Zach Zappala (he/him) doesn’t remember noticing when the Human Genome Project released its first draft sequence. Back then he was a fifth-grader in New Jersey preoccupied with computers and releases of a different kind: the latest Legend of Zelda.
But by the end of high school — and an internship in a biology research lab — he realized he could do something even cooler with coding than build the next blockbuster video game franchise. “You could just see the writing on the wall for where sequencing would enable the future of medicine,” Zappala said. He decided to join the early waves of people starting to use computers to disentangle the coming deluge of DNA data.
What neither he nor anyone else really appreciated at the time was just how much genetic variation all that data would reveal.
During his Ph.D. at Stanford University, Zappala developed statistical methods for uncovering rare variants in non-coding DNA that were contributing to disease — work that helped doctors at Stanford and the Children’s Hospital of Eastern Ontario provide diagnoses to patients with extremely rare disorders.
Wanting to make a bigger impact for more patients is what propelled him to his role as a senior research scientist at Vertex Pharmaceuticals. His efforts there pushed Casgevy — a one-time treatment for sickle cell disease and beta thalassemia — to become the first approved medicine involving CRISPR gene-editing technology last year. Key to that approval was being able to reliably detect the mistakes that CRISPR can make, called off-target effects. This got more complicated when, a couple of years ago, scientists realized that genetic variation could alter the odds of CRISPR screwing up. Regulators were keen to know how big a problem it might be.
At Vertex, Zappala led the charge to answer that question — building a computational framework for predicting potentially problematic variants and combining that with data from experiments with patient cells. They showed Casgevy didn’t have any off-target effects, and in the process set the industry standard for satisfying safety concerns for CRISPR medicines. “It was definitely a stake in the ground,” Zappala said. “But there’s still room for that to evolve.”
Outside of work, his happy place is at the “circus studio” practicing aerial silks — a hobby he picked up after being transfixed by a performance at Burning Man. “I love to dabble so that I can truly appreciate the artistry behind what a professional is doing,” he said. “I probably have that philosophy about a lot of things in life.”
—Megan Molteni
