Scientist and genomic researcher Stacia Wyman ’85 is fine-tuning gene editing for real-world treatments
To understand the work of data scientist Stacia Wyman ’85, it helps to first talk about a rare form of muscular dystrophy. FSHD is a genetic disease in which the muscles of the face, shoulder blades, and upper arms weaken and atrophy. It’s caused by an overactive gene called DUX4. During fetal development, DUX4 has an important job: It helps muscles grow. But in most adults, it does nothing. Its purpose served, the gene turns off. FSHD develops when that doesn’t happen—when a genetic mutation causes DUX4 to turn on in adult muscle tissue.
Wyman is Director of Biological Data Science at Epicrispr Biotechnologies, a San Francisco biotech startup she joined in November after spending most of her career in academia. Epicrispr has a big idea: It wants to turn off DUX4 in patients with FSHD. This, the thinking goes, would stop muscle deterioration and perhaps restore muscle function. It could cure the disease. But how do you turn off a gene? For Wyman and Epicrispr, the answer lies in a technology known as CRISPR.
“I had been working on classic CRISPR, where you edit a mutation in a gene, and that was incredibly thrilling. Then I had the opportunity to work on the next big thing in CRISPR—and that was too exciting to pass up,” Wyman says.
You may have heard of CRISPR. It’s a gene-editing tool in which scientists use a guided enzyme to cut a DNA sequence at a precise location. Once it’s cut, scientists can modify the sequence. Think of pre-digital filmmaking, when movies were edited with scissors. This is not so different.
At Epicrispr, “instead of modifying a gene,” Wyman says, “we want to modify the thing that controls the gene.” And what controls a gene? The epigenome. That’s the collection of chemical marks on a cell’s DNA that regulates how much a gene is turned on or off.
Wyman came to Epicrispr from University of California Berkeley’s Innovative Genomics Institute, where she was part of a team that uses CRISPR to do genome engineering. They developed a treatment for sickle-cell disease and became one of the first groups to get a CRISPR clinical trial approved by the FDA.
“CRISPR was very new, so everybody was learning as we went along,” Wyman says. “We got to be the people figuring out how to use CRISPR to develop therapies that help people.”
For Wyman, what made the project especially rewarding is that sickle-cell disease is historically underfunded and understudied, because it primarily affects Black people. “Someone with sickle-cell disease will go to the ER in incredible pain, and a doctor will think they’re just seeking drugs,” Wyman says. “Having the first approved CRISPR therapy be for sickle-cell disease is maybe some compensation for that.”
As for her time at Williston, Wyman says “Williston is where I first understood that I could enjoy academics. I had amazing teachers, and I have such clear memories of doing my homework in the loft above the main part of the library. You could go up there—it was totally quiet—and just focus. I still love going to a library and hunkering down to study.”
Wyman’s specific role, both at Berkeley and at Epicrispr, is to apply computational algorithms to biological data. Wyman majored in computer science at Smith College and earned a Ph.D. in computer science and computational biology from the University of Texas at Austin, where she studied algorithms for genome analysis. She developed algorithms for reconstructing the evolutionary history of plants until, at a conference, she met a scientist who’d applied computational algorithms to the study of breast cancer.
“It was thrilling to me that computational biology could make such a huge difference in human health,” Wyman says. “That was a turning point for the field, and I switched my focus.” During a postdoc at the Fred Hutchinson Cancer Research Center in Seattle, she analyzed whole genome sequences of tumors and developed algorithms to find cancer biomarkers.
Beyond the chance to help patients so tangibly, she valued the collaborative nature of the work. When cancer biologists did experiments, they ended up with a lot of data, and Wyman’s algorithms helped everyone make sense of it.
With CRISPR, Wyman’s work is similar. Remember the guided enzyme that goes to a specific location? Well, sometimes the guide goes to other locations, too, and the stakes are high. “If the guide happens to be a close match somewhere else, it might create a break in that genome,” Wyman says. If that genome suppresses tumors, let’s say, “then suddenly you’re giving a person cancer as well as curing their sickle-cell disease.” One of Wyman’s areas of expertise is analyzing whole genomes to prevent such “off-target events” from occurring.
Wyman is quick to point out that her mind is not purely analytical. She loves to travel and has visited all 50 states and every continent except Antarctica. One of the best days of her life was spent hiking on a glacier in New Zealand. She’s also a potter. And she sees science as a creative outlet. “What I enjoy most,” Wyman says, “is standing in front of a whiteboard with a colleague and a problem, figuring out how to solve it, writing down ideas, drawing pictures.”
That’s a big part of what drew her to Epicrispr. “At a start-up, the pace is faster,” she says, “and you’re more focused on getting one particular thing done as a single team.”
Ultimately, that thing was FDA approval for their FSHD therapeutic, and in April, Epicrispr received that approval to begin human trials in FSHD patients. Epigenetic editing holds promise for treating many diseases, from high cholesterol to blood cancers, but this would be the first human trial for an epigenetic CRISPR therapeutic in the U.S.
Wyman says the first patient will be dosed in June.
3 Things to Know About CRISPR
1. It’s a gene-editing tool
Traditional CRISPR allows scientists to change DNA.
Here’s how it works: A specialized enzyme is guided by
RNA to a specific location in the genome, where it makes a precise cut. Once the DNA is cut, scientists can add, remove, or modify the genetic material.
2. It has huge potential
“CRISPR is changing the way we look at curing disease,” Wyman says, from genetic disorders to cancer, diabetes, heart disease, and Alzheimer’s. Beyond human health, CRISPR
is helping to reduce pesticide use in crops and develop plants
that can withstand climate change.
3. Wyman is working on the next advance
Epigenetics is a new frontier for CRISPR. Instead of modifying DNA, researchers use the technology to turn a gene on or off. This is safer than traditional CRISPR, and it’s reversible, which is part of what makes it so exciting.