A groundbreaking discovery in the realm of human immunity has earned a scientist the coveted Lasker Award, often dubbed the “American Nobel.” Biochemist Zhijian “James” Chen, director of the Inflammation Research Center at the University of Texas Southwestern Medical Center, has been recognized for his pivotal role in unraveling the secrets of a protein that acts as a key player in the body’s immune defenses.
Chen’s research led to the discovery of a critical enzyme called cyclic GMP-AMP synthase (cGAS), which functions as a fire alarm within the body. Unlike traditional alarms triggered by smoke, cGAS springs into action when it detects the DNA of foreign invaders, such as viruses and bacteria. Before Chen’s discovery, scientists lacked understanding of how this foreign DNA initiated the innate immune system, the body’s first line of defense against harmful substances.
The journey to understanding this crucial mechanism began with Ilya Mechnikov, who received a Nobel Prize in 1908 for his discovery of phagocytosis, a process where one cell engulfs another. This is one way immune cells eliminate disease-causing bacteria. In his Nobel lecture, Mechnikov noted that bacterial DNA somehow activated a “protective army of phagocytes” within the body, but the precise mechanism remained elusive.
Subsequent research in the early 2000s revealed that injecting cells with DNA led to a surge in interferons, immune signals that help curb infections. Scientists pinpointed a group of genes responsible for producing these interferons, which they named “stimulator of interferon genes” (STING). While STING doesn’t directly sense foreign DNA, it gets activated by the DNA in some way.
Chen and his collaborators, starting with a groundbreaking paper published in 2012, finally pieced together the missing links in this chain of events. They discovered that cyclic GMP-AMP (cGAMP), a molecule that triggers STING when foreign DNA is present in cells, plays a crucial role. They also identified cGAS as the enzyme responsible for producing cGAMP in mammalian cells, including humans.
In essence, cGAS acts as the body’s early warning system, detecting foreign DNA and triggering the release of cGAMP. This molecule, in turn, activates the “fire brigade”— the innate immune system, including the cells that engulf invaders. Chen’s team further discovered that this system not only detects DNA but also retroviruses, including HIV, which contains RNA, a genetic cousin to DNA.
While cGAS serves as a critical line of defense, its overactivation can be detrimental. In some diseases, this alarm system can go haywire. cGAS is implicated in autoimmune diseases, where the immune system mistakenly attacks the body. This occurs when DNA leaks out of its usual compartments in the cell, the nucleus and mitochondria, due to stress. While our bodies have enzymes to break down this escaped DNA, some individuals lack efficient enzyme function. Chen and his colleagues have found that this deficiency can trigger the cGAS alarm system, highlighting its potential role in regulating harmful immune responses.
The Lasker Award committee acknowledges the far-reaching implications of Chen’s research, stating that “cGAS has been implicated not only in autoimmune conditions, but in numerous inflammatory illnesses, including age-related macular degeneration and neurological disorders such as Parkinson’s disease, Alzheimer disease, and amyotrophic lateral sclerosis.” They emphasize that “Calming the cGAS-cGAMP-STING pathway might therefore provide benefit across a broad span of ailments.”
Chen’s groundbreaking work has earned him the 2024 Albert Lasker Basic Medical Research Award, recognizing the profound impact of his discovery on our understanding of the human immune system and its potential for treating a wide range of diseases. His findings open new doors for developing innovative therapies that could potentially calm the immune system’s overreaction and pave the way for targeted treatments for autoimmune disorders and inflammatory conditions.
