What Should We Be Worried About?

THE FAILURE OF GENOMICS FOR MENTAL DISORDERS

TERRENCE J. SEJNOWSKI

Computational neuroscientist, Francis Crick Professor, Salk Institute for Biological Studies; coauthor (with Patricia Churchland), The Computational Brain

The Human Genome Project was a great success. Not only do we have the human genome, but after a decade of advances in gene sequencing the cost has plummeted from a few billion dollars per genome to a few thousand. This has had a profound effect on what questions we can ask about biological systems and has generated many important results.

Mental disorders are major health problems for society. Most of us know someone with an autistic child, a schizophrenic cousin, a friend suffering from depression. What impact has genomics had on the treatment of these disorders?

Autism occurs in 1 percent of children under the age of eight and their care is estimated to cost society $3.2 million over a lifetime; the annual cost for all autistic people in the United States is $35 billion per year. Schizophrenia, whose symptoms first appear in early adulthood, affects 1 percent of the population—annual cost, $33 billion. In comparison, the average annual cost of the war in Afghanistan has been $100 billion. We are waging multiple wars against mental disorders, with no end in sight. The burden on families and caregivers is not just monetary: Each person with a major mental disorder can disrupt many other lives.

Both autism and schizophrenia have substantial inherited components, and there was great hope that the origin of mental disorders could be understood by identifying the genes responsible. In studies of monozygotic twins, the concordance for autism is 30 to 90 percent—40 to 60 percent for schizophrenia. Large-scale genome-wide association studies have screened thousands of families with these disorders and concluded that no single gene mutation, insertion, deletion, or copy number variation can account for more than a small fraction of the variance in the population. These studies cost hundreds of millions of dollars and have lists of authors as long as those on the Higgs boson discovery paper. Hundreds of genes have been implicated, many of them known to be important for synapse development and function. Because autism and schizophrenia are far from being Mendelian traits, it is much more difficult to identify therapeutic targets that would be effective for a wide range of patients. This was a great disappointment and a concern for future genomics research on mental disorders.

Although sequencing the human genomes of patients has not yielded direct benefits, genetic tools are nonetheless opening up new approaches for treating mental disorders. Clinical depression is another debilitating disorder, affecting 15 million Americans; 20 percent of them do not respond to antidepressants. The annual cost for depression is $83 billion. A promising new therapy for drug-resistant depression is electrical stimulation of the anterior cingulate cortex, which is connected with other brain regions important for regulating well-being, whether we feel safe or vulnerable, and especially our emotional responses. In some cases, effects are dramatic, with the veil of depression lifting minutes after the onset of electrical stimulation. Although deep brain stimulation is promising, we don’t know why it works; progress will depend on more precise control of neural activity. A new technique that could revolutionize the treatment of depression and other brain disorders, such as Parkinson’s disease, is based on stimulating neurons with light rather than microelectrodes. Optogenetics allows light-stimulated ion channels to be selectively delivered to neurons via viruses. Depending on the ion channel that is inserted, light can cause a neuron to spike or be silenced.

Psychosis is currently treated with drugs that are at best palliative, with debilitating side effects. Progress in improving the treatment of mental disorders has been slow, but there are reasons to be optimistic. That depression can be lifted so quickly suggests that the neural circuits are intact but in an imbalanced state. Gross electrical stimulation may compensate in ways not yet understood. In schizophrenia, there is evidence for an imbalance between the excitation and inhibition in cortical circuits; in particular, there is downregulation of GABA, an inhibitory neurotransmitter, in an important class of inhibitory interneurons that provides negative feedback to the excitatory pyramidal neurons in the cerebral cortex. Plans to record from a million neurons simultaneously using nanotechnology are under way; this will give us a much better map of brain activity in normal and abnormal states. As we learn more about the nature of these imbalances, and as molecular techniques for manipulating neural circuits are perfected, it may be possible to better treat the symptoms of major mental disorders and perhaps even cure them.

There is a wide spectrum of symptoms and severity among those diagnosed with autism and schizophrenia. We now know that this depends in part on the particular combination of genes affected. Environmental factors also have a major influence. To paraphrase Tolstoy: Happy brains are all alike; every unhappy brain is unhappy in its own way.