LSI's newest faculty member aims to expand nucleic acid research and graduate student opportunities
John ‘Jay’ Schneekloth, Ph.D., has joined the University of Michigan faculty as a research professor at the Life Sciences Institute and a professor of biological chemistry in the U-M Medical School. He will also serve as co-director of U-M’s graduate Program in Chemical Biology, alongside co-director Jayakrishnan Nandakumar, Ph.D.
Schneekloth spent more than 15 years developing a prolific research program at the National Cancer Institute, where his lab employed structural, biochemical, molecular and artificial intelligence-based approaches to investigate RNA as a potential target for treating cancers. Now, he aims to further expand that research into basic science applications and new disease areas at the University of Michigan, while preparing graduate students for the rapidly evolving job market they will enter.
Here, Schneekloth explains how he got his start in science, what’s next for his lab, and why U-M is the right place for this new chapter in his research program. (Responses edited for clarity and length)
What made you want to be a scientist?
I had a family member who was very into nature when I was growing up, and he instilled in me an early love of trying to understand the natural world around us. Then later on, when I started taking classes, I realized that I loved chemistry and biochemistry; that was really the origin of it. I've always been fascinated by nature and science, and I feel very fortunate that I have a career where I get make new discoveries that improve our understanding of these subjects.
With this wide-ranging interest in the natural world, what was it about chemistry and biology that drew you to the interface of these two disciplines?
I’ve always been interested in learning how things work. My dad is an engineer, and so, early on, I liked the idea of synthetic chemistry and being able to rationally engineer molecules with new properties and activities. That idea continues to be a driving purpose for my lab: that we can use chemical innovation to invent new molecules with a wide variety of applications across biology, chemistry and more. When I started to study natural products — molecules the microorganisms make for their own survival and growth — I began to think about not only how to synthesize complex molecules, but why nature makes them and what they can do. This led me into investigating more about the biology that’s driven by small molecules and drugs and medicines.
How will that line of investigation play out in your new research program at the LSI, and what do you aim to discover?
My lab studies nucleic acids—primary RNA, but also DNA a bit as well. We use chemical approaches to understand RNA and DNA as biological targets for new medicines. One question we’re interested in is how small molecules recognize nucleic acids, which is a crucial first step if we want to be able to design new drugs that target nucleic acids. This also lets us chemically probe whether any existing drugs serendipitously bind to nucleic acids and cause either toxic or beneficial effects.
There are many tools that enable scientists to ask these types of questions about proteins. But the technologies for nucleic acids are comparatively immature at this point. So, another aim of our program is developing tools and technologies that can provide the basis with which we and others in the field can answer more sophisticated questions about nucleic acid therapeutics.
Can you give an example of when targeting DNA or RNA, rather than targeting the protein output of that genetic code, would be beneficial?
There are many cancers and neurodegenerative diseases that are caused by deregulation of the RNA or DNA itself, and there is no protein to specifically target. If we think about Huntington’s disease, for example, we know that’s driven by expanded repeats of DNA and RNA. Those repeated nucleic acids themselves lead to neurodegeneration, so targeting them directly may offer a more effective approach to this currently untreatable disease.
The human genome is made up of three billion base pairs of nucleic acids. About 90% of that DNA gets transcribed into RNA, but only 3% is translated into a protein. And of those proteins, medicinal chemists have been able to target only about 15% so far. We know that far more of these gene products are disease-causing or important to disease, but we can’t target them with traditional medicinal chemistry approaches. So, this really drives the interest in developing new approaches that target the nucleic acids directly.
I’m really excited about this unique opportunity to expand my research in nucleic acids and nucleic acid targeting therapeutics, while not only training graduate students in my lab but also helping shape graduate education through leadership of the Program in Chemical Biology.
What excites you most about this new phase of your research at the University of Michigan and the LSI?
Well, one of the reasons why I was excited to move to Michigan was the collegiality and collaborative spirit of the people at U-M, particularly at the LSI, and the willingness to do ambitious interdisciplinary research. With respect to my own research program, I see a lot of opportunities at U-M, with its broad mission and expertise, to pursue new questions and collaborations related to both human disease and basic science. In particular, Michigan is a hotbed of research for both chemical biology and nucleic acids research, which is something I'm really passionate about.
I’ve also wanted to teach more and mentor graduate students. So, I’m really excited about this unique opportunity to expand my research in nucleic acids and nucleic acid targeting therapeutics, while not only training graduate students in my lab but also helping shape graduate education through leadership of the Program in Chemical Biology.