In September 2015, Caltech developmental biologist Eric Davidson died of a heart attack. It was a loss for the whole of the scientific community: Davidson had pioneered the concept of gene regulatory networks, which control what genes get read and used. The loss was also acutely felt by Miao Cui (PhD ’16), for whom Davidson served as a PhD advisor. He was a big reason Cui came to Caltech, she says. While studying evolutionary biology at Nanjing University, her advisor—a paleontologist—connected her with his collaborator, the broad-minded Davidson. “Eric was a biologist, but he had such a strong interest in paleontology, evolution—even history,” says Cui. “He approached biological questions at a very high level. He was trying to understand things from a systems level, which was rare at the time in biology.”
Cui worked with Davidson for years, culminating in her PhD thesis on gene regulatory networks in sea urchin embryos. The two became close personally, too; Davidson attended her wedding just a few months before his passing. “Eric was not only a mentor, but he was also a friend,” she says. Ultimately, his death redirected her trajectory. “It made me realize I wanted to do something that’s more disease-related,” she says. Today, Cui runs her own lab at Boston Children’s Hospital and teaches at Harvard Medical School, her research focused on the remarkable ability of the newborn mammalian heart to regenerate after injury.
In this interview, Cui talks to Techer about how she is trying to unlock those same regenerative capabilities in adults, what the path to a potential therapy might look like, and her mentor’s lasting impact.
How did a career path in science become clear to you?
Miao Cui: I always liked problem solving; I really liked puzzles growing up. I was also always very observant by nature. I did my college studies in China and majored in zoology, so there was a lot of fieldwork. During my PhD, I was first exposed to embryonic development and molecular biology, and using the microscopes, working with embryos, and seeing things develop got me really excited. I was watching life happen in front of my eyes—beautifully, deterministically progressing over time. Those were the moments when I felt like, “Okay, I want to do this.”
How did working with Eric Davidson shape your thinking?
He helped me really understand how much determination is required to do science and also what it meant to be good at it. He really was the person who conceptualized the gene regulatory network, which is a very unique way of thinking about biology and about how genes are connected through their function. And it’s the execution of that program that makes us who we are, makes different cell types in our body and makes us different from other species. His way of thinking about science, his ability to see the patterns in things, connect the dots, and, most importantly, understand the logic behind that—that’s probably the biggest fundamental influence that he had on me.
A central fact driving your current research is that the newborn mouse heart can regenerate after a heart attack. Why is that observation so significant?
The newborn mouse heart has incredible regenerative ability, and this is critical because cardiac tissue lacks stem cells. That makes cardiac tissue different from intestine or skin cells, which can regenerate because they have stem cells. It is conceptually stimulating and there’s also a hope that we can do something to reprogram or reinstruct cells back to a neonatal state and then help the tissue to repair, which will alleviate a lot of the clinical burden that we’re seeing in patients.
How has this line of research progressed? And what has propelled it?
I think the most significant discovery we have made is a unique population of cardiac muscle cells in newborn mice that is genetically unique and potentially the source of the regeneration. Without stem cells, what allowed these cardiac muscle cells to repropagate after injury was not clear. We found that not only do those cells share some of the embryonic cardiomyocyte signatures (the molecular fingerprint of a still-developing heart cell), but they also have this signature that allows them to be more resilient, adapting to stress challenges better.
What are the biggest remaining challenges between your current research and developing a therapy for patients?
The research is not in its infancy; we already know quite a bit. We are probably at the prime stage to really figure things out. We have a relatively good understanding of how to manipulate the different cell types in the heart. Within the next few years, we should be able to identify a good cohort of gene targets that will allow us to engineer a regenerative state in each cell type.
One of the challenges now, though, is understanding how we can actually target multiple cell types at once to achieve a tissue-level, coordinated reparative response.
How has working inside a pediatric hospital changed the way you think about your research?
This is actually the first time I am physically working in a hospital department. I share a cafeteria with patients, and I often see sick children. It’s a motivating factor for me and makes me think more deeply about the impact of what I do. I appreciate that my research has the potential one day to be translated into therapies, and I’m starting to be more proactive in planning my research programs with that in mind. I recently started collaborating with colleagues that have access to patient heart samples, and we have found very interesting results that seem to suggest that this key population of cardiac muscle cells we found in mice also exists in human infants.
As you push this research forward, how do you continue to reflect on Eric’s impact on your work?
Scientifically, Eric had a huge impact on the way we think about modern biology, and a lot of the concepts that are so deeply embedded in our research can be traced to his vision.
I also think about Eric’s impact as a person. Seeing how he valued the people he worked with—his trainees, his collaborators, technicians in the lab, and even his housekeeper—made me realize the importance of forming meaningful connections with people.
That has had a really big impact on how I think about interacting with my mentees and with all of the people I’m working with here. I wouldn’t necessarily have had that insight early in my training if I hadn’t worked with him.
