Inside Salk; Salk Insitute

Next generation: Amy Firth

Amy Firth doesn't believe in leaving well enough alone. She has an affinity for demanding sports–she’s competed in two Ironman triathlons and a 50-kilometer trail run, and she trained for the six-day TransRockies Run that took place earlier this month, a 120-mile trail race through the mountains of Colorado. And that’s not to mention the high-level horse competitions that were her passion when she was younger.

“I always like to test how far I can push myself,” says Firth, a postdoctoral researcher in the lab of Salk professor Inder Verma. “Once I’ve done one thing, I have to go to the next level and do the next crazy thing.”

Amy Firth

She could just as easily be describing her career in science, which has taken several twists and turns on its upward trajectory. Firth, who grew up on a farm in Yorkshire, England, was always interested in science because she loved animals and wanted to become a veterinarian.

But she soon realized that in order to treat her patients, she would need to have an understanding of drugs and how they worked. So when she got to the University of Bath, she focused instead on pharmacology– the study of drug interactions with the body.

It was during her final year of college, as part of a three-month capstone project, that the course of her career changed yet again. Landing in the lab of Sergey Smirnov, she learned to record currents across cells that were isolated from the pulmonary artery.

“And that,” she says, “was the start of my interest in lungs.”

Firth remained at the University of Bath to earn her PhD, and when it came time for her to find a postdoctoral position, she was keen for a placement in a world-renowned lab studying pulmonary hypertension. She ended up at University of California, San Diego, working with Jason Yuan, who was studying ion channels and pulmonary disease pathogenesis. “It was a good transition forward to continue what I was doing and apply it to disease pathogenesis,” she says.

UC San Diego, renowned for its clinical program in chronic thromboembolic pulmonary hypertension (CTEPH), provided Firth with unique access to surgically removed lung tissues. Usually blood clots in the lungs, or pulmonary embolisms, resolve without treatment or are broken up through medication. When a clot doesn’t dissipate, or clots recur frequently, however, harmful vascular changes can take place in the lungs and can result in pulmonary hypertension. Pulmonary hypertension is associated with high morbidity and mortality due to right-sided heart failure. Although rare, CTEPH is often misdiagnosed because its symptoms can be similar to those of more common conditions, and it may occur in patients with no overt history of pulmonary embolism.

In studying how blood clots in CTEPH become fibrotic and solid, completely blocking the lungs, Firth began to look at what cell types contribute to the condition. What she found was that cells capable of developing into multiple types of tissues seemed to be involved in the progression of the disease.

And from there, her research began to focus on stem cells. Since joining Verma’s lab four years ago for her second postdoctoral appointment, Firth has been modeling the respiratory tract–specifically, airways. Taking skin cells from patients with lung disease, she has reprogrammed the cells to become induced pluripotent stem cells (iPSCs), then coaxed them to become lung cells in order to study them in a dish. Her method circumvents some of the limitations inherent in existing methods of studying lung disease. Mice, for instance, develop lung disease very differently from humans and don’t manifest it to the same extent, which makes translating information from mouse models to humans difficult. And human lung tissue is especially perishable, providing only a brief window before starting to deteriorate.

“I wanted to find a way to study human disease in a reproducible way, and having iPSCs basically gave me a pool of cells with the capacity for indefinite growth and generation of any cell in the body,” she explains.

Once she has guided the iPSCs into becoming lung cells, Firth can use gene editing techniques to remove a mutated gene and replace it with a corrected one. Or, conversely, if donated patient tissue is unavailable, she can remove a normal gene and insert a mutation.

“It gives us a reproducible way of looking at the role of mutations in disease and looking at what the downstream signaling pathways are that occur after you have a mutation,” she says. “The nice thing about the system is that with little tweaks here and there, I can essentially use it to model nearly any lung disease, and I can take this wherever I want.”

Her research was published in March in the prestigious Proceedings of the National Academy of Sciences. But Firth is quick to caution that her technique is still in the early stages and needs some refinement. She’s hoping it can eventually be used for high-throughput screening to identify new drugs, as well as to uncover the underlying mechanisms for diseases where the mechanisms aren’t well known.

“Everyone asks me if I’m trying to regenerate a lung in a dish,” she says, “but I think being able to put cells back and remodel a lung is a ways off.” That said, she’s begun forging collaborations with other scientists, using the cells she generates to begin exploring that possibility. Her expertise in lung stem cells also led to an invitation last year to edit a book on the subject, which is slated for publication this fall.

“Amy is fearless, exacting and demands the best from herself and her colleagues,” says Verma, who holds the Irwin and Joan Jacobs Chair in Exemplary Life Science. “I can always count on her to deliver.”

As if all this isn’t demanding enough, Firth continues to test the limits outside the lab, as a Category 2 bicycle racer for the South Bay Wheelmen in Los Angeles, as well as racing for the Rehab United Elite triathlon team in San Diego. Her biggest extracurricular challenge may lie ahead, however. She recently joined her lab’s softball team, which has left this diehard fan of Britain’s Tottenham Hotspur soccer team a bit out of her element but game to learn.

“They were having so much fun, I decided to join them,” she says. So every Monday, she dons a baseball glove and takes her place behind the infield, ready for whatever the players, science and life bat her way.