COMMENTARY

When 'Sparks Fly': Unique Collaboration Behind 'Momentous Discovery' in Brain Diseases

; Beth Stevens, PhD

Disclosures

July 05, 2017

Embarking on a Career in Biology

Eric J. Topol, MD: Hello. I'm Eric Topol, editor-in-chief of Medscape. I'm delighted to welcome Beth Stevens from the Broad Institute at Harvard and Children's Hospital in Boston. We are going to be talking about some of the great work you've been doing. Welcome, Beth.

Beth Stevens, PhD: Thank you for having me.

Dr Topol: You're a Massachusetts native, so you are back to where you started. And you were in Maryland for your PhD?

Dr Stevens: Actually, I was at the National Institutes of Health (NIH) before that as a technician with Doug Fields for several years. I got the science and neurobiology bug in his lab. At the time, I had already been invested for so many years in the lab that I started my PhD. It worked out really well—I could get my degree through Maryland and stay at the NIH to do my research.

Dr Topol: I didn't realize that. You then went to Stanford. What did you do there?

Dr Stevens: When I was at Doug's lab, glial cells—which are the other half of the brain—were a really exciting new field. People weren't thinking of glials doing anything except supporting the neurons. Right around that time, some very exciting work was being done that got me interested in studying glia. The work I did with Doug was looking at the role of glial cells during development. That led me to Ben Barres, who was another pioneer in the glial field, to do my postdoctoral work. That's what led me into thinking about glia in the context of synapses, connectivity, and brain development in a new way.

Dr Topol: All of these people were zooming in on neurons and you were working on the other space—finding out what's going on.

You are a product of a principal and a school teacher—your father and mother, respectively. You followed a path that was very different from their world of education.

Dr Stevens: I always was interested in science, but I didn't think it was a career option. I didn't have scientists in my family, but fortunately I had a number of mentors and teachers who opened my eyes to this possibility—in particular, my advanced placement biology teacher. He was the teacher who changed everything because he made me realize that I could do this—major in biology.

Dr Topol: That's an exceptional biology teacher.

Dr Stevens: That was my senior year and it's what led me to think about science and research. The neuroscience part came from, again, the NIH, where my first job was in a neuroscience lab with Doug Fields. It goes to show how one's path can change, and that people and mentors are often critical in shaping the direction in which you go. I've been fortunate to have many such mentors along the way.

Dr Topol: That reinforces how important it is for each of us to serve as mentors and to try to inspire others.

Mice, Microglia, and a Momentous Discovery

Dr Topol: I'm going to fast-forward. You were working on glia. You made an amazing discovery; in fact, it was reported above the fold in The New York Times in January of 2016,[1] about schizophrenia and the immune system. Tell us the backstory of that discovery.

Dr Stevens: It's an exciting backstory. It started when I was a post-doc. I was interested in the role of glia in brain development and wiring. At the time, Ben Barres was looking at the role of glia in this context. Centrally, through an unbiased screen, we unexpectedly identified a role for these immune molecules (called complement) in the pruning (or elimination) of synapses, which is a normal developmental process. It's very important for brain wiring.

Back then, in 2005, this was surprising, because we didn't typically think about immune molecules being in the brain. We thought about immune molecules when someone had an infection or if there was a breach of the blood-brain barrier. We discovered that a number of these molecules that were traditionally associated with the complement system were actually being expressed in neurons and in healthy glial cells in the normal brain. We then discovered that they played a role in this pruning process.

This was a perfect way to launch a lab because nothing was known mechanistically. Over the first 5 years, we tried to dig into that using mouse models, and we started thinking about how this might work. That led to our discovery that another type of immune cell, called "microglia," were at play here. As a glial biologist, I completely ignored microglia because they are immune cells and they weren't really born in the brain. Neurobiologists didn't think about them in the context of the healthy brain.

We put these two ideas together and realized that the microglia are actually part of the pruning process. Much of the work that we have been doing over the past 8 years has just been digging in and trying to understand how this immune pathway is involved in something as important as pruning.

Meanwhile, Steve McCarroll, who led the genetics on our schizophrenia work, and his student, Aswin Sekar, and his lab and colleagues at the Broad, were uncovering some genetics that were pointing to the same pathway that we had been studying all these years in a mouse.

A Convergence of Ideas Over Coffee

Dr Topol: You had not had any crosstalk?

Dr Stevens: No. Of course, I knew Steve's work but we were not in the same circles. He's a human geneticist; he's in the genetics department across the street, not that far away, and at the time I was not involved as much in the Broad. We had coffee one day, and he said, "I have some interesting but very preliminary findings." He knew that I worked on complement in the context of pruning. We started having some very exciting discussions. This led to our labs having joint lab meetings and then bringing in Michael Carroll, an immunologist who has spent his entire career studying complement in the context of immunity and the immune system.

The three labs started to converge on a regular basis. That was around the time when the complement component 4 (C4) paper[2] was starting to come together. The genetics of that were already amazing, beautiful, and important, but together we started thinking about the biological significance and whether the C4 genetics could also be linked to the pruning process that we had been studying. The only way to tackle that was to bring together this intradisciplinary team, which has been very exciting.

This is so extraordinary—the idea that you can get immunology, neurobiology, and human genetics all together and make such a momentous discovery.

Dr Topol: This is so extraordinary—the idea that you can get immunology, neurobiology, and human genetics all together and make such a momentous discovery—a true mechanistic breakthrough. It's fantastic.

Dr Stevens: There is a little bit of serendipity in the sense that we were all together. For events to happen the way they did, it required all of us to be located literally one block from each other. Of course, the students played major roles. They started working together in the different labs and then sparks started to fly. Honestly, that is why we do this. It's so exciting. We're only at the beginning of really understanding how it works, but we're well positioned now to try to make some progress.

Schizophrenia: Only the Beginning?

Dr Topol: You're onto something that's exceptionally important, which is the immune system in neurologic diseases. It could extend well beyond the schizophrenia story that you've worked on, and I'm sure that you are working on other areas. Alzheimer's has been shown recently to have involvement with the immune system. We didn't even know that there was an immune system in the brain, and now it seems to somehow be linked to many diseases. Do you want to comment about where you think this is going, that it's not just related to one area?

Dr Stevens: That's what I'm most excited about, because I don't think it's one disease. What's really exciting about the schizophrenia work is that the genetics point to the same pathway. We were also excited about the possibility that this pathway may be relevant in Alzheimer's disease, because the hallmark of so many neurologic disorders—including the neurodegenerative diseases of the aged brain—is the loss of synapses, the connections between neurons. In fact, that's the strongest correlative of cognitive decline in Alzheimer's. More than plaques and tangles in pathology, it's the synaptic loss that happens, presumably years before you start to get the symptoms. That's also been shown in animal models.

The same year that we started the lab, we took a chance and hypothesized that the same pathway we've been studying in development could be aberrantly reactivated in the adult brain to mediate the synapse loss. This was just an idea that came from the work I did as a post-doc, and we started working on this in the early days. We now have evidence that indeed the same pathway that is a good thing during development gets aberrantly turned on in vulnerable brain regions like the hippocampus, an area involved in memory. This leads to early synapse loss, at least in animal models.

What's even more exciting now is the genetics. If you look at the emerging genetic data from Alzheimer's disease, almost half of the genes are immune- or microglia-related.

Dr Topol: It's amazing.

Dr Stevens: Which again is pointing to these cells not just being downstream; they are actually a major contributor and causally related. Finding out whether that relates to the pruning in terms of human Alzheimer's disease patients is the next big step—to put these ideas together. We think this might be a common mechanism that makes synapses vulnerable in a host of diseases.

Dr Topol: We're expecting to see that from you in the future. It's so exciting because it has been disappointing not to have a breakthrough in Alzheimer's, but maybe that's because we didn't understand it well enough. The work that you, your colleagues, and your collaborators are doing is fantastic. We hope that you go full force. Thank you, Beth.

Dr Stevens: Thank you for having me. It's been wonderful.

Dr Topol: It's been a fun discussion. I would like to talk to you for several more hours. I want to thank everybody in the Medscape community for tuning in to this One-on-One with Beth Stevens. Thank you.

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