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$3 Million to Provide Foundational Knowledge: The Pediatric Cell Atlas of Skeletal Muscle

Updated: Aug 4, 2022

On the road toward treatments and a cure for congenital muscular dystrophy, we’ve come a long, long way to learn about causes and complications. Sometimes, it can seem like the more we learn, the more there is to learn. A bit of good news in our journey toward more comprehensive knowledge is that a new project offers a new foundational understanding of our family of conditions: The Pediatric Cell Atlas of Skeletal Muscle. It’s an important step in building knowledge and subsequently, therapies for CMD and other neuromuscular conditions.

Funded by the Chan-Zuckerberg Initiative and led by some of the neuromuscular community’s most prominent minds, the Pediatric Cell Atlas of Skeletal Muscle will develop a comprehensive picture of what healthy skeletal muscle cells look like. A diverse set of donor tissues—across ages, genders, and ancestry—will create this picture, and will benchmark typical development of tissue.

Implications for the Community

There’s a limit to what we can understand about our conditions if we don’t know the ins and outs of what healthy tissue looks like. If we recognize and benchmark what’s typical, then we are better able to understand where and how muscle tissue affected by a neuromuscular disorder deviates from that typical pattern.

Dr. Monkol Lek, Assistant Professor of Genetics at the Yale School of Medicine and one of the Project Co-Investigators for the Pediatric Cell Atlas of Skeletal Muscle, explains further: “Researchers working in CMD can eventually take advantage of this atlas of skeletal muscle library, and use it as a comparator for diseased tissue. They can potentially learn answers to questions such as ‘why does one fiber waste before other types or other muscle groups?’”

Dr. Lek points out that this project offers a missing piece of the puzzle in the study of human cells. As of February 2020, the open-science Human Cell Atlas project had participation from 1,027 institutes in 71 countries, from which 81 labs had already posted data for 34 organs and tissues, including the liver, lung, blood, immune cells, colon, and retina. Yet, as Dr. Lek says, “skeletal muscle, though it is the majority of mass in the body, was neglected in the Human Cell Atlas. This step is a natural progression from that project.”

As far as the affected community’s responsibility, perhaps the best way to help is by encouraging the donation of healthy tissue. Lek says, “Raising awareness is the first step.”

For biopsies of healthy tissue, all fresh samples are processed within 24 hours. Researchers break out individual cells from the extracellular matrix then extract RNA, or expressed genes. They then barcode it so that when they send for sequencing, it is clear what genes were expressed in what cell. With a frozen sample, they must use only the nucleus since the cellular structure will be destroyed in the freezing process. Each bit of information provides a snapshot in time, helping researchers understand what genes are being expressed.

“Every group or subtype of cells we find in the muscles should have similar profiles, switching on the same set of genes. The thought is, if we do enough of the samples, we’ll actually find other groupings of cells that tell us about disease—how healthy tissue develops and what happens when a disease is affecting it.”

Monkol Lek, PhD: The Right Person for the Job Dr. Lek has a personal stake in this project as well as a professional one. Diagnosed as an adult with LGMD2G (TCAP), he remembers what it was like to have only a vague understanding of his condition. He is proud to be a co-leader of this project. “There won’t be another PI that will push like I will,” he explains. “The study of healthy tissue and diseased tissue as the yin and yang of the same effort... We must leverage this project and pave the way for the next steps.” He reached out to Cure CMD to help broadcast the work being done, to ensure that the affected communities across all neuromuscular conditions are involved in helping to push for those next steps.

The 10 co-PIs working with Lek include trained pathologists who will pinpoint and examine healthy tissue, those who are doing patient outreach, and those who do the processing, analysis, interpretation, and data-sharing. Each focus is just as important as the next; outreach to the community is just as important as the scientific data.

Dr. Lek’s hope is that at the end of the three-year project, the investigators working on the pediatric muscle cell atlas will have built atlas an incredible resource for the entire neuromuscular research community, who will use it to better understand muscle conditions. He hopes that it parallels with GTEx project. [Author’s note: the Genotype-Tissue Expression (GTEx) project is an ongoing effort to build a comprehensive public resource to study tissue-specific gene expression and regulation.]

Lek adds, “We may be years from therapeutics, but by understanding the types of cells in skeletal muscle and how they are different in the disease state, maybe we’ll find a subset of fibers, which would determine how a treatment could be used to help that cell type perform better. This could lead to biological markers (an objective measure that captures what’s happening in a cell or organism at a given moment)... Across cultures, within our multilingual efforts, we must standardize the work, and get everyone on the same page in a democratic way.

“The human atlas is a work in progress. The aim of this project is to improve it, and make the data publicly available as soon as possible. It’s not just for us to benefit from. It’s for all.”


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