Susan L. Lindquist

Susan L. Lindquist (born June 5, 1949, Chicago, Illinois, U.S.—died October 27, 2016, Cambridge, Massachusetts) was an American molecular biologist who made key discoveries concerning protein folding and who was among the first to discover that in yeast, inherited traits can be passed to offspring via misfolded proteins known as prions.

Lindquist received a bachelor’s degree (1971) in microbiology from the University of Illinois at Urbana-Champaign and a doctorate (1976) in biology from Harvard University. She then became a postdoctoral researcher at the University of Chicago, where she later joined the faculty (1978) of the department of molecular genetics and cell biology. She remained there until 2001, when she became a professor in the department of biology at the Massachusetts Institute of Technology (MIT). From 2001 to 2004, she served as director of the MIT-affiliated Whitehead Institute for Biomedical Research.

While working as a graduate student at Harvard in the laboratory of American molecular biologist Matthew Stanley Meselson, Lindquist learned of heat-shock proteins—proteins synthesized rapidly and in large quantities following cellular exposure to sudden increases in temperature. Throughout the 1980s and ’90s, Lindquist explored heat-shock proteins in various model organisms, including the fruit fly Drosophila melanogaster, the yeast Saccharomyces cerevisiae, and the flowering plant Arabidopsis thaliana. Her studies revealed that heat-shock proteins directly regulate RNA splicing (the removal of introns from messenger RNA), RNA transport across the nuclear membrane, and RNA degradation in order to prevent new RNA transcripts from being processed while the cell is under stress. Lindquist and colleagues concluded that those activities reset the cell’s damaged regulatory systems and thereby restore protein homeostatis following stress. Once the cell resets, the heat-shock response is turned off. Lindquist’s characterization of that process was groundbreaking, providing scientists with what was then the most complete example of gene regulation for eukaryotic cells (cells possessing a clearly defined nucleus).

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In the mid-1990s, Lindquist’s research on heat-shock proteins led her to several major discoveries about prions that shed light on nongenetic mechanisms of inheritance and evolution. In 1995, for example, she and colleagues reported that a heat-shock protein known as Hsp104 was required for the production of a yeast protein called [PSI+], which was thought to be prionlike. The following year, she published evidence indicating that [PSI+] was in fact a prionlike aggregate of a conformationally altered cellular protein, that it was cytoplasmically inherited in yeast, and that it modified and triggered the aggregation of newly formed proteins of the same kind. She also found that yeast prions do not cause disease in their host, are inherited without changes in genotype (genetic constitution), and expose hidden genetic variation, giving rise to new phenotypes (observable traits) that enable yeast to adapt and evolve in response to environmental change. Lindquist subsequently applied that knowledge to investigations of the cellular mechanisms driving cancer progression, since cancer cells are also able to adapt and mutate rapidly in response to environmental factors.

Lindquist later investigated prions and prionlike proteins found in the mammalian brain. Working with Austrian-born American neurobiologist and Nobelist Eric Kandel, she discovered a neuronal protein that could be converted naturally to a prionlike state and hypothesized that the prion form maintained changes at synapses (neuronal junctions) required for memory storage. She also studied a protein known as amyloid to determine its role in memory and inheritance. That work led to her discovery of a yeast protein capable of breaking down amyloid—a discovery that opened up new avenues of research into the development of treatments for neurodegenerative conditions such as Alzheimer disease and Parkinson disease, which are associated with the formation of abnormal amyloid aggregates.

Lindquist was a Howard Hughes Medical Institute investigator and was elected to membership in multiple organizations, including the American Academy of Arts and Sciences (1996) and the National Academy of Sciences (1997). She also received a number of awards, including the National Medal of Science (2009), the Max Delbrück Medal (2010), and the Mendel Medal (2010).