2007 : WHAT ARE YOU OPTIMISTIC ABOUT?

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Professor of Neurobiology and Psychiatry, UCSF; Author, Making Sense of People
Neurobiologist and Psychiatrist, University of California San Francisco; Author, Better Than Prozac

Finding Mental Illness Genes                            

When I trained in psychiatry in the 1960s, schizophrenia and bipolar disorder were blamed on bad mothering. Now we know that the pathogenic stuff that mothers (and fathers) transmit is genes.

Once this was established, scientists began searching for the genes that are involved. The main thing we have learned so far is that variants of quite a few different genes (maybe dozens or even more) may each increase the risk of developing one of these disorders; and that several (or more) of these variants must work together in a particular person to produce an appreciable increase in risk. Because so many combinations of gene variants may each produce the same pattern of  mental  illness, it has proved to  be very difficult to identify any one of them with the techniques that identified the single genes that cause some other disorders, such as  rare  forms of Alzheimer’s disease.

To have a good chance of identifying the combinations of genes that influence the development of schizophrenia or bipolar disorder two things are needed: thousands of DNA samples, each from a person who is clearly suffering from the disorder being studied (to compare with controls); and an affordable technique for scrutinizing each DNA sample in  sufficient detail to identify all the salient genetic variations. Both these requirements are now being met. Groups of researchers have been collecting the requisite number of DNA samples from patients with clear-cut cases of schizophrenia or bipolar disorder; and the costs of  detailed genomic analyses keep coming down. When the numbers of samples are big enough and the costs of analysis are small enough, the relevant genes should be found. Already a few gene variants have been tentatively implicated as risk factors for schizophrenia.

Nevertheless, there are skeptics. Unconvinced by the tentative findings, their biggest worry is that there may be so many different kinds of schizophrenia or bipolar disorder that any collection of DNA samples, no matter how large, will be a jumble, and that the many relevant gene variants in the samples will all elude detection.

This is where optimism comes in. I am optimistic that this approach can work now, if it is adequately funded. And I am disappointed that there are enough influential pessimists to limit the wholehearted support that it needs to succeed. What makes this so important is that identification of these genes will have important practical consequences in the design of new treatments to replace the unsatisfactory ones that we presently employ.

We are at the point where a concerted effort to find the gene variants that predispose to disabling mental illnesses has a high probability of success.  It is a time for optimism. It is a time for funding with a full hand.