2023 Sherman Prize Recipient

Thaddeus S. Stappenbeck, MD, PhD

Sherwick Endowed Chair in Inflammation & Immunity; Chair of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH

Through his microscope, Dr. Thaddeus Stappenbeck makes groundbreaking discoveries in the underlying causes of IBD to unlock new treatment strategies.

Exploration Plus Collaboration Equals Discovery

A math aficionado with a fascination for science and the natural world, Dr. Thaddeus Stappenbeck learned through a series of experiences with some of the world’s top research labs that the best discoveries come from the least expected places.

“For college, I went to a very small program within a very big university,” said Dr. Stappenbeck of the Integrated Sciences Program he enrolled in as an undergraduate at Northwestern University. “It was thrilling because of the kinds of unique conversations you could get into with people. It taught me that a lot of the great opportunities for discoveries are between fields.”

Lab work brought together Dr. Stappenbeck’s love of nature, science, and math. He was working in a bone physiology lab when his mentor, Dr. Paula Stern, helped him land a summer job at a urology lab at Northwestern. That’s when he realized he wanted to pursue medical research.

“As a graduate student with Dr. Kathleen Green at Northwestern, it was very much about doing basic discovery,” he said. “It wasn’t so much about direct implications for translational work though this was always the goal. The major goal for MD/PhD programs was to take people who were going to be physicians and train them to be excellent basic scientists.”

Dr. Stappenbeck’s journey exposed him to world-class scientists and labs that inspired him to think big and keep the patient in the front of his mind.

“I had really amazing mentors who can see the patient in front of them as they’re looking at the slides or thinking about a research question.”

His medical training in pathology was an opportunity to see all of the complexity that is in tissue sections of various diseases. He said, “It wasn’t just simply an exercise in trying to make a diagnosis. It really inspired me.”

One of Dr. Stappenbeck’s first big breakthroughs was in the Immunology division at Washington University. His view of immunology was, as he says, ‘between fields,’ enabled by different disciplines coming together for a common purpose. He had been lamenting that the current methods of studying internal healing in the mouse intestine were inadequate. Then one of his immunology colleagues, Ken Murphey, challenged him to develop a new, more precise model, which led Dr. Stappenbeck to innovate the use of endoscopic biopsies in mice to study wound healing in the colon. He says this was “the missing piece.”

“Mucosal ulcerations are a feature of patients with moderate to severe IBD. And we didn’t understand fully why these lesions weren’t healing or even what the process was for healing.”

The groundwork was laid for further discovery of host and microbial mechanisms that affect different stages of intestinal repair.

“Once we had a system in place, we started doing really serious science,” said Dr. Stappenbeck, who is currently the chair of Inflammation and Immunity at Cleveland Clinic. “We found a population of specialized epithelial cells that create a sort of a “band-aid” over an open wound that must occur before the stem cells increase their cell division to make new crypt structures. It is a very elegant process. We’ve been working to define these molecular mechanisms behind these processes for the past 10 years.”

In this mouse model, Dr. Stappenbeck also discovered that intestinal healing is inhibited by a type of yeast called Debaryomyces hansenii. When he began looking at the colonic ulcers of people with Crohn’s disease, he found this yeast — a product used by the food industry with increasing frequency over the last 50 years to make processed meats, cheeses, and alcoholic beverages. It’s also sprayed on fruits and vegetables in the grocery store to kill other microorganisms.

“All of us are exposed to it, and if you’re healthy it just passes through your gut,” said Dr. Stappenbeck. “But what we found in people with Crohn’s disease who had open ulcers is that this microbe could get into the wounds and actually stop the latter phases of repair. In our society, I think it’s almost impossible to eliminate this yeast,” he said. “But now we know the drugs that it’s sensitive to, and so we’re developing an oral drug to give to IBD patients so that they can clear it.”

Dr. Stappenbeck readily shares his novel methods for studying wound healing so others can also push this research forward. This generosity stands out in the field, as do his contributions to a deeper understanding of the microbiome, which is crucial to discovering cures for IBD. To make these types of breakthroughs, Dr. Stappenbeck coaches younger colleagues to work with scientists outside of their discipline, as he has done throughout his life.

“There might be solutions you never could have come up with that other fields figured out, or new solutions that come out of collaboration,” he said.

Dr. Stappenbeck approaches his work with a quiet humility, and an inner drive to solve intractable problems and advance the field. He sees a future where mathematical modeling, big data, and artificial intelligence will be used to solve problems that up until now have seemed unsolvable.

“As physicians of modern medicine, we’re pretty good at diagnosing problems. But I think we can do better.”

“If we model the complex mathematical data surrounding these disease processes, I believe we can get to a point where we’re actually able to ward off disease before it starts”, he added. The computational methods still need development. In support of these goals, Dr. Stappenbeck said Cleveland Clinic has the first quantum computer in the world dedicated to healthcare research, which will allow his team to store and analyze vast amounts of data.

“It’s estimated that there are between 300,000 and 400,000 enzymes in the microbiome,” said Dr. Stappenbeck. “Sifting through these enzymes trying to find interesting bioactive molecules in the microbiome is going to be very interesting and challenging.

“We know that there’s a number of things that go wrong before patients develop full-blown IBD,” he said. “The question is, can we actually uncover early markers of inflammation and damage in the gut and then intervene? This is the mission of Cleveland Clinic, to improve health, not to simply ameliorate sickness.

“It’s a lofty goal. But I think it’s something that we should aspire to and it’s why I’m here. It’s going to be a really exciting time for discovery.”

As a board member of Color of Crohn’s & Chronic Illness for the past three years, Dr. Stappenbeck has become acutely aware of the challenges that people of color, indigenous, and low-income patients with IBD face every day in terms of access to care and information on how IBD affects them differently than the general population.

“It’s been really eye-opening for me to be involved with this group,” said Dr. Stappenbeck. “I’m not the same scientist that I was three years ago because of it. It’s become a really important mission for me, and it’s something I’m very passionate about.”