Yong-Hui Jiang: Unlocking Genetic Mysteries to Treat Brain Disorders

As a young doctor at a pediatric hospital in Shanghai, Yong-Hui Jiang, MD, PhD, looked into the faces of parents and saw desperation. Working in a clinic for children born with Down syndrome and significant cognitive delay, Jiang could do little more than tell parents what they already knew.

Family after family asked him the same questions: Why couldn’t their child speak? What had caused the cognitive delay of their child’s Down syndrome? How could they be cured? Even though Jiang had graduated from one of China’s top medical schools, he didn’t have the answers.

“I didn’t know anything that could help,” he recalls. “I felt like everything I learned in medical school was not enough.”

Nearly four decades later, Jiang’s career as a physician-scientist has led to breakthrough developments in the biology of neurogenetic disorders like Angelman syndrome and autism. As Dorys McConnell Duberg Professor of Neuroscience, professor of genetics, of pediatrics, and of obstetrics, gynecology, and reproductive sciences, and chief of medical genetics at Yale School of Medicine (YSM), he has built on that research to lead national consortium projects in gene editing-based therapeutic development, rare and undiagnosed disease diagnosis, and precision medicine, while also continuing to see rare disease patients in the clinic.

Now, he hopes to take that work to the next stage, as one of the leading principal investigators of a Yale-led consortium developing and applying a novel genome-editing platform that could implement targeted therapies for neurodevelopmental disorders directly in the brain. The project, which received a $40 million grant from the National Institutes of Health (NIH), focuses initially on Angelman syndrome and H1-4 (HIST1H1E) syndrome, rare neuro-genetic disorders that cause significant neurodevelopmental delays and autism. Phase I clinical trials could begin as early as 2027.

The goal is to show that gene editing-based treatments for human neurodevelopmental disorders are safe and effective. If successful, the team could significantly improve the symptoms of, or even cure, Angelman syndrome with a single treatment dose.

The project is a full-circle moment for Jiang, whose work as a PhD student helped discover the Angelman gene. He also developed the first Angelman mouse model, which researchers worldwide have used to develop new therapies.

“My motivation always comes from the patients I serve, going back to when I was a medical student,” he says. “Now, I’m hoping that we can finally deliver real hope for these patients and families.”

Jiang grew up in a small mountain village in rural China, where his father was a school principal and his mother worked as school staff. He credits his family, especially his maternal grandparents, with instilling in him a lifelong value of caring for others.

“They were illiterate farmers, but they were very caring,” he says. “They taught me that even if you don’t have anything, you can still help other people.”

A high school teacher recognized Jiang’s academic potential and encouraged him to take national exams so he could continue his education. The decision to apply for medical school was a pragmatic one. His father, who had lost his job and spent time in a labor camp because of political persecution, advised him that if he became a doctor, he would always have a job, no matter the political climate.

In the fall of 1981, Jiang began his studies at Shanghai Medical University, now called Shanghai Medical College of Fudan University, where he went on to graduate first in his class of 600 students. After graduation, Jiang was recruited to stay on as junior faculty, working in the area of maternal and child health under the mentorship of Wenwei Cai, MD. It was in this position that he began working at a pediatric hospital, in a clinic for children with developmental disabilities.

Jiang was frustrated by his inability to help the children and their families. But he was also fascinated. Why were these children unable to learn like their peers? Even though he had very little research training during medical school, he wanted to understand the biological mechanisms that had affected their brain development so profoundly.

“I had a naive idea that if I could figure out Down syndrome, which is a common intellectual disability syndrome, I would know everything,” he says with a chuckle.

After five years teaching and working in the clinic, a World Health Organization/UNICEF fellowship offered Jiang the opportunity to receive advanced biomedical training in the United States. He arrived at the University of California, Berkeley, where he studied in the program of maternal and child health, and spent time in the genetics clinic at the University of California, San Francisco, working with children with intellectual disabilities.

“I thought, oh, that’s quite interesting, you can learn a lot from molecular genetics about intellectual disability,” he says. “So I decided to pursue more training.”

Jiang decided to pursue his PhD at Baylor College of Medicine, one of the country’s leading research training programs on the molecular genetics of neurodevelopmental disorders at the time.

Even in a lab full of ambitious students, Jiang stood out, says Arthur Beaudet, MD, professor and chair of the Department of Molecular and Human Genetics at Baylor, who supervised Jiang’s PhD work and mentored him through his postdoctoral program. Along with his intelligence and curiosity, Jiang had an intuitive understanding for research and the scientific process, Beaudet recalls.

“He clearly was very talented, and he was a joy to work with, because he was able to figure out exactly the right details of how an experiment should be done,” Beaudet says. “You could see he had the potential to be very successful.”

Jiang focused his PhD research on Angelman syndrome, a rare neurogenetic disorder that causes severe intellectual and neurological disabilities, including an inability to speak or make words, impaired physical movement, and seizures. During this initial work, he contributed to the discovery of the Angelman gene, UBE3A, a breakthrough that set him on a lifelong path of gene discovery in other neurogenetic disorders and rare diseases.

As Jiang dove deeper into the genetics of brain disorders, he also began studying neuroscience, learning more about fields like electrophysiology and behavior, driven by a desire to understand how a genetic mutation could lead to such changes in the brain. He also developed the first Angelman animal model, a line of mice with the Angelman mutation that enabled researchers to study the pathophysiology of the disorder and test new treatments.

A year after the initial discovery of the Angelman gene, researchers unlocked the surprising biology of how it worked, a finding that Jiang later helped confirm. Everyone has two copies of each gene, one from their mother and one from their father. Normally, both copies are expressed equally. However, the team found that for the gene involved in Angelman syndrome, only the mother’s copy of UBE3A is expressed. The father’s copy is present but silenced, like a switch that never gets turned on.

This phenomenon, called genomic imprinting, is quite rare. What was even more unusual in this case was that it was specific to the brain. In the rest of the body, the Angelman gene worked as usual. For Jiang, the discovery was thrilling.

“I thought, many people worked on this disease for many years, and they didn’t figure it out, because this phenomenon was not in a textbook,” he says. “Science is fascinating, but sometimes it’s a surprise. It’s not something you can anticipate. That made it even more exciting.”

The discovery not only helped explain the biology causing Angelman syndrome, it also pointed to a tantalizing therapeutic target. If the father’s copy of the gene was turned off, could it be turned back on?

As he finalized his PhD, Jiang seemed on the cusp of a long career in research. Then a laboratory accident upended it all.

“A summer student intern asked me for a bottle of alcohol,” Jiang recalls. “But behind him was a Bunsen burner. And I didn’t see it."

When Jiang reached over with an open bottle of alcohol, it caught the flame and exploded, splattering his upper body. Jiang was engulfed in fire for around 15 seconds, sustaining second- and third-degree burns on his hands, arms, chest, and face.

While three people were rushed to the hospital, Jiang’s injuries were the most severe, with burns across 50% of his body. He spent six weeks in intensive care, eventually undergoing 10 skin graft surgeries.

Along with the emotional trauma—Jiang had nightmares for months after the accident—his injuries threw his future plans into doubt. With severe scarring tightly pulling the skin over the joints in his fingers, Jiang never fully recovered the use of his hands. How could he continue as a researcher if he couldn’t pick up a test tube or operate equipment in the lab, he wondered.

“It felt like my research career would end,” he recalls. “I decided, maybe it’s better to go back to my original medical training.”

After recovering, and thanks to the strong support of his wife, Jiang embarked on a pediatric residency at Texas Children’s Hospital, with a clinical genetics fellowship at Baylor, undergoing the time-consuming process of redoing his clinical training so he could become board certified to see patients in the United States.

Then his career took another unexpected turn when the Cure Autism Foundation offered him a junior faculty grant for research.

“I was still in the middle of my clinical training, but I felt like, OK maybe I still have the capability to do research,” he recalls. “I decided I wanted to take the physician-scientist track.”

Jiang eventually accepted a position at Duke University, where he spent more than a decade advancing gene discovery and research that helped explain the genetic drivers of autism and other neurodevelopmental disorders. Although he wasn’t yet developing treatments, he hoped that by understanding the basic science and genetic underpinnings of these conditions, his findings could someday be used to help patients.

Then in 2019, he was recruited by YSM to the Department of Genetics as both professor and chief of medical genetics in the clinical realm. For Jiang, the Yale connection was special. His medical school in Shanghai had been founded by YSM’s first Chinese graduate, Yan Fuqing, MD. His mentor, Arthur Beaudet, a YSM graduate, had modeled Baylor’s genetics program after the combined basic science and clinical program created at Yale by Leon Rosenberg, MD. Jiang knew this role was an opportunity he could not turn down.

In the seven years since joining YSM, Jiang has tripled the size of the Clinical Genetics Division and expanded the group’s research program with major projects, including a multicenter study on the genomics of recurrent pregnancy loss and research into rare diseases such as H1-4, TUSC3, SHANK2/3, MSL2, and PURA syndrome.

He directs the Yale Center of Excellence for Rare Diseases, part of the National Organization for Rare Disorders (NORD). He also leads the Yale Diagnostic Center of Excellence in Undiagnosed Disease with a $3.5 million grant from the NIH Undiagnosed Disease Network; the center will use advanced genomics techniques to help diagnose patients with rare diseases and unexplained symptoms, especially in underserved populations.

With the new Angelman project, Jiang hopes to build on his decades of research to achieve his ultimate goal: developing a life-changing treatment or even a cure.

Along with Angelman syndrome, which affects about one in 15,000 people, Jiang has focused his research on other rare neurogenetic disorders, including H1-4, TUSC3, SHANK2/3, MSL2, and PURA syndrome, which affect only a few hundred people worldwide. But why study such rare diseases?

Along with the belief that every patient deserves research and support, studying rare diseases can often pave the way to a better understanding of more common conditions, Jiang says.

That’s because rare disorders often represent a severe form of more common health problems. This extreme presentation can make the underlying biology more apparent.

“You start with the severe form because it’s easier to figure out, then you apply that biology to common diseases and benefit a wider population,” Jiang explains. “The hope is that by understanding rare diseases, we can gain insight into more common diseases.”

Allyson Berent, DVM, chief science officer for the Foundation for Angelman Therapeutics, a partner on the Yale-led NIH Angelman syndrome grant, recalls an early meeting with Jiang, who joined a panel of experts assembled by the foundation to discuss gene therapy. Some researchers proclaimed that, even if an Angelman therapy was possible, it likely would not help children unless they were treated at birth, or even in utero.

For Berent, whose daughter living with Angelman syndrome was a toddler at the time, the dismissiveness was tough to hear. She recalls how Jiang spoke with sensitivity and compassion, addressed her respectfully as a parent, and challenged his colleagues to keep an open mind about the potential.

“He stood up and said, very respectfully, ‘I don’t agree with that. We’ve never traveled this road before, and we don’t know what’s possible,’” she says.

The new project is not the first attempt to develop a treatment for Angelman syndrome. Other therapies currently being studied try to tackle the unusual biology of the dormant paternal gene by inactivating the RNA strand that runs in the opposite direction, unsilencing the gene and improving symptoms. However, Jiang notes, these effects are temporary and inefficient. They require a spinal injection every few months to renew the results, which can be extremely stressful for families.

The Yale-led consortium’s approach is different because it would use a CRISPR-based gene-editing platform to unsilence the dormant gene itself, activating it permanently.

“With this technology, just one dose may fix everything,” Jiang says.

A key piece of the puzzle fell into place when Jiang connected with Jiangbing Zhou, PhD, Nixdorff-German Professor of Neurosurgery at YSM, who developed a new non-viral, non-nanoparticle method that allows for more efficient delivery of gene editing into the brain. Zhou is a co-leader on the project.

“The biggest hurdle for neurologic drug development has been delivery,” Berent explains. “To have a delivery option that could get to every part of the brain, including the deep brain structures, is huge.”

The project could have a significant impact beyond Angelman syndrome. If successful, the approach could be applied to hundreds of other neurodevelopmental disorders.

“My bigger goal is to help these kids with brain disorders, if not with a cure, then to make their quality of life improve in a dramatic way,” Jiang says.

After that, Jiang isn’t sure—and that’s what excites him.

“I don’t have expectations, I just keep working,” he says. “I credit my academic success to the training I received and the contribution of the trainees I’ve mentored. I never know if another discovery will come to me or not, but if you keep working, and working with young and talented students and postdocs, there’s always a chance. You just don’t know when it’s coming.”