Research News

The National Institutes of Health High-Risk, High-Reward Research program has recognized Frank Xie, PhD, with a New Innovator Award. This recognition marks Dr. Xie as an "exceptionally creative" early career investigator, supporting his research into how the physical structure of an unusual form of our DNA affects gene regulation in disease development.

The "New Innovator" category of the NIH's Health Director Awards is designed to encourage investigators to think beyond traditional bounds and to pursue trailblazing ideas in any area of research relevant to the NIH's mission to advance knowledge and enhance health. Dr. Xie received $1.5 million for his project.

Dr. Xie founded his lab in December 2021, and is an investigator in the Infection Biology and Cancer Biology Departments. His passion for advancing knowledge and enhancing healthcare came from working with patients first-hand as a medical student in China. So, Dr. Xie decided to figure out the answers himself. 

"Patients would ask me questions about their conditions that the field just does not have answers for yet," he says. "It was frustrating and demoralizing for both me and for my patients." 

His research led him to develop new tools to study chromatin, DNA structures that help regulate how our bodies function.

Our DNA is more than 200,000 times longer than the compartment in our cells where it is stored. To fit, the DNA must coil and fold around itself into extremely tight, dense structures called chromatin. Chromatin is just as important to our body as our genes themselves because its shape influences how the genes behave. Genes that normally would be far apart in a linear piece of DNA are brought closely together when the DNA is folded up in chromatin, where they can influence each other. Genes folded deep within chromatin are inaccessible to our cells and kept "off." Chromatin can rearrange itself and change shape to alter which genes are "on" or "off" and influence gene regulation. 

Most aggressive cancer types have incorrectly packaged rings of DNA called extrachromosomal DNA (ecDNA) that can form when chromatin becomes destabilized and rearranges itself incorrectly. These rings can replicate themselves hundreds of times, driving excessive expression levels of the genes on them and making the cells highly cancerous.

In a cell's nucleus, linear DNA (pink) is coiled tightly around itself into complex structures called chromatin (blue).

What's next for exploring ecDNA rings

Dr. Xie will use his award to integrate synthetic genome engineering, machine learning, state-of-the-art live-cell super-resolution microscopy and quantitative analysis to study chromatin biology and ecDNA in cancer. Chromatin and ecDNA rings are notoriously difficult to study in real time with current technology. Regular DNA sequencing ignores the shape of the chromatin and does not report the physical positioning when cancerous genes become activated. Technologies that assess the structure of the chromatin itself do not work in real time and aren't ideal to use when studying the highly dynamic chromatin regulatory processes. 

Dr. Xie says developing the necessary technology to assess the hidden structures and dynamics of these "weird" rings will help him uncover an "Achilles' heel" in ecDNA-driven cancer. 

"As a principal investigator of such a young lab, I am truly thrilled to receive this tremendous support from the NIH," he says. "With this money we have expanded our bandwidth to develop new tools and address fundamental questions about cancer genome regulation. I appreciate the unwavering support from my department chair Jae Jung, PhD, and institute leadership and will continue to collaborate with the outstanding clinicians and physician scientists here at Cleveland Clinic to promote the cure of cancer." 

Pictured: Frames from a video Dr. Xie took of ecDNA rings (green) "dancing" across cancer cells (purple) using his imaging technology. The orange arrow follows one ring as it moves across the cell in real time.