Chemical biologist bridges basic discoveries to treatments for disease

Countless articles written about basic biomedical discoveries include some version of the sentence, “The researchers hope this can help develop new treatments for disease.”  The basic scientists studying genes, proteins, and cellular mechanisms, however, often aren’t the same people doing the development. At some point, they need a partner with the right expertise to build the tools or design a drug molecule to translate those discoveries into clinical therapies.

Hening Lin, PhD, James and Karen Frank Family Professor of Medicine and Professor of Chemistry at the University of Chicago, is the unique brand of scientist who can do both. He’s part of a growing roster of scientists at the university working in the burgeoning field of chemical biology, which bridges the disciplines of chemistry, molecular biology, and medicine to fulfill the promise of those hopeful closing words typed by many a science writer.

A career of serendipity

Lin’s office in the Knapp Center for Biomedical Discovery overlooks the Center for Care and Discovery hospital building at UChicago Medicine, and the construction site of the new AbbVie Foundation Cancer Pavilion. That view, he says, explains his decision to join the faculty at UChicago in 2024 after a successful career at Cornell University.

“If you look at the top 20 institutions in the country, how many places have a top-ranked cancer program and a highly ranked medical school that are right next to each other? And then have a chemistry department within five minutes walking distance?” he said. “That’s why I really wanted to come here, to utilize that and promote translational research, not just in my own lab, but the whole campus.”

Lin didn’t necessarily get to this place by design; he says his early interest in science was more a matter of serendipity. As a kid growing up in a rural village of Shandong Province in China, he participated in science competitions at school and realized he had a knack for chemistry. “Those kinds of experiences made me realize, ‘Oh I’m pretty good at this.’ So, when I went to college [at Tsinghua University in Beijing] and chose what major I would be studying, I naturally picked chemistry,” he said.

He later came to the United States to pursue a PhD at Columbia University. His advisor was Virginia Cornish, a pioneer in the relatively new field of chemical biology, which uses the tools of chemistry to manipulate biological systems and living organisms. “She really showed me how we can use chemistry to understand and control biology. That really started my scientific career,” Lin said.

As a postdoctoral fellow at Harvard Medical School, Lin worked with Chris Walsh, another pioneering scientist who studied enzymes, special proteins that speed up chemical reactions. Walsh studied the enzymes that bacteria produce to protect themselves and kill competitors. Working at a medical school, however, Lin saw the possibilities for studying the many enzymes in the human body instead.

The grammar of biology

Lin joined the faculty at Cornell in 2012, where his lab began studying enzymes and other regulatory mechanisms of the genome. Lin compares the human genome to a dictionary. It provides the vocabulary, but to write a novel, you still need to connect words together and form sentences and paragraphs. “That’s where regulatory mechanisms come in,” he said. “They are the grammar of biology. You need to know how those work to really be able to understand biology and what goes wrong in human diseases.”

Regulatory mechanisms come in many shapes and sizes. Some, known as epigenetic modifications, act like on/off switches for genes when certain molecules are attached to a gene. Others may change the way a protein works under certain conditions, like the way the meaning of a word can change depending on sentence context. Lin’s team focuses on three types of mechanisms: chemical modifications that alter proteins, interactions between proteins, and small molecules like metabolites that can bind to proteins and change their functions.

One of his big successes has come from studying a group of enzymes called sirtuins, which are involved in processes related to aging, metabolism, stress resistance, and inflammation. Researchers originally thought their purpose was to remove a modification called an acetyl group from proteins. There are seven of these enzymes in humans, but Lin realized that not all of them work the same way. His team discovered that some of them remove completely different modifications from proteins.

Lin wanted to know what purpose this different activity could serve, so his lab began developing small molecules that could turn off the different sirtuin enzymes. Some of these molecules showed promising anti-cancer effects; Later research showed that inhibiting one of these enzymes also suppresses inflammation and could be used to treat conditions like inflammatory bowel disease.

Bridging basic science to applications

This progression of research shows how to build the bridge from basic discoveries to clinical medicine. “Finding that those enzymes can remove previously unknown modifications was unexpected. I think really changed the field,” Lin said. “That’s what makes you really excited about doing discovery research. Once you understand what’s going on, it’s not only satisfying, but it allows you to predict things about what kind of human disease you can treat.”

Besides his own lab’s studies, the first order of business for Lin at UChicago is to build a core facility for chemical biology and therapeutics that will provide a service for other researchers looking to develop molecules that can target genes, proteins, and leverage regulatory mechanisms. The center will offer technology and scientific staff to purify proteins and understand how different molecules bind to them, and then help design, build, and test the right compounds to manipulate their function. Normally this process can take two to three years; Lin plans to speed this up to less than six months.

Building on the critical mass of expertise already on campus, Lin hopes to fulfill the bench-to-beside promise of biomedical research. “This core facility will provide a service to biologists and clinical scientists who haven’t had the resources to develop drug molecules,” he said. “The goal is to promote collaboration among clinical scientists, biologists, chemists, and engineers who can come together for translational research.”