Solving the Mystery of the Body's Defenses

Discoveries by Zhijian “James” Chen, Ph.D., illuminate how innate immunity is triggered, inspiring new approaches to treat many diseases, including cancer.

Innate immunity serves as the body’s first line of defense, fighting off invaders such as microbial infections, inflammatory diseases, and even cancerous tumors. But exactly how immunity gets triggered and why it sometimes fails has long baffled scientists.

Thanks to a series of significant discoveries by biochemist Zhijian “James” Chen, Ph.D., Professor of Molecular Biology and Director of the Center for Inflammation Research at UT Southwestern Medical Center, this mystery is being solved. Dr. Chen’s groundbreaking discovery of the cGAS enzyme, which he describes as the body’s “burglar alarm” that sets off immune and inflammatory responses, has opened up new approaches to the treatment of cancer, autoimmune diseases, and more.

Award-Winning Research

In 2024, Dr. Chen received the prestigious Albert Lasker Basic Medical Research Award, known as “America’s Nobel,” in recognition of the cGAS discovery. His work on innate immunity has also been honored with the Paul Ehrlich and Ludwig Darmstaedter Prize, Germany’s highest honor in the field of medicine (2024); the Louisa Gross Horwitz Prize (2023); the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology (2020); the Breakthrough Prize in Life Sciences (2019); the Switzer Prize (2019); the Lurie Prize in Biomedical Sciences (2018); and the National Academy of Sciences Award in Molecular Biology (2012).

“To be able to discover something that nobody has ever discovered before is extremely exciting,” says Dr. Chen, a Howard Hughes Medical Institute Investigator since 2005 and an elected member of the National Academy of Sciences (2014) and the National Academy of Medicine (2022).

His findings on the inner workings of innate immunity have been recognized not only for their originality and elegance but also for their significance among the scientific community around the world.

“Dr. Chen’s creative and meticulous work exemplifies our commitment at UT Southwestern to fundamental research that has the potential to lead to new and better ways to treat disease,” says W. P. Andrew Lee, M.D., Executive Vice President for Academic Affairs, Provost, and Dean of UT Southwestern Medical School. “His discovery of the cGAS-cGAMP-STING pathway is a product of the UT Southwestern scientific environment, where talent is actively recruited, nurtured, and promoted.”

A Legacy of Discoveries

Originally from rural China, Dr. Chen earned an undergraduate degree in biology from Fujian Normal University and a Ph.D. in biochemistry from State University of New York at Buffalo. After a brief stint in the biotech industry, he joined UT Southwestern in 1997.

Early in his career, Dr. Chen identified key functions of a small protein called ubiquitin that activates other proteins key to regulating immune and inflammatory responses. This led, in 2005, to the detection of a new protein that showcases the role of mitochondria in immunity. While other misfolded proteins are known for causing disease, the mitochondrial antiviral signaling (MAVS) protein that Dr. Chen discovered was the first prion in humans to show a benefit, in this case fighting off RNA viruses such as influenza, West Nile virus, SARS-CoV-2, and Ebola. Dr. Chen created an acronym from the protein’s function, dubbing it MAVS after his favorite basketball team, the Dallas Mavericks.

Then, in 2012, Dr. Chen discovered the cyclic GMP-AMP synthase enzyme now known as cGAS. He and his colleagues found that cGAS produces a small molecule called cGAMP, which in turn acts as a secondary messenger to activate STING (stimulator of interferon genes) and trigger an inflammatory response. This research into how a cell communicates with its surroundings and responds to foreign stressors containing DNA is fundamental to human health.

“James Chen is a true wizard of biochemistry,” says Eric Olson, Ph.D., Professor and Chair of Molecular Biology, who sought out Dr. Chen as his first recruit when he launched the department in 1996. “His ingenious biochemical strategy to unveil the signaling system that senses rogue DNA in the cytoplasm is truly breathtaking. I vividly remember how awestruck my colleagues and I were when James first presented this work in a faculty meeting.”

Lasting Impact

Dr. Chen found that cGAS works as a sensor to identify pathogens containing DNA. And because cGAS can be activated by any double-stranded DNA, it plays an essential role in a variety of physiological and pathological processes:

• Autoimmune and inflammatory diseases, including a rare disease called AicardiGoutières syndrome (AGS), lupus, arthritis, and severe COVID-19 infections

• Neurodegenerative diseases, such as Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease

• Antimicrobial infections caused by bacteria, viruses, and parasites

• Cellular senescence, which acts as a defense mechanism by halting cell division

• Autophagy, which plays a key role in antiaging principles as cells remove damaged or dysfunctional parts and repair themselves

The goal now, Dr. Chen says, is to understand how to harness the power of this cGAS-cGAMPSTING pathway for the treatment of human diseases, whether by inhibiting cGAS or using cGAMP and its derivatives as adjuvants for vaccines or cancer immunotherapies.

“Immunity is all about balance,” explains Dr. Chen, member of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and Professor in the Center for the Genetics of Host Defense. “If the immune system is not active enough, infectious diseases or cancers can take hold. An overactive immune system, on the other hand, can cause autoimmune diseases like lupus, and neurodegeneration such as Parkinson’s disease and Alzheimer’s disease.”

Dr. Olson says his colleague’s research will have a lasting impact as its applications in medicine are developed.

“Dr. Chen’s discoveries of the mechanisms whereby cells detect viral RNA and misplaced DNA in the cytoplasm of cells will stand for all time as a cornerstone of immunology,” he says. “We are only beginning to comprehend the range of biomedical implications of his discoveries, which connect virology, autoimmune disorders, cancer, immunotherapy, and other areas yet to be discovered.”

Zhijian “James” Chen, Ph.D., Professor of Molecular Biology and Director of the Center for Inflammation Research at UT Southwestern Medical Center

W.P. Andrew Lee, M.D., Executive Vice President for Academic Affairs, Provost, and Dean of UT Southwestern Medical School

Eric Olson, Ph.D., Professor and Chair of Molecular Biology