evolution of biopolymers. Jack was born in 1952, in London, England. He received his B.S. degree at McGill University of Montreal in 1972, and a Ph.D. degree at Cornell University (Ithaca, NY), in the laboratory of Professor Ray Wu. In 1979, he became an assistant professor at the Dana Farber Cancer Institute and the Department of Biological Chemistry of Harvard Medical School in Boston. Over the next two decades Jack stayed at Harvard, becoming professor of genetics in 1988, Investigator of the Howard Hughes Medical Institute, and more recently the Alex Rich Distinguished Investigator at the Department of Molecular Biology, Massachusetts General Hospital. In 1981, Szostak and Rodney Rothstein made the discovery that a free end of a double-stranded DNA molecule is highly recombinogenic in yeast transformation experiments. Subsequent characterization, in Szostak's lab, of recombination events stimulated by a double-strand break revealed that they shared almost all properties of meiotic recombination events. Szostak and colleagues made an insightful proposal, controversial at the time, that double-strand breaks could be the initiating event in normal meiotic recombination. Szostak went on to provide strong support for this conjecture, showing that double-strand breaks do occur at the time and place of initiation of meiotic recombination and that genetic defects that block the appearance of double-strand breaks also block the initiation of recombination. Detailed genetic analysis by Szostak and co-workers of meiotic recombination events at the ARG4 locus extended the classical work of Fogel and showed that meiotic recombination followed the bidirectional gradient expected from double-strand break initiation, with the peak of the gradient corresponding to the location of the observed double-strand breaks; deletion of the presumed initiation site also showed the predicted disparity of recombination. Although the double-strand break repair model remained controversial for a number of years, subsequent work by the Szostak, Kleckner, Nicolas, and other laboratories has abundantly confirmed the role of double-strand breaks as the initiating lesions in the normal meiotic pathway of Saccharomyces cerevisiae. Yet another, and major, consequence of this advance was the method for single-step gene replacement using linearized DNA molecules. This method, stemming from Szostak's and Rothstein's original insight, ushered in a revolution in targeted mutagenesis that has allowed gene knockouts to be done on a genomic scale in yeast. Through the work of Capecchi and Smithies, this approach has also become the central technique of mouse genetics. In 1982, Szostak collaborated with Elizabeth Blackburn to show that Tetrahymena telomeres could be attached to the ends of linearized yeast plasmids to yield linear plasmids, which in turn served as vectors for the cloning of yeast and other eukaryotic telomeres. Analysis of telomere modification reactions in yeast led to the prediction by Szostak and Blackburn of the telomerase enzyme activity. This early work on telomeres also led Szostak to the first creation of artificial linear chromosomes. He and his student Andrew Murray achieved this by combining all of the then-known chromosomal elements (telomeres, centromeres, and replication origins). Further work by Szostak identified total length as another critical determinant of chromosome stability, allowing him to produce the first yeast artificial chromosomes (YACs). This advance has transformed the approaches to dissection of the human and other large genomes and continues to play a major role in the technology that enables the current Genome Projects. In the mid-1980s, Szostak became interested in the new field of catalytic RNA. His early studies of the Tetrahymena self-splicing intron focused on combining phylogenetic and genetic tools for the analysis of ribozyme structure and function. These studies led to the first evidence bearing on the physical location of the guanosine substrate binding site on the ribozyme and for the existence of several other tertiary nucleotide interactions. Despite the success of these studies, it became clear to Szostak that classical genetic analysis was not powerful enough in this setting. He began to search for new genetic tools that could provide a less biased and wider sampling of sequence space. This led to the in vitro selection technique, which was immediately applied in the Szostak lab as a genetic tool for the analysis of RNA structure, both for ribozymes and for the HIV Rev binding site structure. The power of this approach was most conclusively demonstrated by selecting for novel functional RNAs from large samples of completely random RNA sequences. An essentially identical method, referred to as SELEX, was developed independently by Tuerk and Gold, and the laboratory of Gerald Joyce also developed similar technology, referred to as directed evolution. In vitro selection has been the basis for much of the Szostak laboratory's work on the directed evolution of RNA in the 1990s. As before, he brought to this field his originality and systematic rigor, a rare combination of gifts that is characteristic of Szostak and underlies all of his major successes. Szostak and co-workers have selected RNA aptamers that bind specifically and tightly to many biologically important small molecules, including ATP and several cofactors. Over the last several years, this work has been extended by a number of other laboratories. These critical experiments by Szostak and co-workers provided direct genetic evidence that RNA can form structures that contain binding sites for essentially any small molecule, a remarkable and, for many, unexpected conclusion. Szostak then explored the possibility of evolving new types of catalytic RNA molecules. In a landmark paper, Bartel and Szostak isolated large numbers of new ribozymes directly from random sequences, showing that catalytic RNA sequences were far more common than previously thought. Subsequent selection experiments by the Szostak lab have shown that many different catalytic activities can be isolated this way, including kinases, alkylating ribozymes, and acyl transferases. These experiments extended the range of known ribozyme activities far beyond those found in nature and have provided considerable support for the RNA World hypothesis, by showing that RNA-based organisms could indeed have maintained a chemically diverse metabolism, including the core reactions of protein synthesis. Recently, Szostak has pioneered a new approach to the directed evolution of peptides and proteins. This method, developed by Richard Roberts and Szostak, subverts the normal cellular translation apparatus, with the remarkable result that a newly translated protein becomes covalently attached to its own mRNA. Selection for a particular function can thus be applied to the protein, while the linked RNA allows for the amplification of the protein-coding genetic information. This approach has great promise as a tool for the study of protein evolution, folding, and function. Over the last two decades, Szostak made several exceptionally important contributions to genetics, including molecular genetics. His discoveries and inventions in the fields of recombination, telomeres, and chromosome structure have opened up new areas of research. One of his major contributions is the development of in vitro selection. Since this selection operates directly on molecules instead of organisms, it is a true hybrid of genetics and biochemistry. In vitro selection is particularly well suited for the exploration of sequence space, because it allows the sampling of huge numbers of sequences (>1015). Jack Szostak is one of the most original thinkers in genetics today. His name will grace the roster of GSA Medal awardees.

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