NATE SILVER ‘02

Some kids grow up and know they want to follow in the footsteps of their parents. Other kids grow up determined to blaze their own trail. On rare occasions, you get to do both. That’s the case for Nate Silver ’02.

Silver has a PhD from MIT in computational chemistry and is currently VP, Head of Discovery for Generation Bio, which is developing innovative genetic medicines to provide durable, redosable treatments for people living with rare and prevalent diseases. Silver’s path to his current position was neither a straight line nor a zig zag.

“I grew up in a household that was very science-oriented,” Silver said. “My father is a virologist who worked at the NIH and my mother is a physician. I was surrounded by the sciences from the beginning, and while I naturally gravitated towards them, I was always open to where I was going to go and how I would get there.

“I was blessed to have had a great experience at St. Andrew’s, with wonderful teachers who let me explore my interests in the sciences and elsewhere. I continued this open-ended exploration in college, before eventually pursuing a degree in physical chemistry.”

For Silver, chemistry was a nice middle ground that bridged the gap between his interest in physics (“very mathematical but often abstract”) and biology (“tangible but extraordinarily complex ”).

“I had a really wonderful chemistry teacher in Ms. Walsh,” Silver said. “I have fond memories of her class and really appreciated the enthusiasm she brought to the classroom. She provided a very approachable introduction to the field and ample opportunities to explore and get a feel for what worked for me and what didn’t.”

What eventually worked for Silver was computational chemistry, a broad discipline that at its core is the study of chemical systems. Silver’s expertise within that space is structure-based modeling.

“How can we develop computational models to understand molecular interactions,” Silver said, when going into detail about the field and his specific area of study. “My PhD was really a study of how small molecule drugs interact with their protein targets. How does this relate to everyday people? It is intimately involved in the design and discovery of new medicines. Many of the drugs that people take, Lipitor for example, are small molecules that bind to and inhibit a particular protein in the body. The details of that interaction are what underpin a drug’s therapeutic effect and can be understood and structurally modeled on an atomic level.”

While at MIT, Silver was a computational chemistry intern at Merck for a summer. Upon earning his PhD he went to work at Axcella Health as a scientist. After two years, he was promoted to director of discovery research and three years later, he moved on to Modulus Discovery where he was associate director of computational drug discovery. In July of 2018, he joined Generation Bio, first as director of preclinical sciences, before eventually taking on the role of vice president and head of discovery research.

“Drug discovery encompasses a large number of steps,” Silver said of his current role. “It all begins with identifying a suitable biological target, whose function or disfunction you believe is related to a given disease. From that starting point, you need to develop an effective in silico and in vitro screening strategy to assess a library of potential molecules for their ability to interact with that target. Once you identify initial hits, these molecules often need to be further optimized to enhance potency and specificity, which means building better computational models and developing additional screening assays in an iterative fashion. Ultimately, however, that’s just the beginning.

“Eventually, you need to test your candidate molecules in vivo, to understand how the body metabolizes the drug and, critically, how the drug affects the body. Often this means leveraging mouse models of disease as well as higher order species more closely related to humans in order to assess whether your drug works as intended. All of that work - from early computational modeling to testing for efficacy in an animal - that’s discovery. It covers a wide breadth of activities and requires expertise across many scientific disciplines.”

Silver’s work is about to get even more exciting as Generation Bio and Moderna recently announced a collaboration to develop non-viral genetic medicines.

“I am really looking forward to being a part of the collaboration.” Silver said. It’s an exciting time for non-viral gene delivery and nucleic acid therapeutics more broadly. The COVID-19 mRNA vaccines that many of us received are a clear demonstration of how impactful those technologies can be.”

While the science portion of Silver’s academic career jumps off the page, it’s the more humanities side of his St. Andrew’s education that he points to as playing an important role in his undergraduate and graduate school experience.

“I learned a great deal from my math and science teachers at St. Andrew’s, but I think some of the most valuable skills that

I carried with me in college and beyond came from the broader focus on a liberal arts education,” Silver said. “Technical know-how is obviously important but knowing how to learn and how to communicate effectively, regardless of subject matter, are probably the most critical skill sets that I’ve used during my career. I remain thankful for all my teachers at St. Andrew’s for giving me the opportunity to develop those skills, as they are what I have held onto and further refined in the years since.”