From The Quarterly, Summer 2012

Like most researchers, Schahram Akbarian, M.D., two-time NARSAD Young Investigator Grantee, winner of the prestigious Brain & Behavior Research Foundation Klerman Prize and a member of its Scientific Council, has a broad curiosity about nature and its workings.



But there is something about the human brain, he says, that makes it, for him, an almost irresistible object of study—something he’s devoted his life to.



“What always strikes me is that all of the nerve cells in your cerebral cortex, and most of the nerve cells throughout your brain, have been there since the end of your first trimester in the womb. And if you are lucky enough to live to 90, the DNA in those brain cells is the same DNA that was there the day you were born.”



While the DNA in brain cells will remain the same throughout a person’s life, the expression of individual genes and the resulting impact on the brain ‘network’ can vary greatly. “This raises the question of what goes on inside those cells over the many decades of our lives,” says Dr. Akbarian, Professor of Psychiatry in the Department of Psychiatry and Neuroscience at New York’s Mount Sinai School of Medicine.



How do brain cells register change, and as time passes, reflect our encounters with the environment that surrounds us? And how do those changes differ in healthy people versus those with brain and behavior disorders?



This last question is all the more compelling, Dr. Akbarian says, when one thinks of brain-based disorders in which there is no obvious degeneration of nerve cells, such as the visible knots and tangles in the brain that one sees in people with a neurodegenerative illness such as Alzheimer’s Disease.



It is precisely the ‘superficial appearance of normality’ of nerve cells in serious disorders like depression, autism or even schizophrenia that intensifies the mystery of what is going on inside the center of nerve cells, the nucleus. In this tiny compartment within every cell, 3 billion pairs of DNA ‘letters’ are organized into chromosomes, and an army of specialized proteins ‘service’ this genetic material, enabling the genes within the chromosomes to ‘express’ their individual messages. Those messages are the basis of every working part in our system, including the hundreds of millions of intricately networked brain cells that enable us to think, perceive, speak and react to our environment—in short, to behave like human beings.





NARSAD Grants at two pivotal points



When Dr. Akbarian was a postdoctoral student at the University of California, Irvine (with Dr. Edward G. Jones and Brain & Behavior Research Foundation Scientific Council Member Dr. William E. Bunney, Jr.) in the early 1990s, he had the opportunity to study this grand mystery of the brain at the level of genes and the proteins they instruct nerve cells to make. Or, to be more precise, abnormalities in the level of

a particular protein found in neurons called GAD67.



It takes 15 to 20 years after birth for GAD67 to reach levels that would be considered normal in adults. GAD67 is not unique in this respect. The long developmental interval following birth defines human childhood and adolescence and “it is during this same period, into the early twenties, that many serious brain and behavior disorders become manifest,” Dr. Akbarian observes. His first important discovery was that in the brain tissue of people with schizophrenia, GAD67 levels tend to be abnormally low. Since GAD67 expression is necessary for the function of inhibitory GABA neurons, it was an important bit of early evidence connecting GABA deficiency with schizophrenia.



Dr. Akbarian recalls, “When I was a young postdoctoral researcher, I quickly realized that there was nothing comparable to getting a NARSAD Grant. I applied and was fortunately selected to receive a Young Investigator Grant. It was that first NARSAD Grant that made possible my work on GAD67 in human postmortem tissue, and I’m proud to say that the papers we published about it are still recognized today.”



In the 1990s, it was just becoming feasible to look at the ways individual genes express themselves. A revolution was under way in the form of the Human Genome Project, and by the beginning of the new century, for the first time the DNA sequences underlying all human genes were finally revealed. At the same time, new technologies were making it possible to study the expression levels of many genes at once.



In the late 1990s, with the genome project well underway, Dr. Akbarian wanted to acquire important new techniques to genetically model brain disorders in mice. While a medical resident at Massachusetts General Hospital, he was accepted for special training at nearby Whitehead Institute, a mecca for genome scientists. There, working with Dr. Rudolf Jaenisch, Dr. Akbarian gained “exposure to experimental model systems and all that I needed to learn to work effectively with genetically engineered mice.” And immediately afterward, “at the end of my residency training, I received a second NARSAD Grant. This is what enabled me to collect an important set of preliminary data that ultimately led to a much larger NIH grant which sustained my work.”





Looking for ‘epigenetic signatures’ of illness



As his career progressed, Dr. Akbarian became intensely interested in the study of epigenetics. It’s a field that sheds light on when and how genes are expressed but on a level, one might say, mechanically a step ‘above’ the DNA of the genome itself. Epigenetics is the study of the way certain chemical groups attach themselves at particular points to the long, twisting double-helix of DNA, and by so attaching, change the ability of the underlying genes to be expressed (or not).



Why epigenetics? Dr. Akbarian refers by way of explanation to that great mystery of what happens to our essentially static DNA over the long course of our lives. The DNA itself does not change; but the context in which it is expressed constantly changes, as our bodies respond to experience and the environment. “There are so many years, from birth, and even during the prenatal period, during which the environment has a chance to impact what is ‘given’ by our genes. This is part of what epigenetics can tell us.”



Epigenetics reveal the state of the protein complexes called histones that bundle the DNA in all of our cells. Histones are very much like the spools around which a thread is wound. They’re essential because of the vast amount of DNA in every cell. If unraveled, the DNA ‘thread’ in each cell nucleus would measure six feet in length, almost unimaginable, given that we have so many hundreds of millions of cells and that cells themselves, much less their tiny nuclei, can’t be seen without a microscope.



The presence or absence of epigenetic marks in specific genome locations determines whether the cellular machinery that ‘reads’ genes can obtain physical access to them. Sometimes, an epigenetic mark will cause changes to the ‘spooling’ of DNA so as to block the underlying DNA, rendering a gene or genes inaccessible, and therefore in a ‘hidden’ or compressed state where they can’t be read or copied. In such cases, a gene cannot be ‘expressed.’



Dr. Akbarian’s work takes us to the frontier where an attempt is being made to measure the relationship between the pattern of epigenetic marks and the risk for brain and behavior disorders, particularly autism and schizophrenia.



In research published late last year, in Archives of General Psychiatry, Dr. Akbarian and colleagues revealed what they described as an ‘epigenetic signature’ of autism. In this pioneering work, they looked at a particular kind of epigenetic mark called methylation groups of methyl molecules that attach to DNA-spooling histones in brain cells of the prefrontal cortex sampled from 32 people, half of whom were diagnosed with autism.



The study revealed certain characteristic abnormalities in the ‘epigenetic landscape’ of prefrontal nerve cells in a quarter of the autism patients, that appeared in none of the healthy controls. Importantly, Dr. Akbarian and his team noted that the irregularities specifically affected areas of the genome containing genes whose functions govern connections between neurons, social behaviors and cognition.



Moreover, and perhaps most intriguing, the researchers observed that many of these same affected genes had been previously flagged as irregular in autism by scientists using not epigenetic but rather traditional genetic screening. “We can say then that there is considerable overlap in the genetic and epigenetic risk profiles,” Dr. Akbarian says, “which at the same time makes us more confident of the findings of earlier genetic research, and raises our confidence that the epigenetic signature we detected is indeed significant in the mechanisms responsible for autism.”