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Protein origami is her passion

Biologist not limited by either glass ceiling or scientific dogma

As a child, Susan Lindquist loved to read, and recalls being especially moved at age 12 by a biography of Elizabeth Blackwell, the first female physician in America. On finishing the book, she announced proudly her intention to follow in Blackwell's footsteps. Her mother burst out laughing.

"She didn't mean to embarrass me or belittle me," Lindquist said. "It's just that girls, if they had any ambition at all, it was to be a teacher or nurse. Doctor was simply not in my mother's universe."

As it turns out, medical school is one of the few hurdles that Lindquist, director of the Whitehead Institute for Biomedical Research in Cambridge, hasn't vaulted in her enviable life in science, a life she has never taken for granted.

"When I was a graduate student, at Harvard, it was just awful for women," she said. "I took a lot of hard blows, never imagined that I'd have my own laboratory, and felt blessed just to participate. But a passion for science kept me going."

That passion has led Lindquist to a series of scientific epiphanies that have brought renown as well as controversy. Among these is a theory of inheritance that challenges Darwinian dogma, a theory of evolution that explains gaps in the fossil record, and a theory of disease that forces a reconsideration of the term "infectious." What these seemingly disparate ideas have in common is that they all began with Lindquist's abiding fascination with proteins.

Proteins are delicate yet tenacious, sinuous chains of amino acids folded like origami figures into intricate three-dimensional shapes. The function of a cell is determined by the proteins within it, and the shape of the protein to some degree ordains its function. But, in the hurly-burly of the cell -- packed as tight, Lindquist said, "as the Boston esplanade on July 4th" -- accidents happen, and proteins unravel. Most of these misshapen molecules are ushered harmlessly out of the cell, but when a distorted protein sticks, it can change everything.

Lindquist reckons that roughly half of all disease and most genetic disorders are rooted in protein malfunction. Rogue proteins that no longer hold their shape are to blame for cystic fibrosis, and a number of cancers. Amyloid proteins clumping like sludge in the brain are associated with Alzheimer's disease. The notorious prion proteins not only change their own shape, but transmit that distortion to neighboring proteins, prompting the lethal chain reaction known as mad cow, scrappy, and Creutzfeldt-Jacob disease.

Lindquist, 53, is a world expert on these and other protein-folding behaviors, which she describes as "the overarching theme" of her professional life. She stumbled into the field in graduate school in the early 1970s while studying the classic problem of gene expression. "We knew we had all these genes, and there was pretty good evidence that they got turned on and off, but we didn't know why," she said. "Each cell was using a different set of them: How does that happen? It was pretty much a black box at the time."

During the course of her work, she said she learned that, under stress, such as heat, "proteins start to misfold, they open up and they get stuck on each other, or newly made proteins are not protected properly and then they aggregate.

"This is the price life has paid for being efficient. The concentration of proteins inside our cells is staggering, and being right next to each other means that they can take components from each other immediately, and act efficiently. But it also means getting these newly made proteins folded properly is a huge, huge problem."

In the thick slurry of the cell, proteins crash around like bumper cars, constantly sticking together, and unraveling. This damage can be undone by "chaperone proteins," that, like so many intrepid chambermaids, neatly fold their distorted compatriots back into shape. Lindquist has found other proteins that help prevent the misfoldings from happening in the first place, and still others that in yeast untangle deadly protein clumps. These beneficial proteins work as a quality-control system in the cell -- a system that tends to break down over time, which explains why age is a risk factor for diseases like Alzheimer's and Parkinson's.

Lindquist's dearest hope is that her research might lead to interventions to stymie this mechanical breakdown, and prevent or even reverse disease. Her goal, she said, is to decode the underlying mechanisms of normal and abnormal cell function that control life.

Among Lindquist's many distinctions, supporters agree, is her drive to integrate research among several disciplines, and to inspire young researchers to dare to cross the threshold of conventional thinking into uncharted realms.

"She's got science on the mind, always has another new idea," said Whitehead senior scientist Robert Latek, whose field is bioinformatics. "You'll go to your computer in the morning, and there's a message, some truly amazing idea, that she's sent in the middle of the night. She's about the most creative person I've ever met."

Lindquist's collaboration with physicists and chemists has her delving into nanotechnology, trying to harness the power of the protein to build extremely small things. Exploiting nature's own methods for building organic structures, Lindquist said, will enable the building of devices far smaller than current manufacturing allows, ultimately increasing efficiency and decreasing the cost of consumer goods.

Such bold, unexpected thinking is typical of Lindquist, said former Whitehead director Gerald R. Fink, a biologist. "Early in her career, she wrote a number of papers that many thought were off the wall. But she made us look at that wall, and it turned out to be true. She has that rare mix of intelligence, vision and concern for others that make a natural leader."

Lindquist is the first female director of the Whitehead, and has appointed women to a number of top posts there, a consequence, she said, not of affirmative action, but of choosing the best person for the job. Still, she has made no secret of her belief in diversity. "We benefit when we enrich the tapestry," she said.

Lindquist herself is a product of what she describes as a union of opposites. Her father, a tax accountant, was Swedish, and her mother, a homemaker, Italian. "I've been told I have an unusual tolerance for a wide variety of personalities," she said. "Well, you can't imagine two more different personalities."

Lindquist said her parents' ambition for her was to get a good education, get married, and have a family. She did not disappoint. She studied biology at the University of Illinois, and did her graduate work at Harvard. She met her husband, Edward Buckbee, at the University of Chicago, where, until moving to the Whitehead in 2001, she was a professor in the department of Molecular Genetics and Cell Biology.

In her unassuming office at the Whitehead, her desk is cluttered with photos of her two teenage daughters, who, she said, prefer watching the Red Sox to "NOVA." She said she doesn't have much time for baseball, or for the leisure reading she loved as a child, but she does confess to one abiding distraction:

"My husband and I love to Tango. I'm talking about the Argentine tango, not that `international' or British style, which is so stiff and formal." Warm and unassuming, Lindquist shows no signs of formality, or of the driving ambition that almost certainly helped launch her into one of the most coveted leadership roles in science. She seems to have the time and patience for everything that matters, and shrugs off the idea that family life and science don't mix. "I feel so fortunate to have both a supportive, loving family and a challenging career. Frankly, I'm not sure I could have either one without the other."

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