Eric Kandel on the Year in Neuroscience


December 29, 2008

What were the most significant neuroscience discoveries of 2008? Eric Kandel, a professor of biochemistry and biophysics at Columbia University, weighed in on the topic at an event at the Dana Center in Washington, D.C., in November. Kandel was a co-recipient of the 2000 Nobel Prize in Physiology or Medicine for his work on the physiological basis of memory. Here is an edited transcript of his remarks during a reception for members and guests of the Dana Alliance for Brain Initiatives.

Dana [Foundation] Chairman William Safire asks me every year to review some of the key issues that emerged in brain science in the past 12 months. In thinking back, I was struck that there were two advances that made a big impact on my thinking.

The first relates to the genetics of mental illness. Since the late 1970s we’ve begun to identify specific mutations in the genome associated with neurological diseases. Huntington’s disease was the first example in which restriction fragment polymorphisms led us to localize the huntingtin gene and to sequence it and then to pop it into experimental animals to see how the pathogenesis of the disease progresses.

There was enormous hope that this set of developments would also be applicable to psychiatry—to schizophrenia and depression. The fact is that progress in that field has been terribly disappointing.

The basic idea has been that there’s very good evidence for inheritance of these major psychotic illnesses. We know there’s a major genetic contribution—anywhere from 50 to 70 percent. But in the search for those genes, we’ve been stymied. The general thought has been that each of these diseases is what is called a complex disorder—it’s caused not by a single gene but by several genes, each having a weak effect but acting together. So people have used the general idea of a mutation in a single nucleotide, a single base of DNA, to try to identify genes that are important in schizophrenia and depression. And they’ve come up with occasional candidates, usually not confirmed; very few of them have stood the test of time. So this has been disappointing.

Recently a completely new approach came along, called copy number variation, which Michael Wigler at Cold Spring Harbor has helped pioneer, which has given us a new perspective on this. There are in the genome many chromosomes in which a part of the chromosome is missing or deleted or part of the chromosome is duplicated. This is called copy number variation. So these are not single nucleotides, nor single genes, these are sets of genes that are altered—either two copies are present or copies are missing. And it’s now been shown that there are lots of copy number variations in the human genome, and methodologies are coming along to characterize them, to see whether they could be contributing factors to genetic diseases.

One case in which the progress has been spectacular is in autism. A peculiar set of features surround autism. To begin with, one has the feeling that autism is becoming more frequent in the last 10 or 15 years—some sort of an epidemic—and no one quite understands that. The other interesting thing is that you often have a family in which the father doesn’t have autism, the mother doesn’t have autism, the siblings don’t have autism, but a given child has autism. So how do you explain that? Copy number variations have now been shown to explain a significant fraction of people with autism. Not a huge, but a significant, fraction.

And it explains both of these components. It turns out that some of these copy number variations are de novo mutations, so they don’t exist in the parents, they don’t exist in the siblings. They occur in the sperm or the egg, so they’re not in the rest of the genome, and they occur with age. Old sperm is particularly likely to give rise to copy number variations.

People marry later, they have children later, and that may very well explain the increased incidence. In addition, it explains why the siblings don’t have it, because this is a de novo mutation.

This is a major step forward, and there’s now some evidence it also contributes importantly, not necessarily as a de novo mutation, but as a mechanism, to schizophrenia. And it differs from single nucleotide polymorphisms in the sense that there each gene is thought to have a weak penetrance [or likelihood of occurring in a person with the diseases]. Here the mutated genes are thought to have a powerful penetrance.

The other thing that has impressed me is that in the last 20 years we’ve had no advances in pharmacotherapy. We started off with interesting antipsychotic agents, interesting antidepressants, but they really have progressed very modestly. Selective serotonin [re]-uptake inhibitors—each company’s copying from the other using exactly the same assays to develop it. Twenty years, and there’s general agreement that there is no difference between most of the selective serotonin [re]-uptake inhibitors and no improvement either. A drug sells not because it’s any better than any other but because there are major names associated with it.

In schizophrenia, the issue is even worse, because for 45 years there probably hasn’t been a better drug. There are drugs that have better side effects, but there have not been major developments in drugs.

The one thing that has become better is the legitimacy of psychotherapy. There are several behavioral therapies out there—interpersonal therapy, cognitive behavioral therapy—that have been shown in rigorous control studies, in depression, for example, to be at least as good as selective serotonin [re]-uptake inhibitors for mild and moderate depression and to be synergistic with drugs in severe depression.

Moreover, we’ve beginning to identify—particularly in depression—certain areas of the brain that function abnormally. For example, [Emory University psychiatry professor] Helen Mayberg showed that [Brodmann] area 25—the subgenual cingulate cortex—is hyperactive in depression. This area connects to the amygdala; the amygdala also is hyperactive in depression. When patients respond to psychotherapy, those abnormalities reverse. So for the first time we not only have a psychotherapy that works but we have an independent, biological measure, an assay, and we can see to what degree this works.

If we get markers for most psychiatric illnesses, and we can see to what degree drugs or psychotherapy affect them, we now will have much more effective ways of seeing how they combine. And also in psychotherapy, what type of psychotherapy is helpful for a particular indication and under what circumstances a female therapist is better than a male therapist, one [therapy] orientation is better than another. We’ll be able to make a science out of psychotherapy, which I predict is going to happen over the next 20 to 40 years.