A GPS for the Developing Human Brain

One of the most surprising gaps in our knowledge about brain disorders is our ignorance about the human brain. With 100 billion neurons and a thousand times that many connections, mapping the human brain is not a trivial undertaking. Of course, early in the last century, the general regions were mapped out with numbers assigned to different cortical areas. But even a century ago, it was clear that these regional maps would not be adequate to define the location of the hundreds, perhaps thousands of different types of cells in the brain, along with all of their connections. As an analogy, we had the map of the states and, in some areas, maps of the counties, but we lacked the addresses for all the houses and we had little information about the occupants of those houses.

In 2007, the first comprehensive atlas with the regions, the houses, and the occupants was published for the mouse brain. The Allen Institute for Brain Science created an extraordinary resource for neuroscience by mapping the patterns of gene expression across the mouse brain.

Gene expression -- technically known as “transcription” -- is the process by which DNA is read out as RNA prior to being converted into protein. What can you do with a gene expression atlas of the mouse brain? A scientist who finds a gene associated with schizophrenia can surf this free, web-based atlas to find out where the putative schizophrenia gene is expressed in the mouse brain and what other genes are expressed in the same cells. Or a scientist who finds a specific brain area involved in learning or fear or addiction can use this atlas to identify the genes expressed uniquely in a specific part of the brain.

For these kinds of research projects, two years of laboratory work have now been collapsed to two minutes of web searching. Not surprisingly, the Allen Institute mouse brain atlas has become a daily search tool for labs across the world, a GPS for the mouse brain.

What about the human brain? The sheer complexity and size of the human brain was formidable, but the Allen Institute scientists developed tools, first with non-human primates and later with humans, to permit partial maps of gene expression in the brain. Of course, for NIMH, which focuses on developmental brain disorders, the most important achievement would be a map of the developing human brain. With the American Recovery and Reinvestment Act, we funded a major research effort on this goal, building on a unique NIMH Intramural collection of brains across the lifespan, expertise at Yale and University of Southern California, and the previous mapping success of the Allen Institute.

The results, the first “transcriptional” (gene expression) map of the developing human brain was posted last week at http://www.developinghumanbrain.org/External Link: Please review our disclaimer.. This initial release contains data from up to 16 different brain regions in 25 donors spanning ages from 9 weeks gestation through 40 years of age. Along with the map of gene expression, several tools are posted to allow anyone to begin to surf through this unprecedented harvest of developmental information. While there will be more to come in the near future, and the current data fall short of a comprehensive GPS, already we can see some remarkable and absolutely unexpected insights into human brain development.

For instance, about 80% of genes in the human genome are expressed in the brain. This is more than the percentage of the genome expressed in other organs and the pattern of expression within the brain is highly localized. The pattern of expression in development is markedly different than in the adult brain; so different that the fetal brain appears to be a different organ. But what is perhaps most surprising is that many of the transcripts are unique to development. That is, the same gene is spliced in novel ways to produce different RNA fragments and potentially unique proteins during development. Some have suggested that the genetic variations associated with mental disorders may selectively influence these developmental “splice variants”. (1) Now we have a catalogue of when and where these variants occur in the human brain, we can begin to compare the findings of genetics with the maps of development.

This new developmental human brain resource is a landmark. Much remains to be done, but already we have a resource that can serve the clinical neuroscience community the way the mouse atlas has served basic neuroscientists. As this atlas grows with more counties, more houses, and more occupants, we can expect a new era in our understanding of mental disorders. Indeed, a GPS for the human brain is no longer science fiction.

1. Kleinman JE et al., Genetic neuropathology of schizophrenia: new approaches to an old question and new uses for postmortem human brains. Biological Psychiatry, 69: 140-145, 2011.