Top Canadian prize goes to Stanford scientist Lucy Shapiro for bringing cell biology into three dimensions

- By Krista Conger

Lucy Shapiro

Lucy Shapiro

STANFORD, Calif. - Lucy Shapiro may be the only artist who ever truly enjoyed organic chemistry. So much, in fact, that the newly graduated Brooklyn College fine arts major set aside her paintbrushes and devoted her life to biological research.

"It was clearly as much of a challenge as Dante, but more fun," said Shapiro, PhD, a professor of developmental biology at the Stanford University School of Medicine who also studied literature and wrote her undergraduate thesis on the Florentine poet. "Science is so beautiful, and you get real answers. I knew right then that ‘this was it.'" Obviously, wavering is not her style.

Shapiro's dogged pursuit of real answers has since fueled a lifetime of research and garnered a wall of awards. Along the way she's forged a new path in developmental biology research and fostered a growing interest in infectious diseases and global public health. Now Shapiro, who is also the Virginia and D. K. Ludwig Professor at the medical school, can add a Canada Gairdner International Award to her list of accolades. The award, which carries a $100,000 cash prize, will be announced on March 31, and formally presented in Canada in October.

Considered to be one of the most prestigious awards in biomedical science, the Canadian-based foundation honors individuals who have made outstanding and original contributions to medical research. It can also be a harbinger of things to come: One of every four recipients has gone on to win Nobel Prizes for their work.

"Lucy Shapiro has spent her career at the leading edge of developmental biology, exploiting a simple bacterial model to forge creative new research directions and yield novel insights about cell differentiation that are applicable to higher organisms," said Jeremy M. Berg, PhD, director of the National Institutes of Health's National Institute of General Medical Sciences, which has funded Shapiro's research since 1986.

Shapiro is currently the director of the Beckman Center for Molecular and Genetic Medicine. She has been a faculty member at Stanford since 1989, when she founded the School of Medicine's new Department of Developmental Biology.

Science seems a good match for the artist-turned-researcher who still enjoys painting watercolor portraits.

"Lucy is always doing something and always in a hurry," said her Stanford colleague Stanley Falkow, PhD, the Robert W. and Vivian K. Cahill Professor in Cancer Research. "She talks fast and is very, very rigorous in everything that she does. It's not just a matter of understanding something, she has to master it."

Shapiro completed her PhD at Albert Einstein College of Medicine in four years in the laboratory of biochemists Tom August, MD, and Jerard Hurwitz, PhD, working on the first RNA-dependent RNA polymerase. Six months into her post-doctoral studies at the same institution, she was asked to join its faculty. Within 10 years, she was professor and chair of the department of molecular biology at Albert Einstein College of Medicine, and, in 1981, Shapiro became the director of its Division of Biological Sciences.

Fortunately for the field of developmental biology, Shapiro took a few weeks between her post-doctoral and assistant professorship positions to ponder her future career. "The chair of my department told me to take three months to figure out what I might want to work on," said Shapiro. "It was an incredible opportunity. I really wanted to tackle an important unsolved problem." The course she set for herself was ambitious, to say the least.

"I wanted to know how the genetic code, or DNA, that exists in one dimension, is somehow translated into organisms like you and I that occupy space in three dimensions," explained Shapiro. "How does this work? How are the cellular positions of proteins and nucleic acid polymers inherited? This fundamental question set out the whole research program that I'm working on to this day."

Shapiro hit upon the unusual idea of using a one-celled organism (an asymmetrically organized bacterium called Caulobacter) to investigate what are, essentially, questions in developmental biology - formerly considered to be the purview of multi-celled organisms. "I found the simplest organism I could, and set out to learn how the multiple components of a living cell work together," she said.

"Lucy recognized this was a great model system long before anyone else did," said Stanley Cohen, PhD, who was a post-doctoral fellow in the Hurwitz lab when Shapiro was a graduate student there in the 1960s. "And when she did, she knew how to ask the right kind of scientific questions."

Shapiro's work showed for the first time that bacterial DNA replication occurs in a spatially organized way, and that the act of replication and the subsequent segregation of the DNA to opposite ends of the cell dictates the cellular position and time of function of the cell division machine.

Members of her lab also proved the existence of master genetic regulators of the bacterial cell cycle. As they began taking apart specific events - DNA replication, flagellum biogenesis and cell division - in a process Shapiro refers to as "in vivo biochemistry" - they found that some genes were involved in more than one event. For example, a regulatory gene involved in building the flagellum was also essential to the bacteria's viability.

"This made no sense at first," said Shapiro, "because Caulobacter doesn't need a flagellum to live. But then we discovered that these different events that we had been studying as if they were individual boxes, or silos, in the bacterial life cycle were actually connected by these global regulators - one of which controlled the expression of 95 other genes. It absolutely blew my mind." In response, she began to map the interwoven genetic circuitry responsible for connecting cell morphology, or how the cell looks in three-dimensions, with gene expression.

"Nobody expected this," she said. The discovery of the highly organized nature of the bacterial cell, which had been assumed to be just a bag of DNA and proteins, revolutionized the fields of bacterial cell biology and single cell developmental biology. But her career has encompassed more than just advances in scientific knowledge.

"She's always been a very intense person, very serious," said Cohen. "But she can also be very warm and caring. I love and respect her as a friend as well as a colleague."

Shapiro's ability to nurture friendships and cultivate the careers of those in her lab is also well known. "She's a very involved, caring and thoughtful mentor," said Cohen, who, together with Falkow, has served on a number of Shapiro's students' thesis committees. "The science that these students are doing is absolutely world class," marveled Falkow.

"I do everything I can to foster the confidence of the young people in my lab," said Shapiro. It must be working. "When I started, there were really only a few Caulobacter labs in the world. Now there are 19 around the world headed by my students alone. I feel like an oak tree dropping acorns."

In addition to planting the seeds of Caulobacter research in many countries, Shapiro has been politically active. What started as an interest in bioterrorism even before Sept. 2001 and evolved into an advisory role in both the Clinton and Bush administrations has become a focus on the threat of infectious disease in developing countries. She's now a member of the Center for International Security and Cooperation at the Freeman Spogli Institute for International Studies at Stanford University.

"It's very important to me that people know what to be afraid of - and what not to be afraid of," said Shapiro, who believes that increasing levels of both antibiotic resistance and novel infectious agents are likely to be a larger threat than bioterrorism. "It's not that the threat of bioterrorism doesn't exist. It does," she said. "But we are now sitting in the center of a perfect storm with regards to global health and natural outbreaks of infectious disease."

In trademark Shapiro fashion, she didn't stop at just talking about it. She and a collaborator, chemist Stephen Benkovic, PhD, at Pennsylvania State University, started a biotechnology company in Palo Alto called Anacor Pharmaceuticals to test and develop unique boron-based antibiotics and antifungals designed after identifying critical nodes in the Caulobacter cell cycle control circuitry. This work was the result of an interdisciplinary collaboration between Shapiro's lab and the lab of physicist Harley McAdams, PhD, also a professor of developmental biology at the medical school and to whom Shapiro is married.

"Lucy is very direct and outspoken," said Falkow. "She's a whirlwind. If you could bottle Lucy Shapiro's energy, we'd no longer have an energy crisis in this country."

"I don't know what my parents did right, but I was always very confident," said Shapiro. "I was so passionate about the science, and so sure as to where I was going and what I wanted to do, that I didn't spend much time worrying about what other people thought or said. It didn't matter. And I still can't wait to get into the lab every morning. That's never changed."

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