Jay Shendure: A mindset for scientific creativity

Pursuing innovation has always been a way of life for Jay Shendure, MD, PhD, professor of Genome Sciences at the University of Washington School of Medicine


Jay Shendure BBI's Scientific Director Dr. Jay Shendure: 'Our mantra in the lab is to look for bottlenecks and then try to address those bottlenecks using clever methods.' Photo courtesy Matt Hagen

[Editor's note: This feature piece was published in the UW Medicine Huddle on April 3, 2023]

Pursuing innovation has always been a way of life for Jay Shendure, MD, PhD, professor of Genome Sciences at the University of Washington School of Medicine. Even before a college genetics class inspired him to abandon a major in cultural anthropology, Shendure had a mindset for scientific creativity.

“While growing up, the adults in my life offered a lot of encouragement. I designed a perpetual motion machine that my mom told me would work,” says Shendure, director of the Allen Discovery Center for Cell Lineage and scientific director of the Brotman Baty Institute for Precision Medicine. “My second stupidest idea was probably a paper mache hot air balloon. It never occurred to me that it would light on fire. But my science teacher let me launch it.”

He laughs about those experiments now, but the support he received from an early age put him on a career track filled with curiosity. It contributed to his unique approach to research that has spawned several start-up companies. Most recently, his investigative journey led him to receive the 2022 UW Medicine Inventor of the Year award for pioneering exome sequencing technology and its applications to gene discovery with his research group.

A focus on technology

As an investigator at the Howard Hughes Medical Institute, Shendure takes an outside-the-box approach to genetic research. Rather than focusing on biology, his lab concentrates on the technologies needed for investigations.

“We’re much more of a technology-oriented lab with a mindset that what we do returns to biology. Technology is the rate limiter on progress in the biological sciences,” Shendure says. “Our mantra in the lab is to look for bottlenecks and then try to address those bottlenecks using clever methods.”

It’s a dedication to delving into and developing advanced technologies for genetic research, he says. As a result, he leads a trailblazing lab. To date, his group has pioneered several technologies, including:

  • Exome sequencing, a technique that sequences all protein-coding regions of a gene to improve gene discovery for Mendelian disorders and autism.

  • Massively parallel reporter assays that can screen and evaluate the regulatory activity of thousands of DNA sequences simultaneously.

  • Cell-free DNA diagnostics that analyze DNA floating in the blood for cancer and reproductive medicine care.

  • Saturation genome editing, a method that assays thousands of genetic variants at the same time.

Most recently, the lab has focused on deciphering the developmental blueprint of mice because every mouse gene has a human equivalent. They hope their findings will one day contribute to better treatments and cures for human diseases.

“As we watch normal and abnormal development in the mouse model, we get direct insight into how specific molecular and cellular events give rise to diseases of development that affect kids,” he says.

An impact on disease__

As a result of their groundbreaking work, Shendure’s lab has launched several start-up companies making a positive impact on genetics and health within the community. One example is Bellwether Bio. Founded in 2017 and acquired by Guardant Health in 2019, the company employs the epigenomics of cell-free DNA for earlier cancer diagnosis.

“We’re all walking around with DNA in our blood. It’s basically the detritus of cells turning over in normal health,” Shendure says. “If you have cancer, some of that DNA comes from the tumor. We can pick up the signature that could potentially monitor or detect early growth of cancer based on the fragmentation patterns of that DNA.”

In addition, his group also developed an algorithm that predicts how any possible genetic mutation can affect the human genome. This technology, licensed by over 50 companies, uses existing knowledge to assess whether individual mutations may cause disease.

“It’s far from perfect,” he says, “but to my knowledge it was the first attempt to associate a prediction with every possible single nucleotide change.”

A supportive environment

While Shendure has enjoyed many successes with his technology-heavy research, his work may not have been as fruitful elsewhere. But when he joined the UW Medicine faculty, the department embraced his investigative approach.

“The Genome Sciences department at UW Medicine is technology friendly. It has a very long view of technology in an unconventional way compared to traditional genetics departments,” Shendure says. “Just being in a place that values technology as a goal in itself is very liberating.”

That unique perspective will keep the door open for the next chapter of his groundbreaking work.

“We have quite a few exciting irons in the fire,” he says. “Leveraging new technologies and new opportunities is something I remain very excited about.”