Daniel S. Levine

Science fairs were not a part of my elementary or secondary education, but they were for my children. I have consulted and participated in numerous experiments involving biology, chemistry, and psychology.

My children have demonstrated that Coca-Cola will not dissolve a tooth, lemon juice is the best household agent for removing bubble gum from hair, and people prefer red ketchup to green ketchup even though they can’t taste the difference.

When I was invited to speak to Daniel Schaffer, a finalist in the Regeneron Science Talent Search, I felt well prepared. The talent search is a program of Society for Science & the Public. It’s the nation’s oldest and most prestigious science and math competition for high school seniors and previously had been sponsored by Westinghouse and later Intel. It carries a top prize of $250,000.

Schaffer’s project involves a rare disease, but I thought I could impress him with my vast experience in school science projects.

That wasn’t the case.

Schaffer is a senior at Montgomery Blair High School in Silver Spring, Maryland. His project was called “Evolutionary Origins of Animal ER Calcium Signaling and a Proposed Role for the Channelopathy Protein Wolframin.”

Wolframin is the toxic protein underlying Wolfram syndrome, which is named for Don Wolfram, a physician who first described the rare genetic disorder in 1938. The disease, which manifests itself in childhood, causes diabetes, optic atrophy, and deafness.

Schaffer jumped right in to explaining his work with all his fancy scientific terms. I imagine if I spent my lunch periods during high school reading the Journal of Computational Biology or tweaking algorithms for discerning the hidden structures of proteins. I too could have regaled him with impressive banter. Unfortunately, I tended to do homework I should have completed the previous night.

It turns out Schaffer has had an interest in computational biology for some time. The work he submitted for the competition had evolved from a science project he did in sixth grade. (He was careful to note he had a classmate who was a partner on his sixth-grade project lest anyone think he took on a project that was a bit much for a single sixth grader).

The original project involved looking at data from two public databases to try to determine certain combinations of original and replacement amino acid that were associated in a statistically significant way with pathogenic proteins. He used the Python programming language to do the work.

In seventh grade, instead of looking at the amino acids, Schaffer turned his attention to variants in the non-globular domains of proteins. Globular domains are three-dimensional structures with characteristic folds within different proteins and serve a functional role. Schaffer found that variants in globular domains are more likely to cause disease than variants outside the globular domain.

Schaffer said the “key insight of his entire scientific career” came next. He noticed that there were proteins with a lot of pathogenic mutations in his data that had no corresponding domain. He wondered what if where these clusters are were actually domains that were just not known. He came across an obscure method from 1999 for how to quantitatively identify a cluster of mutations and applied that to identify candidate regions for containing unannotated domains.

“At that point,” he said, “I reached out to one of my mentors because I was over my head.”

I could relate. There were many times in eighth grade when I too was over my head.

Using this method, Schaffer decided to look for candidate proteins that might contain unannotated domains. In essence, he was looking for proteins with structures that were not known to see if he could use computational biology methods to discern the structure of the protein.

“It was kind got to a point in ninth grade when I had a list of proteins with a domain that is not known. And one of them was wolframin.”

Wolframin was one of three proteins he chose to focus on, but it proved to be so interesting and complicated on its own that he decided it merited its own project.

By knowing the domains and combining them with interaction data, along with some other knowledge, Schaffer said you can come up with a pretty good guess as to what wolframin does and why, when its broken, people develop Wolfram syndrome. Though it is known to knock out cell lines and is involved in regulating intracellular calcium signaling, the specific role and structure was not understood.

“We now know all the domain architecture. We can make some very educated guesses about what these bind to and how,” he said. “This can be confirmed with very targeted experiments. It is a step toward understanding the function of the protein.”  

His research has the potential to make an impact on the understanding of the disease and could be a step toward finding drugs to target the condition.

Schaffer, whose father is a computational biologist at the National Institutes of Health, was a summer intern at the NIH’s National Center for Biotechnology Information. He still volunteers there after school. In high school I cleaned toilets, made cold calls for an insurance agent, and worked in a Chinese take-out.

He’s been mentored through his work with scientists there who are coauthoring a paper on his research. Schaffer is the lead author and it is expected to be submitted to a journal soon. With that, Schaffer expects his work on wolframin is complete. He will be attending Carnegie Mellon University to study computational biology in the fall.

As much as I enjoyed hearing Schaffer’s story, I admit being disappointed in how he had come to study the wolframin protein. I was expecting to hear that his sister had Wolfram syndrome, or that a childhood friend did. He’s never met anyone with Wolframin syndrome. I thought that was a shame.

One of the pleasures of my work has been to spend my time talking to people who are smarter than me, even if they are still in high school. One thing I have noticed, though, is that the best scientists I have met share a common humanity that drives them. Curiosity may have been their spark, but at some point, the abstractions of chemistry and biology in the lab are connected to real people who are suffering. Schaffer has scientific talent. Here’s hoping he makes that connection to greatness.

Photo: Daniel Schaffer, finalist in the Regeneron Science Talent Search

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