2013 : WHAT *SHOULD* WE BE WORRIED ABOUT?

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 dollars. This has had a profound impact 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, or a friend suffering from serious depression. What impact has genomics had on the treatment of these disorders?

Autism occurs in 1% of children under 8 years and affects the development of their social and communication skills. Care for an autistic child is estimated to cost society $3.2 million over a lifetime, and the annual cost for all autistic people in the United States is $35 billion per year. Schizophrenia is also a developmental disorder, though symptoms first appear in early adulthood, and affects 1% of the population. Our annual cost for those with schizophrenia is $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 since 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 that are responsible. In studies of monozygotic twins, the concordance for autism is 30-90% and is 40-60% for schizophrenia. Large-scale genome-wide association studies (GWAS) have screened thousands of families with these disorders and have 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 that affects 15 million Americans and 20% of these do not respond to antidepressant drugs. The annual cost for depression is $83 billion. A promising new therapy for drug-resistant depression is electrical stimulation of the anterior cingulate cortex, a part of the cortex that 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 the 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 actually know why it works and 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 microelectrodesw Optogenetics allows light-stimulated ion channels to be selectively delivered to neurons with 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 side effects that are themselves debilitating. Progress in improving the treatment of mental disorders has been slow but there are reasons to be optimistic that this will change. The fact 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 that are 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 underway that 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 someday to better treat the symptoms of major mental disorders and perhaps even cure them.

There is a wide spectrum of symptoms and severity amongst those diagnosed with autism and schizophrenia. We now know that this in part depends on the particular combination of genes that are 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.