Nature paper provides new insights into the brain's structural and cellular complexity
Results published by the Allen Institute for Brain Science lay groundwork for advancing understanding of brain function
December 6, 2006 | Download PDF
The Allen Institute for Brain Science, a non-profit medical research organization founded by investor and philanthropist Paul G. Allen and Jody Allen Patton, today announced a series of key findings that shed light on the structural and cellular complexity of the brain. The results are reported online today in Nature (accessible via http://dx.doi.org, the DOI reference number is10.1038/nature05453) and will be published in a future print edition of the journal.
The peer-reviewed paper, based on global analysis of gene expression using the Allen Brain Atlas, reports new subregions of known brain structures; reveals novel markers for major classes of brain cells; and documents the complexity of gene expression patterns in the brain.
"The results in this paper represent the tip of the iceberg, as we and other scientists worldwide have only begun to mine this immense data set," said Allan Jones, Ph.D., the Allen Institute's chief scientific officer and an author on the paper. "Moving forward, we will continue to conduct research using the Allen Brain Atlas with a particular interest in the neocortex."
The Allen Brain Atlas is a Web-based three-dimensional map of gene expression in the mouse brain detailing expression of more than 21,000 genes at the cellular level. Freely and publicly available at www.brain-map.org, the Atlas provides scientists with a uniquely comprehensive data set that is being used by researchers around the globe to accelerate their progress toward understanding the brain. The Allen Brain Atlas, thus, has the potential to help make critical inroads into human brain diseases and disorders and to help expedite development of safe and effective therapies.
"This landmark paper represents the first attempt to see what we can learn from a global analysis of gene expression across the entire brain," said Marc Tessier-Lavigne, Ph.D., chairman of the Allen Brain Atlas Scientific Advisory Board and senior vice president, research drug discovery at Genentech, Inc.. "The completion of the Allen Brain Atlas represents a huge leap forward in one of the great frontiers of medical science—the brain."
Key New Findings about the Brain in Nature Paper
The Nature paper reveals, in a series of vignettes, several findings that reflect the utility of the Allen Brain Atlas for helping to better understand the brain.
- New Subregions Identified
Analysis of Allen Brain Atlas data revealed previously unrecognized subregions within known brain structures, such as the hippocampus, which is involved in learning and memory, and the cerebellum, which helps to coordinate movement. Within the hippocampus, genes encoding two neural signaling chemicals, the neuropeptides Grp and Nmb, are expressed in two distinct areas, suggesting functional differences between the two parts. Similarly, the expression of the gene Rasgrf1 reveals a previously unrecognized, but large subregion of the cerebellum. The identification of such subregions is a step toward a more detailed understanding of the working parts of the brain, and thus may lead to a clearer picture of how the brain executes its functions, including learning and coordinating movement.
- New Cell-Type Specific Markers
A search for genes expressed in each of the major cell types in the brain revealed a number of previously uncharacterized genes that each appear to be specific to one cell type. It is well known that the particular subset of genes that are expressed, or "turned on," in a cell determines that cell's identity, unique characteristics and function. The identification of novel cell-type specific markers may lead to a better understanding of cell-type specific functions in the normal brain as well as in diseases in which particular brain cell types are dysfunctional.
- Complexity of Gene Expression in the Brain
Several of the findings in the paper indicate an extraordinary degree of heterogeneity in the brain. Although 80 percent of all genes are expressed in the brain, the analysis of over 21,000 genes revealed that most genes are expressed in relatively few cells. Only a small fraction of all genes are expressed at high levels in all cells in the brain, whereas the majority of genes -- 75 percent -- are each expressed in fewer than 20 percent of the cells in the brain.
In addition, gene expression patterns across brain regions show variable degrees of restriction to single brain structures. Examination of the 100 genes most specific to each brain region showed that expression in some regions, such as the hypothalamus and midbrain, overlaps significantly with expression in others. Conversely, in other regions such as the hippocampus and olfactory bulb, which is associated with smell, gene expression was more contained.
The discovery that gene expression is often not regional has significant implications for understanding and predicting side-effects of therapeutic drugs. Such drugs act through specific proteins, which are built from expressed genes, and the ideal drug is one that targets a protein whose associated gene is expressed only in the regions affected by disease. Drug activity in regions unaffected by disease can cause unwanted side-effects. By revealing gene expression patterns throughout the brain, the Allen Brain Atlas can help researchers rapidly home in on therapeutic drug targets that should yield favorable side-effect profiles.
"These data underscore the power of a single comprehensive, internally consistent data set," said Dr. Ed Lein, Director of Neuroscience at the Institute and co- author of the paper. "With insights such as these, scientists will be able to design specific, targeted experimental manipulations that will enable great leaps forward in our understanding of brain organization and function."
The Allen Institute for Brain Science will continue to mine Atlas data to better understand the functional organization of the brain and further characterize its incredible cellular diversity. Starting from the vast data contained in the Atlas, the Institute is embarking on a focused exploration of the neocortex, the part of the brain associated with "higher order" functions such as language, sensory perception, and thought in humans.
"We are now beginning an effort to map gene expression in the human neocortex and possibly other areas, which will provide a complementary data set that will help scientists advance their research programs toward an understanding of the human brain in health and in disease," said Dr. Jones.
Additionally, the Institute has an active collaborations program through which it aims to work with scientists to address a range of neuroscience topics, such as autism, epilepsy and schizophrenia. In keeping with the original intent to build a self-sustaining organization, the Institute is pursuing grants and partnerships with funding agencies and foundations to advance these collaborations as well as its own internal research programs.