When Zhijian “James” Chen was just a boy in an isolated village in Fujian Province, China, his father handed him a government-sanctioned newspaper article that changed his life. It was 1978, and the story, pushed out to revive an economically ravaged nation after the Cultural Revolution, might seem a strange source of inspiration for a child. But this was no typical propaganda theme.

It described a man called Chen Jingrun, one of China’s greatest mathematicians, who lived and breathed math, an existence both eccentric and tantalizingly alien to a 12-year-old boy in a remote mountain village most famous for its tea. The way James Chen relates it now, this man’s life story, promoted even in comic books, motivated a generation of Chinese children to pursue science, including James Chen himself.

Perhaps unconsciously, Chen has since walked a similar intellectual path to that of Chen Jingrun, living his own life-of-the-mind in an unrelenting quest to uncover minute details of the inner lives of cells. And the Chinese authorities had a hand in that outcome, too. Chen initially hoped to study physics, but the powers that be determined that, instead, he should study biology at Fujian Normal University. “Maybe the government knew better,” he says today, smiling. Given that he’s now a member of the U.S. National Academy of Sciences (NAS) and is sitting in a sunlit upper-floor office at a premier U.S. research center, maybe so.

Chen’s path from China to the United States began with an undergraduate biochemistry exam. His first-place score opened the way for him to attend graduate school at the State University of New York, Buffalo, studying with the late biochemist Cecile Pickart and earning his PhD in 1991. From there, Chen journeyed across the continent to La Jolla, California, and the Salk Institute for Biological Studies for a postdoc position with famed cancer geneticist Inder Verma, globally recognized for his seminal contributions to gene therapy discovery. Verma writes in an email that Chen had a “quick smile” and “was not afraid of going into the cold room to do biochemistry” – high praise, indeed.

After a stint in the biotechnology industry on both the U.S. east and west coasts, Chen landed in 1997 at the University of Texas Southwestern Medical Center (UT Southwestern) at Dallas, where he is now a professor and the George L. MacGregor Distinguished Chair in Biomedical Science in the Department of Molecular Biology. Speaking of this longtime institutional home with quiet but sincere admiration, he says, “It’s a very special place here – it is all about excellence. The people who have been very successful here do not rest on their laurels.”

Those laurels – and a set of distinguished awards – continue to accumulate as a result of Chen’s key work in molecular biology. When he arrived at UT Southwestern, he says his goal was to “fully dissect” a complex biochemical pathway that included ubiquitin, a chemical tag that provokes destruction of damaged proteins, as well as NF-kB, a protein central to stress and immune responses. Chen had already spent time uncovering some of ubiquitin’s secrets, but he intuited that there were many more to find. So he locked his radar on this pathway that showed a seeming link between the demolition signal and the immune system. 

Chen has since tracked his target down through the molecular cascades that keep cells ticking and shown that ubiquitin does, indeed, do more than red flag proteins for destruction. It’s best known for triggering activation of a complex called the proteasome, which does the dirty work of shredding proteins.

But in a separate pathway that Chen discovered, ubiquitin is assembled into chains and sets off chemical cascades that switch on a set of critical proteins called kinases. These kinases add phosphates to other proteins – switching them on, too. When a ubiquitin chain binds to the specific kinase TAK1, for example, the newly activated kinase adds a phosphate to the protein IKK, energizing it. The freshly awakened IKK frees NF-kB to enter the nucleus and interact with genes in response to stress or immune system demands.

After his IKK work earned Chen selection as an HHMI investigator in 2005, he chased down another startling finding that has had a large impact in immunology. He discovered a protein that sits on the outer membrane of mitochondria, the cell’s energy generator, and found that it is crucial in immune defense against RNA viruses like influenza and Ebola. Chen describes this finding in a characteristically low-key way, saying that it’s one that he and his team were “very happy about.” 

In that same year, another team was pursuing a different kind of happiness: the Dallas Mavericks had high hopes of winning the NBA playoffs. Chen confesses to not being a sports fanatic – although, he says, “we like to watch especially when they are doing well” – but in 2005, the Mavs were hot. In a burst of fan fervor for the local-boys-made-good, Chen and his own team decided to name the new protein they’d identified MAVS (for mitochondrial antiviral signaling protein). It was one of the first proteins to be associated with mitochondrial-mediated immunity – certainly the first to honor a professional basketball team. 

Chen’s team went through a few trials of their own before MAVS was ready for the pro leagues. Lijun “Josh” Sun, a faculty member at UT Southwestern who has worked with Chen for years, describes the journey as one of pursuing truth, regardless of cost. “He would examine every piece of raw data before being convinced,” says Sun. “He always wants to vigorously challenge a conclusion by designing experiments aiming to disprove it – in many cases, he chose truth over publication.”

The work with MAVS ultimately passed Chen’s stringent requirements. The group found that this newly discovered protein interacts with sensors in the cell’s cytosol that set off alarms if viral RNA is detected, signaling infection. It does this by behaving like a prion, an infectious protein best known for its role in conditions like “mad cow disease.” Prions are infamous as rogue molecules that trigger other proteins like them to misfold and clump, and appear in an array of neurodegenerative diseases. But in the case of MAVS, the aim is defense, not disease. As the protein aggregates, it piles up like rocks at the mitochondrial membrane. The self-perpetuating rockpile serves as a beacon to the presence of even a tiny amount of viral RNA, turning up the immune heat on the intruders.

And once more, in what one might call a ubiquitous motif of Chen’s work, his own most valuable protein, ubiquitin, has part of the action. Ubiquitins, it turns out, help bridge the signal between the cell sensors in the cytosol and MAVS on the mitochondria, transmitting the alert.

Then came another discovery, this time in the form of a molecule that responds to the presence of DNA, not RNA, in the cytosol. Just like viral RNA, DNA is a cytosolic molecule non grata (it’s supposed to exist only in the nucleus and mitochondria). When it gets into the cytosol, it acts as a danger signal that activates interferons, which are high-alert signals in the immune system warning network.

In the process of uncovering how DNA activates the interferon response, Chen’s group discovered a previously unknown biochemical pathway. In it, a protein called cGAS sticks to any DNA in the cytosol and produces a signaling molecule, cGAMP (cyclic GMP-AMP), which activates another protein called STING to induce the interferon response. Their work indicates that the cGAS­‑cGAMP-STING pathway also may trigger alerts to self-DNA, suggesting a possible association with autoimmune diseases. Several companies are now targeting the cGAS pathway to develop new therapies to treat cancer (by activating the pathway to boost anti-tumor immunity) or autoimmune diseases (by inhibiting the pathway when it is overactive). 

Making novel discoveries like these, one painstaking pathway dissection after another, “is an unbelievable feeling,” Chen says, ruffling his hair and smiling. “You are the first one in history, in the world, to discover this.” The awe and novelty are key ingredients of the pep talks he gives his lab team. “I tell the postdocs and students: MAVS, cGAS, and cGAMP – these have existed for a long time, more than 500 million years, and you’re the first to see them.”

Members of his lab respond in kind to his enthusiasm. “I look to him as an example of the kind of scientist I hope to be in the future,” says current graduate student Nicole Varnado. In addition to being “very attentive and attuned to students’ specific needs” as scientists in training, she says, Chen’s “love for biochemistry and molecular biology is infectious – in the way his face lights up in lab meeting discussions, in his eagerness to discuss the hottest topics from a conference he just attended, and in his excited and welcoming smile when help is needed in troubleshooting a difficult experiment.” 

Josh Sun echoes Varnado’s sentiments about Chen’s sensitivity to the needs of his team. Chen had encouraged Sun to pursue an independent faculty position at one point, but for personal reasons, Sun couldn’t. Not willing to let it go at that, Chen pushed for Sun to get a faculty position in his own lab. “Because of his support,” says Sun, “I was able to turn my potential into achievements and enjoy research as much as possible. It has been a wonderful journey to me.”

For Chen, as exciting as payoffs like MAVS and cGAS are for him and his team, the journey is as important as the destination. “I try to enjoy the process of scientific discovery and always look to the next challenge,” he says. “It is the process of discovery that is the most satisfying.”

Chen never seems to stop looking ahead and thinking about that process. In his spare time, he says, now that his children are in college, he travels more – but not for pleasure. “If I am not in here,” he says, gesturing around his spare office, “I travel for work.” At one time, he had a lot of hobbies, including playing ping-pong. But now that traveling is such a big part of the job – he has lately traveled to China, Brazil, and Switzerland – there is no time. “I have to make the most of it,” he says of his globe-trotting.

To do that, this precise investigator of the inner world of the cell turns to the outer world’s free online encyclopedia. Whenever he goes to a new place, Chen looks it up on Wikipedia. “I like to look up maps, history, and know the culture – that is something that I enjoy quite a bit. Besides science, I learn about the world.”

Before departing his office to lead a mini-tour of his lab, a typical workspace packed with the tools of molecular biology and biochemistry, Chen pauses at a cabinet just below two framed photographs of his family. One shows him with his wife, years ago, a shimmering Pacific Ocean in the background. The other photograph is of his two daughters, both now in college. Chen’s lab web page features their pictures as well, his daughters younger, laughing, and making silly faces. He has these photos posted under a tab labeled “Fun.”

And it was fun for him. “I tried to spend as much time as possible with my daughters” before they left for college, he says. He drove them to school and music lessons whenever he could. “I did treasure and enjoy it,” he says. “I knew it wouldn’t last long.”

Opening the cabinet door, Chen reveals a messy stack of papers and file folders. He’s put them there, he says, in anticipation of someone visiting the office; he wanted it to look neat. The office is not only tidy but also undecorated except for the two photographs and a green pillow, which reads “Noel,” in the desk chair. Chen admits to having occupied the office space for more than a year and not hanging a single thing on the wall, including any of the awards he’s received for his work ─ not even his 2012 NAS Award in Molecular Biology. When asked about those, he makes a quick reference to having a “stack of them somewhere.” But, he adds, “I don’t remember them all. It’s all about what you can do next, not what you have done in the past.” 

Then, Mr. Rogers-like, he pulls a jacket from a coat hanger and dons it over his pullover sweater and button-down shirt, ready for the tour through his lab. He leads the way forward, walking his own pathway to a world of future discoveries. ■

Story by Emily Willingham
Photography by Trevor Paulhus