The Human Genome Project’s successful completion 15 years ago gave us a new genomic lens to read our 20,000 or so protein-coding genes. Since then, a surge in next-generation sequencing technologies is generating new insights daily that sharpen our view of how the human genome works.
Yi Xing, PhD, was on the cusp of this revolution in medicine as he finished his PhD training in molecular biology and bioinformatics at University of California Los Angeles (UCLA). His research career began to rise during the incredible takeoff of big data science, and he became a prominent scientist in this cutting-edge field. The immense challenges of synthesizing diverse data sets from many sources come with vast opportunities to change pediatric medicine, which is why Dr. Xing is eager to assume his new role as the inaugural director of the Center for Computational and Genomic Medicine at Children’s Hospital of Philadelphia.
“Our vision is to develop research programs that use computing and big data and genomic technologies as the driver for making new biological discoveries and medical innovations,” said Dr. Xing, who also is a professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. “There will be tight interaction from both the basic science and technology side, as well as the translational and clinical side of genomics and computational biology. The Center will contribute to CHOP’s entire ecosystem of research.”
CHOP is an ideal environment for the Center to grow, Dr. Xing said, because it has rich resources and a supportive infrastructure in place, including its biorepositories and electronic health record, to yield unique insights into children’s health and disease. The Center will leverage CHOP’s strength in developing molecular and cellular therapeutics and its success in recognizing the underlying genetics of devastating inherited pediatric disorders. It also will provide an intellectual home for recruiting tenure track faculty in the space of computational and genomic medicine.
Over the summer, Dr. Xing moved his lab and team of about 20 investigators from UCLA to CHOP’s research campus. They work in a hybrid computational and experimental lab with a focus on how gene regulation is controlled at the level of ribonucleic acid (RNA) molecules — specifically messenger RNA (mRNA) processing. It’s useful for computational biologists to have wet lab operations, Dr. Xing said, because it facilitates synergy among investigators who have the in-house expertise to develop new genomic technologies, generate data quickly, and then validate their computational tools and predictions.
From a single gene, there are many ways to generate different RNA species from the DNA, through alternative processing and modifications of RNA, which then could be translated into different types of proteins with distinct biological functions, Dr. Xing explained. Some RNAs do not code for proteins at all, but they have different cellular and molecular functions. Identifying how these RNA-based molecular switches can be disrupted and possibly alter cellular pathways is an underexplored area of medicine that scientists are beginning to link to a wide spectrum of diseases.
“The key interest of our lab is to understand how these RNA-level complexities are generated and what is the function or medical relevance of this extreme level of complexity,” Dr. Xing said. “It’s estimated that 60 percent of the mutations that cause human disease are because they disrupt RNA processing. In almost every organ system, you’ll find examples of defects in RNA causing disease.”
In a review article appearing this year in the American Journal of Human Genetics, Dr. Xing and his colleagues described the expanding landscape of RNA variation in human populations and how refining researchers’ ability to pinpoint RNA defects can eventually lead to new diagnostic approaches and therapies. They also discussed how rapid developments in sequencing technologies and computational biology have accelerated the speed, scale, and precision of biomedical discoveries related to RNA variation.
“A fun part about working in the area of genomics and computational biology is the technologies are constantly changing, and they generate a lot of interesting problems to solve,” Dr. Xing said. “In turn, those technologies generate a huge amount of data. A big part of our lab is to develop innovative computational methods for integrating those larger scale data sets in order to translate big data into knowledge.”
Dr. Xing and his team not only interact with technology in novel ways, they also develop transformative technology. Their series of work has addressed stimulating concepts in the field, such as defining the fundamental data structure and algorithms for looking at the complexity of RNA. One example is a computational tool, called rMATS, to detect differential alternative RNA processing events from large scale RNA sequencing data. The genomic research community widely uses rMATS and other software Dr. Xing’s lab has developed to answer important biomedical questions.
As the Center recruits new faculty members, Dr. Xing is looking for candidates from diverse areas of scientific and clinical expertise who can speak the multiple “languages” of interdisciplinary science, from molecular and cellular biology; to genomics, proteomics and bioinformatics; to cancer genetics and immunology; to computational medicine and beyond.
“We want to bring new faculty who are very research driven and also are technology innovators,” Dr. Xing said. “If you’re situated in a place like CHOP that has a lot of basic science and clinical resources and opportunities to interface with patients with a wide variety of genetic diseases, we can use data and technology to make a difference in people’s lives.”
Dr. Xing holds the new Francis West Lewis Chair in Computational and Genomic Medicine at CHOP. Dr. Lewis persuaded two fellow physicians to join him in co-founding CHOP in 1855.