Two million people in the United States live with limb loss, either due to traumatic injury or illnesses such as diabetes, infection or cancer. When a human adult’s limb is amputated, tissue does not regenerate but if a child’s fingertip is amputated, it can regenerate without a scar. Similarly, the mouse digit tip can regenerate after amputation.
Jessica Lehoczky, PhD, of the Department of Orthopaedic Surgery, and her lab are focused on understanding the molecular pathways and genes necessary for digit tips to naturally regenerate with the goal of inducing regeneration after larger limb amputations. Lehoczky recently answered questions from CRN about her path to the Brigham and the big questions that she and her team are tackling.
Your bachelor’s degree is in biology and mathematics — how did you become interested in these two fields, and how did your dual degrees lead you to the Human Genome Project?
JL: I went to college at Lehigh University. Like a lot of undergrads, I couldn’t decide on my major, so I chose both. I loved my biology classes and especially working in the lab, but I also found the proofs and problem solving in my math classes really satisfying. I love solving puzzles—looking back, I think that’s the common thread to my double major and also the motivation behind choosing a career in research.
Can you tell us more about your work on the Human Genome Project? What was it like to be a part of that endeavor?
JL: This was such an amazing experience! After college, I worked as a research technician at the Whitehead Institute Center for Genome Research (which is now called the Broad Institute) with the Human Genome Project. Today, sequencing someone’s genome (all of their DNA) is common, but 20 years ago the technology we have today didn’t exist yet. My job was to help “map” the genome, which meant isolating large pieces of DNA in the lab, sequencing them, and then using that sequence to isolate the next piece of DNA on the chromosome — basically, building long DNA roadmaps. This was incredibly time-consuming, but it resulted in the first publicly available DNA sequence of the whole human genome, which has been the foundation of so much research since then.
That work really sparked my interest in genetics, so I decided to go to graduate school and joined the Human Genetics Department at the University of Michigan. I did my PhD research on limb development in Jeff Innis’ lab and my postdoc in Cliff Tabin’s lab in the Genetics department at Harvard Medical School. His lab is also well known for limb development research, and that’s where I started studying limb regeneration.
What drew you to the Brigham?
JL: I was already familiar with Harvard Medical School and the Longwood Medical Area from my postdoc, so I was excited to stay in this research community. All of my previous lab experiences had been in basic research academic departments and I was intrigued by the idea of starting my lab in a clinical setting. The Brigham is a world-class hospital and my clinical colleagues in this department routinely treat the types of patients I hope my research could one day help.
Let’s talk about human limb regeneration. Do you think this may be possible someday?
JL: It’s no secret that if you amputate your arm or leg, it doesn’t grow back. However, in my lab we think it might be possible to induce a limb to regenerate given the right conditions — it could just be a matter of figuring out how to coax the body to do it. Some mammals can naturally regenerate a small part of the limb after amputation—the digit tip. That’s the part of the finger or toe where the fingernail is. Even though it’s small, the digit tip has lots of different tissues in it like bone, tendon, nerves and blood vessels. The fact that the body can correctly regrow all of these at once makes us optimistic that broader regeneration of the limb might be possible. But first, we need to understand how the digit tip regenerates
What big questions about digit tip regeneration are you exploring?
JL: A lot of the big questions in my lab focus on the blastema—the group of cells that appear at the site of an amputation. We want to understand where these cells are coming from, how they form so many different tissue types, and how the regenerated tissues have the correct shape and organization. Ultimately, we want to figure out what cells and molecular signals are necessary for this naturally occurring digit tip regeneration and use this information to try to induce tissues to regenerate that normally don’t, like limbs.
You recently had a paper published in Developmental Cell. What did your work add to the field and our understanding of what cell types participate in digit tip regeneration?
JL: Gemma Johnson is the graduate student in my lab that led the study. We characterized mouse digit tip blastema cells at multiple stages throughout regeneration and compared them to the cells normally found in an uninjured digit tip. To do this, we analyzed nearly 40,000 cells and generated a “cell atlas” of all the cell types participating in mouse digit tip regeneration and the genes they are expressing. We deposited the data in a public database so the regeneration research community can use it as a resource. We were excited to find dozens of distinct populations of cells including immune cells, progenitor cells for specific tissues like blood vessels or nerves, and at least 13 different populations of fibroblasts. Moving forward, we are focusing on the blastema-enriched fibroblasts and the regeneration-specific genes we have identified. This study was largely computational, so there’s a lot of work to do in the lab now!
What are the immediate future directions of your research/next steps you’d like to take?
JL: Our recent work has opened the door to understanding which cells and/or genes may be essential for digit tip regeneration. There’s a lot of hard work ahead of us to test our new ideas, but I’m optimistic that we are beginning to identify some of the critical pieces in the mouse digit tip regeneration puzzle. I’ll admit it’s not clear yet how all these pieces might fit together, but I’m really excited to try to solve it!