Chasing RNA and its Secrets About Diseases
Xiangbo Ruan, Ph.D., is working to unravel the secrets of ribonucleic acid (RNA) to better understand how RNA modifications affect human organs and potentially cause disease.
To say that a scientist is carrying out “cutting edge research” may be a cliché. But for Xiangbo Ruan, Ph.D., newly arrived at Johns Hopkins All Children’s Hospital in St. Petersburg, Florida, and an assistant professor in the Division of Endocrinology, Diabetes and Metabolism, “cutting edge” is a true and accurate assessment of his research. To unravel secrets of ribonucleic acid (RNA), present in all living cells, Ruan is using high-tech methods to “slice and dice” strands of RNA at the molecular level to better understand how RNA modifications affect human organs and potentially cause disease.
Rural China as a “Biology Lab”
“Growing up in a rural area of China, I watched plants and animals around me and became very curious about how genetic information is passed on to offspring,” Ruan recalls.
That interest led to him studying biology in high school, and fortunately, he had an excellent and supportive science teacher who further sparked his interests in biology.
After high school, it was off to university to study life science. Ruan was able to initiate his first research project aiming to produce and screen for mutant bacteria that have enhanced glutamine production. In 2006, he received his B.S. in biotechnology.
With his interest in molecular biology expanding, he entered graduate school in Shanghai, China, where he completed his Ph.D. in biochemistry in 2012 at the prestigious Institute of Nutrition and Health of the Chinese Academy of Science.
“After getting my Ph.D., I had a dilemma,” says Ruan with a smile. “I didn’t know whether I should go into industry, or into academia.”
Unsure of his future path, he began “networking” and found Chinese colleagues in the United States who were working at the National Institutes of Health (NIH). In 2012, he successfully landed a post-doctoral research position at NIH’s National Heart, Lung and Blood Institute (NHLBI)) outside of Washington, D.C. It was at NHLBI that his research interests in RNA became a priority, if not a passion.
What is RNA?
Many of us know that deoxyribonucleic acid (DNA), the twisted “double helix” first identified in 1953, is a “blueprint” for life. DNA carries genetic coding information from our parents that determines not only what we look like, but the nature of our individual biological selves. RNA is perhaps not as well known or well understood as DNA.
“New strategies to study human RNA metabolism are crucial to understanding the development of diseases,” Ruan explains. “While similar DNA is shared by many living species, it is RNA that likely makes species different.”
According to Ruan, RNA’s principal role in our cells is to act as a “messenger” carrying instructions from DNA for controlling the synthesis of proteins. That messenger function has recently come into sharper focus with the COVID-19 pandemic.
“Many people have become more familiar with messenger RNA (mRNA) because some of the COVID-19 vaccines are built on mRNA,” Ruan says. “That is because viruses, including SARS-CoV-2, use RNA, rather than DNA, as the carrier for their genetic information. In my post-doctoral studies, I began studying the molecular mechanisms controlling the activity of a kind of RNA called ‘long noncoding RNA’ (lncRNA), which are strands of RNA longer than 200 nucleotides that, unlike mRNAs, do not encode proteins. Instead, lncRNAs play an important role in regulating multiple biological functions through diverse mechanisms.”
During his post-doctoral work, lncRNAs and some of the mysteries of their function became the focus of his research that culminated in many experiments and several high-profile published research papers.
For example, in 2016 Ruan and colleagues published a study in Cell Reports describing how a lncRNA regulates glucose metabolism in the liver tissue. More recently he used cutting-edge technology to “humanize” the mouse liver by replacing the liver of a mouse with human liver cells. This provides a unique experimental platform to investigate human liver function in the laboratory mouse. He took advantage of this technology to uncover novel human specific lncRNAs that regulate human liver metabolism. This work resulted in more recent high-profile publications in Nature Communications and the Journal of Clinical Investigation.
In 2017, five years into his postdoc, the novelty of his work paid off. He won the “NHLBI Director’s Award for Outstanding Basic Science” and became a full research fellow. He remained a research fellow at NHLBI until coming to Johns Hopkins All Children’s in June 2021.
“We were very fortunate to attract a new colleague with the creative mind and scientific accomplishments of Dr. Ruan,” says Timothy Osborne, Ph.D., associate dean for Basic Research at Johns Hopkins All Children’s and director of the Institute for Fundamental Biomedical Research. “His infectious enthusiasm will be a key driver for the successful growth of our basic science research efforts at Johns Hopkins All Children’s.”
The Ruan Lab is “Open for Business”
“This is my dream job!” says Ruan who, never one to waste time, opened his lab soon after his arrival as a member of the Institute for Fundamental Biomedical Research.
He is already many steps closer to unraveling more about RNA and the causes and potential cures for a variety of diseases related to RNA dysregulation.
“Research in our lab is aimed at understanding how genetic and environmental factors affect RNA metabolism in humans,” Ruan says. “RNA is less stable than DNA and dysregulation of RNA can affect gene expression in both health and disease.”
When studying RNA metabolism, Ruan and his colleagues investigate modifications, synthesis, transportation and degradation of RNA. He explains that RNA quickly renews, or “turns over,” and the knowledge about that characteristic may be an important, useful tool for modifying RNA by either slowing down RNA turnover (slowing down its metabolism) or speeding it up to, for example, burn more energy in the liver to prevent fatty liver disease.
Newly developed tools, such as CRISPER-based “gene editing,” a type of genetic engineering that, among other functions, provides ways to activate or specifically alter gene expression, will help define RNA-protein interactions and answer important questions about a variety of diseases.
For example, in a 2020 paper published in Nature Communications, titled “In vivo functional analysis of non-conserved human lncRNAs associated with cardiometabolic traits,” Ruan and colleagues investigated how human lncRNAs contribute to obesity by examining their functions in humanized mouse models mentioned above.
“We will keep using humanized mouse models and gene editing tools to study RNA metabolism in different human organs to better define regulators of RNA metabolism, especially lncRNAs,” Ruan says.
Three Big RNA Projects
Three big projects are already on the bench in the Ruan lab:
- Studying the molecular mechanisms controlling the recently identified human lncRNAs associated with cardiometric traits;
- Revealing how the RNA degradation pathway is regulated by overnutrition and exploring its role in fatty liver disease;
- Identifying lncRNAs that regulate mRNA splicing in the liver and brain and investigating their roles in aging
Life is Not All Work
Although a hard worker, Ruan happily says that life should not be “all work and no play.” He loves sports, especially basketball. He is also a runner and has completed several marathons, going the 26.2-mile distance in both China and the United States.
All of his scientific work-related success from China to the United States, however, may have been eclipsed by his fortuitous meeting with New York City user experience designer Yiruo, who became his wife. The arrival of their daughter, Ella, two years ago was a happy event, and the family is now patiently waiting for Ella’s little brother, scheduled to arrive in August.