Mapping Molecular Pathways of Neuropsychiatric Disorders

“I am so grateful to the Weills – the Trailblazer Award means a lot, both in terms of financial support and professional endorsement,” Jeremy Willsey, PhD

The genes triggering many baffling psychiatric disorders have been found, but how mutations in these genes cause neurodevelopmental conditions such as autism, intellectual disability, and epilepsy is still a mystery. 

Jeremy Willsey, PhD, has made it his mission to solve it.

“We are at a very exciting time,” notes Dr. Willsey, an assistant professor in UCSF’s Institute for Neurodegenerative Diseases and Department of Psychiatry. “In the past five years, gene discovery has accelerated. We started with a very small number of genes identified with autism spectrum disorder (ASD), and now we have 65 or more very strongly associated genes. These molecular clues are the foundation to understanding the biology behind the disorder.”

Winning the Weill Award has accelerated Dr. Willsey and his team’s efforts to develop the Psychiatric Cell Map Initiative, which aims to map the molecular pathways in brain cells so scientists can understand how genetic mutations result in ASD and how diseased states differ from healthy states. 

As Dr. Willsey describes it: “The genes are the parts list for the engine. Now we need the instructions to assemble those parts into a functioning unit so we can see what goes wrong when a part is changed. If you understand how the engine works, it’s much easier to repair.”

Thanks to the Weill Trailblazer Award, Dr. Willsey and his team are off to a strong start. “I am so grateful to the Weills – the Trailblazer Award means a lot, both in terms of financial support and professional endorsement,” he says.  

ASD currently afflicts more than one in 59 Americans. Experts call its rising incidence a public health emergency given the global burden of mental illness in health care costs, lost productivity, and personal suffering. 

Dr. Willsey hopes his team’s research will result in identifying biomarkers, the biological indicators that could make ASD easier to diagnose, particularly in young children; lead to early intervention for the millions affected; and monitor whether treatments are successful. 

To map the molecular pathways underlying ASD, the team “reprograms” human blood and skin cells to become neurons. Next, the scientists use genetic engineering tools to mimic the mutations identified in ASD and powerful genomics approaches to map the biological pathways affected by these mutations. Essentially, this approach allows the team to reconstruct the “engine of ASD” and then break it down to understand the functional biology of the disorder. 

This field is very promising, Dr. Willsey notes, predicting that the day will come when brain diseases will be understood in the same way doctors now understand diabetes, cancer, and hypertension.  

“Unlike many medical diseases, we do not know the cell types that are involved in psychiatric disorders,” he says. “The brain is one of most complex organs in the universe, but recent scientific advances and public and private research support – such as the Weill award – are paving the way for foundational breakthroughs in our understanding. 

“There’s a lot of excitement,” he adds. “We can see a path forward toward more effective treatments. It is still far away, but the road map is there.” 
 

UCSF Weill Awards

Joseph DeRisi, PhD; Samuel Pleasure, MD, PhD; and Michael Wilson, MD