Mood Genes

Samuel Barondes, Robertson Professor of Neurobiology and Psychiatry at the University of California, San Francisco, is one of the true pioneers in the field of 'Molecular Psychiatry'. Barondes is a member of the Institute of Medicine of the National Academy of Sciences, President of the McKnight Endowment Fund for Neuroscience and recently Chairman of a Workgroup on Genetics for the National Institute of Mental Health and author of Mood Genes: Hunting for Origins of Mania and Depression.

Manic-depression has afflicted some of the most creative minds, Dickens, Byron, van Gogh, Schumann and Newton among them. This very association gives the story an interesting subtext - many 'patients' either do not believe they are ill or do not wish treatment (principally due to the enticement and energy of the manic phase). Theoretical geneticists have inferred the genes have actually been selected into the genome. Still, the costs are steep and often entail appallingly bad or even dangerous judgments - sexual indiscretions, fiscal calamities, family and work woes, and even suicide.

The New York Times described his book as ''unputdownable'' and other reviews have likened it to a spy thriller. Pert words for a science book, but I too found Mood Genes engrossing. It is substantive yet highly readable, in large part due to the clear language, coherent progression of subject and the avuncular tone that Barondes maintains. One would hardly know he is himself among the leaders in the field, amid all his clarity, affection for the science, and personal modesty. Yet his team has persevered in research with affected families in the United States and Costa Rica.

The hunt for mood genes is significant and timely since, Barondes notes, bipolar manic-depression affects "about one in a hundred of us in its flagrant form, and possibly several times as many of us in its milder version." Moreover, the long-standing observation that mood disorders often run in families - often imminent families - strongly suggests a basis in hereditary and genetics. Hence, psychiatric geneticists are avidly studying DNA samples in family lineages to identify genes and molecular mechanisms characteristic of the disease. Such mechanisms will be the foundation for more precise treatments in the future.

Barondes begins with a painlessly concise introduction to modern genetics that specialists may readily pass over but it is worth a read if only as an example of crisp writing. It generally achieve avoids technical terms or otherwise clarifies what are ''centimorgans,'' ''lod scores,'' ''riflips'' and such like.

But then the tale picks up speed.

In the course of the book's 10 chapters, 193 text pages and an exceptional set of notes, Barondes interweaves a peppy historiography of recent, pivotal research with an explanation of the scientific strategies and advanced technology by which genetic linkage analyses proceed. Barondes invokes the metaphor of a screenplay in which ''the enemy spy with the secret radio transmitter is tracked down by gradually homing in on the source of the radio waves.''

A typical method of mood-gene sleuthing is to identify a family with a lot of mania and deprssion, then ascertain whether any association with known genetic markers (DNA fragments with known chromosomal loci). If so, this is a 'hot lead' that narrows the search since it is likely a relevant gene is present nearby. The trail is indeed 'hot', but the case is not closed. 'Leads' have been found along the "long arm" of chromosome 18 as well as chromosomes 4, 6, 13, and 15.

Of course, such searches for genes that affect behavior run the gamut from schizophrenia, autism, Tourette's syndrome, substance abuse onto Alzheimer's disease and beyond. Likewise, linkage analyses are underway for almost every medical condition thought to have a significant genetic basis. As Barondes says, "Over the long run as genes that predispose people to specific mental disorders are found, we will begin to understand that these are illnesses like other kinds of physical illnesses and that some people are especially vulnerable."

This progress in genomics already feeds a lively debate over ethical, legal and social dimensions. But almost certainly, the identification of genes linked to mood syndromes will give rise to new tests and treatments. One sharp controversy is to do with the nigh-inevitability of pre-natal testing and selective abortion. While some expectant parents may understandably opt to terminate pregnancies at great risk of carrying bipolar disorder, might such culling also deprive such individuals and society as a whole of persons with extended range of affect and ability? Novel medications may derive from an increasing grasp on the proteins, enzymes, or hormones products and/or how such products specialized molecules affect the brain and mind. These eugenic concerns may be transcended if new medications may render the disease harmless or even allow the manic tendency to be effectively harnessed. Ever the optimist, Barondes is confident the enhancement of treatment options will outweigh many of these concerns.

If Mood Genes is a detective story, it is a cliff-hanger: there is no clear 'culprit'. That manic-depression is a robustly genetic syndrome was documented rather early in the 20^th Century. However, the elucidation of the more precise genetic loci and effects of the syndromic DNA remain an object of 'hot pursuit' even now in the early 21^st century.

© 2001 Daniel R. Wilson

Daniel R. Wilson, MD, Ph.D., Chairman of the Department of Psychiatry and Professor of Psychiatry and Anthropology.