FEATURE STORY — September/October 2006

The unfolding wonder of Susan Lindquist’s world

By Mary Timmins

This is no mosh pit, dude. This is what goes on under the microscope of Susan Lindquist ’71 LAS, a biologist who studies proteins in all their bad (and good) behavior – research that has brought her to the pinnacle of her field.

Working with proletarian fruit flies and humble baker’s yeast, Lindquist has contributed elemental knowledge to concerns as wide-ranging as brain disease, nanotechnology and the theory of evolution. “She is held in universally high regard by her peers, not only for the rigor and importance of her work but the elegance and diversity of her experimental approaches,” wrote John Cronan and Charles Miller, her University of Illinois colleagues in the biological sciences.

The years since she graduated from the University of Illinois have led to a doctorate at Harvard, prestigious positions at the University of Chicago and the Massachusetts Institute of Technology and a lively collection of honors, including membership in the National Academy of Sciences, the American Academy of Arts & Sciences and the American Philosophical Society. Recipient of a range of elite prizes for her research, Lindquist has been named among the 50 Most Important Women in Science by Discover Magazine. And Nobel laureate Thomas R. Cech has described her as “a star biologist and a strong leader of scientists.”

Poised and articulate, Lindquist is a compelling spokeswoman for the marvels of biological research, which she has described as “the greatest intellectual revolution that has happened in the history of mankind.” She’s also an advocate and role model for women in science and is passionately devoted to her family.

In May, the UI Alumni Association honored Lindquist with the University of Illinois Alumni Achievement Award. Despite battling an onslaught of Midwestern allergens, she was radiant in her acceptance speech at the association’s annual awards banquet. “We are actually learning what life is,” she said of the wonderment of working in biology. “It’s phenomenally beautiful. It’s intellectually captivating. And … it has the power to transform our lives.”

Her forte can be reduced to two words – protein folding. It’s a process best explained with a quick review from BIO 101. All matter – and hence all life – consists of cells. Within living cells, proteins crowd together and, acting on instructions from DNA, jostle frantically to do what they must – get strung together from amino acids (which encode the genetic information in the DNA) and take shape by folding. The latter process has been likened to origami, though comparisons to the Japanese art of paper folding, seem, frankly, understated.

“The proteins have to fold up into very, very complicated, very precise shapes,” explained Lindquist. These shapes, moreover, are of a variety and number so complex – perhaps even infinite – as to make possible an orchid that can lift its roots, or fingernails that are stiff and translucent, or cats with fine fur feathering their ears.

Such processes are vastly involved and vastly imperfect. An estimated one-third of all protein foldings go wrong. Misfolding is serious stuff – a single incorrect amino acid in a protein sequence in a human cell accounts for the ensuing devastation of cystic fibrosis. Some misfolded proteins start a gang and go on a rampage. These are prions (pronounced “pree-ons”), and they are linked to disorders such as mad cow disease. Cells retaliate, expending a tremendous amount of energy on quality control systems, aka chaperone proteins. Some chaperone proteins act like nannies, helping proteins that can’t quite get it together to fold themselves. Other chaperone proteins are more like medics at a riot scene, frantically refolding and repairing injured proteins and hauling away those that are past help.

Within every living cell, millions of proteins thus follow their genetic destinies in a manner so complicated and chaotic that it’s hard to understand the fact that we all exist, much less function. How and why is a mystery at the soul of Lindquist’s research.

“Biology is very complicated,” she said. “It seems just impossible to conceive that there could be something like an eye that can perceive light, and that the image of the light it perceives can be transmitted to the brain, and the brain can decode that, and then the brain can decide, ‘Oh, that looks like an apple. I’m hungry. I’m going to go pick that.’”

Lindquist arrived at the U of I in the fall of 1967, her ego less than inflated and her expectations pretty flat. Her mother thought she should go to college to meet a man. Her father didn’t understand why she should go to college at all. “Due to the fact that I was a citizen of Illinois and the fact that I had very high test scores, I was able to basically get a free ride there [via a legislative scholarship],” Lindquist said. “And that meant all the world of difference to me.”

In biology classes, she reconnected with a girlhood penchant for sludging together weird concoctions and fermenting them under plastic wrap. “It was in biology that I was simply transformed,” she said. “I really did not come [to the U of I] with the slightest thought that I could have a career and I could actually do something with my life.”

Lindquist also found that she just plain liked being at school. “I started realizing that I was actually looking forward to getting up for an 8 o’clock organic chemistry laboratory,” she said, “and that was not my normal way of doing things.” Invited to take a summer research job in the lab of UI microbiologist Jan Drake, Lindquist accepted and got “hooked.” After graduation, she went on to Harvard and studied with biological warfare expert Matthew Meselson. For a thesis topic, Lindquist chose to study proteins produced by the larvae of heat-stressed fruit flies.

“Over a couple of billion years, these systems have been honed from really basic principles into very elaborate, beautiful mechanisms,” she said. “And it really is just gorgeous when you start to study it.”

Fruit flies are a laboratory staple of BIO 101 because they reproduce and adapt to environmental changes with astonishing facility, apparently motivated by a genetic imperative to maximize their annoyance to still-life painters and people with fruit bowls.

When manipulated in the lab, fruit flies can shape-shift into vastly altered progeny in months – acquiring, in Lind-quist’s words, “different wing structures, different legs or different eyes.” Lindquist accelerated the fruit-fly mutations by blasting the larvae with heat. In so doing, she found that dormant mutations wake up, producing fruit flies with more new features. Stress on proteins may thus speed up mutations and adaptations – hence the process of evolution.

On a wholly different level, the benefits of bad times have long been known to wine growers – stress on vines (such as drought and cold) can concentrate and improve the flavor of grapes. From athletics to studying for finals, dozens of other examples accord with this insight.

So – stress is good? Believe it, dude.

Lindquist’s career has had its own allotment of jostling and chaos. In 1971, being a female in the sciences was tough. Harvard had just one woman on the biological sciences faculty – a woman who was, according to Lindquist, “not a full professor and never would be.

“When I went to graduate school, it didn’t even occur to me that I could actually run a lab some day. I was going there to get credentials such that maybe I could work in some other person’s laboratory and would be worthy of being able to contribute,” Lindquist said.

The life to come was thus not the life she had been expecting. After Harvard, Lindquist did postdoctoral research at the University of Chicago, eventually rising to become the Albert D. Lasker Professor of Medical Sciences and an investigator for the Howard Hughes Medical Institute. In the late ’90s, she led a team that used cellular structures to develop fibers of gold and silver one-thousandth the diameter of a human hair and strong enough to conduct electrical signals. In 2002, Lindquist accepted the directorship of the prestigious Whitehead Institute for Biomedical Research – the first woman so appointed. Affiliated with MIT, Whitehead has been the site of major breakthroughs in the biomedical sciences and genomics and was a leading contributor in mapping the human genome, an enormous and celebrated project completed in 2003.

The transformation that she had undergone at Illinois held her in good stead for the arc of her career path. “I had started with this passion that I had acquired [at the U of I] and that really saw me through a lot of difficult times and into some really, really wonderful times,” she said.

Lindquist has since stepped down from the Whitehead directorship but remains on the faculty there and at MIT and is again an investigator for the Howard Hughes institute. She is a founder of Fold Rx, a company that develops drug therapies based on research in protein folding. She lectures all over the world, at universities and at high schools, committed and inspired, letting the world know about her strange, alluring and potent molecular universe.

A science consultant for museums and filmmakers, Lindquist frequently discusses her work in the media and has a gift for describing research in terms that even non-techno types who write for alumni magazines can understand. Her Web site at web.wi.mit.edu/lindquist/pub is a wonder of technical yet accessible information, with links to her publications, bibliographies and descriptions of what goes on in her lab. There’s even a podcast in which she talks about “Futures in Biotech.”

Thanks to leaders such as her, futures in biotech are more open to women than ever. Lindquist observed that today more than 50 percent of the doctoral candidates graduating from MIT in the biological sciences are women. Yet, she noted, “that does not translate into women having an equal chance at the level of faculty appointments.” Lindquist is an advocate of mentoring and higher pay for graduate students, as well as the importance of both personal happiness and professional fulfillment. “We need to support not only women but men as well who want to have this phenomenal career and who want to have families,” she said. “And we haven’t done that yet.”

Lindquist herself has balanced on the work/family seesaw for years. Her husband, Edward Buckbee, is a development officer for Harvard Business School; their daughters, Alana and Nora, are 17 and 19, respectively. “My family has been a psychological anchor in my life,” Lindquist said. “Careers go up and down, but my family is there for me. They’ve just been phenomenal. And I’ve tried to be there for them, too.”

Lindquist recalled “the joy of coming home to see my kids every day when I would come home from the lab. … even though it was really hard work to raise children and pay attention to my career … they refreshed my brain. They wiped the slate clean at night.” She and Edward love to tango, a dance she described as a process of linking together “many elements in constantly changing ways.”

The description curiously echoes the phenomena Lindquist observes in the lab, using fruit flies, rat embryo neurons, roundworms and yeast.

Yes, baker’s yeast. It’s an easygoing, laid-back kind of microorganism that is, as she explained, “responsible for beer and wine and bread – mankind’s best friend in many ways.” When Lindquist first began exploring cells in yeast, skeptics questioned the relevance of the research. Yet, her work with this humble, facile and genetically tractable material has leavened her rise to the top of the world of cellular microbiology. Using genetically engineered, cultured yeast cells, Lindquist found that genes counteract the effects of certain misfolded proteins – the same misfolded proteins responsible for damage to human brain cells caused by Parkinson’s disease. The research could prove critical in developing new drugs to treat that illness.

“We use simple organisms and our understanding of really fundamental processes that are shared by all organisms to start really in a much more rapid way attacking really very difficult, complex problems for mankind,” Lindquist explained.

Her quest, long-going and intense, aims for the far horizon of human understanding – the knowledge of how life forms and sustains itself.

“The same kinds of molecules that control our immune systems actually are involved in insect immune systems,” Lindquist observed. “The same kinds of molecules that actually control aging and things like protein folding are the same in yeast as they are in man. When you start focusing in on that, you start to see there are some really very simple, basic, fundamental principles by which all biological systems work. And the beauty of seeing those, the simple logic of it.

“Over a couple of billion years, these systems have been honed from really basic principles into very elaborate, beautiful mechanisms,” she said. “And it really is just gorgeous when you start to study it.”

Oh, that’s some crowd under her microscope, dude. Some crowd, all right.