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Cartographer of the brain

Medicine@Yale, 2008 - Mar Apr


On a quest to decipher how a complex brain arises from a single cell

The cerebral cortex is comprised of distinct, orderly regions that subserve particular cognitive functions such as vision, hearing, movement and language. The function of every neuronal cell depends on its position and pattern of connectivity. How this complex neuronal map arises from a single fertilized cell during development is one of the most intriguing puzzles in science. “This map holds the secret of unique human mental abilities,” says Pasko Rakic, M.D., Ph.D., director of the Kavli Institute for Neuroscience at Yale, “and I have long wondered how it is made and reproduced from individual to individual.”

A Croatian, born in the former Yugoslavia, Rakic’s first forays into neurobiology began during his medical education, followed by graduate training in developmental biology and genetics at Belgrade University. He entered residency in neurosurgery but became restless, and in 1969 immigrated to the United States to join the Department of Neurosurgery at Harvard. However, an inclination toward basic science soon inspired him to transfer to Harvard’s Department of Neuroscience. “I felt that I could help more by doing research,” he says, “since so much was unknown.” In 1978 Rakic was recruited to Yale School of Medicine by famed cell biologist and Nobel laureate George E. Palade, M.D., as professor of neuroscience and the founding chair of the Department of Neurobiology, a position he continues to hold as Dorys McConnell Duberg Professor.

Rakic was fascinated by his initial experiments using DNA markers of cell division on slices of embryonic human brain, which showed that none of the billions of our cortical neurons are generated locally. Thus, unlike those in other organs, cortical cells must migrate to their final destinations from a proliferative zone in the embryonic cerebral brain that becomes increasingly distant from the cortex as the brain grows. Perhaps Rakic’s greatest contribution is that he provided the first cellular and molecular explanations of how this migration could occur.

His studies of the remapping of the proliferative zone upon the expanding cerebral cortex in various species led him to publish a unifying hypothesis of cortical development and evolution in the journal Science in 1988 that has since been confirmed in his as well as other laboratories. Over the years he and his colleagues have identified genes and molecules involved in the regulation of the production and migration of cortical neurons. His 4-dimensional model of the developmental events that take place over time, from the initial divisions of neuronal stem cells through their migration and stratified settlement in radial cortical columns, is reproduced in virtually every neuroscience textbook. Further, by manipulating neuronal migration using genetic and environmental factors, Rakic has discovered the hidden abnormalities of neuronal positioning that cannot be discerned by routine postmortem examination of the human brain, opening a new insight into the pathogenesis of a variety of the so-called idiopathic disorders of higher brain functions, such as childhood epilepsy, autism, developmental dyslexia and mental retardation.

Rakic is also known for his assertion that the adult human cerebral cortex does not generate new neurons—in other words, you get what you are born with. He postulated that the stability and longevity of the human neuronal population may be a biological necessity for the retention of long-term memory and learned behavior over the life span, since we rely heavily on acquired knowledge soaked up through schooling and experience. In other words, “it is actually an advantage that no new neurons are generated,” he says, “lest the brain’s slate be continually wiped clean.”

Rakic’s conclusion that cells subserving the most precious human mental functions are irreplaceable has repeatedly been corroborated, inspiring researchers to study how to best preserve the cortical neurons and their circuits, in which our lifelong experience is stored.

Even after four decades of effort, Rakic can hardly contain his enthusiasm for his research on the cerebral cortex. “This is the most appropriate study of humankind,” he says, “because it is this particular part of the brain that distinguishes us from all other species.”