How Frog Brains Are Helping Understand Autism
Colorful imaging helps Willsey assess the results of her work. This tadpole’s brain and neurons are shown in green, muscle in red, and DNA in blue.

Helen Willsey, PhD, is unlocking a new understanding of autism. And she’s doing it with frog brains.

First, Willsey gives frogs the human pregnancy hormone, which causes them to produce thousands of embryos at once. Then she takes each frog embryo and, at the stage when it’s only two cells, mutates genes in one of those cells. The mutated cell develops into one half of the frog, and the unchanged cell develops into the other.

In this way, Willsey says, “you can alter the genes of half of the frog’s brain, leaving the other side untouched.”

This helps understand how gene mutations affect the brain during development. “By comparing the altered half of the brain to the other, fully functional half, you can pick up subtle differences,” she explains.

Specifically, Willsey wants to know how certain mutations might cause symptoms of autism. Many of these mutations were discovered by Matthew State, MD, PhD, chair of the UCSF Department of Psychiatry and the Oberndorf Family Distinguished Professor, whose work inspired Willsey to join his lab in 2016 as a postdoctoral fellow.

To mutate her frogs’ genes, Willsey uses the revolutionary CRISPR-Cas9 DNA-editing tool. “This is powerful technology,” she says. “It enables us to study many genes at once – whereas historically, you could only study one at a time.”

Willsey has found that the gene mutations she imposes on her frogs take effect quickly. “Six days into development – the equivalent of about 25 weeks for a human – we see differences in the size of the frogs’ forebrains,” she says. The forebrain is responsible for social intelligence and higher-order thinking and learning – areas where people with autism tend to struggle.

The ultimate goal of this work is to illuminate how the mutations that State has helped identify lead to autism. “This is the essential step required to really understand what’s going on in autism and eventually find drugs to reverse it,” Willsey says.