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2015 Neuroscience Prize

Michael Greenberg

Michael Greenberg was born in Florida, but spent most of his childhood in Brooklyn, New York growing up as the youngest of four children. His mother, an artist and psychologist, and his father, a film producer, divorced when he was young. “My parents — in particular my stepmother, who was a teacher — encouraged me in academics and instilled in me the importance of making a contribution to the world,” he recalls. “She also insisted that I try different things, and I had a lot of opportunities to do that growing up in Brooklyn.” 

One of those opportunities was to participate in a National Science Foundation summer program at the Roswell Park Memorial Institute (now the Roswell Park Cancer Institute) in Buffalo where he worked in the laboratory of Dr. Jake Bello. “I got hooked on biochemistry and biophysics — obsessed, really,” says Greenberg. “This was unexpected since no one in my family was a scientist — not even remotely.” After graduating from high school, Greenberg was invited back to the Institute for three subsequent summers. “I got paid to do science at a time when my family’s resources were very limited” he says. “It was an exceptional opportunity.” 

Greenberg did his undergraduate studies at Wesleyan University, graduating magna cum laude in 1976 with a degree in chemistry. “I went to Wesleyan because it was known for having a strong intellectual environment, but also for allowing its students a great deal of independence,” he recalls. That desire for academic independence led him to pursue his doctoral studies at The Rockefeller University in the laboratory of biologist Gerald Edelman, who had won a Nobel Prize in 1972 for his discoveries related to the chemical structure of antibodies. “At Rockefeller, you just chose a lab and got to work,” he says. “There were very few courses, but there was a lot of emphasis on the graduate students and on what they were doing in the labs.” In the late 1970s and early 1980s the Edelman lab was notorious for being a difficult place for a student to train. Greenberg recalls.  “However, I think it was there that I learned to conduct rigorous experiments and to focus my attention on important scientific questions.”  After receiving his PhD, Greenberg spent three years as a post-doctoral fellow in the New York University lab of molecular biologist Edward Ziff. “What Ed was doing at the time was virology, which wasn’t exactly what I wanted to do,” recalls Greenberg. “But when I went to speak with him, it turned out that his thinking was evolving along the same lines as mine. So we managed to develop some experiments that proved to be very fruitful. Ed was essential to my development as a creative scientist.  Working in his laboratory was a wonderful experience for me.”

In 1984, with Ed Ziff, Greenberg designed an experiment to investigate the process by which growth factors send signals within a non-dividing cell telling it to re-enter the cell-division cycle.  They found that growth factors do this by instructing cells to turn on (transcribe) a particular gene, c-fos. “It was one of the very first examples of how a growth factor in a mammalian cell affects gene transcription,” says Greenberg. “It also led us to discover that neural activity affects gene transcription,” — a landmark finding that is now a central tenet of neurobiology. Subsequent to these initial discoveries involving c-fos, Greenberg and other researchers have identified hundreds of additional genes that are activated in the brain response to sensory stimuli. 

In 1986, Greenberg accepted an assistant professorship position at Harvard Medical School’s Department of Microbiology and Molecular Genetics, where he stayed until 1994, when he joined the neurology faculty at Children’s Hospital Boston to direct the Division of Neuroscience.  At both institutions, Greenberg continued his investigations into the molecular mechanisms that underlie the effects of experience on the brain. His lab focused on identifying new features of the genetic program activated by neuronal activity, as well as how the program varies in response to different stimuli.  Using  — and often pioneering — advanced laboratory techniques, Greenberg and his team were able to describe in elegant detail the neural pathways by which various proteins and developmental cues activate gene transcription in neurons. In one of the most notable of these discoveries, published in Science in 2001, Greenberg uncovered how a particular calcium channel — the “L-type” voltage-gated Ca2+ channel — leads to the expression of genes important for learning and memory, as well as for the survival of the neuron itself. 

Another major discovery involves a class of RNA known as enhancer RNA (eRNA). Scientists had known for several decades that certain sections of DNA enhance the process by which messenger RNAs (mRNAs) are synthesized and then transmit genetic information from a cell’s nucleus to the cell’s cytoplasm to form proteins. In particular, how enhancers function to activate gene expression remained a puzzle. Working with cultured mouse neurons, Greenberg found that not only do environmental stimuli activate the “enhancer regions,” but these areas also create strands of eRNA that play a role in driving gene expression. These findings, which were published in Nature in 2010, provided the first evidence of widespread enhancer transcription.  According to Greenberg “there’s now a whole new cottage industry developing around eRNA function”.  In other recent studies, Greenberg  and his colleagues have begun to identify how neural activity restricts the number of excitatory synapses, and promotes an increase in inhibitory synapse number, by regulating gene expression during brain development after birth —  findings with profound implications for developing an understanding of the biochemical underpinnings of brain abnormalities, including autism spectrum disorders.

Recently, Greenberg and his team have been doing transformative work related to Rett syndrome, an autism-like disorder whose symptoms appear at a very young age, primarily in girls. Early in 2015, Greenberg’s lab reported that the lack of the protein MeCP2 in patients with Rett syndrome — a hallmark of the disease — selectively disrupts the expression of exceptionally long genes in the brain. “This is an exciting finding, because it suggests that the misregulation of long genes may be what’s behind the disorder,” says Greenberg. 

In 2008, Greenberg returned to Harvard Medical School to chair its Neurobiology Department. “It seemed like a great opportunity to give back to the neuroscience community in Boston,” he says. “A lot of my time now is spent toward developing neuroscience at Harvard University in general — and that’s very rewarding.” Among Greenberg’s many honors and awards are memberships in the American Academy of Arts and Sciences and the National Academy of Sciences. He has also helped to mentor numerous undergraduates, graduate students, post-doctoral fellows, and junior faculty, and in 2006 received Harvard Medical School’s A. Clifford Barger Award for Excellence in Mentoring.

Greenberg lives in Brookline with his wife, Rosalind Segal, MD, PhD, who is a professor of neurobiology at Harvard Medical School and the Dana-Farber Cancer Institute. They have two grown children, Rachel, who is pursuing her PhD in developmental biology at Stanford University, and Daniel, who is currently working as a legal assistant.  Greenberg enjoys biking, running, and hiking with his family, and when he has the time, plays clarinet as part of an amateur chamber music group.