A research project on RNA biology by a Johns Hopkins All Children’s Hospital scientist could open new avenues for biomedical discovery in innate immunity and neuro-development.

Rui Zhou, Ph.D., recently received a five-year National Institutes of Health grant to continue his research into a type of circular ribonucleic acid (RNA) and how they impact immune response. Zhou’s award is at the NIH’s major Research Project Grant Program level, known as R01. Zhou previously has received three NIH grants at a smaller scale.

For many years, molecular biology relied on the idea that the primary function of RNA was to convert information stored in DNA into proteins. As more advanced technology allowed more in-depth analysis, scientists have discovered that RNAs—including those called “non-coding” because they do not directly contribute to protein production—have a variety of functions, including modulating cell proliferation, differentiation, development and immunity.

Although circular RNAs were identified several decades ago, the scientific community only recently began to focus on these enigmatic RNA species. Circular RNAs are more stable than their more common linear RNA siblings and recent research indicates they are relevant to normal development and physiology as well as to disease pathology.

With previous NIH grants, the Zhou lab found that anti-bacterial immunity is enhanced among fruit flies that have a decreased amount of RNA Edis, the circular RNA molecule that the lab is studying. Conversely, they found that over-production of Edis compromised immunity. Subsequent testing, however, indicated that improved immunity in Edis-depleted flies came with a price—an impaired ability to climb and a shortened lifespan.

“This is an evolving project,” Zhou says. “Immunity is what we started looking at, but when we noticed the climbing defects, we suspected that these fruit flies have neurological defects.” Subsequent studies confirmed their suspicion–these flies indeed display severe defects in the formation of certain brain structures. Under the new grant, Zhou and team will further investigate the role of the circular RNA Edis in the development and function of both immune and neural systems.

Zhou joined Johns Hopkins All Children’s in July as a scientist in the Cancer & Blood Disorders Institute and a member in the Center for RNA Biology. He has a secondary affiliation with the hospital’s new Institute for Fundamental Biomedical Research and is an assistant professor of oncology in the Johns Hopkins University School of Medicine.

The new institute represents a commitment by the hospital to basic science, which seeks to understand the origins of disease at a fundamental level. Scientists are studying cells and metabolic systems to learn how they behave. Understanding how diseases develop can lead to further research into how to prevent or treat them.

Zhou’s grant is the fourth award at the NIH’s R01 level or equivalent since the hospital integrated with the Johns Hopkins Health System in 2011.

A Background for Biology

Growing up with his grandparents in northeast China, Zhou was fascinated by insects and other “critters.” He spent much time in the family garden catching bugs and developing a healthy interest in biology.

Zhou went on to study biochemistry and molecular biology at Peking University and biochemistry at Shanghai Institute of Biochemistry, Chinese Academy of Sciences. He then came to the United States and enrolled at Harvard University for his doctoral studies in molecular and cellular biology. He joined the lab of Tom Maniatis, Ph.D., a distinguished molecular biologist.

“Most people in the Maniatis lab were studying the regulation of immunity in mammalian systems at that time,” Zhou recalls, “I was one of only three who decided to investigate the immune system of fruit flies—called Drosophila—and learned how this simple organism had strong parallels to how the human body worked, a concept scientists refer to as evolutionary conservation.”

For post-doctoral training, Zhou joined the group of Norbert Perrimon, Ph.D., at Harvard Medical School, where he developed research projects focusing on the function and regulation of non-coding RNA in Drosophila immunity, a line of investigation that he continues to pursue today.

“You can use a simple organism to crack the basic code of the problem,” Zhou says, “and then you can apply the knowledge learned from the simple organism to translate into more complex systems such as human beings.”

After postdoctoral training, Zhou joined Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, where he worked as an independent investigator for seven years before joining Johns Hopkins All Children's Hospital.

A New Opportunity

Zhou had an ongoing collaboration with Ranjan Perera, Ph.D., and interacted extensively with three other Sanford Burnham colleagues who were based in the research institute’s branch in Lake Nona, Florida. Because of a change in state funding, Sanford Burnham was closing the Lake Nona facility. Perera, Tim Osborne, Ph.D., Laszlo Nagy, Ph.D., M.D., and Masanobu Komatsu, Ph.D., all opted to join Johns Hopkins All Children’s.

“I knew these colleagues from Lake Nona, their scientific expertise and their personalities,” Zhou says. “That they were joining this institution was truly attractive.”

Zhou, the two postdoctoral fellows on his team, and the other basic scientists who recently joined will work in the hospital’s new 225,000-square-foot Research and Education Building, which is intentionally designed to encourage interaction between fundamental scientists, clinical and translational scientists, and clinicians.

“Since the recruitment process, I have been thrilled to learn the Johns Hopkins All Children’s leadership’s vision to expand into basic science,” Zhou says. “I am truly grateful that I have been provided precious resources. In particular, I am fortunate that I will have the opportunities to interact with clinical colleagues and clinical investigators. By learning more about disease symptoms and patient populations, we hope that we can synergize our research down the road. The knowledge goes back and forth from bedside to bench side and then back to bedside. I am looking forward to this exciting opportunity.”