By altering genes in one half of the brain, scientists can compare how gene mutations affect the organ during development.
Don’t get Helen Willsey, PhD, started on frogs. Or actually, do – because, let’s be honest, they’re really cool.
For one thing, if you give frogs the human pregnancy hormone known as human chorionic gonadotropin (hCG), they mate like crazy, producing thousands of embryos at once. Then – if you’re Willsey – you can take each frog embryo and, at the stage when it’s only two cells, mutate genes in one of those cells. As the embryo grows, the mutated cell will develop into one half of the frog, while the unchanged cell develops into its other half.
In this way, Willsey says, “you can alter the genes of half of the frog’s brain, leaving the other side untouched.” That’s important if you want to 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 Behavioral Sciences and the Oberndorf Family Distinguished Professor. State’s work inspired Willsey to join his lab in 2016 as a postdoctoral fellow.
In revealing autism’s underlying biology, Willsey and State’s unique collaboration – which combines clinical genetics with developmental biology – could usher in new approaches to treatment. Their pioneering work is also part of the broader Psychiatric Cell Map Initiative, a partnership between UCSF, UC Berkeley, and UC San Diego to understand mental health on a molecular level.
To mutate her frogs’ genes, Willsey uses the revolutionary CRISPR-Cas9 genome-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 – and in a very cost-effective way.”
Willsey has found that the gene mutations she imposes on her frogs start to have an effect early in development. “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.
Willsey hopes to illuminate how each gene functions within a cell and 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,” she says.