In Part 1a, Dr. Lindquist explains the problem of protein folding. Proteins leave the ribosome as long, linear chains of amino acids but they need to fold into complex three dimensional shapes in the extremely crowded environment of the cytoplasm. Since protein misfolding can be disastrous for cells, proteins known as heat shock proteins (HSPs) have evolved to facilitate proper protein folding. Lindquist explains that sometimes the heat shock response becomes unbalanced resulting in human disease. In the case of cancer, HSPs help cancer cells survive many stresses that would typically kill them. In contrast, many neurodegenerative diseases are a result of protein misfolding and aggregation suggesting that, in these diseases, HSPs are not activated when they should be.
Yeast have many of the same cellular processes as humans including a stress response to aid in protein folding and prevent protein aggregation. In Part 1b, Lindquist describes how genetic screens in yeast helped scientists identify mutations that increased the formation of aggregates similar to those found in neurodegenerative diseases. Furthermore a screen in yeast of ~500,000 chemicals identified a number of compounds that prevented protein aggregation. Results from both experiments have since been validated in mice and human neuronal models.
When cells undergo stress, the expression of HSPs increases. In Part 2, Lindquist explains that while most HSPs are expressed only as needed, Hsp90 is expressed in excess. This “buffer” of Hsp90 facilitates the folding of some mutant proteins (such as v-src) that would usually misfold and be degraded by the cell. Thus, Hsp90 potentiates the impact of these mutations. Interestingly, the Hsp90 “buffer” can also act to hide or suppress the impact of other mutations. These “hidden” mutations are found when cells are stressed reducing the pool of available Hsp90. Thus, Hsp90 provides a plausible mechanism for allowing genetic diversity and fluctuating environments to fuel the pace of evolutionary change.
In her last talk, Lindquist focuses on prion proteins. Prions are perhaps best known as the infectious agents in diseases such as mad cow disease. However, Lindquist argues that there are many great things about prions too. They provide a protein-based mechanism of inheritance that allows organisms to develop new traits, quickly and reversibly, and thereby adapt to new environments. Working in yeast, Lindquist and her colleagues were able to identify numerous prion-like proteins that are induced at different levels, depending on the temperature, pH or presence of bacteria. Expression of prions caused heritable, phenotypic changes in the yeast demonstrating that prions are another mechanism by which environmental changes can induce new traits that can be passed onto progeny. As Lindquist says, perhaps it is time to give Lamarck back his dignity.
Susan Lindquist is a member and former Director of the Whitehead Institute for Biomedical Research. She is also a Howard Hughes Medical Institute Investigator and Professor of Biology at the Massachusetts Institute of Technology. She received her Ph.D. in biology from Harvard and was a postdoctoral fellow of the American Cancer Society. Lindquist was on the faculty of the University of Chicago for over 20 years before moving to MIT in 2001.
A pioneer in the study of protein folding, Lindquist found that the chaperone Hsp90 potentiates and buffers the effects of genetic variation, fueling evolutionary mechanisms as diverse as malignant transformation and the emergence of drug resistance. Her work established the molecular basis for protein-based mechanisms of inheritance and she demonstrated that Hsp90 and prions each provide distinct but feasible mechanisms of Lamarckian inheritance.
Dr. Lindquist is an elected member of the National Academy of Sciences, the Academy of Medicine and the Royal Society. Her honors also include the Dickson Prize in Medicine, the Otto-Warburg Prize, the Genetics Society of America Medal, the FASEB Excellence in Science Award, the E.B. Wilson Medal, the Vanderbilt Prize for Women’s Excellence in Science and Mentorship and the National Medal of Science.