Science & Psychiatry: Interview Series
Drs. Ronald Rieder and Eric Nestler discuss how the field of epigenetics can help inform psychiatry
Drs. Rieder and Nestler at the Science & Psychiatry Seminar on September 27, 2011. Dr. Rieder invites leading scientists to describe their work and the potential their fields have to impact our knowledge of the causes and treatments of psychiatric disorders. Watch video
Providing a Translational Education
Dear Friends and Colleagues,
The Department of Psychiatry at Mount Sinai School of Medicine is fortunate to be in an institution whose leadership is committed to the translation of basic research on disease processes into better methods of clinical care. This is especially true with regard to psychiatric disorders, for these leaders – Kenneth Davis, MD, President and Chief Executive Officer of Mount Sinai, and Dennis Charney, MD, Dean of Mount Sinai School of Medicine – are themselves psychiatrist-scientists who have done and continue to do exactly this type of translational research.
We are also fortunate to have at Mount Sinai noted research programs led by scientists whose investigations are likely to have a foreseeable impact on the field of psychiatry. They are involved in genetic, brain imaging, molecular biologic, neurophysiologic and treatment studies that are being published in leading psychiatric and neuroscience journals.
As Vice Chair for Education, I see part of my job is to do another type of translation; I call it “translational education.” Some of our psychiatric residents and medical students are neuroscientists (we have a physician-scientist track in the residency), but most are not. All, however, need to understand the nature of these scientific studies, and especially the way that they may impact clinical practice over the next decade. This is why we introduced our Science & Psychiatry Series. The below transcript is an example of what goes on in our residency training program — discussions with scientific leaders about the nature, findings, and future impact of the many studies being conducted both here and elsewhere in new disciplines, such as epigenetics, brain imaging and genomics.
We hope that you enjoy reading the report, and would be very pleased if you distributed it to residents or faculty members who might also find it useful. Watch my interview with Dr. Nestler
Sincerely,
Ronald O. Rieder, MD
Professor of Psychiatry Residency Program Director, Vice Chair for Education
Science & Psychiatry Seminar: Interview Transcript
Eric J. Nestler, MD, PhD is the Nash Family Professor of Neuroscience; Professor of Psychiatry, Pharmacology and Systems Therapeutics; Chairman of the Department of Neuroscience at Mount Sinai School of Medicine and Director of the Friedman Brain Institute at The Mount Sinai Medical Center. His laboratory studies include the molecular mechanisms of drug addiction and depression in animal models.
Dr. Rieder: Eric, what is epigenetics?
Dr. Nestler: Epigenetics is a word that has many meanings and is used differently by different people. Strictly speaking, epigenetics describes changes in function that are caused by alterations that do not involve a change in DNA sequence. So it’s a very broad definition. There’s environment, there’s genetics, and epigenetics is everything else. We should drill into it at several levels to understand exactly what that is.
Epigenetics is best understood from a developmental perspective. Every cell in the body, to at least 99 percent accuracy, has exactly the same complement of DNA. So as stem cells begin to differentiate into different cell types and different tissues, it’s the epigenetic modification of genes, turning genes on and off, that lead to tissue/cell-specific traits. Humans have roughly 25,000 genes; only a subset of those genes is expressed in each of our adult tissues. And that selective expression occurs through epigenetic mechanisms.
The same processes continue to occur throughout adult life. In the brain, a brain cell can never become a liver cell, but at a finer level of analysis, brain cells can change in a stable way over time. In fact, presumably that’s what makes it possible for us to learn and remember and feel and think and so on. And it is the selective turning on, turning off genes in specific nerve cells in the brain, mediated through these epigenetic mechanisms that underlie most advanced aspects of brain function.
Dr. Rieder: How might epigenetics be important for psychiatry?
Dr. Nestler: In several ways, eventually. We’ve been discussing for a century or more that most psychiatric phenomena result as a combination of genes and environment, nature and nurture. Epigenetics defines the vehicle or the mechanism by which that intersection occurs. So, the extent to which nutrition or viral infections prenatally influence a child, for his lifetime, is probably mediated through epigenetic mechanisms. The extent to which stress, in early childhood or going through adult life, alters an individual’s susceptibility to stress or other events later in life is also mediated through these very stable changes in gene expression that occur through epigenetic mechanisms.
I should describe the biochemistry of epigenetic mechanisms so people know what I’m referring to. If the DNA in a single cell were stretched out linearly — we have about 3 billion nucleotides in our DNA — that DNA would be two meters long. It’s an amazing expanse, and in every neuron, every single cell in the body, that two meters of DNA is somehow compacted into a microscopic cell nucleus. We now understand a great deal about that process of compaction. DNA, a double helix strand, is wrapped around a sphere, around octamers of histone proteins, and that unit is called a nucleosome. Thus, the DNA forms a structure that looks quite a lot like a strand of pearls where the pearl is the nucleosome and the spacing in between is what’s called linker DNA. Then those nucleosomes are packed still further to fit into a microscopic nucleus. So, you can appreciate the degree of compaction that’s required.
When DNA is compact it cannot be expressed into messenger RNA and protein; it’s inactive. When it’s stretched out it can serve as a substrate for RNA polymerase that transcribes DNA into messenger RNA and so on. There’s not enough space in the nucleus for all the DNA to be stretched out all the time. That’s why in every Nucleosome cell only a subset of the genes is available for expression. We have a great deal of detailed understanding of the biochemistry underlying the opening and closing of the DNA. When the nucleosomes are spread further apart, genes are active; when nucleosomes are compacted, genes are inactive.
The spreading results from biochemical processes that modify the histone proteins or the DNA itself. Methylation, acetylation, and phosphorylation are the processes that add chemical groups that remain in place until removed.
Resident Laili Soleimani, MD: My question was about non-biological methods of treatment. Are there any data that they actually affect the methylation or epigenetic expression?
Dr. Nestler: Absolutely. There are a lot of examples where behavioral experience has been shown to produce epigenetic modifications. You’d expect that. You take a mouse, put it in a maze, and it learns the maze. That learning, which can then last a lifetime, is encoded in part through changes in gene expression in particular parts of the brain. And the ability of the brain to effect those permanent changes in gene expression is through epigenetic mechanisms. And that’s just one example of a behavioral experience resulting in epigenetic modification.
So by analogy we would fully expect that psychotherapies that can alleviate symptoms of mental illness are working partly through epigenetic modifications. It depends on how you formulate the positive, active ingredient in psychotherapy. If you think of it as a form of learning or experience, then it’s very easy to extrapolate from these studies in animals to imagining what’s happening in humans.
Dr. Rieder: Can we now study epigenetic mechanisms in humans?
Dr. Nestler: We cannot at this point because it requires having access to the brain tissue itself. One of the goals of current research would be to define brain imaging methods that would begin to provide glimpses into epigenetic mechanisms in living humans. It’s a long way off, but I think there are some tangible ways that that might be accomplished.
Dr. Rieder: Then we will invite you back for an update. Thanks very much for this wonderful presentation.