Xiaowu Gai, PhD, Professor of Pediatrics, has built his career around a single ambitious goal: bringing genomic medicine into everyday care for children.
As Director of Child Health Bioinformatics and Associate Director of the Linda A. and John T. Mellowes Center for Genomic Sciences and Precision Medicine at MCW, Dr. Gai is focused on translating DNA-level insights into meaningful clinical applications. A molecular geneticist by training, he has spent much of his career uncovering the genetic foundations of rare diseases and pediatric cancers. From developing cutting-edge diagnostic tools to mapping the genetic drivers of disease, his work is grounded in a belief that understanding the genome is essential to improving care for children today and shaping their long-term health.
As a new member of the Cancer Control Research Program, he’s expanding that vision by building the infrastructure, collaborations, and systems needed to make genomic medicine more accessible, scalable, and impactful across the institution and beyond.
“I take pride in being an enabler—someone who helps turn genomic discovery into something that can be used widely and meaningfully,” said Dr. Gai. “My vision is that every rare disease patient has their genome sequenced, and every tumor is thoroughly profiled to guide treatment, inform decisions, and support lifelong health.”
Get to Know Dr. Gai
Why did you choose to become a Cancer Center member?
Pediatric cancer is one of the areas where genomics has the most urgent and immediate potential to change lives. While at Children’s Hospital Los Angeles (CHLA), I contributed to OncoKids, one of the most comprehensive genomic tests for pediatric cancers. I also conceptualized an exome capture-based RNA sequencing assay for genome-wide identification of clinically important fusions, which led to the discovery of several novel fusions.
I am particularly interested in characterizing the landscape of mitochondrial DNA (mtDNA) mutations across childhood cancers: understanding how these variants arise, what they do, and how they might be used therapeutically or as biomarkers.
Becoming a member of the MCW Cancer Center provides an opportunity to connect that work more directly with the clinical questions being asked at the bedside, and to collaborate with colleagues who share a commitment to improving outcomes for young patients and their families. Great science does not happen in isolation, and the Cancer Center is where those connections take shape.
What first drew you to genomics?
I began my graduate studies at the start of the Human Genome Project. Early in my career, I became fascinated by how a single amino acid change in a retrotransposon could determine its target specificity and have profound consequences for genome evolution. This work was made possible by the complete sequencing of the yeast genome in 1996.
As sequencing technologies rapidly advanced and became more accessible, it became clear that genomics would fundamentally transform medicine. I wanted to be part of that future, especially for children with rare genetic diseases and cancers who had long been told their conditions were a mystery. Genomics offers a way to find answers and increasingly, a way to anticipate disease before it even appears.
I was fortunate to be part of that progress, including developing a bioinformatics software package that supported one of the first single nucleotide polymorphism array-based chromosomal microarray tests at Children’s Hospital of Philadelphia, and later leading the implementation of a clinical exome sequencing assay at CHLA.
Tell us about a project you’re excited about right now.
I have a specific interest in mitochondrial diseases and mitochondrial genomics. I currently serve as Co-Chair of the NIH Clinical Genome Resource Mitochondrial Disease Gene Curation Expert Panel, and the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, roles I have held since 2017.
My work centers on one of the biggest unanswered questions in mitochondrial medicine: how to determine which variants of mtDNA—the small but vital genome housed in our cells’ energy-producing organelles—are truly disease-causing. While mtDNA is essential to cellular energy production, the clinical significance of many variants remains uncertain, even after decades of study.
In 2019, my team mapped the landscape of germline and somatic mitochondrial DNA mutations in pediatric malignancies. Since then, we have advanced our understanding of these mutations in pediatric chordoma, Ewing sarcoma, central nervous system tumors, and pediatric B- and T-cell acute lymphoblastic leukemia. While these studies have suggested clinical significance using large genomic datasets, direct functional evidence is still lacking.
To address this, my collaborators and I are using state-of-the-art mitochondrial DNA base editing to introduce specific variants into human cell lines and zebrafish models. Our goal is to generate the functional evidence needed to definitively classify these variants, helping provide answers for patients and accelerating the development of precision therapies for mitochondrial diseases.
Where do you see the field heading in the coming years?
We are moving toward a future where genome-guided care is the standard for both sick and healthy children. As that future takes shape, genomic privacy concerns will become increasingly prominent. My colleagues and I coined the term Genomic Dignity, which we later detailed in an article in The American Journal of Bioethics. Genomic Dignity holds that individuals should define their own privacy preferences, govern how their genomic information is used, and share in the benefits it generates.
Genomic Dignity must be a foundational principle, reframing the conversation around omics data from simple concealment to ownership, control, transparency, and reciprocity. In a world where every child’s genome may be sequenced at birth, we cannot afford to treat that data as an institutional asset. It belongs to the individual, and our systems must be built accordingly.
At the same time, technological advances will continue to drive the evolution of genomic medicine. Long-read sequencing will uncover structural and epigenetic variants we have systematically missed. Single-cell and spatial genomics will help us better understand tumor heterogeneity and progression. The field of mitochondrial genomics, in particular, is poised for a major leap. As functional validation tools like mitochondrial DNA base editing mature, we will be able to resolve the many variants of uncertain significance that currently leave patients without answers and begin to pursue precision mitochondrial therapies.
As a bioinformatician, I am convinced that artificial intelligence will play an essential role in translating massive genomic datasets into actionable clinical decisions, and that shift is already underway. Ultimately, these advances must reach all children, because personalized medicine only matters if it is truly universal.
How do you spend your time outside the lab?
I enjoy mountain biking, hiking, and simply being in nature.