Ahmed Badran

Cells contain complex molecular machinery to build proteins, and Ahmed Badran is an expert at tinkering with one step in that process: translating RNA into protein sequences. At Scripps Research, he’s developing synthetic biology tools and applying them to generate enzymes that might synthesize complex molecules or help plants grow faster and capture more carbon dioxide.

Badran is “fearless and creative at drawing from different fields and developing useful new technologies as needed to achieve highly ambitious goals,” says David R. Liu, Badran’s graduate adviser at Harvard University. “He is not afraid to take on problems that, in some cases, the field has been hammering away at without too much breakthrough success for decades.”

As a graduate student, Badran used his understanding of molecular biology—acquired over 6 years as a high school student and as an undergraduate in Indraneel Ghosh’s lab at the University of Arizona—to help improve the directed evolution method called phage-assisted continuous evolution, or PACE. Directed evolution techniques like PACE mimic natural selection by making many mutated genes for a protein and then sifting through the resulting proteins to find ones that perform in a desired way. Liu’s team invented PACE shortly before Badran joined the group.

After earning his PhD, Badran ran his own research group as a fellow at the Broad Institute of MIT and Harvard. There, he used directed evolution to generate ribosomes—the cellular machines that translate RNA into proteins—with new and improved abilities. For example, his group made ribosomes that could better incorporate noncanonical amino acids into proteins. By including amino acids beyond the 20 that cells normally work with, scientists could coax cells to produce proteins with new or enhanced properties. But Badran also achieved this feat with nonengineered ribosomes. “Even without altering the ribosome, we have developed new technologies that can incorporate many noncanonical amino acids into the same protein incredibly efficiently,” he says.

At Scripps, one of the enzymes that Badran targets with these synthetic biology tools is ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), which plants use during photosynthesis to incorporate CO₂ into biological molecules. Despite its centrality to life, RuBisCO is a surprisingly inefficient enzyme. With faster, more selective versions of it, plants could become even better at capturing CO₂ from the atmosphere and bolster their role in combating climate change.

For decades, researchers have been stymied in their efforts to boost RuBisCO’s catalytic turnover and affinity for CO₂, which has led people to assume these properties couldn’t be enhanced. “By trying to understand why prior efforts failed to improve RuBisCO, we came to a deeper understanding of how to create systems that could discriminate better between RuBisCOs of varying activities,” Badran says.

His team is developing genes that encode for molecular sensors capable of monitoring what RuBisCO is doing in cells. With about 200,000 data points collected on hundreds of modified RuBisCOs, the researchers are starting to understand how the enzyme’s behavior changes under different temperatures and CO₂ levels. One concerning conclusion the team has come to: RuBisCO will become even less efficient as Earth’s temperature increases. “Modeling and experiments show us that it won’t capture more CO₂; it will capture less,” Badran says.

By combining directed evolution, machine learning, and computational protein design, Badran and his team are finding versions of RuBisCO that are markedly more efficient than the ones found in nature. He eventually wants to incorporate improved RuBisCO into plants like corn. By taking advantage of the scale of agricultural infrastructure, these engineered crops could capture millions of additional tons of CO₂ from the atmosphere, he says.

In addition to his work on RuBisCO, Badran is using directed evolution and genetic code expansion to develop metalloenzymes that work with metals not typically found in biology. For example, his team would like to leverage transition metals, especially palladium and ruthenium, that chemists regularly use as catalysts when synthesizing organic molecules. “We’ve become very excited about bringing that power to an enzyme that is evolvable or engineerable,” Badran says. “We could potentially build whole biosynthetic cascades that transform simple molecules into much more complex products.”

Liu says the metalloenzymes work might seem ambitious, if not impossible. “And then you realize, if it’s Ahmed, I wouldn’t bet against him because historically betting against Ahmed is a pretty bad bet.”