At its heart, chemistry is about building blocks — combining different types of molecules to spur chemical reactions or create materials. The more versatile the building block, the more interesting and valuable it can be.
That’s the guiding principle that has led Sam Gellman, the Irving Shain Chair of Chemistry, Vilas Research Professor and Ralph F. Hirschmann Professor of Chemistry, to devote countless research hours to the properties and utilities of foldamers, artificial chain molecules that can be synthesized in a lab and “folded” into discrete shapes that can then potentially be engineered in multiple directions.
“A foldamer is a kind of molecule built from a series of sub-units that takes on a defined shape,” says Gellman. “That defined shape becomes a basis for engineering function into the molecule.”
Using support from the National Science Foundation (NSF), Gellman and his graduate students, including Phillip Lampkin, are studying the different ways that process can be manipulated. In essence, what foldamers could be used to do. So far, those scientific pathways have involved everything from using foldamers as the basis for a potential treatment for Parkinson’s Disease — a project that’s now in clinical trials supported by the Michael J. Fox Foundation and developed by Gellman’s start-up company Longevity Biotech Inc. — to development of antiviral foldamers in collaboration with a group at Columbia University and support from the National Institutes of Health to more fundamental work supported by NSF.
“We’re trying to see how many different scaffolds we could create,” explains Gellman. “And in the last few years, we’ve been trying to accomplish a particularly challenging functional goal, which is to create catalyst molecules that facilitate the reactions of other molecules. We’re trying to understand how reactions can be made to proceed under the influence of a foldamer.”
Amping speed is one of the primary goals. Depending on the application, accelerating safe chemical reactions could hold significant commercial value — think about developing life-saving pharmaceutical interventions or critical building materials more quickly. Gellman and his students have been experimenting to see if the key may be connecting reactive types of reactive groups at specific points on the foldamer scaffold.
Gellman has discovered that foldamers are good at making very large rings, rings that could become the building blocks for other types of useful molecules.
“We’re still very much at the fundamental level, really just trying to understand whether we can control reactivity with these scaffolds, and, if so, what principles guide or determine the ability to control reactivity,” he says.
One of Gellman’s early hypotheses involved the idea that the way in which the reactive groups were oriented on the foldamer scaffolding could hold the key to speeding up the reactions. The data haven’t supported that conclusion, so Gellman and his team have pivoted to a simpler possibility — that more flexible scaffolds may have advantages for catalyst development. Ultimately, the inspiration for this work comes from biology and the ubiquity of enzymes, which are protein catalysts.
“We know that enzymes catalyze reactions incredibly effectively. There must be a set of principles that underlie that catalysis,” Gellman says. “If we’ve invalidated one or suggested that the easiest one to try to implement isn’t a major factor, then we have to start exploring other ones. The enzymes tell us there’s a goal to be reached.”
Like a lot of scientific researchers, Gellman has been concerned about seeing NSF support for fundamental research like his come under scrutiny — or be cut altogether. One of his antiviral NIH grants with Columbia was terminated last March but restored more recently. A major NIH grant supporting his laboratory has taken a mandatory cut. While most of the funding that supports his work remains intact for now, he knows keenly not to take the support for granted. Both for himself and the graduate students he’s mentoring.
“Science doesn’t advance because of my ideas,” says Gellman. “Science advances because we attract energetic young people who want to become scientists, and, while learning, they must advance the science themselves. It takes resources for those students to have that time to learn to be scientists, and that’s really what we’re losing when funding for basic science is cut. That’s the seed corn for future discoveries.”