Many of us have a story of how Susan Lindquist touched us, whether through our being inspired after listening to her seminars, hearing her pose an attentive question at a poster session, reading her scientific work or public comments about our roles and responsibilities as scientists, or having the pleasure of a more private discussion with her. We will remember her passion, imagination, enthusiasm and joie de vivre. After a life much too short, Sue died on 27 October 2016, fighting to the last moment after a year-long battle with cancer. It is poignant that she was certain that an understanding of cell stress responses and protein quality control in cancer would one day contribute to taming this disease.
My own story with Sue goes back to 1974, when, as a first-year graduate student with Murray Rabinowitz at The University of Chicago, I was wandering through the old Whitman Laboratory in search of an electron microscope to visualize R loops and to map yeast mitochondrial transcripts. Instead, I found Sue, then writing her PhD thesis for the research that she had completed with Matt Meselson at Harvard. I vividly remember her enthusiasm to show me something fascinating: that Drosophila cells exposed to a transient heat shock induce synthesis of a small set of proteins (heat-shock proteins) while repressing preexisting protein synthesis. Together with her Meselson lab partner Steve Henikoff (now at the Fred Hutchinson Cancer Research Center), she showed that the newly transcribed heat-shock mRNAs hybridize to heat-shock chromosomal puffs, thus directly linking heat-shock puffs, inducible gene transcription and the selective translation of heat-shock proteins. This observation later provided the basis for the cloning of heat-shock genes. Their seminal paper (S. Lindquist McKenzie, S. Henikoff and M. Meselson, Proc. Natl. Acad. Sci. USA 72, 1117–1121, 1975) established a new field of inquiry. My own path was profoundly influenced by discussions with Sue and by Meselson's 1975 visit to The University of Chicago, which led me to study the heat-shock response in Meselson's laboratory several years later.
After a short postdoctoral fellowship with Hewson Swift in the Department of Biology at The University of Chicago, Sue was recruited to the faculty in the Department of Molecular Genetics and Cell Biology, where she remained for the next 23 years as a Howard Hughes Investigator and the Albert Lasker Professor. Many of Sue's most insightful discoveries during this period were fueled by her devotion to her favorite model organism, Saccharomyces cerevisiae. She was fond of saying that she was not a geneticist, a cell biologist, a biochemist or a molecular biologist, but that she used all systems to answer the questions at hand. For example, studies from Sue's laboratory on Hsp90 in yeast, flies, plants and vertebrates led to the provocative idea that molecular chaperones function as capacitors for morphological evolution by regulating cryptic variation. Likewise, her characterization of the chaperone Hsp104 provided insights into prion transmission and consequently led to discoveries on how prions affect protein conformation and stably alter inherited traits in the absence of genetic changes in DNA or RNA.
During this period, there was a major shift in perception of the heat-shock response: once viewed as a mere curiosity in fruit flies, heat-shock proteins became recognized as molecular chaperones, essential and central to all aspects of protein biogenesis and quality control. By the mid-1990s, the potential link between diseases of protein conformation and the dysregulation of cell stress responses began to permeate biochemistry, biology and medicine. A great stimulus to the field was provided by Cold Spring Harbor Laboratory, which sponsored several meetings in the 1980s and added the conference to their permanent meeting schedule in the 1990s. The 1994 and the 1996 Cold Spring Harbor Meeting on Molecular Chaperones and the Heat Shock Response, co-organized by Sue, Costa Georgopoulos (University of Utah) and myself, captured this excitement as that nascent band of happy heat-shockers embarked in all directions, investigating areas as diverse as the biochemistry of protein folding and diseases of protein conformation. Also in 1996, together with Elizabeth Craig (University of Wisconsin), we converted our megagroup meetings into the Annual Midwest Stress Response and Chaperone meetings, which rotated between Northwestern University and The University of Chicago for the following five years and are now in their twenty-second year.
In 2001, Sue joined the Massachusetts Institute of Technology as the Director of the Whitehead Institute (2001–2004), a member of the Department of Biology, and an associate member of the Broad Institute and the Koch Institute for Integrative Cancer Research. This 15-year period was defined by continued elegant studies on prions and chaperones but was distinguished by the recognition that underlying the cell stress response was a 'double-edged sword' that could prevent misfolding and aggregation in degenerative diseases or cause cancer by enabling tumor cells to express mutant proteins. Studies on a-synuclein and Huntingtin expressed in yeast revealed features of common cellular mechanisms between yeast and humans that reinforced Sue's long-held belief that the tools provided by S. cerevisiae would yield rapid access to underlying mechanisms. In 2004, together with Jeff Kelly (The Scripps Research Institute), Sue founded FoldRx, which was purchased by Pfizer for the development of Tafamidis, a drug currently used to treat familial amyloid polyneuropathy. In December 2014, together with Tony Coles, she founded Yumanity Therapeutics to identify drugs to treat neurodegenerative diseases caused by protein misfolding.
For these and many other accomplishments, Sue received multiple honors, a few of which include election to the American Academy of Arts and Sciences (1997), the National Academy of Sciences (1997) and the Institute of Medicine (2006), and induction into the Royal Society as a Foreign Member (2015). Perhaps her greatest honor was the National Medal of Science—the highest scientific honor in the United States—which was bestowed on Sue in 2010 by President Obama, a fellow Chicagoan.
Ulrich Hartl (Max Planck Institute of Biochemistry), a long-time friend and colleague, captured the sentiment of many after the loss of Susan Lindquist, saying, “We are not only losing an eminent leader of the field but also [losing] a warm-hearted and generous colleague and an advocate for young scientists. She will live on in our memory and through her fundamental contributions to science.” Sue loved her laboratory, training new generations of scientists and providing the inspiration that could convince someone to pursue a life of science.
For now, I will close with a fond memory. Sue's gusto for life was never more evident than it was when we shared some time at a karaoke bar in Kitakyushu, Japan, together with Bob Kingston (Harvard University), John Lis (Cornell University) and Kazu Mori (Kyoto University) in November 1992. There, in our small private space, Sue, guided by the bouncing ball on the screen, happily belted out songs from the 1970s and 1980s, as if there were no tomorrow.
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Disease Models & Mechanisms (2017)