John Rittle: Putting the Pieces together

Photo of John Rittle

Undergraduate students are rarely the first authors on articles in leading scientific journals. But that’s what happened in Nov. 2010, when Science published an article by Jonathan Rittle, a Penn State undergrad.

Rittle impressed the scientific community by solving a long-standing mystery concerning cytochrome P450 enzymes. His sleuthing was just the start of his successful scientific career, one that will continue here at Berkeley. This July Rittle will join the College of Chemistry faculty as an assistant professor.

Rittle was born in Reading, PA, about 60 miles NW of Philadelphia. As he explains, “Reading is best known as the source for the Reading Railroad card in the game Monopoly. Although I was born there, I grew up nearby in the town of Wernersville, a town of a few thousand people, where the outskirts of suburbia meet farmland.”

Like many College of Chemistry faculty members, Rittle developed his interest in research in his high school lab. “We had an excellent agricultural science program at our local high school,” he explains. “The local farmers donated a lot of money to the program. We had the typical Future Farmers of America competitions, but the program wasn’t just about raising animals. We grew plants in test tubes and studied microbiology and molecular biology — it was hands-on and very rigorous.”

Rittle graduated from high school in 2006 and enrolled at Penn State University, where he studied chemistry in the lab of his adviser, Michael T. Green. The Green group studies metalloprotein chemistry, with an emphasis on a class of enzymes called cytochrome P450s, named for their strong spectroscopic absorption line at the wavelength of 450 nm.

The group focuses on the P450 enzymes for several reasons. They are a biologically important class of enzymes that appear in many diverse life forms. In humans, these enzymes take part in the metabolism of about 75 percent of pharmaceuticals. In addition, these enzymes catalyze the oxygenation of otherwise inert carbon-hydrogen bonds, which is, according to the group’s website, “a Holy Grail of chemical synthesis.”

Rittle’s assignment in the Green research lab was to explore the mysterious Compound I, a critical intermediate in the activity of the P450 enzymes whose structure had flummoxed researchers for 30 years. His eventual success, which resulted in the 2010 Science article, is a classic example of what is known as normal science. In this often unglamorous process, dozens of researchers, working over many years, keep adding pieces to the puzzle, until one day the picture becomes clear. Says Rittle, “For me it was a combination of luck and meticulous science. Thanks to the encouragement of my adviser Michael Green, I was the one who finally was able to put all the pieces together and confirm the result.”

In 2010, with his Penn State chemistry B.S. in hand, Rittle began his chemistry Ph.D. studies at Caltech. There he worked in the lab of Jonas Peters, another chemist with an interest in metalloenzymes. (Peters had been a Miller Fellow at Berkeley, where he worked with Professor of Chemistry Don Tilley.) Rittle’s area of research was understanding and developing catalysts that fix nitrogen.

Rittle began studying synthetic model complexes of nitrogenase as a grad student at Caltech. It was a task that took him back to his roots in the Pennsylvania farmland. He says, “Humans have figured out how to convert atmospheric nitrogen into ammonia and fertilizers via the Haber-Bosch process. But this process requires high temperatures and pressures and must be done on a large scale.”

“If we could learn to mimic the action of nitrogenases, we could have local, distributed ammonia production under normal temps and pressures. It’s something you could do on a farm, maybe in conjunction with solar power. This could be a good model for Africa and other developing regions where farmers lack access to commercial fertilizers. An added benefit is that ammonia can be used as a biofuel.”

In 2016 Rittle completed his Ph.D. thesis, “Proton-Coupled Reduction of N2 Facilitated by Molecular Fe Complexes.” Says Rittle, “In my Ph.D. research I synthesized metal complexes that mimic the structure and functionality of nitrogenases.” He was one of three recipients of Caltech’s 2016 Herbert Newby McCoy Award, which is given in recognition of outstanding achievement in research by chemistry graduate students.

Adds Rittle, “While I learned a lot, and I hope my work provides a basis for further research, we have a long way to go before we can use nitrogenase-based enzymes as substitutes for the catalysts used in Haber-Bosch.”

For his postdoctoral research, Rittle chose to work with the group of chemist Akif Tezcan at UC San Diego. He explains, “I chose the Tezcan lab because, although the group shared my interest in metalloproteins and nitrogenases, the researchers there were more focused on synthesizing novel protein structures, including those that can support catalytic activity, like enzymes. I wanted to learn how to make new protein structures.”

Rittle is now commuting between San Diego and Berkeley, measuring his new lab space and meeting with incoming students and prospective group members to tell them about his research program.

Says Rittle, “Here is what I tell students: Research in my group will focus on unique metalloenzymes composed of earth-abundant transition metal ions. We want to understand how their active sites functionalize unreactive organic molecules and develop new strategies to synthesize reactive inorganic cluster compounds. Our long-term goal is to develop powerful and selective synthetic catalysts that use multiple transition metal ions to inspire new therapeutic strategies and useful chemical processes.”

“Researchers in the lab will use the tools of synthetic chemistry, structural biology and various spectroscopic methods to explore molecular and electronic structures. To facilitate these investigations and to expand upon the diverse biocatalytic potential of these enzymes, we will develop biosynthetic and computational strategies to rationally improve the stability and solubility of these enzymes.”

Looking back on his career to date, Ritter reflects, “Although my hometown of Wernersville was on the edge of farm country, it was still just about an hour’s drive to Philadelphia. There were many diehard Philadelphia Eagles football fans in town, including my father. I was happy for him that he finally got to see the Eagles win the Superbowl. As a scientist, I think there’s a lesson there. Like the Eagle’s victory, science takes years of perseverance, some good coaching, and in the end, a bit of luck.”