Since 2016, the Streck Award has been shining a spotlight on chemical innovations that push the boundaries of biomedically-related research. A collaboration between the University of Nebraska-Lincoln Chemistry Department and Streck, this award has attracted some of the brightest minds in science. Past recipients have included influential researchers, including Nobel Prize winner Carolyn Bertozzi, Ph.D., whose work has shaped the future of health and medicine. This year, Neil Kelleher, Ph.D., Professor and Director of the Chemistry of Life Processes Institute and Proteomics Center at Northwestern University, joins their ranks for his pioneering research into proteoforms. It’s clear his contributions are setting the stage for transformative advancements in understanding human biology.

To really appreciate the potential impact of Dr. Kelleher’s work, we need to spend some time on this admittedly complicated subject matter. To begin, let’s talk about proteins.

Proteins are tiny building blocks that help your body grow, stay strong and work properly. They’re made when specific genes in DNA get transcribed into something called RNA, which is like a smaller, portable version of the instructions. This RNA then travels to a part of the cell called a ribosome, which is like a factory that makes proteins. The ribosome translates the RNA instructions and puts together the building blocks of the protein, called amino acids, in the right order. Once all the amino acids are connected, the protein folds into a specific shape so it can do its job.

But certain proteins have multiple jobs, and each job requires a slight modification to that final folded form. These modified proteins are called proteoforms, and Dr. Kelleher has spent the last 25 years studying them. “You have all sorts of molecular decorations [of proteins], reversible and not, that govern our biology,” he tells me, “The world really needs to create tools to capture that.”

Imagine you have a basic sandwich with bread, meat, cheese. That’s your original protein. If you add some mustard or a pickle, swap out the bread for a bagel or toast the whole thing and you’ll get versions of the sandwich (proteoforms) that taste a little different and are suited for different moods. Your body does the same thing, customizing proteins depending on what it needs at the time. These modifications (think chemical tweaks or structural changes) turn one protein into its many proteoforms.

Dr. Kelleher explains, “If I’m a human gene and I get transcribed and translated into protein, it’s not the end of the story. You have things like different isoforms. . . different length variations from different sources of processing. . . post translational modifications. Once you have the protein, you can read, write and erase.” In other words, one gene can give rise to several proteoforms. That means for our nearly 20,000 genes, there’s at least 10 times as many proteoforms!

Why does this matter? If the wrong proteoform is in play – or if one isn’t correctly modified – it can cause chaos in your body. In some cases, major chaos. There are instances of diabetes, cancer or neurodegenerative conditions being traced back to proteins that have gone rogue or with the wrong modifications. So how can we know which proteoforms are “right” or “wrong” for the job?

Enter the Human Proteoform Project, Dr. Kelleher’s effort to map out every single proteoform in the human body.

“If you made the technology capable of reading out proteoforms at the single-molecule level with molecular precision, you then have that proteoform knowledge. And it can be distilled then into whatever diagnostic readouts are the most economically viable that are informed [and] not ignoring the truth of our biology”

The goal here is to give us a clearer picture of what’s going on in our bodies, from the healthy stuff to the not-so-healthy stuff. Imagine being able to figure out why certain diseases happen, create better treatments, or even detect illnesses way earlier than we can now. “If you made the technology capable of reading out proteoforms at the single-molecule level with molecular precision, you then have that proteoform knowledge. And it can be distilled then into whatever diagnostic readouts are the most economically viable that are informed [and] not ignoring the truth of our biology,” Kelleher says when asked about the potential for proteoforms in understanding human disease. “It’s going to make diagnostics way more precise, open up whole new markets and opportunities.”

But this is far from easy. Proteins are tiny, complex and annoyingly good at being hard to study. Plus, there are millions of proteoforms. Millions! Scientists have to figure out how to identify them all, sort through the chaos and make sense of it. It’s not a quick weekend project.

The potential payoff, though, is huge. Better understanding of proteoforms could totally change health care. This research could open doors to all sorts of groundbreaking discoveries about how our bodies function and enable positive outcomes for everyone.

The work Dr. Kelleher and his group are doing with the Human Proteoform Project is a great example of science doing what it does best: tackling big questions, even if it makes your head spin.

Want to hear more from Dr. Kelleher about how his work is asking (and answering!) big questions? Check out his interview with The Analytical Scientist here.

Neil Kelleher, Ph.D.

Walter and Mary E. Glass Professor of Molecular Biosciences; Professor of Chemistry, Weinberg College of Arts Sciences Professor of Medicine (Hematology & Oncology), Feinberg School of Medicine; Director, Northwestern Proteomics; Director, Chemistry of Life Processes Institute
Neil L. Kelleher, Ph.D., is both a pioneer and champion of the top-down approach and the Human Proteoform Project (HPfP), a global research initiative to weigh every protein in the human body. He has written more than 300 publications. The ProSight software suite developed by Kelleher is used by more than 1,000 labs around the world.
Click here for his full bio.

Madi Stock, Ph.D.

Madi is a former microbiologist whose journey beyond the lab has led her to working in marketing as Streck’s technical writer. And yes, she actually has a Ph.D. from Loyola University Chicago (she focused on quorum sensing in S. aureus!).

Written by Madi Stock, for Streck on May 29, 2025. Click here to view the story.