Susan Lee Lindquist (1949–2016)— Pioneer in the Study of Cellular Protein Folding and Disease
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE Published online: December 5, 2016 provided by MPG.PuRe Obituary Susan Lee Lindquist (1949–2016)— pioneer in the study of cellular protein folding and disease Franz-Ulrich Hartl role of protein misfolding in disease to tenure at the University of Chicago, led uncovering genetic variation in evolution. to completely unexpected results. Using Her interdisciplinary vision has empowered yeast as a model, her laboratory found that her to devise entirely new experimental Hsp90 was essential for normal growth, approaches and create novel conceptual while Hsp104 was the single most critical frameworks in several fields. factor for surviving extreme stress. In collab- Susan Lindquist’s work began with oration with Keith Yamamoto, she estab- pioneering studies of the heat-shock lished in the early 1990s that Hsp90 was response, a homeostatic mechanism to required for the maturation of the steroid protect cells from protein folding problems hormone receptors and oncogenic tyrosine during heat exposure and a variety of other kinases. Using a combination of genetic and stresses. As a graduate student of Matthew biochemical approaches, she demonstrated Meselson at Harvard in the 1970s, she that Hsp104 promotes survival after heat launched, on her own initiative, an investi- stress by disaggregating damaged proteins gation of the heat-shock response, using it and restoring them to normal function. To do as a model to understand eukaryotic gene so, Hsp104 couples its own conformational regulation. She discovered that the heat- changes, driven by highly coordinated shock response, previously only known successive rounds of ATP hydrolysis, to work from Drosophila salivary glands, also on bound substrates. The functional analysis Susan Lee Lindquist. With permission from occurred in tissue culture cells, demonstrat- of Hsp104 gave rise to another, most Ceal Capistrano/Whitehead Institute. ing its generality and making it tractable to remarkable discovery: In collaboration with molecular analysis. She then revealed that Chernoff and Liebman, Susan established The scientific community is deeply saddened the response was governed by a combina- that Hsp104 regulates the propagation of a by the passing of Susan Lee Lindquist, tion of translational and transcriptional mysterious cytoplasmically inherited Professor of Biology at MIT and a Howard mechanisms. Thanks in large part to her genetic factor known as [PSI+]. Taken Hughes Medical Institute Investigator, on work—and complemented by seminal together with the fact that Hsp104 is a October 27 after a year-long battle with contributions of Pelham, Lis, Morimoto, and protein remodeling factor, this finding cancer. Her nearly 40-year career was distin- Wu—the heat-shock response provides provided a strong genetic argument in guished by groundbreaking research in cell perhaps the most beautiful and complete support of Reed Wickner’s proposal that biology and genetics, and by an extraordi- example of eukaryotic gene regulation docu- [PSI+] is a protein-based genetic element— nary passion for nurturing and mentoring mented to date. a prion. Susan established that the protein the next generation of biologists. After exploiting this system to produce suspected of being a prion, Sup35, under- An inspiring and courageous innovator, groundbreaking work on eukaryotic gene went a self-perpetuating change in state Susan Lindquist has tackled and resolved a expression, Susan studied the function of that was inherited through the cytoplasmic remarkable variety of difficult problems, the stress response and of two of its individ- transmission of protein aggregates from ranging from delineating cellular responses ual proteins, Hsp90 and Hsp104. These mother cells to their daughters. Remark- to stress, prion-based inheritance, and the investigations, carried out during her 23-year ably, once the protein has switched states, Max Planck Institute of Biochemistry, Martinsried, Germany. E-mail: [email protected] DOI 10.15252/embj.201670040 2626 The EMBO Journal Vol 35 |No24 | 2016 ª 2016 The Author Published online: December 5, 2016 Franz-Ulrich Hartl Obituary The EMBO Journal from random coil to amyloid filament, it fungi develops in an Hsp90-dependent friendly exchange at conferences. Furthering can rapidly catalyze the conforma- mechanism. excellence in science and providing support tional conversion of soluble protein. This In 2001, Susan moved to the Whitehead for young scientists was of great importance established the fundamental biochemical Institute in Cambridge, serving as its Director to her. She was highly regarded as a mechanism for prion conversion that is until 2004. During more recent years, much passionate mentor and a role model for not only the basis of human prion disease of her research focused on understanding the women in science. She leaves a legacy of but is also of broad potential biological role of molecular chaperones and stress students and postdocs who went on to significance. Indeed, collaborating with the response pathways in neurodegenerative successful careers. Her views of our profes- laboratory of Eric Kandel, Susan established diseases and in cancer. Using yeast as a sion and of its significance for humanity are in 2003 a remarkable new concept in “living test tube”, they recapitulated the wonderfully summarized in a statement she learningandmemory.Theyfoundthata protein folding transitions involved in the made on the occasion of the 50th anniversary protein known as CPEB, which plays a key pathogenic aggregation of alpha-synuclein in of ASCB (http://www.molbiolcell.org/conte role in the maintenance of synapses in Parkinson’s disease, huntingtin in Hunting- nt/21/22/3804.long). I highly recommend metazoan brains, has a prion-like ability to ton’s chorea and PrP in prion disease, and reading it, especially to the young. sustain itself in an altered self-perpetuating through ingenious genetic screens deci- Susan Lindquist received many presti- conformation. phered key cellular pathways that are gious awards and honors, including the The role of Hsp90 in the maturation of impaired by the aggregation process. Recon- President’s National Medal of Science—the steroid receptors and tryosine kinases necting with her very early work on the highest scientific honor bestowed by placed the protein in a unique position to heat-shock response, she discovered that the United States—as well as the Dickson couple environmental contingency with heat-shock transcription factor, HSF1, also Prize in Medicine, the Otto-Warburg Medal, evolutionary change. In the mid-1990s, drives a transcriptional program distinct from the FASEB Excellence in Science Award, the Susan made the stunning discovery in heat shock to support the progression of Max Delbru¨ck Medal, the E.B. Wilson Drosophila that Hsp90 buffers naturally highly malignant human cancers. The Medal, a Vallee Visiting Professorship, the occurring genetic variation. The presence of insights gained from these studies inform on Vanderbilt Prize for Women’s Excellence in Hsp90 allows flies to accumulate a multi- new therapeutic strategies for neurodegener- Science and Mentorship, and the Albany tude of mutations by keeping them in a ation and cancer. Indeed, not only was Prize. She was a member of the National silent state. Under stress, the effects of the Susan’s advice sought by major pharmaceuti- Academy of Sciences, the American variation are exposed creating new traits, cal companies, as a biomedical entrepreneur Academy of Arts and Sciences, and the and the variation can therefore be enriched she co-founded FoldRx Pharmaceuticals British Royal Society. by selective breeding. Once the mutations and founded Yumanity Therapeutics and In Susan Lindquist we are losing not only have been sufficiently enriched, the pheno- REVOLUTION Medicines. a towering figure of basic biomedical types are retained, even when the environ- It is impossible to imagine a more research, but also a wonderful human being. ment has returned to normal. Subsequently, fulfilled and productive scientific career than I will never forget her warmhearted friend- the Lindquist laboratory extended this that of Susan Lindquist. But Susan had ship, her youthful enthusiasm and her great novel concept to Arabidopsis, demonstrat- many other qualities that make losing her so sense of humor. Susan is survived by her ing that Hsp90’s capacity to buffer and much harder. She was an outstanding husband, Edward Buckbee, and her two release genetic variation is conserved across communicator and science advocate. Her daughters, Alana Buckbee and Nora Buckbee. enormous evolutionary distances. They also infectious enthusiasm for science always She will live on in our memories and through showed that drug resistance in pathogenic helped to create an atmosphere of open and her extraordinary achievements. ª 2016 The Author The EMBO Journal Vol 35 |No24 | 2016 2627.