Susan L. Lindquist, PhD

Member, Whitehead Institute Professor of Biology, MIT 617.258.5184 lindquist_admin@wi.mit.edu

Whitehead Member Susan Lindquist is a pioneer in the study of protein folding. She has shown that changes in protein folding can have profound and unexpected influences in fields as wide-ranging as human disease, evolution and nanotechnology and discusses her work in a video [ protein folding 220 kbps QuickTime] and TWiT.tv "Futures in Biotech" podcast [96 kbps QuickTime mono audio stream, 32.4 mb mp3, or http://futuresinbiotech.blogspot.com/2006/05/fib-episode-001-protein-
folding-at.html].

Protein misfolding has been implicated as a major mechanism in many severe neurological disorders including Parkinson’s and Huntington’s diseases. Lindquist and colleagues have developed yeast strains that serve as living test tubes in which to study these disorders, unraveling how protein folding contributes to them. They have succeeded in reproducing many of the biological consequences of Parkinson’s disease in yeast cells and are screening for drugs to prevent and treat the disease.

Prions are proteins that can change into a self-perpetuating form. They have only been discovered recently, but one of them is already well known as the cause of mad cow disease. The Lindquist lab investigates both how prions form and the diseases they cause. In addition, Lindquist is convinced that other prion proteins play many important and positive roles in biological processes. The first evidence for this was shown in her work with Nobel Laureate Eric Kandel, which demonstrated that prions may be integral to memory storage in the brain. The Lindquist lab has also used yeast to prove that inherited traits can be passed on via prion proteins, without any change in DNA or RNA, findings that have added a twist to traditional understanding of inheritance.

Heat shock proteins are a group of molecular chaperone proteins that, as their name might suggest, guide other proteins to fold and mature correctly. Lindquist has established that heat shock protein 90 (Hsp90) can reveal hidden genetic variation in fruit flies and in cress plants (Arabidopsis) under certain environmental conditions. Most of these variations are likely to be harmful, but a few unusual combinations may produce valuable new traits, spurring the pace of evolution. This mechanism has great potential for use in creating better crop plants by conventional breeding methods, without the need for transgenic manipulations of crops. The lab is currently investigating closely related mechanisms involved in the progression of cancerous tumors and in the evolution of antibiotic resistant fungi.

Lindquist is a Member and former Director (2001-2004) of Whitehead Institute, a Professor of Biology at MIT, and a Howard Hughes Medical Institute investigator. Previously she was the Albert D. Lasker Professor of Medical Sciences from 1999-2001, and a Professor in the Department of Molecular Biology, University of Chicago, since 1978. She received a PhD in Biology from Harvard University in 1976, and was elected to the American Academy of Arts and Sciences in 1997, the National Academy of Sciences in 1997 and the Institute of Medicine in 2006. Lindquist’s honors also include a spot on Discover magazine’s 2002 list of the top 50 women scientists.

Selected Publications

Gitler, A.D., Bevis, B.J., Shorter, J., Strathearn, K.E., Hamamichi, S., Su, L.J., Caldwell, K.A., Caldwell, G.A., Rochet, J.C., McCaffery, J.M., Barlowe, C., and Lindquist S. (2008). The Parkinson’s Disease Protein Alpha-Synuclein Disrupts Cellular Rab Homeostasis. Proc Natl Acad Sci USA 105(1): 145-50.

Dai, C., Whitesell, L., Rogers, A.B., and Lindquist, S.(2007). Heat-shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell, 130: 1005-18.

Tessier, P.M., and Lindquist, S. (2007). Prion recognition elements govern nucleation, strain specificity and species barriers. Nature 447(7144): 556-61.

Steele, A.D., Jackson, W.S., King, O.D., and Lindquist, S. (2007). The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington's and prion diseases. Proc Natl Acad Sci USA 104(6): 1983-88.

Cooper, A.A., Gitler, A.D., Cashikar, A., Haynes, C.M., Hill, K.J., Bhullar, B., Liu, K., Xu, K., Strathearn, K.E., Liu, F., Cao, S., Caldwell, K.A., Caldwell, G.A., Marsischky, G., Kolodner, R.D., LaBaer, J., Rochet, J.-C., Bonini, N.M., and Lindquist, S. (2006). alpha-Synuclein Blocks ER-Golgi Traffic and Rab1 Rescues Neuron Loss in Parkinson’s Models. Science 313(5785):324-8.

Cowen, L.E. and Lindquist, S.L. (2005). Hsp90 potentiates the rapid evolution of new traits: Drug resistance in diverse fungi. Science 309: 2185-89.

Krishnan, R. and Lindquist, S. L. (2005). Structural insights into a yeast prion illuminate nucleation and strain diversity. Nature 435:765-72.

Si, K., Lindquist, S., and Kandel, E.R. (2003). A neuronal isoform of the Aplysia CPEB has prion-like properties. Cell 115:879-91.

Queitsch C., Sangster T.A., and Lindquist S. (2002). Hsp90 as a capacitor of phenotypic variation. Nature 417:618-24.

Patino, M.M., Liu, J.J., Glover, J.R. and Lindquist, S. (1996). Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273:622-626.

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