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When Impatience is a Virtue

James Potash, M.D.

Dr. Potash James Potash came into the world at The Johns Hopkins Hospital, where his father was a psychiatrist. After Yale and the Peace Corps, Potash returned to Hopkins for a public health degree, med school, a psychiatry residency. He joined the faculty in 1998. Perhaps it’s his ease with the place that’s let him step into uncharted research territory for a psychiatrist, even one comfortable with genetics.

Potash joined the search for genes just as his mentors were starting to clear the underbrush, the work able to link symptoms of mood illness with chromosomal areas. Still, areas aren’t genes. And Potash was more than keen to seek an alternate approach, one based on mood disorder subtypes—traits like having suicidal tendencies or having oddly distorted thinking—that can accompany the disorders.

Because subtypes tend to bunch in families, surveying genomes of "purer" groups can force subtype genes into the open. That, in turn, narrows the search for the “main” genes for bipolar (BP) or major depressive disorder. Potash had his eye on psychosis, for example. In some BP families, he noticed, most everyone affected also has delusions or hallucinations. By sampling a whole family’s DNA, he and colleagues narrowed symptoms of psychosis to chromosomes 13 and 22, the same areas linked with such abnormal thinking in schizophrenia. The find not only gives a toehold for the fine-mapping that will likely yield genes; it also builds insight into the closeness of the two disorders.

Potash's studies in epigenetics are truly exciting. The field deals with ways to control gene expression operating outside of the genetic code, even though it's still heritable.

Epigenetics may offer a scientist's heaven of sorts, the much-sought tie between mood disorders and environmental factors like stress or diet.

Also, there’s the suggestion that therapies such as lithium and Depakote work, in part, by changes in the epigenetic control of key genes.

As the Center’s research director, Potash is making epigenetic mood disorder studies a priority. He’s begun, for example, by comparing postmortem brains of people with and without major depression for differences in epigenetic patterns.

The potential of a whole new approach to mental illness waits, untapped.

Epi at the Forefront

Now that the genome is sequenced, scientists realize it’s but a backbone for understanding how genetic programs direct development. Superimposed on the human DNA sequence, like so many Post-it notes, is a layer of heritable epigenetic information that we’re only beginning to appreciate.

It’s sure that added-on epigenetic controls play a part in human disease. In 1983, Hopkins researchers showed that, in certain cancers, for example, the "post-its" were lost in ways consistent with each variety.

But what of mood disorders?

“Some connection is likely,” says the Center’s James Potash, who heads efforts in the field. “We know, for instance, that Depakote, the most common bipolar medicine, alters epigenetic patterns.”

In 2007, Hopkins opened the first epigenetics center. And its new Brain Science Institute, a group of world-class basic scientists, confirms epigenetics as a frontier. Prodded by Potash, it’s set up the Epigenetics Microarray Lab to uncover epi-effects on the brain in health and disease.

GENE WORK: A SAMPLE
Center research has shown that:

Bipolar disorder (BP) II is a common, genetically distinct illness.
Some chronic depression, especially one beginning in childhood, runs in families.
Certain BP subtypes likely have a genetic basis, with a chromosomal “home.” They include panic disorder (chromosome 18), psychotic symptoms (chromosomes 13 and 22), suicide attempts (chromosome 2) and early-age onset (chromosome 21).
A gene called NTRK3 codes for a protein for brain cell growth and development.
A flawed form of that gene, on chromosome 15, may raise risk of depression.
The gene FKBP5, which produces a protein tied to the brain’s stress response, likely plays a part in BP susceptibility.
Two genes, HMG2L1 and NRG1, that code for signaling proteins within the nervous system appear tied to the risk of psychosis in BP.

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