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In Memoriam Sue was a spectacular scientist who com- at the University of , where she Susan Lee Lindquist bined a searing intellect with deep wis- would later join the faculty (1978) and rise dom, sagacious intuition, and limitless to full professor (1988). While at the Uni- (1949–2016) creativity. These characteristics enabled versity of Chicago, Sue married Edward Sue to make connections across dispa- Buckbee and would have two wonderful 1, James Shorter * rate disciplines that nobody else could daughters, Alana and Nora. She also make. Her infectious esprit for scientific launched a remarkable and radical series Lindquist was a visionary and pio- discovery was combined with disarming of trailblazing discoveries. These contin- neer who transformed our under- warmth, positivity, openness, directness, ued when Sue moved her research pro- standing of how folding and generosity, which made her an inspi- gram to the for sculpts biology, evolution, and dis- rational, nurturing, and indefatigable men- Biomedical Research at Massachusetts ease. She revealed several unantici- tor. These synergistic traits empowered Institute of Technology (MIT), which is pated mechanisms by which protein extraordinarily effective collaborations where I trained with Sue as a postdoctoral – folding can buffer, release, and between scientists from diverse back- fellow (2002 2007). Sue would spend the grounds and disciplines. Indeed, rest of her career at the Whitehead Insti- potentiate genetic variation in researchers from diverse backgrounds – tute as Director (2001–2004), Institute response to environmental stress, physicists, chemists, biochemists, biolo- Member (2001–2016), and Professor of thereby enabling the rapid evolution gists, mathematicians, and physicians – Biology at MIT (2001–2016). fi of bene cial new traits. Her discov- wanted to work in her laboratory. Sue eries provide a rich framework for wrote papers that were accessible to wide Early work from Sue's group established innovative therapeutic interventions audiences and her seminars were capti- how Hsp expression was coordinated and in several fatal diseases, including vating and clear. I was inspired to postdoc regulated in response to environmental Alzheimer's disease, Parkinson's in her laboratory during my Ph.D. after stress. She brought Flp recombinase disease, and cancer. hearing her present a seminar at The technology to Drosophila for the first time Imperial Cancer Research Fund at Lin- [7]. Her focus shifted to define Hsp func- Susan Lee Lindquist was a heroic pioneer coln's Inn Fields in London, U.K.[2_TD$IF] hosted tion, which yielded innumerable profound and iconic visionary who revolutionized in late 1998. The pursuit of science with insights. Perhaps the most vivid advance our understanding of how alterations in Sue was invariably filled with verve, cour- concerned , an abundant and spe- can sculpt biology, evolu- age, and good humor. cialized molecular chaperone with a selec- tion, and disease [1]. Among many great tive clientele of metastable signal achievements, perhaps the most striking Born in Chicago in 1949, Sue was the transducers that regulate a diverse array was the revelation of multiple unprece- granddaughter of Swedish and Italian of critical biological processes [1]. She dented mechanisms by which protein immigrants. Her proud parents, Iver and found two surprising roles for Hsp90 in folding can buffer, release, and potentiate Eleanor, were not college graduates, but evolution (Figure 1). First, Sue's group genetic variation in response to environ- they greatly valued education. As early as established that by folding its clients, mental stress, thereby enabling the rapid fifth grade, Sue became enthralled by the Hsp90 maintained signaling pathways evolution of beneficial new traits [1–6].In question: what is life? This passion and could even buffer the effects of muta- her wake, she leaves a rich legacy of fun- inspired Sue to gain her B.A. in Microbiol- tions in these pathways [2–4]. This Hsp90 damental, path-breaking discoveries and ogy from the University of Illinois at buffer enabled storage of cryptic genetic perduring insights, which provide a frame- Urbana–Champaign (1971), where she variation [2–4]. Compromising Hsp90 work for innovating therapeutic interven- received a National Science Foundation function via environmental stress revealed tions in several fatal diseases, including fellowship. Sue then earned her Ph.D. in this genetic variation and caused new Alzheimer's disease, Parkinson's disease, Biology from (1976) traits to appear, which could be assimi- and cancer. Among her countless honors where she worked with Matthew Mesel- lated [2–4]. Second, Sue's group estab- and prestigious awards were the National son. It was during her Ph.D. where Sue lished that Hsp90 could also potentiate Medal of Science (2009) and the Albany first became interested in how cells genetic variation, allowing new Prize in Medicine (2016). She was elected respond to environmental stress by to produce immediate , which as a member of the National Academy of expressing heat-shock (Hsps). could also be assimilated [2,6]. Here, Sciences (1997) and the Royal Society compromising Hsp90 function caused (2015). Sue died of cancer on October Sue returned to her beloved Chicago for a new traits to be lost [2,6]. These powerful 27 at age 67 years. brief postdoctoral stint with Hewson Swift mechanisms of evolutionary change were

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captured during evolution for beneficial The world feels horribly smaller without purposes [11]. Thus, were recast Sue. Her startlingly prescient insights as adaptive conduits of memory and and her sage advice have empowered inheritance [10–12]. so many in science and beyond. She will be remembered long into the future for her In more recent years, Sue[1_TD$IF]focused on game-changing, visionary science, as well tackling two major barriers that prevent as the many wonderful and talented sci- us from living longer, more fulfilling lives: entists she nurtured and trained. It was a neurodegenerative disease and cancer. great privilege to know her and to pursue Sue championed as a powerful science with her. model to study neurodegenerative dis- ease reasoning that protein misfolding is Acknowledgments a universal problem and that profound Thank you to Aaron Gitler, Brooke Bevis, Kent Mat- insights could likely be obtained from lack, and David Ish-Horowicz for helpful feedback. I our most powerful yet humble model apologize to all those whose important work could not organism [13]. This endeavor may have be cited owing to space limitations.

seemed like a gamble, but Sue was 1Department of and Biophysics, Perelman dauntless, and importantly, she was right. School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104,[2_TD$IF] USA Figure 1. Susan Lindquist Reflecting on Her[1_TD$IF] Yeast models have now enabled the dis- Discoveries with Hsp90 and Evolution at the covery of genetic and small-molecule *Correspondence: [email protected] Whitehead in 2006. Photo credit, Justin Knight. modifiers that rescue animal models of (J. Shorter). disease [13]. I strongly suspect that these http://dx.doi.org/10.1016/j.tibs.2016.12.002 findings will lead to urgently needed ther- References found to operate in diverse model organ- apeutics. Indeed, these profound discov- 1. Lindquist, S. (2009) Protein folding sculpting evolutionary isms and are likely ubiquitous in eukar- eries led Sue to co-found FoldRx change. Cold Spring Harb. Symp. Quant. Biol. 74, 103–108 fi 2. Jarosz, D.F. and Lindquist, S. (2010) Hsp90 and environ- yotes [1]. (acquired by P zer) and Yumanity Thera- mental stress transform the adaptive value of natural peutics. Sue's group would also make genetic variation. Science 330, 1820–1824 In another seminal advance, Sue shat- stunning insights into Hsp90, heat-shock 3. Queitsch, C. et al. (2002) Hsp90 as a capacitor of pheno- typic variation. Nature 417, 618–624 tered the dogma that protein aggregates factor 1, and transcriptional responses in 4. Rutherford, S.L. and Lindquist, S. (1998) Hsp90 as a capaci- were intractable structures. Sue's group cancer, which also inspire hope for ther- tor for morphological evolution. Nature 396, 336–342 discovered that Hsp104 possessed a apeutics [14,15]. 5. True, H.L. and Lindquist, S.L. (2000) A yeast provides a mechanism for genetic variation and phenotypic diversity. powerful protein-disaggregase activity Nature 407, 477–483 capable of dissolving protein aggregates We are massively diminished by Sue's 6. Cowen, L.E. and Lindquist, S. (2005) Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse and restoring previously aggregated pro- death. Sue strongly believed that scien- fungi. Science 309, 2185–2189 teins to native form and function [8,9]. tists had a binding moral obligation to 7. Golic, K.G. and Lindquist, S. (1989) The FLP recombinase These transformative findings led Sue into serve society and solve important conun- of yeast catalyzes site-specific recombination in the Dro- sophila . Cell 59, 499–509 the field of yeast prions, which are tightly drums that would have global, wide- 8. Parsell, D.A. et al. (1994) Protein disaggregation mediated regulated by Hsp104 [10]. Prions are reaching consequences. Importantly, by heat-shock protein Hsp104. Nature 372, 475–478 infectious proteins that can adopt self-per- Sue was not only a great scientist. She 9. Glover, J.R. and Lindquist, S. (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously petuating conformations, which cause was a wonderful person. She would invite aggregated proteins. Cell 94, 73–82 debilitating neurodegenerative disease in group members to her house to work on 10. Shorter, J. and Lindquist, S. (2005) Prions as adaptive conduits of memory and inheritance. Nat. Rev. Genet. 6, humans [11]. Sue's group enabled us to manuscripts at the weekend, and here 435–450 understand how yeast prions assemble you could really get to know Sue and meet 11. Lindquist, S. (1997) Mad cows meet psi-chotic yeast: the and are regulated by Hsp104 [10]. Impor- her family. In my view, it would be in this expansion of the prion hypothesis. Cell 89, 495–498 tantly, Sue's group established that yeast setting where the most insightful writing 12. Newby, G.A. and Lindquist, S. (2013) Blessings in disguise: biological benefits of prion-like mechanisms. Trends Cell deploy a variety of prions for beneficial would happen. Although exceptionally Biol. 23, 251–259 purposes, including the rapid evolution busy with numerous responsibilities, Sue 13. Khurana, V. et al. (2015) Toward stem cell-based pheno- typic screens for neurodegenerative diseases. Nat. Rev. of beneficial and heritable new traits in would somehow find time to sit on the Neurol. 11, 339–350 response to environmental stress [12]. grass near the goal and watch her stu- 14. Scherz-Shouval, R. et al. (2014) The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Sue made us view prions in a new light. dents and postdocs play soccer on Friday Cell 158, 564–578 They were no longer merely villains that afternoons in East Cambridge – always 15. Whitesell, L. and Lindquist, S.L. (2005) HSP90 and the cause disease [11]. They had been there to cheer us on. chaperoning of cancer. Nat. Rev. Cancer 5, 761–772

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