Protein folding: Life’s vital origami

6 min read

Scholar explains how proteins fold rightly and wrongly, and the consequences of each

Fold a napkin wrong, and you lose points with Miss Manners.

Fold a protein wrong, and you could set off a chain of genetic malformations that can lead to disease, or (more happily) to evolutionary change.

The way proteins fold, and the good and bad effects of this molecular phenomenon, are what keeps biologist Susan L. Lindquist busy.

Lindquist Ph.D. ’76, a Radcliffe Fellow this year, is an award-winning professor and researcher at the Massachusetts Institute of Technology (MIT) and a former director of the Whitehead Institute. She shared her insights on protein folding with an audience of 70 last week (March 5) at the fellowship program’s 34 Concord Ave. headquarters.

“Two-thirds of the people in this room think proteins are food,” said Lindquist, leading off her lively one-hour presentation spiced with movie clips, arresting charts, and jokes that even nonbiologists could laugh at. “But we’re mostly made of proteins.”

Proteins constitute about 50 percent of the dry weight of animals and bacteria. They transport chemicals in and out of cells, speed up chemical reactions (as enzymes), and comprise the building blocks of cellular structure. They also only work the way they are supposed to when they fold properly, said Lindquist.

Folded the right way, proteins “help an organism stay the same,” she said.

Protein folding is normally kept in check by “chaperone” systems that clamp proteins in place during cellular transport. Lindquist said that “very specific degradation machinery” helps dispose of nonstandard — “misfolded” — proteins.

But sometimes misfolded proteins overwhelm this protective system. To blame are inherited genetic mutations or environmental stressors like heat, oxygen deprivation, and aging.

If proteins fold the wrong way, they can lead to disease states — cancer, cystic fibrosis, or neurological disorders like Parkinson’s or Huntington’s disease. Lindquist and her research team (including 2005-06 Radcliffe Fellow Luke Whitesell) are using yeast-based models of protein-folding diseases to develop novel approaches to therapy. (Lindquist is also co-founder of the Cambridge-based FoldRx Pharmaceuticals.)

“Misfolding is a big part of diseases,” said Lindquist of the side of her research looking into therapies. “[We] really want to make people who are sick better.”

But misfolded proteins can also help organisms evolve — “reach new forms and functions,” as Lindquist put it. Organisms can store protein misfolding variations in a “silent form” until — awakened by environmental stressors — they may prompt evolutionary change.

Most evolutionary change is slow, she said. But protein folding — “conformational change” — may be a new frontier in understanding some forms of rapid evolution.

Lindquist showed a picture of two different-looking Rocky Mountain monkey flowers, one that has evolved to be pollinated by bumble bees and the other by hummingbirds. Their “massive changes” in appearance and function, she said, were the result of only a handful of major gene changes. (A gene is a unit of DNA that codes for a protein.)

But saying that protein misfolding is an agent of change “is by no means completely accepted” among evolutionary biologists, she said of her controversial claim. “This is a work in progress.”

As a graduate student in biology at Harvard in the 1970s, Lindquist didn’t mind a little controversy. She was already bucking the system by being where she was — a female in a department where female faculty members were outnumbered by males 65 to two.

The disparity, she said in one interview, freed her to take risks. That included changing her laboratory work, before she had tenure, from fruit flies to yeasts.

“Yeasts are our best friends,” said Lindquist. After all, they perform the chemistry responsible for making bread, beer, and wine.

But in the lab, yeasts are also a handy means of studying protein mutations, and getting at the root of how those mutations contribute to disease.

One mechanism Lindquist studies is heat shock proteins (Hsp), which help other proteins fold correctly and which buffer (i.e., hide) small mutations. In yeast, she’s investigating Hsp90. It’s an abundant type of heat shock protein that a normal, self-regulating cell only needs a little of — but which floods to rescue when protein misfolding occurs.

Here’s the catch. Hsp90 rescues not only normal proteins, but also the unstable mutant proteins that cause cancer. “The cancer is actively subverting our protective activities,” said Lindquist.

But the catch comes with a hope: that scientists can manipulate levels of Hsp90 as a clinical strategy. That takes care. Inhibiting levels of Hsp90 early may be good, said Lindquist; doing it later may unleash mutations.

About 20 different clinical trials are currently under way, looking at how to use Hsp90 inhibitors against cancer.

While at Radcliffe, Lindquist is one of 13 scientists this year who as fellows are actively pursuing research with Harvard entities. She’s working with the Broad Institute, the Harvard-MIT research collaboration that, along with the Whitehead Institute, investigates the connections between genomics and medicine.

“Susan is an extraordinary scientist, teacher, and mentor — all of which are clearly reflected in her presentations,” said Barbara J. Grosz, interim dean of the Radcliffe Institute for Advanced Study. “Her cutting-edge research with Harvard scientists has greatly enriched Radcliffe and Harvard this year.” (In her earlier role as dean of science, Grosz undertook several initiatives to attract leading scientists like Lindquist to Radcliffe.)

Lindquist has brought talent and insights to the fellows program, “including her penetrating questions at talks by fellows from all across academic fields and the arts,” said Grosz. “We are delighted to have her with us.”


Why proteins misfold, for good or ill, is explained in part by the environment of the cell itself. Cells are always jam-packed with proteins, and very busy.

“It’s not like Fred Astaire and Ginger Rogers,” said Lindquist, who showed a clip of the two graceful dancers gliding around on a big dance floor. “It’s more like a Marx Brothers movie.”

Remember the crowded stateroom scene in “A Night at the Opera?” Lindquist showed that as an example of how crowded cells are. And crowded cells are an environment that makes protein misfolding more likely.

Lindquist showed another video clip, a Harvard product called “The Inner Life of the Cell,” an animated rendering of a cell’s inner landscape. The cell’s protein workforce has been trimmed by 90 percent, said Lindquist, to allow enough room to show a little of what happens.

You’ll see an aquarium-like hive of rolling leukocytes and lily-pad lipid rafts. Motor proteins cakewalk along wavering microtubules. Restless mitochondria bulge like fat worms just beneath the surface of glistening membranes.

You won’t see this astonishing film at your local multiplex, but you will find all eight minutes of it, with narration, at the web site of Harvard’s Department of Molecular and Cellular Biology (