Susan L. Lindquist – Scientific Profile

Overview

Susan L. Lindquist, director of the Whitehead Institute for Biomedical Research, is best known for ground-breaking work on how such diverse processes as stress tolerance, neurodegenerative disease, and heredity can be governed by changes in protein conformation.

Widely known for work on a special set of proteins that are dedicated to helping other proteins behave, Lindquist was thrust into the limelight when her research provided the definitive evidence for a new form of inheritance. Her laboratory established that new genetic traits can be based upon old proteins that have taken on new, self-perpetuating shapes.

Established scientific thinking had held that new biological properties are acquired and passed from generation to generation when mutations change the sequence of DNA—and this is still true in most cases. But Lindquist's group showed that such changes could also be passed on through proteins called prions. Prion proteins change their functions by acquiring a new shape. And this shape is “catching.” It propagates from protein to protein, and its influence can span generations. This work is helping to provide a biochemical framework for understanding other biological mysteries, including mad cow disease.

Another groundbreaking piece of research from Lindquist's lab may provide a missing piece in the puzzle of evolution. This work shows that hidden genetic traits can be revealed by environmental stress and bred to produce new forms. That some organisms secretly harbor instructions for sudden, complex changes provides a new window on how life may evolve.

Recently, Lindquist has been working also in the interdisciplinary area of biomaterials and nanotechnology. Her group has joined with others in physics and chemistry to determine how protein fibers organize themselves into new structures. They hope to build devices much, much smaller than current methods of manufacturing allow.

Protein Folding

A common theme underlies the diversity of Lindquist's work—the concept of protein folding. Proteins are both the building blocks of life and its workhorses. They form muscles, nerves, and sinews. They carry messages, harness energy, and put everything to work, defining life as we know it. For proteins to do their jobs, they must have just the right shapes. Each starts life as a long skinny strand that folds up in an intricate, very precise way. If they misfold, cells usually just get rid of them. But certain types of misfolded proteins persist, and, when they do, they change the normal life of the cell. In some cases change is good, in others deadly.

Lindquist's studies of protein folding have focused on two classes with special properties. One consists of the “chaperones,” proteins that are dedicated to helping other proteins fold. Like their human counterparts, protein chaperones either prevent highly interactive immature forms from making bad connections or wrest them apart when they do. Why should it matter? When certain types of proteins go bad, they influence others to do the same. These renegade proteins, “prions” and “amyloids,” are the second focus of Lindquist's research.

Because the problem of protein folding is shared by all forms of life, Lindquist has concentrated on simple organisms like yeast and fruit flies, which are fast-growing and easy to study. As the forces that control protein folding in these cells are laid bare, her laboratory is beginning to exploit them to study much more difficult problems. These studies have provided many new and startling insights.

New Insights from Prion Biology

One of these insights concerns a new type of inheritance. Lindquist and her colleagues provided the first biochemical evidence that certain genetic traits may be transmitted entirely by prions, without any changes in DNA or RNA. The details are complicated but the general scheme is simple. Prions can live in a wobbly, sticky shape until they find others in the same state. When enough of them get together they acquire a stable new structure. Other prion proteins soon join the act, taking on the same new shape. Lindquist's lab revealed the basic mechanism.

In a more provocative vein, work from Lindquist's lab suggests that these prion proteins may have an important biological purpose, allowing cells to use new types of food and survive biological warfare (antibiotics). Her laboratory is now asking how many proteins are capable of these heritable switches in structure and function. They also want to determine how the process can be deliberately manipulated to produce new forms and functions.

Elucidating Human Disease

“The yeast system also provides a model for investigating protein misfolding in human diseases,” Lindquist says. “Studies in yeast can greatly accelerate the rate at which we decipher the fundamental nature of protein misfolding diseases such as 'mad cow' disease in cattle and Creutzfeldt-Jakob, Alzheimer's, and Parkinson's in humans, and could lead to new strategies for treating them.”

For example, mutations in the protein huntingtin are responsible for Hungtinton's disease, a devastating neurodegenerative disorder. Normal huntingtin is soluble, but the mutants misfold into sticky, insoluble clumps. Taking advantage of yeast genetics, Lindquist's group finds that, when these mutants are expressed in yeast, they behave just like they do in human neurons. And certain chaperone proteins can block their misfolding. These results provide vital clues to the disease process and offer a new, simpler system to search for drugs that could stop it. In a similar vein, Lindquist and her colleagues are using yeast and mammalian cells to test the widely accepted (but still controversial) “protein-only” hypothesis for 'mad cow' disease, which says that PrPSc is itself the infectious agent, interacting with normal PrPC molecules and inducing them to switch their conformation in a fatal chain reaction.

Conformational Change and Evolution

Using different model systems—fruit flies and plants—work in Lindquist's lab suggests that protein misfolding helps drive the process of evolution. This work might provide scientists with mechanisms for harnessing natural genetic variation to produce better crops without transgenic manipulations.

This work focuses on Hsp90, a chaperone dedicated to folding a very special set of proteins—key regulators of growth and development. Lindquist's group has created an experimental stress response that reduces the level of Hsp90. If applied while flies are developing, some emerge with differently shaped wings, eyes, or legs. Not such a big surprise. But when flies with altered shapes are bred together for a few generations, something amazing happens—most of their progeny keep these traits—even in the absence of stress.

It turns out that those few flies that exhibit altered body plans under stress do so because they carry hidden genetic changes. The changes are too few to affect the organism on their own. Their potential is only revealed by stress. But a few rounds of selective breeding can enrich them in each generation, until nearly all the flies have enough to produce differently shaped wings or eyes under normal conditions. Similar findings with plants suggest that this mechanism is universal. It could even provide an explanation for rapid changes in the fossil record, a phenomenon that has puzzled us for generations. But Lindquist believes this is just the tip of the iceberg. “The process of protein folding interacts with our biology and our environment in so many ways—we've just begun to plumb it. How significant Hsp90 has been in driving evolution we can't yet begin to say, but I'm certain that protein folding mechanisms in general help set the pace.”

Interdisciplinary Approach and New Directions

Research in the Lindquist lab is driven by a unique blend of traditional cell biology, and genetics with state-of-the-art new technologies. She is a catalyst for novel collaborations involving scientists studying yeast, fruit flies, plants, and man. Her current work sparks the interest of physicists, chemists, and engineers, and she confesses to being thrilled by the challenges and insights they contribute.

Producing organic fibers that can self-organize into structures smaller than current manufacturing methods allow provides a new venture that builds on her expertise in protein folding. Over the years, yeast biologists have provided a dazzling array of techniques to change the sequence and composition of the protein fibers to alter structure and function. Taking advantage of nature's own methods to build organic nanomaterials promises to add new territory to the interdisciplinary world of biomaterials and nanotechnology. As her research has so abundantly demonstrated, an interdisciplinary scope and a prioneering spirit can produce illuminating and beneficial results.

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