6
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Susan Lindquist: a tribute

      *

      Disease Models & Mechanisms

      The Company of Biologists Ltd

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Photo by Ceal Capistrano, Whitehead Institute. When I learned that Susan Lindquist had passed away at the age of 67 from cancer, my heart broke. This fierce flame for science and for women had been extinguished, and for a moment the world became a little dimmer. I first met Susan Lindquist in 1994 when I was a postdoc interviewing for a faculty position at the University of Chicago. We met for breakfast at a local diner. We talked about our science and she impressed upon me how supportive an environment the University of Chicago was for female scientists, how they were there for each other, cheering each other's success, knowing that any time one of them succeeded, it became easier for all of them to succeed. And shortly after I returned home from that visit, I received a handwritten note from her, telling me how much she had liked the talk I gave about my research and how much she hoped I would make her university my home. She made me feel that I had what it took, that I could take this path if I wanted to, and that she and other women would have my back and help me thrive in an academic setting. And just like that, Susan Lindquist became a lifelong mentor. I've never worked in her field, and yet she made herself available to me time and again as I embarked upon different projects, giving me her feedback, supporting me however she could. She supported me when I helped launch Public Library of Science (PLOS), hosting me to give a seminar at the Whitehead Institute, where she was then Director; and she supported me when I launched Disease Models & Mechanisms, providing critical guidance as one of its founding editors and even hosting a meeting that led to a special issue on protein-folding diseases (Brodsky, 2014). The issue included a poster review that was co-authored by Susan and is DMM's most-read poster published to date (Valastyan and Lindquist, 2014). It's no surprise DMM interviewed Susan for the first article in its ‘Model for Life’ section (Lindquist, 2008). In that article, she spoke about the criteria she used to select new members of her laboratory: “In terms of my own laboratory, I have two types of criteria. First, that people be bright and creative and rigorous…. Good scientists. But every bit as important, a very high priority in bringing someone in is knowing that they are generous, open, want to share information, like to help other people, and are willing and ready to accept advice from other people.” Born in Chicago, Susan was a first-generation college student at University of Illinois at Urbana-Champaign, a graduate student at Harvard, and a postdoc at the University of Chicago, where she established her first lab. After 23 years at the University of Chicago, in 2001 she became the first woman to direct the Whitehead Institute, when she also joined the biology department faculty at MIT. She stepped down as Director of the Whitehead Institute in 2004 and remained a Whitehead Institute member, an associate member of the Broad Institute of MIT and Harvard, an associate member of the David H. Koch Institute for Integrative Cancer Research, and a biology professor at MIT for the rest of her career. Susan Lindquist with former post-docs Kendra Frederick, Ruth Scherz-Shouval and Gabriela Caraveo Piso. Photo by Ceal Capistrano, Whitehead Institute. Other obituaries focus more extensively on her science, which was spectacular by any standard. I got to hear during that breakfast meeting about her studies with PSI and Sup35 and the support her work provided for the prion hypothesis (Patino et al., 1996). This work was the beginning of what became a major focus for the rest of Susan's career: using yeast as a way to elucidate the biology of protein folding, and to understand and treat protein-folding diseases, including both neurodegeneration and cancer. She has published numerous significant papers in this field, including several papers within weeks of her death (Chakrabortee et al., 2016; Landgraf et al., 2016; Vincent et al., 2016). In brief, Susan has used yeast as a ‘living test tube’ to recapitulate many of the diseases of protein folding and to screen for drugs that might treat these diseases. To hear Susan lecture about her work, go to iBiology (https://www.ibiology.org/ibioseminars/protein-folding-infectious-disease-cancer.html). Some recollections will highlight her awards and honors, and there were many, including, to name just a few, membership in the National Academy of Sciences, the National Academy of Medicine, and the Royal Society; the Genetics Society of America Medal, the EB Wilson Medal of the American Society of Cell Biology, the Otto Warbug medal, the Max Delbruck medal, and the National Medal of Science. For the National Medal of Science, Susan was cited “for her studies of protein folding, demonstrating that alternative protein conformations and aggregations can have profound and unexpected biological influences, facilitating insights in fields as wide-ranging as human disease, evolution, and biomaterials.” Still others will point out her entrepreneurship and her deep passion to leverage basic science discoveries to tackle diseases linked to abnormal protein folding. In addition to being a professor at MIT and a Howard Hughes Medical Investigator, Susan founded or cofounded several companies including FoldRX Pharmaceuticals (now a wholly owned subsidiary of Pfizer Inc.) and Yumanity Therapeutics, and served on the board of Johnson & Johnson, where she chaired its Science, Technology and Sustainability Committee. But for me, the focus has to be on Susan as an exemplary mentor, as a fierce advocate for science and for women in science, and as a friend. Aptly, Johnson & Johnson recently endowed the Susan Lindquist Chair for Women in Science at the Whitehead Institute, to be awarded to a distinguished female scientist who is advancing biomedical research. Susan demonstrated that it is possible to perform spectacular research, garner your share of accolades (although some would suggest she was overdue for a Nobel Prize), and still support the people around you – your family, your colleagues, your students, and your friends. She made it clear that you can live in a web of collegiality and connection where each success lifts everyone up, and for that example, I will be eternally grateful. And for those of us whose lives have been forever changed by knowing Susan, we know too that her flame burns in each of us, and that we honor her memory with our support for each other, for the next generation, and for science itself. Footnote: Donations in Susan's honor can be directed to the Whitehead Institute Fund to Encourage Women in Science. Programmatic efforts supported by this fund will complement the new Lindquist Professor's mentoring and public outreach efforts, and may include K-12 programs, a lecture series, or a symposium for women in science (https://donations.wi.mit.edu/lindquistfund).

          Related collections

          Most cited references 4

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Mechanisms of protein-folding diseases at a glance

          For a protein to function appropriately, it must first achieve its proper conformation and location within the crowded environment inside the cell. Multiple chaperone systems are required to fold proteins correctly. In addition, degradation pathways participate by destroying improperly folded proteins. The intricacy of this multisystem process provides many opportunities for error. Furthermore, mutations cause misfolded, nonfunctional forms of proteins to accumulate. As a result, many pathological conditions are fundamentally rooted in the protein-folding problem that all cells must solve to maintain their function and integrity. Here, to illustrate the breadth of this phenomenon, we describe five examples of protein-misfolding events that can lead to disease: improper degradation, mislocalization, dominant-negative mutations, structural alterations that establish novel toxic functions, and amyloid accumulation. In each case, we will highlight current therapeutic options for battling such diseases.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Support for the prion hypothesis for inheritance of a phenotypic trait in yeast.

            A cytoplasmically inherited genetic element in yeast, [PSI+], was confirmed to be a prionlike aggregate of the cellular protein Sup35 by differential centrifugation analysis and microscopic localization of a Sup35-green fluorescent protein fusion. Aggregation depended on the intracellular concentration and functional state of the chaperone protein Hsp104 in the same manner as did [PSI+] inheritance. The amino-terminal and carboxy-terminal domains of Sup35 contributed to the unusual behavior of [PSI+]. [PSI+] altered the conformational state of newly synthesized prion proteins, inducing them to aggregate as well, thus fulfilling a major tenet of the prion hypothesis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Scarless Gene Tagging with One-Step Transformation and Two-Step Selection in Saccharomyces cerevisiae and Schizosaccharomyces pombe

              Gene tagging with fluorescent proteins is commonly applied to investigate the localization and dynamics of proteins in their cellular environment. Ideally, a fluorescent tag is genetically inserted at the endogenous locus at the N- or C- terminus of the gene of interest without disrupting regulatory sequences including the 5’ and 3’ untranslated region (UTR) and without introducing any extraneous unwanted “scar” sequences, which may create unpredictable transcriptional or translational effects. We present a reliable, low-cost, and highly efficient method for the construction of such scarless C-terminal and N-terminal fusions with fluorescent proteins in yeast. The method relies on sequential positive and negative selection and uses an integration cassette with long flanking regions, which is assembled by two-step PCR, to increase the homologous recombination frequency. The method also enables scarless tagging of essential genes with no need for a complementing plasmid. To further ease high-throughput strain construction, we have computationally automated design of the primers, applied the primer design code to all open reading frames (ORFs) of the budding yeast Saccharomyces cerevisiae (S. cerevisiae) and the fission yeast Schizosaccharomyces pombe (S. pombe), and provide here the computed sequences. To illustrate the scarless N- and C-terminal gene tagging methods in S. cerevisiae, we tagged various genes including the E3 ubiquitin ligase RSP5, the proteasome subunit PRE1, and the eleven Rab GTPases with yeast codon-optimized mNeonGreen or mCherry; several of these represent essential genes. We also implemented the scarless C-terminal gene tagging method in the distantly related organism S. pombe using kanMX6 and HSV1tk as positive and negative selection markers, respectively, as well as ura4. The scarless gene tagging methods presented here are widely applicable to visualize and investigate the functional roles of proteins in living cells.
                Bookmark

                Author and article information

                Journal
                Dis Model Mech
                Dis Model Mech
                DMM
                dmm
                Disease Models & Mechanisms
                The Company of Biologists Ltd
                1754-8403
                1754-8411
                1 January 2017
                1 January 2017
                : 10
                : 1
                : 1-2
                Author notes
                [* ]Author for correspondence ( vivians@ 123456mit.edu )
                Article
                DMM028696
                10.1242/dmm.028696
                5278528
                28067627
                © 2017. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                Product
                Categories
                302
                Obituary

                Molecular medicine

                Comments

                Comment on this article