Hank Cheng (right) and Andrew Stergachis with poster explaining IsoRanker: 'He has the rare combination of technical expertise and a genuine drive to make sure his science actually helps patients'
At age 14, Hank Cheng planned to spend the summer flipping burgers at the local McDonald’s. He applied but did not get the job. With that job no longer an option, he decided to look for volunteering opportunities and applied to a local museum, an animal shelter, and a hospital.
The museum and animal shelter never responded, but the hospital in the suburbs of Madison, Wisconsin, did. Cheng spent the summer helping at the front desk, escorting patients, and delivering flowers, among other tasks.
“I saw a lot of things at the hospital that left a very strong impression on me,” said Cheng, now an M.D.-Ph.D. candidate at the University of Washington. “A mother crying in the emergency department because her son was dying. Patients celebrating as they were leaving the hospital with balloons. I gained an appreciation for the power of medicine, as well as a deep respect for patients and the healthcare workers. It sparked my interest in a career in medicine.”
His steps toward a career in medicine accelerated when he and his family moved to Washington from Wisconsin. Cheng was 15 and was accepted to the University of Washington Academy, an early admission program for academically advanced and highly motivated students.
“I love to learn and wanted to learn at a pace that could challenge me,” said Cheng. “I also wanted to make progress towards my career earlier to enable me to support my family and myself.”
To some, “progress” may be an understatement. Starting as a freshman and throughout his entire time as an undergraduate, he researched the genetics of rare neurodevelopmental conditions in the Department of Pediatrics with Dan Doherty, M.D, Ph.D. Working with families affected by rare genetic conditions showed Cheng both the promises and the limitations of modern medical genetics. For many patients, years of testing can end without an explanation for their symptoms. He was drawn to the challenge of using genetics to find answers for families who had often spent years searching for them.
During his junior year at the UW, Cheng was selected for the National Institutes of Health Undergraduate Scholarship Program and spent a summer investigating infections of the nervous system in the lab of Avindra Nath, M.D. Two years later in June of 2020, after completing a Bachelor of Science degree in Biology, he returned to NIH as a post-baccalaureate fellow. For the next year, he used machine learning to study neuroinflammation and degeneration in individuals with HIV.
Cheng has a mantra that empowers his work on rare diseases: 'Unsolved does not mean unsolvable.'
Cheng came back to UW in June of 2021 to begin his M.D.-Ph.D. training at the UW Medical Scientist Training Program and work with BBI’s Andrew Stergachis, MD, PhD, an Associate Professor in the Division of Medical Genetics and the Department of Genome Sciences. With Stergachis’s mentorship, he was determined to return to the field of medical genetics and help address one of the greatest hurdles facing researchers and physicians.
“A major problem in medical genetics is our diagnostic rate for genetic conditions,” Cheng said. “Fewer than half of the people with genetic conditions who receive genetic testing receive a diagnosis.”
In the Stergachis lab, he worked on the “long-read multi-omic approach,” a new method of genetic testing.
“The conventional approach is to use just the genome,” he said. “With this new multi-omic approach, we have an unprecedented view of a patient genome, but we also now have their epigenome and transcriptome. The idea is that this more comprehensive view will enable us to provide patients with more answers.”
That work has led to an innovative framework to improve the diagnosis of rare diseases.
“Hank led the development of IsoRanker, a long-read transcriptome approach for finding non-coding variants that cause unsolved rare diseases, and he didn't stop at the method,” said Stergachis. “Using it, he identified the variant causing one patient's condition, which in turn led to finding five more individuals with the same condition who may now benefit from targeted treatment.”
Cheng is the first author on the IsoRanker paper, “Long-read transcriptome analysis using IsoRanker for identifying pathogenic variants in Mendelian conditions,” which was published in September in the American Journal of Human Genetics. In a recent blog for the BBI website, Cheng noted:
“IsoRanker is not intended to make diagnoses on its own. Instead, it provides another layer of functional evidence that can be considered alongside clinical phenotypes and genomic variants. Tools, such as IsoRanker, are part of a broader effort at the University of Washington to make functional genomic measurements useful at scale. At the Stergachis lab, we are developing technologies and tools that integrate information across the genome, epigenome, and transcriptome to better understand how genetic variants cause disease. By connecting changes in DNA to their downstream molecular consequences, we hope to uncover diagnoses that would otherwise remain hidden.”
The paper finds that IsoRanker can use long-read RNA sequencing data to:
- Find disease-causing variants that are currently difficult to interpret;
- Understand how those variants change RNA;
- Improve the diagnosis of rare genetic diseases, and;
- Identify potential treatments for some patients.
These four outcomes underscore Cheng’s commitment to precision medicine that best serves individual patients. Stergachis agreed: "Hank has the rare combination of technical expertise and a genuine drive to make sure his science actually helps patients. That instinct to turn technical expertise into real clinical impact is what will make him an outstanding physician-scientist.”
Indeed, Cheng has a mantra that empowers his work on rare diseases: “Unsolved does not mean unsolvable.”
