COMMENT OBITUARY Susan Lee Lindquist (1949–2016) Biologist who found unexpected power in folding.

usan Lee Lindquist revealed the human neurodegenerative disease . profound ramifications of a process As in the brain, these proteins formed that most scientists had overlooked: aggregates and were toxic in . She iden- Sprotein folding. Through elegant experi- tified yeast genes that reduced the toxicity ments in yeast, plants, flies and human of protein misfolding connected to Parkin- CEAL CAPISTRANO cells, Lindquist demonstrated how this pro- son’s disease and established that these same cess by which proteins adopt their proper genes are protective in mice and rats. shapes fuels evolution. It can buffer the She co-founded two Cambridge compa- effects of genetic variation, allow new traits nies, FoldRx Pharmaceuticals (acquired by to emerge and enable the rapid evolution of Pfizer in 2010) and Yumanity Therapeutics new adaptations. Her insights have paved to uncover therapies for neurodegenera- the way for innovative strategies to treat tive diseases caused by protein misfolding. diseases including Alzheimer’s, Parkinson’s Her use of yeast in drug screening is now and cancer. accepted practice. Lindquist was a visionary who connected Researchers from diverse backgrounds — concepts across disparate disciplines. When from physicists to physicians — wanted to her bold ideas were met with doubt, she work in Lindquist’s lab. Both of us pursued persevered, gathering evidence until she postdocs at the Whitehead after being changed biological thinking. Her positiv- inspired by seminars she gave at our gradu- ity and love for discovery were infectious. ate institutions. One of us (J.S.) moved from Lindquist, who died from cancer on the United Kingdom to the United States 27 October, was born in , Illinois, and the other (A.D.G.) shifted discipline to in 1949. Early on, she became enthralled by can allow that would otherwise work with her. a teacher’s question: what is life? In search result in an unstable protein to produce a Sue believed that scientists had a moral of answers, she studied microbiology at the functioning protein with a new . obligation to address important societal University of Illinois Urbana–Champaign. Both roles expand the repertoire of traits problems. In her papers, she used language She earned her PhD in molecular and that can be selected through evolution. that was accessible to wide audiences. She cellular biology from Lindquist demonstrated that these powerful was a nurturing mentor, inviting group in Cambridge, Massachusetts, in 1976. mechanisms are probably universal across members to her house on weekends to write It was at Harvard that she began studying eukaryotes. manuscripts. We were fortunate to get to how cells respond to heat and other stresses Lindquist also shattered dogma about know her in this personal setting, interact- by producing heat-shock proteins (Hsps). misfolded proteins associated with disease. ing with her wonderful daughters and hus- After a brief postdoc at the University of She discovered that Hsp104 could wrest band, and learning that it was possible to Chicago, she joined the faculty there in 1978 clumps of misfolded proteins apart and be a world-class scientist and have a family. and became a full professor in 1988. In 2001, return them to their functional form. This Her unwavering commitment to promot- she moved to the for finding led her to study . These infec- ing women in science is memorialized by Biomedical Research at the Massachusetts tious proteins cause normally folded proteins the Whitehead Institute Fund to Encourage Institute of Technology in Cambridge. She to assume self-replicating conformations that Women in Science. served as its director until 2004, and as a pro- cause fatal neurodegenerative disorders such Somehow, Sue found time in her unre- fessor of biology from 2001 until her death. as Creutzfeldt–Jakob disease and scrapie. lenting schedule to sit on the grass and Lindquist focused on . This abun- She was fond of saying that prions watch her students and postdocs play dant protein acts as a molecular chaperone, transmit perduring molecular memories. soccer on Friday afternoons in Cambridge helping to fold many proteins important for At a time when prions were deemed merely — always there to cheer us on. The world cell signalling. She identified two surprising disease-causing villains, she established that feels smaller without her. ■ roles for Hsp90 in evolution. First, she found they can also confer beneficial functions, that Hsp90 could protect cell-signalling including antibiotic resistance and improved James Shorter is associate professor pathways from the effects of mutations in metabolism. Indeed, Lindquist helped to of and biophysics at the other proteins. If Hsp90 function was com- reveal how prions may function in long- University of Pennsylvania, Philadelphia, promised by environmental stress, genetic term memories by stimulating translation Pennsylvania, USA. Aaron D. Gitler is variants would fold differently and new traits at synapses. associate professor of at Stanford would appear rapidly. Her striking experi- Beginning in the 1990s, Lindquist cham- University, Stanford, California, USA. Both ments in plants, for example, revealed that pioned yeast as a model to probe both worked with Susan Lindquist in the 2000s inhibiting Hsp90 function could yield some cancer and . Scep- as postdocs at the Whitehead Institute beneficial , including altered tics questioned (and still do) why anyone for Biomedical Research in Cambridge, growth of stems and roots, and increased would try to study a brain disease in yeast. Massachusetts. resistance to herbivores. Undaunted, she developed a series of yeast e-mails: [email protected], Second, Lindquist established that Hsp90 models that express each of the major [email protected]

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