1026 ESSAY CREDITS: (LEFT) HEMERA/THINKSTOCK; (RIGHT) EPHRAT LEVY-LAHAD/SHARE ZEDEK MEDICAL CENTER, JERUSALEM genomic states affect the topological organization of chromosomes. Exciting progress has been made recently in mapping the three-dimensional (3D) chromatin architecture. Growing evidence suggests that long-range chromatin interactions are crucial for transcriptional regulation and genome rearrangement, for example, in cancer cells. Ten years ago, the linear composition of the genome was

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... spelled out; I anticipate that in the next 5 to 10 years, we will be able to reveal the 3D topographic map of the human genome within cells, which will help us uncover new insights into development, as well as into the basis for disease. The past 3 years have witnessed a series of replicable, credible, and increasingly useful genetic discoveries in autism, schizophrenia, and bipolar disorder. I cannot emphasize enough the signifi cance of this progress. Neuropsychiatric disorders are outsized contributors to global disease burden, yet treatment development has reached a near standstill. The problem is that the brain, with its myriad cell types and complex circuitry, represents such a diffi cult scientifi c frontier. Because genes play powerful roles in neuropsychiatric disorders, identifi cation of causal variation could provide invaluable clues to their pathogenesis. Sadly, the genetic architecture of neuropsychiatric disorders is fi endishly complex, but unlike other areas of medicine wrestling with genetic complexity, psychiatry lacks objective phenotypic markers. When I became director of the National Institute of Mental Health (NIMH), NIH, in 1996, I did not foresee quite how complex the genetics would prove, but did recognize that the contemporary technologies were overmatched. (I ruefully joked that I had the only institute with no lowhanging Mendelian fruit to pluck.) With expert advice, I decided that the only rational approach was to amass large collections of patient DNAs with extensive phenotype information. Some investigators resisted sharing of samples, but for most, that day has long passed. I am pleased that these NIMH collections have proven useful, albeit as only a small fraction of the needed sample sizes. It was not, of course, the fi rst human sequence per se that turned the tide for neuropsychiatric disorders. As for much of medicine, the associated technologies and analytic approaches (above all, the availability of ever cheaper and more accurate DNA sequencing) are proving decisive. These advances have given investigators, clinicians, and patients hope that genetics will fi nally yield tools that neurobiologists have dreamt of to study the brain in health and in illness.