At the Frontiers of Neuroscience 36 May - June 2002 by PATRICIA THOMAS Reprinted from Harvard Magazine

Brainy Women At the frontiers of neuroscience 36 May - June 2002 by PATRICIA THOMAS Reprinted from Harvard Magazine. For copyright and reprint information, contact Harvard Magazine, Inc. at www.harvardmagazine.com human brain rests in cupped hands as easily as a cantaloupe. It is softer and spongier to the touch, of course, and its surface is more deeply ridged and wrinkled than the melon’s skin. Since the time of Hippocrates, physicians and scientists have contemplated the brain and wondered not only how it gives rise to everything we feel, know, accomplish, and create, but also how all this can be stolen by injury or disease. It wasn’t until the invention of the microscope, in the seven- teenth century, that scientists were able to examine nerves in any detail. By the early nine- teenth century, pioneering physiologists had traced those fibers to the brain and made Asome observations that hold true today. They figured out, for example, that pulling back from a hot stove was a reflex, not a conscious action. They also learned that di≠erent re- gions of the brain govern distinct functions, knowledge that enabled doc- Carla J. Shatz (opposite), chair tors to examine a head injury and predict—at least in a crude way— of the neurobiology department whether it was more likely to leave the patient crippled or sightless. at Harvard Med- ical School, maps In 2002, these insights seem primitive, dwarfed by the twentieth-cen- neural transmis- sions in her labo- tury revolution in neuroscience and its clinical partner, neurology. Mod- ratory. Below, an image of the ern science has reduced the throwing of a ball—or a tantrum—to mil- lateral geniculate nucleus showing lions of details that can be described in the precise language of the millions of connections biochemistry, genetics, and molecular biology. Although medicine has made by retinal ganglion cells benefited from knowing millions of individual facts about the brain, the from the left eye (red outer ring) dean of Harvard Medical School (HMS), Joseph B. Martin, a neuroscien- and the right (turquoise tist himself, says that the next step is “putting Humpty Dumpty back center). together.” He is confident that assembling a more holistic, integrated model of brain function will lead to better, safer treatments for stroke, memory loss, Parkinson’s disease, and other major disorders. As neuroscience shifts gears, something else remarkable is happening at HMS: the latex-gloved hands that hoist the brain like a melon or, more accurately, feed a few of its cells into a high-powered analyzer, are in- COURTESY OF CARLA J. SHATZ Photographs by Tracy Powell Harvard Magazine 37 Reprinted from Harvard Magazine. For copyright and reprint information, contact Harvard Magazine, Inc. at www.harvardmagazine.com creasingly likely to be the hands of a woman. Carla J. Shatz ’69, Jf ting-edge technology of their time, Hubel and Weisel used tiny ’76, Ph.D.’76, chairs the department of neurobiology and is the electrodes to stimulate a single nerve cell and then recorded the first and only woman to head a basic-science research depart- chain of electrical messages it sent to other cells. Thousands of in- ment at the medical school. Anne Buckingham Young, M.D.- dividual measurements were required to construct a map show- Ph.D., is chief of the neurology service at Massachusetts General ing how input from the eyes journeys to the back of the brain, Hospital (MGH); she is not only the sole female department where the visual cortex transforms these signals into what we head, but also the only female neurology chief at any academic see. They also discovered that these pathways are established medical center in the United States. As prominent as Shatz and during a critical period early in life, and that blocking signals dur- Young are in the world of brain research, they are not alone at the ing that time will result in permanent visual impairment. These medical school. Around them are numerous researchers who are findings earned them the 1981 Nobel Prize in physiology. not only young and gifted, but female as well. Investigators Li- Shatz’s own research built on theirs. En route to the visual cor- Huei Tsai and Junying Yuan, Ph.D. ’89, who have each made im- tex, signals from the eye are channeled through circuits in the lat- portant discoveries about disease and injury in the brain, are rep- eral geniculate nucleus (LGN), a part of the thalamus. Shatz was resentatives of neuroscience’s next wave. the first to show that before birth, the fetal retina sends messages that begin sorting “a jumble of wires” in the LGN into layers. “Cells that fire together, Once a human baby or animal is born, light striking the retina wire together”: Mapping Brain Function triggers electrical impulses that bombard the LGN, refining its arla shatz and the department she now chairs structure into highly organized layers that e∞ciently transmit in- grew up together. In the summer of 1966, after her first year formation to the visual cortex. Brain cells that don’t see any action Cat Radcli≠e, HMS elevated neurobiology from mere labora- are “pruned” as a part of normal development. Although Shatz tory to full-fledged department. People were turning on, tuning in, has used the visual system to demonstrate this “use it or lose it” and dropping out, and by the standards of the time, Shatz was principle, the same process holds for other forms of learning and probably a bit of a grind. Her father, a scientist, and her mother, an memory. “Cells that fire together, wire together,” she says. artist, had encouraged her to excel in West Hartford’s demanding Electricity and microscopes were nearly all that neurobiolo- public-school science curriculum. At Radcli≠e, she was one of only gists had to work with 30 years ago. Now their laboratories are two women concentrating in chemistry. By the start of her senior crowded with new gizmos. “Everybody is incredibly opportunis- year, however, she realized that it wasn’t her true calling. tic, always reaching out for any and every technology that they “I was really interested in how we see,” Shatz recalls. She had think might help,” Shatz says. Since the late 1970s, recombinant been captivated by Nobel laureate George Wald’s course on the DNA technology has made it possible for neuroscientists to zero chemistry of vision and Rudolf Arnheim’s class on visual percep- in on one gene at a time, testing to see which ones are activated as tion, which emphasized that science could contribute to debates the brain wires itself, and which of their proteins strengthen es- about art. But even more important was her mother’s influence. sential connections or prune extraneous ones. “Her painting got me interested in vision from the artistic side, Now the one-at-a-time approach is being supplanted by all-at- and in some subliminal way guided my decision to work on the once technologies that make it possible to study thousands of visual system.” cells, genes, or proteins. “Even the simplest action involves more Shatz’s undergraduate adviser suggested that she seek a tutor- than one nerve cell at a time, so the goal is to study the function- ial with David H. Hubel, a physiologist at the medical school (and ing of many, many cells simultaneously—and we can’t do that now research professor of neurobiology) who studied vision. A without computers,” Shatz says. For example, her lab uses a high- tutorial would allow her to graduate with honors and still enable tech imaging system that takes tiny blips of electricity emitted by her to begin the transition from chemistry to biology. Shatz tele- whole groups of neurons and converts them into pictures so that phoned “out of the blue, and at first I was skeptical,” Hubel re- scientists can watch as thousands of brain cells pass along a mes- calls. “But I said, “What the heck.’” Every week she handed him sage. Viewed on a monitor, this looks like “the wave” rippling an essay about a scientific article he had given her to read, and through the bleachers at Fenway Park. Not surprisingly, in a mod- every week, he adds, “I covered them with red ink.” ern biology lab the computers outnumber the people. A Marshall Scholarship took Shatz to University College Lon- In 1998, a massive gene screen led to one of the most remarkable don, where she earned a master’s degree in physiology. Mean- findings yet to emerge from the Shatz lab. Postdoctoral fellows while, back in Boston, women were registering gains on campus. Gene Huh and Lisa Boulanger set out to identify every gene acti- In 1969, the year that Shatz graduated, anatomist Elizabeth Hay vated in nerve cells during normal development. Mostly they (now Pfei≠er professor of embryology) was named the first fe- found genes they already knew well, but one was as out of place male full professor in a basic research department at HMS. as a peach pit in a melon: the gene encoding a major immune-sys- When Shatz returned from London, she immediately peti- tem molecule, class I MHC, was turned on while normal neural tioned Hubel and his research partner, Torsten Weisel, to accept connections were forming. Class I MHC proteins are common her as a Ph.D. student, even though they rarely took anyone more elsewhere in the body, where they bind tiny snippets of invading lowly than a postdoctoral fellow. “I told her she could do it, but viruses and bacteria and display them on the surface of infected she would have to work like hell,” Hubel says with a chuckle.

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