Ben Barres, M.D., Ph.D. is the newest member of the Reeve Foundation International Research Consortium
By Sam Maddox
Ben Barres, M.D., Ph.D. is the newest member of the Reeve Foundation International Research Consortium on Spinal Cord Injury. Dr. Barres, a neuroscientist on the faculty of Stanford University, was formally introduced to the Consortium at a recent meeting in Cambridge. “I am thrilled to be joining the Consortium,' he said. “It's a wonderful group of scientists; they are all very interactive and there is clearly a high level of trust among the investigators. We've already discussed several potential collaborations with various labs.'
Dr. Barres spoke to Reeve staffer Sam Maddox about his work and how his lab might fit into the collaborative model of the Consortium.
More Progress in Research
Q. While your work hasn't been directed to spinal cord injury per se, you are well-known to the greater neuroscience field.
Ben Barres: I've been a neuroscientist my entire career so, yes, I know all of the members of the Consortium. What I'm known for, my lab, is neuroglial reactions and glial cells. We have in recent years come to understand what a critical role glia play in regenerative failure. So I think that's why I was asked to join. As collaborative groups evolve, you pick people with different expertise; that way there's better brainstorming. You put those brains together and start talking and ideas fly.
Q. We'll get back to the science; first let me ask you about your own career, you always wanted to be a physician first?
Ben Barres: I was at MIT, I was going to be a computer scientist or a chemist. But then I took this course by Hans-Lukas Teuber who was – they called themselves psychologists or brain scientists back then. He taught about brain function in the injured brain. From the second I took that course, I think I was a sophomore, I was just hooked on neurobiology. I got the idea that it would be fun to study the brain and that by being a physician, I could learn more about the brain. So I went to med school. I did my training in a very unusual order compared to most M.D. Ph.Ds. I finished my complete medical training and my entire internship and residency, and became board certified in neurology. And then I went back to graduate school and did a seven-year Ph.D. at Harvard, and a three year post-doc at University College in London. But as soon as I got in the lab and discovered research I never went back to seeing patients again. One of the things that compelled me to leave neurology more than anything was working with quadriplegic patients and realizing that I was helpless to do anything for them.
Q: And so you've been at Stanford what, almost 20 years?
Ben Barres: Yes. After London I came straight here, in 1993. I feel lucky every day to be at Stanford. What makes it great is not only the remarkable faculty, of course that's wonderful, but just the quality of the students and postdocs. I take graduate students in my lab for my neuroscience Ph.D. program; we typically have over 500 applicants a year and we take about 10 of them; you can imagine what the competition is like. I always tell the students, when I was their age, I couldn't even get an interview at this Ph.D. program or medical school; here I am now, a professor teaching these guys who are way better than I am; I'm very lucky.
Q. What attracted you to glial cells?
Ben Barres: I learned about astrocytes, that they were half the cells in the human brain. People really didn't know what they did, they thought they were kind of passive work cells that mopped up after the neurons and really weren't that interesting. But because of my neuropathology training, what I noticed was that the astrocytes are always very involved in disease processes; any kind of disease or injury to the brain causes the astrocytes to undergo incredible morphological changes, changes in their molecular properties, changes in gene expression. And so I just couldn't help but be curious about whether astrocytes are beneficial in injury or whether the changes were actually harming or adding to the injury process.
Q: Glia -- that's what you're known for?
Ben Barres: One of the biggest discoveries my lab is known for is developing purified specific brain cells: neurons, astrocytes, oligodendrocytes. We've purified all the major classes of brain cells, the microglia. Now we're doing reactive astrocytes and cell types after injury. The brain is a complex mixture of cells and they're all talking to each other. Our approach is to purify the cells and then study how they're interacting with each other in a culture dish. And then once you define those signals, you can manipulate them in an animal model.
We figured out how to separate the neurons from the glia, which include the astrocytes and the oligodendrocytes; this had never been done before. There were two main problems. One was getting utter purity, the other keeping the pure cells alive in a culture dish. It turns out that cells of different types are constantly signaling each other not to die. For example, as soon as you get neurons away from the glia, the neurons instantly undergo cell death – the glia send signals to keep them alive, and vice-versa. All the textbooks said that glia don't require survival signals; that wasn't true. When we purified the astrocytes, just like the neurons, they died as quickly without signals coming back from neurons. We have a paper in press now showing that astrocytes get their survival signals from blood vessels.
We got very interested in this question: Are glial cells doing other things, more active things, at synapses [the branched structure that allows passage of electrical/chemical signals between neurons or other cells].To get at that, we purified neurons and asked, “Okay, what can these neurons do by themselves and what, if anything, do they need glial cells for?' What we found is that neurons could pretty much do most things for themselves: They retained their morphology as neurons; they retained their polarization so they could still make dendrites and axons; they were still excitable and able to initiate action potentials and so forth. They looked pretty normal. But the one thing that we discovered, to our amazement, because we would never have predicted this in a million years, is that the neurons are completely unable to form synapses without glial cells. They can't hook-up, they can't wire-up, they can't connect. That was first a culture observation, and of course we wondered is that also true in vivo. And so to get at that we needed to figure out what the signals were; in other words, what are the astrocytes creating that tell the neurons to form synapses?
Q. That's what astrocytes are good at?
Ben Barres: This is what I believe astrocytes do: They control every aspect of synapse formation, synapse function, synapse maintenance, and even synapse elimination. We've spent the last 10 years biochemically identifying the exact molecular identity of the signals astrocytes release that tell the neurons to form synapses, to make the synapses function. The first signals we showed were a family of molecules called thrombospondins. They are very specifically made by astrocytes, particularly in the developing brain. They reappear after injury, which is very interesting, for repair of synapses.
Thrombospondins were the first known proteins that actually induced synapse formation between neurons. Everybody thought neurons could do it by themselves; they can't. There's molecular machinery in the neurons necessary to form the synapse, but the neurons need a signal to tell them to put all that machinery together.
Q: So what does it mean? Take this in a clinical direction.
Ben Barres: Everything I do is because I'm interested in neurological disease. To me this is all about the clinic. In the case of glia, the relevance is first of all, whenever you have a disease, you're losing synapses; synaptic connections are falling apart. You want to rebuild those synaptic connections. The signals that astrocytes make and the targets they interact with are all new drug targets for repairing synapses and controlling their function. I would like to have better memory now that I'm middle-aged. Well, by understanding how our brains form synapses and stronger synapses, these are all potential new drug targets for memory improvement.
After a stroke or a spinal cord injury, the Holy Grail for a long time has been “How do you get the axons to regenerate?' People are starting to come up with ways to do that now. There's still a lot of work to be done. But the writing is on the wall now that this is probably going to be doable. So now the big question is, when you get those axons back, are they going to make the right synapse – are they going to make synapses at all? And if they do make synapses, are they going to make the specific connections they're supposed to make? That's completely unknown.
The other thing is that neurodegenerative disease is all about synapse loss, synapse degeneration. Alzheimer's disease for example, is a disease of massive synapse loss. Parkinson's disease, glaucoma, these are all diseases where you have massive synapse loss. If a neuron loses enough synapses, the neuron itself dies. And we've provided some evidence that glia are actually intimately involved in the synapse degeneration process. And so we think that glia will be targets to block certain neurodegenerative disease.
And one last example of the connection to disease comes back to the thrombospondins. We wanted to figure out how the thrombospondins can tell neurons to form synapses. If you have neurons in a culture dish and you throw in thrombospondins, they form synapses. Therefore, there has to be a receptor, a thrombospondin receptor, on the neurons. And so we spent about four years figuring out what that was; we were surprised that it turned out to be a protein called Alpha-2-Delta-1, a well-described protein that was thought not to do much of anything. It is a receptor for a blockbuster drug called Neurontin or Gabapentin, commonly used to treat pain. We went on to show that what Gabapentin does is antagonize the ability of thrombospondins to bind to receptors. At its therapeutic dose, Gabapentin powerfully blocks glia from inducing new synapse formation between neurons; it's amazing. It's the first known drug that works by blocking synapse formation.
Q. And this is leading to what, new drug targets?
Ben Barres: This suggests a way to make a much better Gabapentin for pain. And so we have patented this discovery and we've licensed it to a new startup company. Our goal is to make drugs to manipulate synapse numbering, to block synapse loss and rebuild synapses in neurodegenerative disease.
Q. Another type of glia, oligodendrocytes, can affect axon growth. True also for some types of astrocytes?
Ben Barres: The first huge question in regenerative failure is to understand why axons don't grow back after they're severed in the central nervous system. This problem has been shown to be in large part glial -- both astrocytes when they become reactive astrocytes and oligodendrocytes, especially in degenerating myelin, are strongly inhibitory to regenerating axons. [Consortium member] Martin Schwab was the one to identify the first axon growth inhibitor, called Nogo, made by degenerating myelin. Reactive astrocytes are strongly inhibitory; one inhibitory signal that's made by reactive astrocytes is chondroitin sulfate proteoglycan [being studied by James Fawcett, also a Consortium member]. There's been very little study of reactive astrocytes and how they prevent regeneration from occurring. We don't yet understand how they know there's been an injury. But, obviously, they're signaled. It could be from inflammation.
Q: You mentioned regeneration...
Ben Barres: The question is, why don't axons regenerate after traumatic injury? There are two parts of this that we've worked on. One, the more traditional part, which we just mentioned, is the idea that glial cells are inhibitory. And the other part is the neurons themselves; they have an intrinsic capacity to regenerate when they're young neurons, when they're first developing. But by the time they become adult neurons, they've actually lost that robust ability to regenerate their axons. And we showed that that is the result of a genetic program built into them.
It is as if there is a switch -- within a 24-hour window on the day of birth, the axons slow down. And forever after, those axons can never grow fast again, no matter what you do. No matter what trophic juice you throw on them. No matter how you stimulate them. No matter what you do, they just have lost, irreversibly it would seem, the ability to rapidly regenerate their axons. Axon growth failure in the CNS, it's not all glial inhibition. Even if you got rid of all the inhibition, you got rid of the reactive gliosis, got rid of the Nogo, and all the inhibitory cues. Those axons, if they grew flat out at this rate, it would take them ten years to grow from the neck back down to the end of the spinal cord. If you could flip the switch and get those axons to grow fast again, maybe they'd grow right over all these supposedly inhibitory molecules.
Q: You don't have to get every axon to work again, right?
Ben Barres: Right. If we could only get a small percent of axons to wire back up again that might actually make a big difference to patients. There's a lot of redundancy within the nervous system. In Parkinson's disease, where dopaminergic neurons are dying in the midbrain, you routinely see that you have to kill something like 90 percent of those neurons, maybe 95 percent, before the patient even has mild symptoms. If you could just get a small percent of those axons to repair and regenerate, that might really make a big difference.
Q: Why is there a reason for people to be hopeful?
Ben Barres: I think the reasons to be hopeful are that the pace of science, now, is faster than ever before. The power of the technology is extraordinary. Also, for the first time, it's sexy to study disease. Thirty years ago, even less than that, Ph.D. scientists looked down on the study of disease. It was considered second-class science, not something that real scientists did. Nobody cared about disease. That has changed dramatically in the last five, ten years.
We are now bringing in the best and brightest minds. Most diseases have never been studied by the very best scientists. Now they are. So yes, I believe there are real grounds for optimism.