Cell Biology, Genetics
Whitehead Institute for Biomedical Research
Dr. Lindquist is a member (and former director) of the Whitehead Institute for Biomedical Research, a professor of biology at the Massachusetts Institute of Technology, an associate member of the Broad Institute of MIT and Harvard, and an associate member of the David H. Koch Institute for Integrative Cancer Research at MIT. She was an HHMI investigator from 1988 to 2001 at the University of Chicago.
The Surprising World of Protein Folding
Susan Lindquist’s pioneering work has demonstrated that alternative protein conformations can have profound and unexpected effects in diverse fields, ranging from human disease, to evolution, to biomaterials.
Prion proteins exhibit an unusual ability to exist in self-perpetuating structural states with altered functions. Lindquist’s work on yeast prions has provided evidence for a mechanism of protein-only inheritance and contributed to a structural understanding of amyloid fiber formation. She has shown that prions function not only as disease agents but also as protein-based mechanisms of inheritance, cellular memory, and cross-kingdom communication, and has unlocked the mechanism by which these proteins operate.
Using multiple genetic models, cell biology, and biochemistry, Lindquist has shown that stress-induced chaperone proteins can influence the expression and evolution of new traits by assisting with the folding of key molecules in signal transduction pathways. For example, the heat-shock response, one of the most ancient and highly conserved homeostatic mechanisms known, enhances cell survival under stressful conditions, regulates a multitude of growth responses, and modulates the degenerative changes associated with aging. However, activation of the heat-shock response is a double-edged sword when it comes to deadly disease: The same responses that can prevent the protein aggregation associated with degenerative diseases of aging also put tissues at risk for cancer by enabling tumor cells to evolve invasive, drug-resistant phenotypes.
Lindquist’s group has also developed yeast models to screen for protein modifications that can reverse toxicity in neurodegenerative diseases like Parkinson’s and Huntington’s. By combining these discovery platforms with state-of-the art chemical genetics screens, Lindquist’s team has identified compounds with high therapeutic potential, and also gained insight into the mechanism of action of these compounds.
Grants from the National Institutes of Health, the JPB Foundation, the G. Harold and Leila Y. Mathers Foundation, the Eleanor Schwartz Charitable Foundation and the Edward N. and Della L. Thome Memorial Foundation provided partial support for these projects.
As a graduate student in the 1970s, Susan Lindquist began investigating a stress-evoked flurry of cellular activity called the heat-shock response, hoping to learn how certain genes were switched on to ramp up protein production.
She soon learned that a cell’s response to stress involves more than just a boost in gene activity. Studying events set off in cells exposed to elevated temperatures led Lindquist to fundamental discoveries about how proteins fold into their proper, functional shapes, and what happens when that process fails. It also launched a research program that has gone on to probe the origins of cancer, neurodegenerative disease, and evolution.
When she started her own lab at the University of Chicago, in 1978, Lindquist began studying stress-induced proteins. A few years later she broadened her research to include yeast, a newly powerful genetic tool, as well as fruit flies. This was a bold move, but Lindquist was more interested in following her curiosity than vying for tenure. She used the cells as living test tubes to demonstrate that a molecular chaperone called Hsp90 helps other proteins fold into their correct shapes and breaks up clumps of misfolded proteins that may have formed.
Those discoveries opened lines of research that Lindquist never anticipated. One was the surprise link she found between misfolded proteins and the evolution of new traits. Her team discovered that Hsp90 can become overwhelmed during times of stress, allowing misfolded proteins with abnormal functions to slip through. The consequences can lead to beneficial mutations, but Lindquist has also linked Hsp90 to the emergence of drug resistance and the malignant transformation of cancer cells. “It ties environmental change to the manifestation of all kinds of new phenotypes,” she explains.
Lindquist’s work branched in another direction when she discovered that Hsp104 cuts misfolded proteins into bits that can be passed on to daughter cells, where they provoke healthy proteins to change shape. The finding explained how self-replicating, shape-changing proteins known as prions can be responsible for inheritance of certain traits and diseases. Her team’s work has illuminated mechanisms of prion assembly and how prions, too, can be drivers of evolutionary change.
Shortly before leaving the University of Chicago for MIT, Lindquist began studying neurodegenerative diseases more deliberately, motivated by a close family friend’s diagnosis of Huntington’s disease. The disease involves the accumulation of misfolded proteins inside neurons, and Lindquist hoped she could make headway into understanding that process. Her team has used yeast to learn about proteins implicated in Huntington’s and Parkinson’s diseases, as well as to screen for genes or chemicals that reverse effects of the diseases. “People thought I was crazy to try to study neurodegenerative disease in yeast, but we’ve proven that you can find out some very interesting things this way,” she says.
Lindquist continues to actively investigate the role of protein folding in evolution and human disease, complementing her yeast research with experiments in other animals and in human patient-derived neurons. “The protein-folding business was originally very basic, and no one knew much about it,” she says. “But it turns out to ramify in many different ways.”