DRI Spring Newsletter 2007

“What do ‘mad cow,’ people with neurodegenerative diseases and an unusual type of inheritance in yeast have in common? They are all experiencing the consequences of misfolded proteins. . . In humans the consequences can be deadly, leading to such devastating illnesses as Alzheimer’s disease. In one case, the misfolded protein is not only deadly to the unfortunate individual in which it has appeared, but it can apparently be passed from one individual to another under special circumstances—producing infectious neurodegenerative diseases such as mad cow disease in cattle and Creutzfeld-Jacob disease in humans.”

—“From Mad Cows to ‘Psi-chotic’ Yeast: A New Paradigm in Genetics,” National Academy of Sciences Distinguished Leaders in Science Lecture Series

Like a crime scene investigator meticulously probing for clues in a murder mystery, molecular biologist Susan Lindquist has spent decades uncovering clues to the culprit for killers like Parkinson’s disease, Creutzfeld-Jacob disease and mad cow disease. Her work has had an enormous impact in fields as diverse as medicine, bioengineering, basic molecular and cell biology and evolution.

The underlying theme of her multifaceted work is protein folding and misfolding. Proteins are the basis of how biology gets things done. They start out in the body as long strings of amino acids and have to assemble themselves into complex shapes—a process scientists call folding—before they can do anything. They are the main constituent of our brains, muscles, hair, skin and blood vessels.

What happens if proteins don’t fold correctly? When proteins misfold, they can clump together, and the clumps can often gather in the brain, where they are believed to cause the symptoms of mad cow or Alzheimer’s disease. Cystic fibrosis, an inherited form of emphysema, and even many cancers are also believed to result from protein misfolding. Protein misfolding has been implicated as a major mechanism in many severe neurological disorders including Parkinson’s and Huntington’s diseases.

In the Lindquist lab, located at the Whitehead Institute for Biomedical Research in Cambridge, Mass., Lindquist and her colleagues have developed yeast strains that serve as living test tubes in which to study neurodegenerative disorders, unraveling how protein folding contributes to them. The scientists 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—renewing themselves indefinitely. Only recently discovered, one of them is already well known as the cause of mad cow disease. Lindquist and her team investigate both how prions form and the diseases they cause. Additionally, 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 the 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 can reveal hidden genetic variations in fruit flies and in cress plants 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.

Many times scientists must also take on the role of inventor, finding new strategies and revolutionary tactics, and Lindquist is no exception. She has designed her own technology when necessary, some of which has transformed the practice of Drosophila genetics—an experimental simulation observing the breeding of the fruit fly—producing the first precise method of inserting and deleting genes in a higher organism.

Her determination to translate her fundamental biological research into clinical treatments and cures for diseases is further illustrated by the fact that she and a colleague, Jeff Kelly from Scripps Research Institute, co-founded a biotech company, FoldRx Pharmaceuticals, Inc., to expedite the discovery of drugs to alleviate the diseases.

Lindquist is a member and former director (2001 to 2004) of Whitehead Institute, a professor of biology at MIT and a Howard Hughes Medical Institute investigator. At the University of Chicago, she was the Albert D. Lasker Professor of Medical Sciences from 1999 to 2001 and a professor in the Department of Molecular Biology since 1978. She received a Ph.D. 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 and Scientific American’s top 50.