Silberg earns NSF CAREER Award

Rice biochemist will use funding to view how proteins function despite mutations

Jonathan Silberg’s students and colleagues would happily raise a glass of BioBeer to him if they could. Because of him, they someday might.

The Rice University professor known to all as “Joff” joined a select club on campus this week as the latest winner of a National Science Foundation (NSF) CAREER Award, a prestigious grant given to young academics expected to become leaders in their respective fields.

Jonathan Silberg

Silberg, an assistant professor of biochemistry and cell biology, won a small measure of fame a few years ago when his students designed BioBeer, a genetically engineered brew whose proteins synthesize resveratrol, a disease-fighting compound found in red wine and other foods. The students won a gold medal in the International Genetically Engineered Machine synthetic biology competition in 2008, and their entry brought them national and international media attention.

BioBeer remains a laboratory creation, but that’s fine with Silberg, who has many other projects commanding his attention. The NSF grant will support research into when and how proteins continue to function despite the constant mutations they experience in nature.

“Half of what we do is laboratory evolution,” Silberg said. “We make libraries of mutations of a particular gene that encodes a protein, and then we say, ‘Who’s functional? Who’s better? Who’s dead?'”

In proteins, form determines function, and Silberg aims to find out how mutations through either natural means or genetic engineering impact both.

In his latest research, Silberg focuses on model proteins called adenylate kinases. He changes and rearranges their amino acids to come up with libraries of protein mutants. The engineered proteins are then introduced into bacteria that require a functional adenylate kinase to reproduce, and microbial growth is used to assess the impact of each DNA mutation on protein function. “For each class of mutation, we’re able to get a map of what’s tolerable,” he said.

“The CAREER proposal is really quite simple,” Silberg said. “We want to measure where a protein tolerates every class of mutation without losing function, and we want to test if the patterns of mutational tolerance measured in the DNA correlate with protein structure, flexibility and stability. If we find that there is a correlation between biophysical properties and mutational tolerance, then simple laboratory evolution experiments could be used to glean biophysical insight into proteins that are hard to study using traditional methods.”

Simplicity is in the eye of the beholder, of course. Creating and analyzing thousands of genetically mutated bacteria for DNA testing seems overwhelming, but Silberg said he and a student, Rice senior Manan Mehta, have already overcome a technical hurdle in cheaply building mutants via their engineering of a minitransposon that creates permuted variants of a protein. The tool to create protein libraries programs every possible variation of a protein in a single step.

Silberg expects that the fundamental methods developed through his research will also result in new strategies for applied protein engineering and even drug design.

Another component of the CAREER grant will strengthen the connection between Silberg’s lab at Rice and Houston Community College.

As a community college student, Silberg developed his passion for science. However, it wasn’t until he transferred to the University of California that he had a transformative laboratory experience that led him down the path of a scientific research career.

To help community college students navigate scientific careers, Silberg will work with Bart Sheinberg, the director of the West Houston Center for Science and Engineering, to run roundtable discussions that show these students how research transforms the facts presented in textbooks. Through discussions with researchers at Rice, Silberg hopes to provide experiences for these students that increase their self-confidence and help them overcome the challenge of finding transformative early career research experiences, while also providing beneficial training for his graduate students.