Developing a Mini Brain to Study a Rare Genetic Disease

What biomedical issue did you address in your research, and what did your studies find?

My graduate research focused on rare genetic disorders known as N-linked congenital disorders of glycosylation, or CDG. These disorders interfere with the pathway that regulates the placement of sugar on proteins and can have a major impact on patients' quality of life. Specifically, I studied ALG13-CDG, an unusual CDG in which the sugar chains in patients' blood or skin cells appear normal even though patients have severe neurological symptoms, including developmental delay, seizure and intellectual disability. Currently, there are no curative treatments, and many patients develop seizures resistant to medication.

Because of the neurological symptoms of this disorder, we hypothesized that ALG13-CDG might be acting in an organ-specific manner and planned to examine brain tissue. However, no translational models of this disease exist. So, we took the help of our patient community who donated skin cells. From these skin cells, we developed stem cells and, subsequently, brain organoids — miniaturized, simplified models of the brain — to assess the molecular differences that occur in ALG13-CDG.

My research showed for the first time that ALG13-CDG causes a reduction in sugars that attach to proteins, a process important for brain development and function. We also saw dysregulation in RNA and proteins crucial for brain development and function. The data indicated that neuronal migration, neuronal excitability, calcium ion concentration and lipid metabolism might be underlying the key neurological symptoms. Further, we found brain development in ALG13-CDG is irregular; excitatory neurons develop later than expected. Our study provides numerous insights into the mechanism underlying ALG13-CDG that may be used as therapeutic targets to help patients.

What opportunities did you take advantage of at Mayo to grow your leadership skills and your career path?

There were many! I had the opportunity to serve as a teaching assistant to help newly entering graduate students in foundational science courses. I also served as co-president of the graduate student association, which helped me develop the skills needed to manage a big team and advocate for others.

I also sought opportunities to expand my research experience across the world. Winning a Mayo travel award provided some of the funds to visit Radboud University Medical Center in the Netherlands, where I learned techniques for measuring 2D neurons in culture and 3D brain activity. With other travel awards and the Mayo Clinic Dean's Fellowship, I attended scientific conferences and networked with other researchers.

What motivates you?

I have always had an affinity for biomedical sciences. My sister was born with a developmental disorder, and as a child, I would often wonder why she couldn't walk and became interested in studying human biology. At Mayo, I fell even more in love with research and the clinics. My next step will be a postdoctoral fellowship at Mount Sinai Hospital in New York. I am also applying to medical school. Being at Mayo, conducting research and meeting patients confirmed for me that I want to be a physician-scientist. Seeing the collaboration between the patients, families, physicians and scientists I have learned that with all of us working together, we can move the field forward.