Creative Minds: Modeling Neurobiological Disorders in Stem Cells
Posted on by Dr. Francis Collins
Most neurological and psychiatric disorders are profoundly complex, involving a variety of environmental and genetic factors. Researchers around the world have worked with patients and their families to identify hundreds of possible genetic leads to learn what goes wrong in autism spectrum disorder, schizophrenia, and other conditions. The great challenge now is to begin examining this growing cache of information more systematically to understand the mechanism by which these gene variants contribute to disease risk—potentially providing important information that will someday lead to methods for diagnosis and treatment.
Meeting this profoundly difficult challenge will require a special set of laboratory tools. That’s where Feng Zhang comes into the picture. Zhang, a bioengineer at the Broad Institute of MIT and Harvard, Cambridge, MA, has made significant contributions to a number of groundbreaking research technologies over the past decade, including optogenetics (using light to control brain cells), and CRISPR/Cas9, which researchers now routinely use to edit genomes in the lab [1,2].
Zhang has received a 2015 NIH Director’s Transformative Research Award to develop new tools to study multiple gene variants that might be involved in a neurological or psychiatric disorder. Zhang draws his inspiration from nature, and the microscopic molecules that various organisms have developed through the millennia to survive. CRISPR/Cas9, for instance, is a naturally occurring bacterial defense system that Zhang and others have adapted into a gene-editing tool.
With the Transformative Research Award, Zhang will turn his toolmaking efforts toward human stem cells. Many of the variants he will introduce into these cells are outside the protein-coding regions of genes, because that’s where many of the DNA variations in neurological or psychiatric disorders have been found. Zhang will utilize CRISPR/Cas9 and Cpf1, a CRISPR genome editing tool recently developed in his lab , to introduce the full spectrum of gene variations that need to be studied.
If all goes well, Zhang’s work will enable neurobiologists to take genetic data and, with great speed and precision, generate large sets of stem cells that contain different combinations of mutations. Those cells can be differentiated into neurons, and can then be tested in a dish to learn how these risk variants contribute to the disease being studied.
While Zhang and his group master simultaneous editing of multiple variations into the genome, they are also making progress on figuring out how to program stem cells to produce the different kinds of neurons and other brain cells that will need to be evaluated in a dish or even a neural organoid, a three-dimensional cellular structure with many of the features of a developing human brain. Ultimately, the goal is to develop these structures into lab-based models for neurological and psychiatric disorders. If successful, they could help to accelerate the development of new approaches for diagnose and treat these conditions.
Zhang notes that he’s got a lot on his plate at the moment to get the technology right. It will be exciting to check back to see what he and his colleagues discover to help the millions of Americans with a neurological or psychiatric disorder, and countless others who may be at risk.
 The microbial opsin family of optogenetic tools. Zhang F, Vierock J, Yizhar O, Fenno LE, Tsunoda S, Kianianmomeni A, Prigge M, Berndt A, Cushman J, Polle J, Magnuson J, Hegemann P, Deisseroth K. Cell. 2011 Dec 23;147(7):1446-1457.
 Multiplex genome engineering using CRISPR/Cas systems. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Science. 2013 Feb 15;339(6121):819-823.
 Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Zetsche B, Gootenberg JS, Abudayyeh OO, Slaymaker IM, Makarova KS, Essletzbichler P, Volz SE, Joung J, van der Oost J, Regev A, Koonin EV, Zhang F. Cell. 2015 Oct 22;163(3):759-771.
Video: Meet Feng Zhang
Zhang Lab (Massachusetts Institute of Technology, Cambridge, MA)
Zhang NIH Project Information (NIH ReRORTER)
NIH Director’s Transformative Research Award Program (Common Fund)
NIH Support: Common Fund; National Institute of Mental Health
Thank you, Dr. Collins and Dr.Zhang! Through knowledge you inspire us all.