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GENES AND THE BRAIN
Week of September 15. 2004

In this hour, we explore Genes and the Brain. Now that we've mapped the human genome, what clues is this stunning scientific feat providing about how the brain works and why, sometimes, it doesn't? Guests include Dr. Eric Kandel, professor of physiology and psychiatry at Columbia University and the first psychiatrist to win the Nobel Prize in more than 70 years; Dr. Christopher Walsh, professor of neurology at Harvard Medical School and the chief of neurogenetics at Beth Israel Deaconess Medical Center; Dr. Jenae Neiderhiser, associate professor of psychiatry and behavioral sciences at George Washington University; and Dr. Michael Kaplitt, assistant professor of neurosurgery and director of the Center for Stereotactic and Molecular Neurosurgery at the Weill Medical College of Cornell University.

Host Dr. Fred Goodwin begins with an essay in which he says that the discussion of genes and environment, particularly in the media, is usually set up as genes vs. environment - a sort of zero-sum formula in which the more that's attributed to genes, the less can be attributed to the environment. But, according to a study we hear more about later in the show, the opposite is true. Genes and environment work together. Every child's personality is different from birth - some are naturally more sanguine, some more restless or anxious, some shy, some extroverted, and so on. So, not only does the same environment influence each child differently, but each child's genetically influenced personality patterns shape how the parents relate to him or her.

Then, Dr. Goodwin interviews Dr. Eric Kandel, the first psychiatrist to win the Nobel Prize in more than 70 years. Dr. Kandel is senior investigator at the Howard Hughes Medical Institute and University Professor of Physiology and Psychiatry at Columbia University.

Dr. Kandel begins by explaining the basic idea behind the biological basis of behavior. All behavior emanates from the brain -- the ability to laugh, create music, walk, write letters. Every mental function is, in fact, a brain function. He then discusses his groundbreaking research into the role genes play in learning and memory. To get a good handle on this complicated process, he went to a very simple animal -- the marine snail Aplysia. He showed that learning involves altering the strength of the connections -- or synapses -- among neurons in the brain. Then he began to explore this in molecular terms, and he found that there is a pathway within the cell that activates genes and gives rise to the growth of new synaptic connections. One of the most interesting findings was that genes are actually being turned on -- they are not the invariant controllers of behavior, but, rather, they are being turned on and off by environmental stimuli, such as our interactions with other people.

They then discuss the future of psychiatry. Ultimately, Dr. Kandel hopes this biological revolution will give rise to a new science of mind that will open up the scientific underpinnings of psychotherapy. For example, people may be able to use imaging techniques to study the brains of people before and after therapy and see whether specific aims have been accomplished. With regard to the major mental illnesses, he believes there will be a completely new way of categorizing and classifying them once we understand their molecular defects.

To contact Dr. Kandel, please write to: Dr. Eric Kandel, Senior Investigator, Howard Hughes Medical Institute, Columbia University Center for Neurobiology and Behavior, 1051 Riverside Drive, Room 668 Annex, New York, NY 10032. Or visit: http://www.erickandel.org/.

Before Dr. Goodwin interviews a neurologist who has been doing fascinating work to uncover the genes critical in the development of the human brain and human intelligence, we hear from patients of his -- people who have been directly affected by genetic brain disorders. First, Dawn Baxter of Connecticut, who suffers from the same genetic seizure disorder as her mother and daughter. She talks about the heartbreaking experience of watching her daughter have her first seizure, at age nine, and feeling as though she were to blame. She imagines her mother felt the same way.

Then, we hear from Isabel Walcutt of Virginia and her daughter, Roberta, who has a rare disorder known as double cortex syndrome. Roberta, who is almost 34, is able to talk a little bit about her own seizures -- she tells us "the doctor feeled my blood and I'm all right and there's no problem with my seizures." Ms. Walcutt then explains that her daughter seemed to develop fine until the age of one, at which point she seemed to become classically autistic. At the time, doctors generally thought autism was a psychological problem, and they often blamed the mother. Ms. Walcutt says she carried a lot of guilt. At age eight, Roberta began having terrible seizures of all types, but it wasn't until 1999 that she went for an MRI. They then discovered that she had a genetic condition affecting the positioning of neurons in her brain. Ms. Walcutt wonders why genes sometimes express themselves and sometimes don't. She says it's mind-boggling that some people can have this genetic flaw and live normal lives and others can barely live at all.

Then, Dr. Goodwin interviews Dr. Christopher Walsh, professor of neurology at Harvard Medical School and the chief of neurogenetics at Beth Israel Deaconess Medical Center.

Dr. Goodwin asks Dr. Walsh about the "big questions" he's trying to answer in his work. He says the ultimate question is, "What are the genes that make us human?" Although we won't have an answer to this anytime soon, his lab is going about exploring this issue by working with children who have had the bad fortune of being born with genetic diseases that rob them of their unique human talents, such as social interaction or intelligence. He looks for the genes that cause these diseases, with the theory that, because these genes are so essential for our normal cognitive development, at least some of may have been important in the evolution of our unique human traits. He gives the example of a condition called microcephaly, in which the brain can be as much as half its normal size. His lab has found the gene for this disease, and, looking at the gene across different species, he can tell is seems to have evolved.

His research also has clinical applications that help families right now. He's able to offer genetic counseling and genetic testing, and, by learning more about a specific disorder on the genetic level, he can better tailor treatments for individual children.

To contact Dr. Walsh, please write to: Dr. Christopher A. Walsh, Bullard Professor of Neurology, Harvard Medical School, BIDMC Room 816, HIM, 4 Blackfan Circle, Boston, MA 02115. Or visit: http://www.bidmc.harvard.edu/neurology/walshlab/.

Identical twins can provide some of the best insights into the role of genes and environment. After a short break, we hear from identical twins Tom Patterson and Steve Tazumi. They were separated as infants in a Japanese orphanage more than 40 years ago and adopted by different families in the United States. Tom, who grew up in Kansas, and Steve, who grew up in south Jersey, were reunited a few years ago. To their surprise, they were similar in more than just appearance. They found that they walked alike, talked alike, and even had scars from injuries they suffered on the same place on their bodies. They are both weightlifters, and they both married Caucasian women and gave their first child a Japanese name and their second a Caucasian name. We originally recorded them for a show on Twins, shortly after they met for the first time as adults.

Listening to the twins, it's hard not to wonder. Genes? Or environment? Truth be told, it's one of the most fascinating questions in modern psychiatry. Dr. Goodwin's next guest is part of a research team that is giving us some intriguing - and surprising - answers. Dr. Jenae Neiderhiser is associate professor of psychiatry and behavioral sciences at George Washington University. She is one of the co-authors of The Relationship Code: Deciphering Genetic and Social Influences on Adolescent Development.

Led by Dr. David Reiss, Dr. Neiderhiser's research team has conducted a large-scale study of more than 700 families demonstrating every degree of relatedness -- from identical twins to full siblings to half siblings to step siblings. They found that parents treat children differently in correlation with their genetic relatedness. In other words, they treat identical twins more alike than siblings, and siblings more alike than half siblings. The most likely explanation is that children's genes are correlating with their environment. Either, the parents share a gene with a child and so it looks like they're parenting more similarly, or, the child's genes evoke a particular response in parents. Either way, environment ends up being at least as important as genes in determining how children develop -- genes shape environment and environment shapes how genes are expressed.

Dr. Neiderhiser says that in some cases, identical twins raised apart end up being more similar than identical twins raised in the same home. She speculates that this may be because, when in the same home, each twin must work hard to differentiate from his or her co-twin. When raised apart, they are able just to "be themselves." Plus, it is likely that, because of their shared genes, they are evoking similar responses from the two sets of parents, thus giving them similar home environments.

She says these findings are important because they let parents know that it's appropriate to treat different children differently -- that is, to respond to their genes. For example, one wants to respond to a child with a difficult temperament differently than one would respond to one with an easy temperament, because the former will need more help managing in the world.

To contact Dr. Neiderhiser, please write to: Dr. Jenae Neiderhiser, Associate Professor, GWU Department of Psychiatry and Behavioral Sciences, 2150 Pennsylvania Avenue, NW Washington, DC 20037. Or visit: http://www.gwupsychiatry.org/.

To order a copy of The Relationship Code, click here.

Gene therapy has been in the news quite a lot in recent years, and not all of the reports have been good. Although there have been great successes, patients in various trials have, on occasion, experienced serious, life-changing side-effects or even died. But many scientists believe gene therapy will, ultimately, be the best treatment option for a variety of diseases - including major brain disorders. Dr. Michael Kaplitt is one of the leaders of a team of international scientists who will be conducting the first ever gene therapy trial in humans to treat Parkinson's disease. Dr. Kaplitt is assistant professor of neurosurgery and director of the Center for Stereotactic and Molecular Neurosurgery at the Weill Medical College of Cornell University.

Dr. Kaplitt begins by explaining the principle behind gene therapy -- the basic concept is to take advantage of our understanding of the sequence of the human genome and to use a gene essentially as a drug, so that the gene becomes a little factory making whatever protein you want inside the cell to treat the disease. In this case, it will allow the cells to perform a function they don't usually perform, and this new function will replace important functions that are abnormal in a particular disease process.

He then explains what went wrong in recent fetal cell trials for Parkinson's disease, in which the patients who showed improvement also experienced a severe side effect. He says the fetal cells actually worked too well -- they constantly pumped out the neurotransmitter dopamine, without any regulation, and that's what caused the side effect. In the new gene therapy trial, they will not be going into the dopamine cells. Rather, they're going into the brain in a later part of the circuit that controls movement.

They then discuss problems that have developed in gene therapy trials for other diseases, such as so-called "bubble boy" disease. Dr. Kaplitt says his trial has been designed with patient safety in mind, and there are built-in safety measures. They are operating on the same part of the brain where they already do surgery for Parkinson's disease, but they hope to have better, safer results. If the genes do end up having any unpredicted effects, the surgeons can go back into the same spot and either put in an electrode, as they would in deep brain stimulation surgery, or destroy that part of the brain, as they would in lesioning surgery. Both of these operations are already performed on Parkinson's patients.

To contact, Dr. Kaplitt, please write to: Dr. Michael G. Kaplitt, Department of Neurosurgery, Weill-Cornell Medical College, 525 E. 68th St., New York, NY 10021. Or visit: http://www.beatparkinsons.com/.

Finally, commentator John Hockenberry gives his --somewhat skeptical view -- of the human genome project and the biotech revolution.

- Marit Haahr

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