In Memoriam

Sue was a spectacular scientist who com- at the University of , where she

bined a searing intellect with deep wis- would later join the faculty (1978) and rise

Susan Lee Lindquist

(1949–2016) dom, sagacious intuition, and limitless to full professor (1988). While at the Uni-

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

rational, nurturing, and indefatigable men- Biomedical Research at Massachusetts

sculpts biology, evolution, and dis-

tor. These synergistic traits empowered Institute of Technology (MIT), which is

ease. She revealed several unantici-

extraordinarily effective collaborations where I trained with Sue as a postdoctoral

pated mechanisms by which protein

between scientists from diverse back- fellow (2002–2007). Sue would spend the

folding can buffer, release, and

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).

of beneficial 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

hearing her present a seminar at The technology to Drosophila for the first time

disease, and cancer.

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. 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

Trends in Biochemical Sciences, March 2017, Vol. 42, No. 3 169

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 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-

lack, and David Ish-Horowicz for helpful feedback. I

insights could likely be obtained from

apologize to all those whose important work could not

our most powerful yet humble model

be cited owing to space limitations.

organism [13]. This endeavor may have

1

seemed like a gamble, but Sue was Department of and Biophysics, Perelman

School of Medicine at the University of Pennsylvania,

dauntless, and importantly, she was right.

Philadelphia, PA 19104, USA

Yeast models have now enabled the dis-

Figure 1. Susan Lindquist Reflecting on Her

Discoveries with Hsp90 and Evolution at the covery of genetic and small-molecule *Correspondence: [email protected]

Whitehead in 2006. Photo credit, Justin Knight. (J. Shorter).

modifiers that rescue animal models of

http://dx.doi.org/10.1016/j.tibs.2016.12.002

disease [13]. I strongly suspect that these

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

change. Cold Spring Harb. Symp. Quant. Biol. 74, 103–108

isms and are likely ubiquitous in eukar- eries led Sue to co-found FoldRx

2. Jarosz, D.F. and Lindquist, S. (2010) Hsp90 and environ-

yotes [1]. (acquired by Pfizer) and Yumanity Thera-

mental stress transform the adaptive value of natural

–

peutics. Sue's group would also make genetic variation. Science 330, 1820 1824

3. Queitsch, C. et al. (2002) Hsp90 as a capacitor of pheno-

In another seminal advance, Sue shat- stunning insights into Hsp90, heat-shock

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

5. True, H.L. and Lindquist, S.L. (2000) A yeast provides

discovered that Hsp104 possessed a apeutics [14,15].

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

of yeast catalyzes site-specific recombination in the Dro-

These transformative findings led Sue into serve society and solve important conun-

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

9. Glover, J.R. and Lindquist, S. (1998) Hsp104, Hsp70, and

infectious proteins that can adopt self-per- Sue was not only a great scientist. She

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

expansion of the prion hypothesis. Cell 89, 495–498

and are regulated by Hsp104 [10]. Impor- her family. In my view, it would be in this

12. Newby, G.A. and Lindquist, S. (2013) Blessings in disguise:

tantly, Sue's group established that yeast setting where the most insightful writing

biological benefits of prion-like mechanisms. Trends Cell

–

deploy a variety of prions for beneficial would happen. Although exceptionally Biol. 23, 251 259

13. Khurana, V. et al. (2015) Toward stem cell-based pheno-

purposes, including the rapid evolution busy with numerous responsibilities, Sue

typic screens for neurodegenerative diseases. Nat. Rev.

fi fi

of bene cial and heritable new traits in would somehow nd 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

chaperoning of cancer. Nat. Rev. Cancer 5, 761–772

cause disease [11]. They had been there to cheer us on.

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