Faculty Spotlight: Q&A With Kathryn Hamilton, PhD - Elucidating Intestinal Stem Cells

Kathryn Hamilton, PhD, our featured faculty member for March, studies gastrointestinal epithelial stem cells.

Editor's Note: This Q&A is the third in a series of monthly Cornerstone stories in which we sit down with faculty members at Children's Hospital of Philadelphia Research Institute to learn more about their research and roles. Through these spotlights, our readers have the opportunity to meet the diverse, dedicated, and distinctive individuals who lead our research community in our mission to improve children's health. In this Q&A, we feature Kathryn Hamilton, PhD, an investigator in our Center for Pediatric Inflammatory Bowel Disease (IBD) at Children's Hospital of Philadelphia, who devotes her time to better understanding intestinal stem cell biology. Stay tuned for more from our Faculty Spotlight series throughout this year!

Tell us a little about your research specialty? What excites you the most about it?

I started my lab at CHOP in July 2017, and our work centers around gastrointestinal epithelial stem cells, including what regulates their growth and survival, in response to stress, damage, or disease.

One of our main themes is understanding the roles that post-transcriptional gene regulation, specifically RNA binding proteins, play in stem cell plasticity. As a postdoc, I discovered a new link between the RNA binding protein I was studying and the autophagy pathway. When we deleted our RNA binding protein specifically in the intestinal epithelial layer, we found that the autophagy pathway was upregulated and that this upregulation seemed to help the epithelial layer recover more efficiently from DNA damaging injury (irradiation) or chemically induced colonic epithelial damage.

Like any interesting new discovery, this initial finding opened up even more questions.

For example, what is the molecular mechanism by which this RNA binding protein regulates autophagy? Is autophagy regulated by this RNA binding protein all epithelial cells of the gut, or just the stem cells? More broadly, is autophagy required for facultative stem cell function after damage? And finally, is this RNA binding protein's affinity for m6A-modified mRNAs required for facultative stem cell function?

Our lab's second theme is understanding how epithelial stem cells from patients with inflammatory bowel disease (IBD) behave differently than stem cells from patients without IBD. If we understand disease-specific differences in stem cells, we can develop new therapies that can support restoration of damaged intestinal tissue — a major clinical problem for patients with IBD and other gastrointestinal diseases.

We are working on projects evaluating the functional consequences of gene variants, some previously undescribed, found in patients with very early onset (VEO)-IBD. One of the most exciting aspects of this work is our ability to generate and utilize tissue stem cell-derived organoids (3D, miniaturized, self-organizing "mini-guts") from patients to uncover previously unknown disease mechanisms.

Why did you choose to study the function of intestinal epithelial cells?

During my senior year of college, I realized I did not want to go to medical school, and upon graduating, I was offered two jobs: one at a pharmaceutical company and one at an academic research lab. I chose the academic lab because the mentor and lab folks seemed like great people to work with. I knew nothing about research careers at that time. While I didn't realize it then, that decision was probably one of the most impactful of my life.

I began working on a project evaluating how hypoxia changed expression of epithelial proteins responsible for regulating neutrophil transmigration in the gut. Among many things, I learned how to grow confluent monolayers from colonic epithelial cell lines and evaluate how hypoxia or small molecules changed the ability of freshly isolated neutrophils (from healthy donors in the lab) to migrate through the monolayer. It only took me a short time in the lab to realize I had found my career passion, and I continued to train in the field of gastrointestinal cell biology and physiology.

Can you tell us about some of your current or past research projects?

We have multiple exciting projects happening in the lab right now, thanks to the outstanding trainees and staff in my group. One of the newest projects in the lab is our work on the Gut Cell Atlas through recent funding from the Helmsley Charitable Trust. This is a collaborative effort between my lab and the groups of Kai Tan, PhD, and Judith Kelsen, MD, at CHOP, Chris Lengner, PhD, and Meena Bewtra, MD, at the University of Pennsylvania.

For this project, entitled "A Crohn's disease epithelial stem cell atlas: pediatric to adult continuum," we are using a single-cell, multi-omics approach combined with functional assays in patient organoids to understand how stem cells from patients with Crohn's are similar and different from stem cells from healthy subjects in both children and adults.

Working in the Gut Cell Atlas international consortium has helped us to integrate into broader Human Cell Atlas initiatives, learn from other groups doing similar work, and share our own expertise and findings with the research community. We are less than halfway through the initial phase of this project, but we have already learned quite a bit during our pilot and optimization phases, and I am excited to see where the project takes us in the coming years.

What are the long-term research questions you hope to answer?

First, I want to contribute to our broader understanding of intestinal stem cell biology, and in collaborations with bioengineers, generate new intestinal tissue (or at minimum, a new intestinal epithelial layer) for transplantation into patients who require surgical resections or could even die due to severe gastrointestinal disease.

Second, in understanding how diseased stem cells may be different than healthy stem cells, I want to figure out if there is anything about these differences that can be exploited to develop new therapeutics for patients with IBD.

Finally, through our mechanistic work on the specific RNA binding protein we're studying, I'd like to answer whether we can develop and use inhibitors to disrupt its interactions with some of its target mRNAs to enhance epithelial repair in patients with IBD or other diseases.

Can you give us a quick summary about your presentation at the upcoming Faculty Luncheon?

I'm excited to share new, hot-off-the-press data from two emerging stories related to how the autophagy pathway is regulated in intestinal epithelial cells and how we've identified autophagic vesicle content as a marker for facultative stem cell activity in the gut.

What words of advice do you have for young scientists or students who aspire to pursue science?

Whether an exciting new paper, a long-accepted textbook paradigm, or even a successful colleague, in science we often only see the final product. In reality, most success is preceded by a series of disappointments, miscalculations, missteps, and rejections, many of which ultimately shape how we think and who we are. There is no single path to success in science, so don't worry too much about comparing yourself to anyone else. Keep your eye on your vision, surround yourself with the smartest, most supportive people you can find, and make sure you're spending your time on the things that are most important to you.

Learn more about Dr. Hamilton's research at April's Faculty Luncheon, April 29.