According to the US Food and Drug Administration, half of rare diseases are found in children, but there is still much that scientists do not know about the underlying mechanisms that drive disease and tissue development in young patients. A $3 million grant from the Chan Zuckerberg Initiative, awarded to a team of researchers led by Monkol Lek, PhD, assistant professor of genetics at Yale, will help uncover these processes as they involve skeletal muscle. in children at the unicellular level. The grant will support Lek and his team in creating a Pediatric Cell Atlas of Skeletal Muscle – a roadmap of healthy skeletal cells and how they change at four key age-group milestones between the ages of zero and 18.
In addition to Yale New Haven Hospital, other institutions involved in this initiative include Cornell and major children’s hospitals in the US, including Children’s National Hospital in Washington, DC. All sites will be involved in tissue collection, one of the most challenging aspects of the effort, says Lek. The researchers will need skeletal tissue samples from healthy individuals via biopsy. To obtain these, he says, they will take samples from children previously suspected of having a muscle disease. The team will also use tissues from existing hospital biobanks and autopsies.
A key goal of this effort, Lek says, is to ensure the samples represent a diverse patient population. “All the research to date has lacked diversity,” says Lek. “When we create a single-cell atlas, we want it to be representative of all people, so we were careful in selecting tissue sources that were reflective of the wider United States.”
Lek’s interest in studying skeletal muscle diseases began nearly two decades ago when he worked as an engineer at IBM and discovered that he had a rare disease called limb-girdle muscular dystrophy, which causes progressive weakening of the limb, shoulder and hip muscles. Lek’s journey to better understand and treat his condition led him to a doctorate in medicine with a focus on genetics. His own experience gives him a rare insight into the urgency of understanding and treating rare diseases.
“I’m in pain every day,” Lek says. “Not only physically, but also psychologically. If you study your own illness, you know your destiny. The more I know, the less hope I have.”
Lek knows firsthand the importance of understanding the mechanisms of rare diseases like his at the most basic single-cell level, of discovering how cells change during the aging process and which cells are most receptive to new therapies. “I think about the long term, not just the project,” says Lek. “I want to contribute to the paradigm shift. To discover which genes and mutations cause disease and to address the genetic cause. I hope to create custom-designed, scalable therapies for each patient and find a funding model that makes treatment accessible to all patients.”
Lek’s disease shares an important feature with other rare diseases of the muscular system, including other forms of muscular dystrophy – symptoms are triggered when a person reaches a certain age. The Single Cell Atlas will help to clarify how children’s development triggers this process and why different diseases affect certain muscles first.
“MRIs from patients with genetic muscle disease tell us that wasting happens differently in different muscles,” Lek says. “We see that consistently in patients.” The Pediatric Cell Atlas of Healthy Skeletal Muscle is expected to last three years. Once completed, researchers will combine their findings with those of the existing Human Cell Atlas to strengthen future disease studies.