In our latest CDN Leadership Team sit down, we welcome Dr. Chris Walsh, a pioneering physician-scientist whose work has fundamentally reshaped how we understand brain development, genetic disease, and human consciousness. As Chief of the Division of Genetics and Genomics at Boston Children’s Hospital and a professor at Harvard Medical School, Dr. Walsh has led groundbreaking research on somatic mosaicism, neurodevelopmental disorders, and the genomic intricacies of individual brain cells. In this conversation, he reflects on the personal and scientific journey that brought him to the forefront of neuroscience, shares surprising discoveries from his lab, and explores the ethical and philosophical questions raised by studying the brain at its most elemental level.
To start off, we usually ask our guests to share a bit about how they got to where they are—your background, where you’re from, and what sparked your interest in science.
Dr. Chris Walsh: I’m the seventh of eight kids. My mom was a teacher, my dad was a businessman. Science wasn’t really part of my upbringing. I went to college without a clear path. In my first semester, I took a psychology class and an organic chemistry course—both really clicked. I wasn’t sure whether to pursue medicine or science, but then I discovered MD-PhD programs, where you can do both. That was a turning point. I was fortunate to be accepted at the University of Chicago, where I did my PhD in developmental neurobiology, very much focused on neuroanatomy.
What fascinates me to this day is how the brain forms—how undifferentiated cells become this incredibly complex organ responsible for thought, creativity, and consciousness. It’s a kind of transformation that feels almost metaphysical.
That’s amazing. I feel like the field is evolving so fast. I’ve been reading Plant Sapiens, which proposes that plants are intelligent. What’s your take on that kind of broader definition of intelligence or consciousness?
Dr. Chris Walsh: I think intelligence exists in context. A plant might be the most intelligent “plant” it can be. Their genomes are huge, filled with enzymes to detoxify poisons—something we don’t need because we can walk away from toxins. Consciousness, on the other hand, likely requires internal sensation—feelings, emotions, and a body to experience them. Yuval Noah Harari made an interesting point: a conscious computer would need a body with sensory inputs. By that definition, many animals—and maybe more—could be considered conscious.
That idea has made me more cautious about animal research. We now do more work with post-mortem human brains.
That’s a powerful shift. Going back to your early inspirations—how has your motivation evolved since you started?
Dr. Chris Walsh: At first, I was drawn to the biology of behavior—conditions like schizophrenia. But at the time, decades ago, the science wasn’t very rigorous. So, I pivoted to something more foundational: understanding how neurons are formed and connected. That eventually led to studying human genetics—looking at what happens when things go wrong, so we can learn how they work. Interestingly, we’ve now returned to psychiatric disorders like schizophrenia, and we recently published two papers on it.
For me, disorders like autism and schizophrenia challenge our basic assumptions about reality. They might help us answer profound questions about consciousness and human potential.
An added result is that it makes us more compassionate along the way!
Dr. Chris Walsh: Absolutely.
You’ve studied many genetic mutations tied to neurodevelopmental disorders. What are some of the most exciting discoveries from your lab recently?
Dr. Chris Walsh: One of the biggest surprises is that neurons, despite being non-dividing, still accumulate genetic mutations over time—just like dividing cells do. We used to think neurons were stable because they don’t divide, which supposedly protected them so we could preserve memories. But when we sequenced the genomes of individual neurons, we found that they collect about 17 single-nucleotide variants per year. That’s as fast as some dividing stem cells.
This changes how we understand aging and neurodegeneration. Diseases like Alzheimer’s speed up that mutation accumulation. It’s as if the neurons in an Alzheimer’s patient reach the mutation load of a 100-year-old when they’re only 80.
That’s fascinating. Do glial cells show the same pattern of mutations?
Dr. Chris Walsh: They do—but it’s different. Oligodendrocytes, for instance, accumulate more single-nucleotide mutations than neurons, but those are often less damaging. Neurons, on the other hand, accumulate more insertions and deletions, which are more frequently damaging to protein structure. So, while glial cells accumulate more mutations overall, the ones in neurons are potentially more harmful. We’ve also developed techniques using 10x Genomics to measure mutation accumulation by cell type, and even found that different layers of cortical neurons mutate at different rates.
And this is all connected to transcription?
Dr. Chris Walsh: Exactly. When a gene is transcribed, the DNA has to unwind. That exposes it to damage—oxidation, deamination, and so on. It’s not that transcription itself is damaging, but the exposure makes those regions more vulnerable.
You’re also doing work with spatial transcriptomics, right?
Dr. Chris Walsh: Yes, our long-term goal is to combine gene expression and mutation data in 3D space. In Alzheimer’s, for instance, we found that microglia—the brain’s immune cells—accumulate cancer-like mutations as the disease progresses. They go from supportive to antagonistic. We want to see whether neurons near these mutated microglia are more affected. That’s the kind of spatial relationship we’re now exploring.
Another big topic in your lab is somatic mosaicism—the idea that different cells in the same brain can have different DNA. Can you explain this for readers who may not be familiar?
Dr. Chris Walsh: Sure. Somatic mosaicism means that as an embryo develops, some mutations arise in certain cells and get passed on only to that cell’s descendants. So not every cell in the body—or even the brain—has the same genome. These mutations don’t come from your parents; they arise during development or later in life.
What we’ve found is that many forms of epilepsy, particularly the ones that don’t respond to drugs, are caused by these somatic mutations. In kids, a tiny patch of neurons—just one or two percent of the cells in a small part of the brain—can carry a mutation that causes seizures. If that patch is found and surgically removed, the child can be cured. These are the same kinds of mutations we see in cancer, but because the cells are neurons, they can’t form tumors—they just behave abnormally.
And in adults?
Dr. Chris Walsh: In adults, the story’s similar. We found that the most common form of adult epilepsy—temporal lobe epilepsy—also involves cancer-like mutations. These mutations don’t cause epilepsy at birth but sometimes not until decades later, possibly because the temporal lobe still has stem cells into adulthood that undergo cell division, which might cause the cells with cancer-like mutations to become more common with time. Over time, enough cells acquire the mutation to cause symptoms. It’s like a slow-motion version of tumor growth—without the tumor.
This model might suggest perhaps that Alzheimer’s and other late-onset diseases may emerge the same way: through mutation accumulation in glia or stem-like cells over many years. Once a critical mass of altered cells builds up, the disease manifests.
Are these findings translating into real therapies?
Dr. Chris Walsh: Yes—and quickly. I’ll give you three examples:
- Pediatric epilepsy: We found that many of these mutations affect the mTOR pathway. Drugs that inhibit mTOR, developed originally for cancer, are now being tested in kids with these epilepsies. They work—but they need to be reformulated to penetrate the brain better.
- Adult epilepsy: The RAS pathway, another cancer-associated pathway, shows up in temporal lobe epilepsy. Companies are repurposing RAS inhibitors from oncology for these patients. Some of these drugs already cross the blood-brain barrier more effectively.
- Alzheimer’s disease: We’ve identified cancer-like mutations in microglia, and these mutations overlap with those found in myeloid leukemias. Since microglia and blood myeloid cells share a lineage, this opens up the possibility of using leukemia-targeting drugs for Alzheimer’s.
So, the genetics are helping us trace a path from disease mechanism to potential treatment.
It’s amazing that cancer research is now helping to drive neurological therapy. What do you see as the biggest barriers?
Dr. Chris Walsh: The blood-brain barrier is a big one. Many effective drugs in cancer simply don’t get into the brain. In fact, they are often designed not to enter the brain, and so that has to be re-considered for these conditions. Another is modeling these conditions. mTOR and RAS mutations are easy to reproduce in mice—they cause seizures just like in humans. But Alzheimer’s is harder. Mice don’t live long enough, and their brains aren’t structured the same way. We may need better models—perhaps brain organoids or better post-mortem analyses.
Your lab spans genetics, neurodevelopment, disease modeling, and informatics. How do you manage such a diverse team and stay at the center of so many moving parts?
Dr. Chris Walsh: I’m trained primarily in anatomy and molecular biology, but I know I can’t do this work alone. Our research relies on collaborations with incredibly talented people. Some of our most important partnerships have been with Peter Park and Alice Lee, bioinformatics experts whose groups have developed computational tools to interpret the sequencing data from single neurons.
Sequencing a single neuron is relatively straightforward these days. The challenge is interpreting the data—distinguishing real mutations from amplification noise, figuring out what’s meaningful. That’s where Peter’s and Alice’s teams have been crucial.
We’ve also built internal expertise by bringing in and training computational scientists. Many of our best ideas have come from students and postdocs—people who saw something unexpected and followed it. Honestly, my job is to support them, guide them a little, and get out of the way.
That really speaks to the collaborative nature of modern science. You also touched on bioinformatics earlier. With the explosion of AI and neural networks, how do you see these tools impacting neuroscience research?
Dr. Chris Walsh: AI has a lot of promise, particularly in summarizing complex data or speeding up routine analyses. It’s helpful for writing, reviewing literature, even generating hypotheses. But I always come back to something Sydney Brenner said: “Progress in science depends on new techniques, new discoveries, and new ideas, probably in that order.”.
The kinds of breakthroughs we’ve had—like detecting somatic mutations in single neurons—were only possible because of advances in sequencing technology. That’s something AI can’t replicate by itself as far as I know. AI can help us analyze what we already know, but it won’t invent the tools that let us see what we’ve never seen before. That still takes human creativity, curiosity, and technical innovation.
You mentioned your medical background earlier. What perspective does being an MD bring to your work as a scientist?
Dr. Chris Walsh: It’s hard to overstate how motivating it is. I’ve cared for kids with developmental disorders, and seen how deeply their families fight for them. That stays with you. It puts a human face on the research.
It also gives me a mental library of what these conditions look like in real life. I don’t need to imagine what epilepsy or autism means—I’ve seen it. That makes it easier to prioritize what matters in the lab, and to focus on work that could lead to real improvements in patients’ lives.
Chris, this has been incredibly inspiring. Before we wrap up, we like to ask a few rapid-fire questions. First: what advice would you give to young scientists who want to study brain development and genetics?
Dr. Chris Walsh: The most important thing is to realize that we know almost nothing. It might feel like all the big discoveries have already been made, but that’s not true at all. In fact, I’d say it took me decades to appreciate just how little we understand.
And second, you don’t need to be the smartest person in the room. You just have to want to contribute. Be curious, work hard, and take advice. Most of all, be humble. If you’re not, science will humble you anyway—better to get ahead of it.
That humility really comes through. What would you say is your favorite scientific finding from your own career?
Dr. Chris Walsh: I feel like I am always most excited about something new. I mentioned already the surprising discovery that neurons—these non-dividing, “stable” cells—accumulate mutations over time. But just when we thought that the genomes of neurons were always getting more damaged with time, we find most recently that the human fetal brain has abundant neurons with very abnormal genomes, and then somehow purges these abnormal nondividing cells, probably by some sort of programmed cell death. This finding again has opened up whole new ways of thinking about development and degeneration.
If you weren’t a scientist or a doctor, what would you be doing?
Dr. Chris Walsh: Probably something with music—I played piano through college. I wasn’t good enough to be professional, but it was a real passion. I’ve also thought about writing. My grandfather was an MD-PhD with a PhD in theology. He spent his life trying to reconcile science and religion. People keep telling me his story deserves a book, so maybe I’d write that.
That would be a great read. Last question—how can people follow your work?
Dr. Chris Walsh: Our lab is based at Boston Children’s Hospital, and we also have a Center for Human Brain Evolution website. A lot of our preprints go up on bioRxiv. I used to be on Twitter, but I’ve stepped back from social media. I’ll probably join BlueSky or something eventually, but for now, the websites are your best bet.
Perfect—we’ll make sure to link those in the blog post. Chris, this was fantastic. Thank you so much for your time and for sharing your insights.
Dr. Chris Walsh: Thank you both. I really appreciate the chance to talk about our work and what makes it meaningful.