2003 Dickson Prize Winner
Susan L. Lindquist, PhD
Member, Whitehead Institute for Biomedical Research
Professor of Biology, Massachusetts Institute of Technology
2003 Dickson Prize in Medicine Lecture
“Protein Conformation as a Pathway to Understanding Cellular Processes, Disease, and Bio-Inspired Materials”
Susan L. Lindquist, PhD, is an acclaimed molecular biologist and pioneering researcher in the study of protein conformation. Alterations in protein conformation are key to most biological processes, and irregularities in the structure and folding of proteins underlie many human diseases. She has studied the factors that influence proteins to fold into normal and abnormal configurations as well as the physiological outcomes of the folding process. Lindquist's work has revolutionized our understanding of cellular responses to stress, genetic variation in evolution, and the role of protein misfolding in genetics and disease.
She is a member of the Whitehead Institute for Biomedical Research and a professor of biology at Massachusetts Institute of Technology. At the time she received the Dickson Prize, she was director of the Whithead Insitute.
Lindquist has made numerous significant contributions throughout her career. Using the heat shock response as a model system, she isolated messenger RNAs from eukaryotic cells and demonstrated that they derive from chromosome structures that are remodeled by heat shock (“puffs”). She further found that one heat shock protein (Hsp), Hsp70, helps cells to survive stress. Lindquist also discovered that the signals required to control translation of Hsp70 are contained within the messages themselves and that this expression is autoregulated at both the transcriptional and translational levels.
Lindquist’s lab developed an important technique for manipulating chromosomes in living cells by inserting the sites for recombination and the genes encoding recombinant enzymes into their DNA. This basic technique, which is commonly known by its acronym, FLIP, changed the way that fruit fly genes are manipulated and influenced the development of new systems for genetic manipulation in many other organisms.
Working with two very different organisms, fruit flies and mustard plants, Lindquist discovered that another protein, Hsp90, influences the accumulation and exposure of genetic variation on a massive, genome-wide scale. Because the mechanism of exposure involves changes in protein folding, it couples environmental change to the appearance of new forms and functions that could influence the pace of evolutionary change.
Lindquist’s lab also provided the first biochemical evidence that certain genetic traits are transmitted entirely by self-perpetuating changes in protein folding, without changes in DNA or RNA. The idea that a protein can be used as an element of inheritance, thus influencing phenotypic traits, has expanded the traditional view of genetic inheritance. Lindquist suggests that self-perpetuating changes in protein folding can either help or harm an organism. They can lead to devastating prion-related neurodegenerative diseases; they can also serve vital roles in normal biology—from helping microorganisms survive biological warfare to serving as biological memory mechanisms. Other focuses of Lindquist’s lab have included identifying the number of proteins that act as heritable on-off switches in certain cellular pathways and developing mechanisms for deliberate manipulation of protein folding, which could lead to new strategies for treating prion diseases like Alzheimer’s, Parkinson’s, and Creutzfeldt-Jakob disease.
Lindquist received her B.A. in microbiology from the University of Illinois in 1971 and her PhD in biology from Harvard University in 1976. She was a postdoctoral fellow at the American Cancer Society in Chicago from 1976 to 1978 and then joined the faculty of the University of Chicago, where she moved up the ranks and in 1999 was named the Albert D. Lasker Professor of Medical Sciences. From 1988 to 2001, before becoming director of the Whitehead Institute, she also served as an investigator for the Howard Hughes Medical Institute.
Lindquist's honors include election to the American Academy of Arts and Sciences in 1996, the National Academy of Sciences in 1997, and fellowship in the American Academy of Microbiology in 1997. Lindquist received the Novartis-Drew Award in Biomedical Research in 2000.
(Originally published Sept. 24, 2003)