Rachelle Copeland, a graduate student in her seventh year at Penn State, in the Chemistry Department’s Graduate Program, has been named the recipient of the 2021 Robert T. Simpson Graduate Student Award for Innovative, “Risky,” Science. The Graduate Student Award for Innovative (Risky) Science was created by the family of Robert T. Simpson in 2005 in memory of the former professor of biochemistry and molecular biology who embraced the concept of high-risk, high-impact research. The award was established to recognize an individual graduate student, working under the direction of a biochemistry and molecular biology faculty member, who has made important and innovative contributions in forwarding their research in their specific area of study.
Copeland earned her bachelor’s degree from Wesleyan University and now conducts her research in the laboratory of both Professor of Chemistry and of Biochemistry and Molecular Biology, Carsten Krebs, and Professor of Chemistry and of Biochemistry and Molecular Biology, J. Martin Bollinger Jr. Broadly speaking, her research focuses on elucidating the mechanisms by which iron-dependent enzymes catalyze challenging chemical transformations. In particular, she has focused on uncovering the steps by which one of these enzymes is able to transform a common metabolite, 2-oxoglutarate, into a high-value compound, ethylene. Ethylene functions in the manufacturing industry as a petrochemical precursor to many of the plastics, textiles, and other compounds upon which modern life relies so greatly. In addition to this, it also functions in Nature as a signaling molecule and is best known for its role in helping fruits ripen.
So why is Copeland’s research characterized as “Risky?” Copeland’s research, and subsequent dissertation project, elucidates the mechanism of a microbial ethylene-forming enzyme known as EFE. EFE was first identified as an iron- and 2-oxoglutarate-dependent (Fe/2OG) enzyme in the early 90's. In the decades spanning then and now, the collective efforts of many different research groups, including the Bollinger-Krebs group at Penn State, have produced a large body of literature generally explaining how this large family of enzymes generally works. Although this previously documented research provided evidence for the elementary chemical steps for a number of enzymes within the family, EFE repeatedly stood out, in the literature, as an enzyme that had not been characterized beyond the rudimentary initial reports made decades earlier. This is most likely, in part, because the main reaction that EFE catalyzes is fundamentally different from all other reactions known to occur within the family. It was this, taking on a project that seemed to defy a well-established paradigm, that characterized Copeland’s research as “Risky.” “At the outset, it was not crystal clear the extent to which the investigative tools and approaches that had been honed on other Fe/2OG enzymes would be pertinent to EFE,” said Copeland. “I suppose choosing this project as the main focus of one’s dissertation over the more tractable projects that were available could be considered risky.”
Both Drs. Krebs and Bollinger commented, “In her Ph.D. work, Rachelle took up a project that seemed impossible at the outset, did herculean work completely on her own, and succeeded spectacularly.” Copeland commented saying, “I didn’t realize at the beginning that the undertaking was “momentous” or that “herculean” effort would be required.” Copeland’s research into EFE grew out of a literature review that she presented to the group shortly after she first joined the Bollinger-Krebs lab. “At the time, the lab had other ongoing projects focused on arginine-modifying iron enzymes and hydrocarbon-forming iron enzymes. EFE, falling under both categories, seemed like an interesting new system to potentially work on,” says Copeland.
Copeland was drawn to the topic due to the fact that, despite lacking any real insight into how EFE makes ethylene, a number of research groups were working on applying EFE for large-scale ethylene production, and she felt that the gap between understanding and application seemed important to address. “Given that so little was known about this enzyme, it was important for us to broadly consider all chemically logical mechanisms by which the reaction of interest could potentially occur and create testable hypotheses that could distinguish amongst them, instead of prematurely picking a “pet” mechanism and designing experiments around that single idea,” said Copeland.
In fact, a key part of the answer to the overarching question that Copeland set out to answer came from detailed characterization of an “off-pathway” reactivity that she observed. For her, this underscores the value in probing broadly and deeply when conducting research. Additionally, the most surprising and significant breakthroughs that she, and her advisors, have made during the course of their investigations so far were enabled by methods not traditionally used in the Bollinger-Krebs lab. Therefore, she says, “being resourceful in accessing facilities outside of the Chemistry department was also instrumental in our success.”
So why is ethylene, and Copeland’s research into its biosynthesis, so important in today’s global climate? Ethylene is one of the most abundantly manufactured compounds on Earth, and is, at present, primarily derived from petroleum. As society aims to move away from exploitation of rapidly diminishing petroleum resources and towards a more circular economy, the engineering of “microbial factories”, i.e., bacteria and fungi, for enzymatic production of commodity chemicals such as ethylene has become increasingly relevant. Copeland’s research seeks to understand how the microbial ethylene-forming enzyme, EFE, works in the hope that the insights thus derived can facilitate improved renewable production of this important compound.
Copeland’s findings have, so far, enabled her, and the Bollinger-Krebs Laboratory, to create a map of the route by which EFE converts 2OG into ethylene. Future experiments will be aimed at providing direct evidence for intermediates formed along the way that are, at this point, only inferred. Now that Copeland has identified what is unique about the initial steps of the reaction, she plans to delve deeper into understanding the factors that enable the key differences and how, perhaps, they could be “tweaked” to make EFE better at producing ethylene and other commodity chemicals.
About Robert. T Simpson:
Simpson was an international leader for more than 35 years on the topic of chromatin, a fundamental component of chromosomes, and its role in gene regulation. Simpson conducted research at the National Institutes of Health (NIH) from 1970 until 1995 when he became the Verne M. Willaman Professor of Molecular Biology at Penn State. His addition to Penn State is considered to have placed Penn State and the Department of Biochemistry and Molecular Biology at the forefront of chromatin research and has greatly enhanced Penn State's research and educational missions.