The 2008 Genetics Society of America Medal: Susan Lindquist
Hopkins, Nancy, Genetics
THE 2008 recipient of the Genetics Society of America Medal is Susan Lindquist. Lindquist has completely transformed our understanding of the role of protein folding in biological systems. Her work has employed, and to great effect, a zoo of powerful genetic systems, including yeast, fruit flies, Arabidopsis, and mice. She is also a fearless biochemist, employing state of the art technologies and inventing new ones. Again and again, she has shown the power of biochemistry to expand and explicate fundamental insights gained from genetic analysis and the power of genetics to disentangle intractable problems in biochemistry. Her work has provided paradigm-shifting insights into the most basic aspects of cell biology, genetics, and evolution.
HEAT-SHOCK RESPONSE, HEAT-SHOCK PROTEINS, AND STRESS TOLERANCE
Lindquist's work began with studies of the heat-shock response when she was a graduate student at Harvard in Matthew Meselson's lab. (At that time she published under the name Susan McKenzie.) As a second-year student, she was casting about for a new project when she bumped into a new assistant professor in the hallway of the biology labs. Sally Elgin told her of some exciting new work by Tissiers and Mitchell: that proteins were made in response to heat shock in the salivary glands of fruit flies. Lindquist decided to see if tissue culture cells had the same response, which would make it tractable to molecular analysis and provide a powerful wedge to explore the then murky waters of eukaryotic gene regulation (McKenzie et al. 1975; McKenzie and Meselson 1977). She discovered that these cells did have the response and that it was governed by both translational and transcriptional mechanisms, making it the strongest most global change in eukaryotic gene expression known (McKenzie et al. 1975;McKenzie andMeselson 1977; Lindquist 1980, 1981). She also discovered that eukaryotic cells have the unexpected capacity to discriminate between coexisting mRNAs and independently regulate their translation. During heat shock they translate heat-shock mRNAs with high efficiency and block normal mRNAs from translation, yet hold them ready for reactivation after heat shock (McKenzie et al. 1975; Lindquist 1980, 1981; DiDomenico et al. 1982).
In a seminal series of experiments Lindquist continued to exploit the heat-shock response to establish how intricate and highly orchestrated the regulation of eukaryotic gene expression can be. Her work revealed regulation operating at the level of RNA splicing (Yost and Lindquist 1986, 1988, 1991), selective RNA and protein transport in and out of the nucleus (Velazquez et al. 1980; Wang and Lindquist 1998), selective RNA degradation (Petersen and Lindquist 1988, 1989), and selective deadenylation (Dellavalle et al. 1994).
Her group also established that it is the heat-shock proteins themselves that turn these mechanisms off, at every level (Yost and Lindquist 1986, 1991; Dellavalle et al. 1994; Vogel et al. 1995). As it became clear that heat-shock proteins help to prevent and repair the damage caused by stress (a story to which Lindquist also made important contributions), the extremely elegant logic of the regulatory circuitry was revealed: as heat-shock proteins (Hsps) restore normal protein homeostasis they reset the damaged regulatory systems that prevent the transcription, translation, splicing, degradation, and deadenylation of normal mRNAs. By restoring regulatory systems to their normal state, Hsps remove their own advantage, turning off the response. Due in large measure to her work (complimented by the seminal work of Spradling, Pelham, Lis, and Wu on transcription), the heat-shock response provides perhaps the most beautiful and complete example of eukaryotic gene regulation documented.
Turning her attention to the function of the induced proteins, in collaboration with Didier Picard in Keith Yamamoto's group, Lindquist established that Hsp90 is required for the maturation of steroid hormone receptors and oncogenic tyrosine kinases (Picard et al. …