Eyes on Fire

Profile: Charles E. Egwuagu, Ph.D.

BY ETHAN SMITH, NINR

There’s a high demand for new treatments for uveitis, an intraocular inflammatory disease that destroys eye tissues and can even render a person blind. Uveitis can be of autoimmune or infectious etiology and may affect the front of the eye (anterior uveitis), back of the eye (posterior uveitis), or all layers of the eye (pan uveitis). Corticosteroids and immunosuppressive agents are often used to treat the disease, but they can also shackle the immune system’s ability to defend the body, leaving patients more vulnerable to cancer and other infectious diseases.

Charles Egwuagu, a senior investigator at the National Eye Institute (NEI), is working to develop new treatments for uveitis that don’t have the dreaded side effects of other therapies. His approach is a unique cell-based therapy using immune cells called regulatory B cells (Bregs). Bregs were first described in the late 1990s for their ability to suppress inflammation, and, since then, many subpopulations of Bregs have been described in various inflammatory diseases.

Long before he took on Bregs, Egwaugu established that Th17 cells (a type of T-helper immune cells that protect the body from bacteria and fungi) play a crucial role in driving inflammation in human uveitis. He published his findings in Nature Medicine in 2007 (Nat Med 13:711–718, 2007).

Then he shifted his focus toward developing biologics (drugs produced using a biological source). For example, the insulin that stabilizes blood sugar in diabetes is mass produced using Escherichia coli. Egwaugu’s goal was to treat uveitis using a biologic that could selectively inhibit Th17 cells and other inflammatory immune cells without suppressing the whole immune system. In particular he was interested in what the immune-regulatory protein interleukin 35 (IL-35) could do. He and his team produced IL-35 in insect cells using baculovirus, injected it into mice, and found that IL-35 suppressed uveitis. But no one expected that the IL-35 would also cause the growth of a new population of Breg cells that could suppress autoimmune disease.

“We found out IL-35 can induce a rare population of B cells that are immunoregulatory,” said Egwuagu.

In 2014, he published his discovery in Nature Medicine (Nat Med 20:633–641, 2014). Now, he is trying to leverage the immunosuppressive capabilities of IL-35+ Bregs to treat uveitis and other autoimmune diseases such as multiple sclerosis.

Early Exposure

Egwuagu’s first interest in science was in hygiene—large-scale practices designed to control and prevent disease. “I come from a place where the burden of disease is too much,” said Egwuagu, who grew up in the Southwest region of Cameroon in the coastal city of Victoria (renamed Limbe in 1982). In Victoria, the sanitation department handled mandatory vaccination programs for infectious diseases such as measles and smallpox. He didn’t know much else about the department other than one of his dad’s friends was the director. “All I knew was that he was the person trying to make everyone healthy,” said Egwuagu.

A Brief Foray Into Biochemistry

At the age of 19, Egwuagu traveled to the United States for college, carrying with him the belief that, whatever direction his career took him, it was important that his work be relevant to the community around him.

He earned a B.A. in biology from Kean University (Union, New Jersey), then an M.S. in biochemistry from Rutgers University (New Brunswick, New Jersey). Although he enjoyed synthesizing chemical compounds at the lab bench, he wasn’t sure whether he wanted to be a biochemist. He was also still passionate about hygiene, specifically infectious and tropical diseases, so he enrolled in the M.P.H. program at the Yale School of Public Health (New Haven, Connecticut) and in the M.Phil. and Ph.D. programs in epidemiology and microbiology at Yale Graduate School of Arts and Sciences.

An Education in New Haven, Connecticut

Joint matriculation in the Yale programs afforded Egwuagu the opportunity to explore various scientific disciplines, such as physiology, pathophysiology, microanatomy, and cell biology (Yale Medical School); epidemiology, virology, and parasitology (School of Public Health); and immunology and molecular biology (Yale Graduate School of Arts and Sciences).

“I was like a sponge,” said Egwuagu. “I would take information from all these places.” He credits the interdisciplinary design of his education in preparing him for a leadership role in biomedicine. “There are few people who have the kind of training and experience that helps you cross-talk with the different scientific and medical communities.”

Occasionally, Egwuagu’s thesis advisor—then the only Black tenured professor at Yale School of Medicine—would send Egwuagu (also Black) to other labs at Yale and at Smith, Kline & French (now GlaxoSmithKline) to learn molecular cloning and gene-expression techniques. The professor warned him that he might face discrimination at some of these places and advised Egwuagu that, no matter what, he should stay focused on gaining skills that would advance his career.

After Egwuagu earned his graduate degrees, he considered doing postdoctoral training at the Centers for Disease Control and Prevention’s (CDC’s) Epidemic Intelligence Service so he could pursue his interests in epidemiology and tropical diseases. But he’d had such good training in molecular cell biology and immunology that two of his Yale mentors (one was George Palade, who shared the 1974 Nobel Prize in Medicine or Physiology) advised him to go to NIH for postdoctoral training in immunology or neuroscience. Egwuagu figured there’d always be a chance to go to CDC later (he never went, however).

Because he was eager to explore the latest advancements in medical research, he took his mentors’ advice and headed to NIH for further training. “At that time [1980s], there was a revolution in [scientific] thought among young molecular epidemiologists at Yale,” said Egwuagu. “The concept of molecular medicine was taking hold.”

In 1987, Egwuagu joined the lab of Igal Gery, an immunologist who is now a scientist emeritus at NEI. Gery’s lab had all the resources Egwuagu needed to gain basic research experience in immunology and study the proteins that were involved in causing eye autoimmune disease. Their cutting-edge work led to the seminal discovery of the molecular basis of susceptibility to organ-specific autoimmune diseases (J Immunol 159:3109–3112, 1997). Less than a year after joining NIH, Egwuagu started his own lab in NEI.

From Point A to Point B

IL-35 is a tricky protein to work with. Making it is “a pain in the neck,” said Egwuagu. “For about three liters of culture, you end up with only about one microgram” of purified IL-35. In addition, it’s made up of two subunits that need to interlock to become active and exert anti-inflammatory effects. Egwuagu was confident that both subunits were made inside Bregs and that his team could isolate the active form of IL-35 in culture. Yet the same question kept coming up: How do both subunits of IL-35 get out from inside the cell and meet to create the active form that the lab team isolates?

This question had Egwuagu at a loss. He remembers chatting at dinner with his wife Michele Evans, a senior investigator in the National Institute on Aging. She works with exosomes, microscopic “bubbles” that contain a variety of molecules, including proteins. After her husband described his dilemma, Evans explained that many cells secrete exosomes and suggested that perhaps Bregs secrete them as well. Egwuagu decided to test his wife’s theory in the lab. He and his team found that the Breg population they study did indeed secrete exosomes containing both subunits of IL-35 and that IL-35-containing exosomes grown in the lab have therapeutic effects in an autoimmune mouse model of uveitis. The findings were published in 2020 in Frontiers in Immunology. (Front Immunol 11:1051, 2020).

“I don’t give my wife enough credit,” said Egwuagu.

Thanks, in part, to Evans’ insight, Egwuagu had shifted his research and found a more clinically feasible, and easier, way to determine the right dose of IL-35 to treat uveitis: Measure the IL-35-containing exosomes instead of the two loosely linked subunits that form the active IL-35. His ultimate goal is to develop Breg immunotherapies for the treatment of CNS autoimmune and neurodegenerative diseases.

In addition to conducting his own research, Egwuagu enjoys mentoring young predoctoral and postdoctoral scientists and tutoring students in the NIH Medical Research Scholars Program (a 12-month residential research immersion program for medical, dental, and veterinary students). “I believe strongly that the mission of NIH is to train young people,” he said. His philosophy involves balancing being hands-on while allowing his trainees the independence to work through problems on their own. He encourages his trainees to figure out what it is they want to do in their careers and tailor their training accordingly.

Egwuagu considers his decision to train—and stay—at NIH as one of the best he’s made. “Dreams change as you grow up,” he said with a laugh. “It all turned out for the best.”

Charles E. Egwuagu, Ph.D.

Senior Investigator, Chief, Molecular Immunology Section, Laboratory of Immunology, National Eye Institute

Education: M.P.H. in infectious diseases epidemiology from Yale School of Public Health (New Haven, Connecticut); M.Phil. in molecular epidemiology and Ph.D. in epidemiology and microbiology from Yale Graduate School of Arts and Sciences (New Haven, Connecticut)

Training: Postdoctoral fellowship in Igal Gery’s lab at the National Eye Institute

Came to NIH: In 1987 for training; started the Molecular Immunology Section in 1999

Other positions: Commissioned Officer of the U.S. Public Health Service, attaining the rank of captain (1990–1997)

Outside of Work: Enjoys playing soccer and tennis

Website: https://irp.nih.gov/pi/charles-egwuagu

Ethan Smith, a postbaccalaureate fellow in the National Institute of Nursing Research, is studying biomarkers for traumatic brain injury. He’s in the process of applying to graduate programs in clinical psychology. Outside of work he enjoys watching television, playing chess, and talking with friends.