Massachusetts General Hospital is home to the largest hospital-based research enterprise in the U.S., with an annual budget of nearly $1.2 billion in 2021. The Mass General Research Institute comprises more than 9,500 researchers working across more than 30 institutes, centers and departments.
But what do each of these groups do? Learn more about the individual labs and centers in our #ThroughTheMagnifyingGlass series, where we take a closer look at the teams that make up the Massachusetts General Research Institute.
In this post, we are highlighting the Chetty Lab within the Center for Regenerative Medicine at Mass General Hospital, led by Sundari Chetty, PhD!
The Chetty Lab at the Center for Regenerative Medicine
What research do you perform, and why is it unique?
The overarching focus of the Chetty lab is to use human induced pluripotent stem cell (hiPSC) models for understanding brain development in Autism Spectrum Disorder (ASD) and other neurodevelopmental and psychiatric disorders.
We have recently made progress in understanding the molecular and cellular mechanisms contributing to brain overgrowth (or macrocephaly) in neurodevelopmental disorders.
Brain overgrowth occurs in about 20% of autistic individuals, who have more severe behavioral and cognitive deficits relative to autistic individuals with normal brain sizes. The increase in brain size precedes the first signs of clinical symptoms, suggesting that understanding the mechanisms regulating brain overgrowth could shed light on strategies for intervention or mitigation of symptoms.
Our work thus far has established that unhealthy brain cells (e.g. cells expressing calreticulin, an “eat me” signal) are not getting eliminated as they should be during neurodevelopment in individuals with certain forms of ASD.
In ongoing work, we are using the stem cell models we have developed to better understand whether certain factors cause some neural brain cells to become unhealthy or damaged in ASD and other neurodevelopmental disorders. For instance, is there a subset of cells undergoing cellular stress or have an accumulation of DNA damage? Are these cells not getting eliminated or pruned properly during early neurodevelopment when there is significant cellular turnover? On the immune side, are microglia defective and not eliminating damaged cells as they should?
The Chetty Lab is led by Sundari Chetty, PhD, who received her PhD. in neuroscience and B.A. in molecular and cell biology from the University of California, Berkeley.
Dr. Chetty started her lab at Stanford University after completing her post-doctoral work in Stem Cell and Regenerative Biology at Harvard University in Douglas Melton’s laboratory. Over the past year, she relocated her laboratory to Mass General!
Meet the Team
The diverse, motivated team of scientists tackling these questions in the Chetty lab includes postdoctoral fellows, graduate students, undergraduates, and research technicians with backgrounds in molecular biology, genetics, immunology, stem cell biology, and social work.
Our lab is united by our passion to make progress in understanding neurodevelopmental disorders that can greatly diminish the quality of life for children. The importance of these issues and our focus in trying to make progress on them underlies all aspects of our work – from high-level decisions about project direction and methods, to the day-to-day tasks that can sometimes be tedious but ultimately are contributing to a bigger-picture goal that inspires us all.
What publication is really important to your ongoing research?
The most severe forms of autism spectrum disorder frequently occur in people with large head sizes, many of whom have deletions of a small piece of chromosome 16, known as 16p11.2.
In a work published in the Proceedings of the National Academy of the Sciences (Li, et al., PNAS 2021), we use human iPSCs derived from patients with 16p11.2 deletion syndrome to understand why they exhibit brain overgrowth.
We found that CD47 (a protein that signals “don’t eat me”) is overexpressed in the neural brain cells of individuals with 16p11.2 deletion syndrome, and their unhealthy neural cells are therefore eliminated at lower rates by their immune cells. Blocking CD47 restores the elimination of unhealthy cells to normal rates.
These findings suggested that targeting the CD47 pathway may be helpful in identifying treatments for neurodevelopmental and psychiatric disorders associated with brain overgrowth.
Following up on this work, investigating whether imbalances in these “eat me” and “don’t eat me” signals regulate brain size in other conditions associated with brain overgrowth or undergrowth may lead to novel therapeutic strategies to prevent and treat these disorders.
What is one thing you wish everyone knew about the research you perform?
Like many other areas of scientific research, this work is not possible without an interdisciplinary team effort – from the talented young scientists in the lab, to the physicians and colleagues working directly with the patients to collect clinical data and samples, and to the numerous families and children who participate in our studies so that novel discoveries and treatments can be developed.
Working with human stem cell models for these complex human disorders can be very fulfilling and rewarding; however, they often require careful, painstaking bench work in order to derive the cells and tissues of interest. The dedication and time bench scientists put into caring for these cells (often on a daily basis!) is truly invaluable.
We hope that the parents who often reach out to us seeking help for their children know that we (and many others) are working hard on these issues. While progress is always slower than one wishes, scientists at Mass General, Harvard and beyond are making discoveries that will ultimately make a difference.
About the Mass General Research Institute
Massachusetts General Hospital is home to the largest hospital-based research program in the United States. Our researchers work side-by-side with physicians to develop innovative new ways to diagnose, treat and prevent disease.
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