The Intramural Research Program (IRP) at NIH is home to some of today’s and tomorrow’s greatest scientific minds. Hundreds of budding biomedical pioneers begin honing their scientific skills here in high school, but very few win distinction as quickly as seventeen-year-old Daniel Schäffer, whose IRP research earned him inclusion among this year’s 40 finalists in the prestigious Regeneron Science Talent Search.
Daniel, now a high school senior, first ventured into the field of computational biology in the sixth grade as part of a school-required science project. Using publicly available data from organizations such as the National Center for Biotechnology Information (NCBI) in the NIH’s National Library of Medicine, Daniel’s initial research examined disease-causing changes to the amino acid building blocks of proteins. The chemical properties of different amino acids cause different proteins to have different shapes, which in turn influences what they do. When a genetic mutation causes one amino acid to be substituted for another in a protein, the change can alter both the protein’s structure and its function.
Eventually, Daniel began attempting to use information about disease-associated amino acid substitutions to identify important parts of protein structure, called domains. Finding he could only get so far on his own, he reached out in 2014 to Max Burroughs, Ph.D., and Lakshminarayan M. Iyer, Ph.D., both staff scientists in the NCBI’s Computational Biology Branch, who agreed to mentor him. Daniel spent the next two years working informally with his mentors, occasionally coming to the NIH after school and over the summer to complete his work with their help. He then continued the project during two full-time summer internships at NIH in 2017 and 2018, during which he also worked with the head of Dr. Iyer’s research team, IRP senior investigator Aravind Iyer, Ph.D.
“It was really valuable for me that I was able to spend two summers working here [at NIH] prior to submitting this project,” Daniel says. “I’ve learned a lot of different techniques, and I also learned how to write, how to present, and how to answer questions.”
Under the guidance of his IRP mentors, Daniel honed in on the cellular system that controls the flow of calcium ions into and out of a part of the cell called the endoplasmic reticulum. He first scrutinized research papers describing the interactions among 170 proteins involved in managing calcium in human cells. Next, he looked for relatives of some of those proteins in 235 other eukaryotes, the group of lifeforms that includes humans along with animals, plants, and some microbes. This analysis yielded insights into how the endoplasmic reticulum’s calcium storage system evolved in eukaryotes.
Along the way, Daniel used what he had learned about protein structure and amino acid substitutions to identify undiscovered domains in the structure of an important but mysterious calcium-regulating protein called wolframin. That discovery, combined with his scrutiny of the interactions among calcium-related proteins, allowed him to propose a theory for what exactly wolframin does. Past studies have shown that cells without wolframin are more likely to die. Daniel believes that wolframin acts to correct small, natural disturbances to cellular calcium levels, and without the protein, those imbalances grow progressively larger until they cause a cell to self-destruct. His theory could have important implications for a condition called Wolfram syndrome that is caused by abnormal or non-functional wolframin. For currently unknown reasons, the mismanagement of calcium in these patients’ cells causes damage to the central nervous system and the insulin-producing cells in the pancreas, leading to diabetes, neurological symptoms, and eventually death.
“Knowing these domains is a pre-requisite for understanding [wolframin’s] specific function,” Daniel says. “We now have a pretty good hypothesis with some support for what its function is.”
Daniel wrote up his research in a scientific paper and submitted it as part of his application to the 2019 Regeneron Science Talent Search, a prestigious science competition for high school seniors. According to its website, the program “recognizes and empowers the most promising young scientists in the U.S. who are creating the ideas and solutions that solve our most urgent challenges.” Alumni of the program include 13 Nobel laureates, 42 members of the National Academy of Sciences, and 19 recipients of the MacArthur “Genius” Grant. In January, Daniel was selected as one of 40 finalists from a pool of nearly 2,000 entrants, earning him a $25,000 windfall and a free trip to Washington, D.C., during which the group toured NIH’s main campus in Bethesda, Maryland, and met with NIH Director Francis Collins.
“I was excited and surprised,” Daniel says of his success in the competition. “I have kind of a niche project — it lacks the sexiness that some other projects have.”
Daniel plans to return to NIH to continue his work with Dr. Aravind’s research group this summer. In the fall, he will enroll at Carnegie Mellon University in Pittsburgh, Pennsylvania, where he plans to study computational biology. Ultimately, he hopes to earn a Ph.D. He says his experience in the IRP has helped him learn the importance of patience and perseverance in scientific research, lessons that will surely help him through the long road of his future education.
“Science can be slow,” Daniel says. “You have to stick with it and keep improving and keep asking questions and trying to answer them.”
Daniel will present his research on Monday, April 15 at 3:00 in the NIH Clinical Center (Building 10), FAES room 7.
By Brandon Levy, science communications editor at the Intramural Research Program.
This article originally ran in the I Am Intramural Blog. It is reposted with permission.