Science is Everyone | Deuteration in Drug Development: Tiny Reactions with Big Promise

To mark National Chemistry Week, TSC invited Dr. Joseph R. Clark, Assistant Professor of Chemistry at Marquette University, to take part in our campaign, Science is Everyone: Voices in STEM. Below, Dr. Clark discusses the science behind his work on drug development, the importance of federal research funding in propelling his career forward, and how the experiments taking place in his lab could have a huge geopolitical ripple effects at a critical inflection point.  

How has federal funding from the National Science Foundation (NSF) and the National Institutes of Health (NIH) furthered your research?

My journey in chemistry has been filled with both excitement and challenges. Completing a PhD is a difficult task, and one that required I move universities to start over along the way. When you have a love and passion for science, you try your best not to let these obstacles get in the way of achieving your goals. Federal funding from NSF and NIH has been critical for me to reach the career level and accomplish my research goals to date. As a postdoctoral researcher in the laboratory of Prof. Christina White at the University of Illinois at Urbana-Champaign, I was fortunate enough to receive the NIH NIGMS F32 Ruth Kirschstein fellowship. While it was difficult to balance writing a full research grant twice (the resubmission was funded), this experience taught me how to balance my work and become more efficient with my time. The funding covered an entire year of my postdoctoral research, specifically my third year. Without this funding, it would not have been possible to complete the project that we published in Nature Chemistry in 2018, and I would never have been able to have the time to write independent research proposals. Consequently, a career as a professor at Marquette would not have been possible. The NIH funds were a lifeline to me reaching my dream job.

In the Department of Chemistry at Marquette University, tenure-track faculty must run their own independently funded research programs. Acquiring research funding is one of the most important activities we perform as chemistry faculty because it grows and sustains growth in our research program. It is also a requirement for tenure, which is common across most major chemistry research departments. I have been fortunate to receive funding from NIH NIGMS in the form or an ESI MIRA grant in 2022. This was followed by a receiving an NSF CAREER Award in 2023. As an early-stage investigator, these awards allow my research to reach its full societal potential. When we begin as faculty, we invest a lot of time in developing our independent research projects that are part of our research program. Without federal funding, this would all be for nothing. Now, my research program has the potential to make a transformative impact in how safer medicines are made and studied.

It’s National Chemistry Week – tell us in layman’s terms what you do in your laboratory.

My research laboratory investigates new chemical reactions to install deuterium and tritium precisely into small molecules. Okay, this is very technical, so here is the breakdown. Deuterium is a naturally occurring isotope of hydrogen and tritium is a radioactive isotope of hydrogen. Their masses are 2x and 3x heavier than hydrogen, respectively. For deuterium (heavy hydrogen), this is significant in the field of new drug discovery. If deuterium can be precisely installed within a target position within a drug molecule, there is the potential for a given drug to be safer for patients. Additionally, because deuterium is so similar to hydrogen, the physical properties are nearly the same between the deuterated drug and the original drug. This means that the potency and selectivity of the deuterated drug is likely the same as the original drug. Therefore, we have a new drug that is fundamentally different from the previous version, yet treats the same indications but with fewer side effects. This project is currently funded by the NIH.

The precision tritiation that we study is a bit different. This is what we define as a radioactive label, or radiolabel for short. In drug discovery, it is a requirement to identify metabolites produced in the body when a drug is administered in clinical trials to a patient. Metabolites are formed in the body when the body “breaks down” or “oxidizes” a drug. The FDA is concerned with the safety and tolerability of these metabolites, and requires these study prior to a small molecule drug receiving approval. Tritiated drug molecules can be used for these metabolic studies, and there are many benefits to using tritium for this process. Despite the benefits, a major challenge exists where chemists do not have the proper reactions (or tools) available to perform precision tritiation. This is a major limitation, and oftentimes very expensive techniques are performed to radiolabel a drug. My research group is investigating the development of new tools to precisely incorporate tritium into drug molecules to address this deficiency in drug development.

What are the potential applications for this work? How might it help people?

This is my favorite question because the answer is so straightforward. My research is fundamental in nature, but directly relates to applications in human health. If we can design more effective and safer drugs, millions of people benefit. We want outcomes where patients no longer have to decide whether they treat a disease with a medicine that will have side effects making them sick, or just deal with the disease to avoid the dangerous side effects.

What is something people might not know about your lab?

We have one of the best views of the city of Milwaukee in the entire university. My lab just happens to be located on the top floor of the chemistry department, so we are pretty lucky. Some other interesting fun facts include that my group is very diverse, and on any given day you might here people speaking Spanish, Farsi, Russian, Chinese, Arabic, and of course English.

What does Russia’s war with Ukraine have to do with the chemistry happening in your lab?

The ongoing war initiated by Russia has so many consequences and it is very tragic and sad to see the devastation in Ukraine when we watch the news coverage overseas. Unfortunately, the consequences of this war reach beyond the scope of what is covered on the news. In the area of chemistry, Russia has the only nuclear facility in the world that is currently producing 14C, the radioactive isotope of carbon that is most commonly used to perform metabolic tracing in clinical trials. This is the process I described above where scientists have to identify all metabolites produced in the body from a drug molecule. As a result of the conflict, financial transactions between Russia and the U.S. are not allowed, therefore access to this critical and necessary isotope for drug discovery is completely cut-off. Suppliers have limited quantities of this isotope, and the situation is becoming dire.

My research is related to solving this crisis by providing the required tools to take an alternative strategy to radiolabeling drugs. Tritium, the radioactive isotope of hydrogen is produced right here in our country at a nuclear facility in Tennessee. We have a much large supply, it is significantly cheaper than the carbon isotope, and we are not running out. My laboratory is investigating the development of new tools to precisely incorporate tritium into drug molecules. If we can accomplish this, the research has the potential to be used in drug discovery and one-day supplant the current techniques that utilize the 14C label. Thanks to funding from the NSF, we are able to carry-out this research and one-day make a transformative impact on health in the United States and abroad.