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Joe Dougherty: Genes and Cells and Mice to Understand Complex Psychiatric Disease

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Recommended by: Barak Cohen, Washington University in St. Louis

Joe Dougherty sees the intersection of genetics and neurobiology as the target for understanding and developing treatments for common, complex psychiatric disorders like autism.

Two years into running his own lab at WashU, Dougherty and his team are using human gene expression and mouse transgenics to develop models of how genes influence different cell types and lead to the network disruptions in the brain that give rise to disease. "The hope is that understanding which genes are expressed in which cell type will help us understand what's going awry in genetic disorders of the mind," he says.

Dougherty's lab mines data from large exome sequencing studies and does its own RNA-sequencing and microarray studies of human gene expression, which the group then uses to create models of autism and other diseases in mice.

"Given the genetic heterogeneity seen in complex psychiatric disorders, if you are talking about treatments, you can't efficiently target the gene as your level of intervention anymore … you need to find some level of commonality in the nervous system," Dougherty says. "Hopefully, our research both contributes to understanding what circuits are likely to be disrupted by mutations in particular genes, and also gives us some access into identifying candidate molecules for working on those circuits."

Paper of note

Currently Dougherty's team is working on building techniques to replicate copy-number variations seen in mouse models of autism. Dougherty says a recent paper in PLOS One showed a "good proof of principle" for the approach the lab hopes to take in modeling human duplications. In the study, Dougherty and his team showed that they could generate triple-colored 'prism' mice using a modification of existing BAC transgenic protocols. "It showed you can get multiple, independently regulated alleles into a single locus. For doing modeling of CNVs, that's going to be important," Dougherty says.

Looking ahead

Dougherty says this CNV modeling is one of the larger challenges his group is tackling. "I think it will be hard to get these CNVs to work and work in different cell types. But I don't think any of this is insurmountable, otherwise I wouldn't be trying to do this," he says.

Dougherty sees the advancement of modeling strategies as something the field as a whole will likely see a lot of in coming years. "In the next five to 10 years we will have sequenced enough genomes from enough patients to have a pretty good understanding of the catalog of variation that contributes to disorders," he says. "But if you are talking about developing treatments, you need an understanding of how those variations actually lead to the disruptions of behavior that mediate the disorder."

And the Nobel goes to…

Dougherty would love to be able to be involved in what he sees as the two main types of Nobel-worthy achievements: either a remarkable technical advance or research that somehow greatly advances human health. "It would be hubris for me to speculate I would be involved in either. But maybe one would be so lucky as to do both," he says.

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