Advancing Basic Science for Humanity
2016 Kavli Prize in Neuroscience: A Discussion with Eve Marder, Michael Merzenich and Carla Shatz
The connections between neurons are shaped by spontaneous rhythmic activity that begins even before birth. Carla Shatz's lab has shown that a class of immune molecules that fend off viruses also help to sculpt the tangle of connections in the developing brain. (Credit: G. Huh et al., Science, 2000)
OUR VIEW OF THE BRAIN as something constantly shaped by thought and experience is only a few decades old, yet it has profoundly influenced how we teach and treat, raise our young and care for the old.
Eve Marder, Michael Merzenich and Carla Shatz are three researchers who, in very different ways, have revealed that the brain is highly changeable, or plastic. In the course of discovering how the structure and function of brain circuits are refined, they pioneered the field of neuroplasticity.
“For the discovery of mechanisms that allow experience and neural activity to remodel brain function,” Marder, Merzenich and Shatz received the 2016 Kavli Prize in Neuroscience.
Their work has revealed that brain circuits are “sculpted” from long before birth through adulthood. They have also helped explain how the brain achieves such a fine balance – between the adaptability that allows us to learn and to heal and the stability that maintains our abilities and memories for a lifetime.
In a roundtable, the three laureates discussed how their work disrupted a central dogma of neuroscience and offers the promise of plasticity-based therapeutics.
The participants were:
EVE MARDER – is Professor of Neuroscience in the Biology Department at Brandeis University.
MICHAEL MERZENICH – is Professor Emeritus in Neuroscience at the University of California, San Francisco. He is also the co-founder of Posit Science and Scientific Learning, two companies developing computer-based training tools for the brain.
CARLA SHATZ – is Professor of Neurobiology and of Biology at Stanford University, and Director of Stanford Bio-X, an institute that brings together faculty from across the university – clinicians, biologists, engineers, physicists, computer scientists – to unlock the secrets of the human body.
The conversation has been amended and edited by the laureates.
THE KAVLI FOUNDATION: When you started your careers, the prevailing idea about the brain was that it was fixed, or unchanging. Today, we see the brain very differently – as something that is capable of profound change, or plasticity. Dr. Merzenich, what are the major consequences of this shift in thinking?
MICHAEL MERZENICH: The science of neuroplasticity is slowly but surely transforming how we think about ourselves and our brains, and how we can build a stronger brain that provides us with a better life. We now realize that the brain is subject to change, and this change can be substantially under our control. On one level, it represents a new appreciation of ourselves, of how the person that we are originated within our lifetime. But it also provides us with an understanding about how plasticity can contribute to illness, frailty and impairment, and how we might deploy it to improve or correct the way our brains function. For example, we might strengthen the brain of a child or adult who is struggling to learn, strengthen a brain that is injured, or strengthen a brain that is at risk for mental illness, or dementia.
EVE MARDER: Who could say it better?
MERZENICH: Before this insight, the predominant belief was in a hardwired brain, incapable of learning once the basic elements were established. This was destructive, especially in education and medicine, as there was little hope for someone who struggled to learn, whether they were a child in school or an older individual suffering from a brain disorder.
CARLA SHATZ: Even the idea that you can tune up brain circuits after stroke, which really comes from Mike’s work, was off the table. Don’t you think it’s true, Mike, that in the 1950s, ’60s and ’70s, people were sitting in wheelchairs without rehabilitation?
MARDER: Not only after stroke, but also after spinal cord injury. People were put in bed rather than pushed into immediate treatment. Had they received therapy, their lives could have turned out very differently.
TKF: Why was the idea of a hardwired brain so prevalent? After all, it seems self-evident that we continue to learn and remember.
Kavli Prize Laureate Michael Merzenich, Professor Emeritus in Neuroscience, University of California, San Francisco
MERZENICH: In the mainstream of neuroscience, people conducted studies that seemed to show that the brain basically developed during a relatively narrow window of time in early life. After that, it became frozen or hardwired in its connectivity. Some people saw what we call synaptic plasticity – that is, changes in the strength of the connections between neurons – but that seemed to be primarily at work in the infant brain. When they looked at older animals, the brain seemed to be less plastic. So an idea became widespread – one complicated by the fact that people didn’t study the brain as it developed over time, or as an older animal acquired new skills or abilities.
SHATZ: One reason for this is, when I started out, many of the people trying to understand how brain circuits worked came from electrical engineering, so they naturally thought in terms of electrical circuits. This meant that they used connectivity diagrams to describe how the brain worked, in much the same way as a circuit diagram would be used to describe how a television or radio worked.
MARDER: Another thing that contributed to this is in the 1950s and ’60s is that it wasn’t easy to record the activity of brain cells. And so people believed that all neurons were basically the same. That reinforced the very digital, fixed notion of the brain.
TKF: Dr. Shatz, how did the work of your mentors David Hubel and Torsten Wiesel, who won the Nobel Prize for their research on the development of the visual system, challenge that notion?
Kavli Prize Laureate Carla Shatz, Professor of Neurobiology and of Biology at Stanford University; Director of Bio-X
SHATZ: In the 1960s and ’70s, Hubel and Wiesel beautifully demonstrated that there is a critical period in the brain, immediately following birth, when the connections in the visual system can be changed. The concept of critical periods in development already existed – famous experiments in psychology had been done with animals showing that the emotional development of babies depends on interaction with their moms. But Hubel and Wiesel’s experiments gave this concept a biological basis.
Unfortunately, I think their work on the critical period in the visual system was misinterpreted. People thought it meant that this developmental window slammed shut and could not be reopened, which really led to the idea that there was no brain plasticity in adulthood. But how could that be?
MARDER: We all knew adult animals learned, right? I think it’s also very important to understand that at the time, there were very different groups of people studying different parts of these problems. And it was actually quite late that people started realizing plasticity in development and plasticity in learning might engage some of the same mechanisms.
TKF: And then, Dr. Shatz, you found that our brains aren’t just constantly changing; this all begins before we’re even born.
SHATZ: Exactly. I found that even before birth, the brain is already working to sculpt connections between neurons – connections that are then used later on. Basically, the brain is rehearsing for use after birth, and these rehearsals are tuning up the circuits.
MARDER: What Carla’s saying is incredibly important. You can’t just build a neural circuit as if you were building an Erector set and switch it on. That’s not the way the brain works. You begin the construction, and then the use of the circuit during development in turn influences how it is constructed. As Carla so beautifully showed, circuits in the visual system are active before an animal actually sees the light of the world. Spontaneous bursts of electrical activity in the neurons of the visual system are what drive the formation of the circuits that eventually allow us to see. And once vision kicks in, those circuits continue to be refined for some time. Likewise, the motor circuits in the spinal cord are active before the animal is born, and that activity is necessary so that the newborn animal can move appropriately.
TKF: Dr. Merzenich, much of your research has focused on plasticity in the auditory system, which eventually led to the development of cochlear implants. Does the auditory system develop the same way?
Kavli Prize Laureate Eve Marder, Victor and Gwendolyn Beinfield Professor of Neuroscience in the Biology Department, Brandeis University
MERZENICH: We and others have shown that exposure to sound in infancy results in a rather remarkable specialization of the auditory processing machinery in the brain, shaped by an infant's early sound environment. By that specialization, the brain more effectively represents sounds that are likely to bear meaning to the individual later in life. We know that when you expose an infant animal or human to complex sounds—for example, to the sounds of an infant’s native language—the brain rapidly sorts those sounds in ways that crucially facilitate later language development and usage. By contrast, when you raise an animal in a distorted or impoverished early sound environment, the animal carries that distortion or impoverishment forward into adulthood. Thankfully, this kind of limitation can usually be overcome by training the brain at that older age!
MARDER: I think there’s a continuum of mechanisms. But all animals start out generating spontaneous activity and fine-tuning networks of neurons that they are then going to use. I mean, a cockroach needs to do it as well. It just isn’t going to develop language.
MERZENICH: How do you know for sure?
MARDER: I was waiting for that. [laughter]
TKF: That sounds like a question for your graduate students to work on! Dr. Shatz, what makes the adult brain different? Do we understand, biologically, why it’s less flexible than a child’s?
SHATZ: We know that in mice, there are molecular brakes that limit brain plasticity with age. If these molecular brakes are removed, then it is possible to generate much more juvenile or childlike plasticity in the adult mouse brain, including the ability to make new functional connections between neurons. That’s exciting because it suggests that the adult brain has much more capacity for change than was previously thought.
TKF: Dr. Merzenich, can brain training exercises help us release those molecular brakes or ease off of them a little bit?
Michael Merzenich is shown at UCSF in 1979, when he was developing a cochlear implant that could restore hearing based on his research in neural plasticity. (Credit: David Powers)
MERZENICH: Beyond that early epoch of wild and crazy plasticity, the older brain is tame. Change is only permitted, in a sense, when the brain interprets that change to be "good" for it. We have studied the way that the machinery of the brain changes its operational characteristics across a lifetime. The average human brain reaches a performance peak in the third or fourth decade of life, then slowly regresses, as all of these plasticity processes are thrown into reverse. In the end, the old brain is very much like the very young brain: it’s very noisy, very plastic, very open to change. On the other hand, its lack of organization and control is not so charming in dementia as it was in the baby. Fortunately, because the processes that underlie plasticity appear to be reversible, we can engage our old brains at any time, to our substantial advantage.
MARDER: I’m not going to disagree per se. But I will say that it is very important to put the brakes on plasticity once you build a really well-functioning circuit. If you build a finely tuned visual system or a finely tuned auditory system, you want it to work extremely well without having to devote too many resources to constantly changing it. For example, once you learn to recognize a tree, you still want to see a tree as a tree for a hundred years. You don’t want the circuits that support that ability falling apart because your plasticity mechanisms are getting out of whack. So it’s really important to remember that there’s a functional benefit to constraining plasticity once you’ve built the adult nervous system. However, you still want some plasticity for learning and repair.
MERZENICH: You need plasticity not just for learning and repair, but also to sustain brain health.
MARDER: But we wouldn’t want to turn back the clock to the time in the womb when the brain is so very flexible. We wouldn’t be better off doing that.
MERZENICH: Absolutely. We want the brain to be operating more like it was in the prime of life.
TKF: In other words, while we all envy how easily and quickly children learn new things, let’s not underestimate the importance of the brain stability that comes with age.
SHATZ: Right. It’s well known that as circuits quickly form during critical periods of development, they are actually a little unstable and more susceptible to epilepsy than later on. So while early in life it may be worth risking circuit instability in favor of quick learning, you’d want to temper that later. And you definitely would want some stability in things you’ve already learned, especially if they’re important for survival.
TKF: Dr. Marder, your work has partly focused on how the brain maintains stability even as it undergoes constant change. What drew you to this question?
Eve Marder's lab studies plasticity in the relatively simple neural circuit that controls digestion in crustaceans. This image shows putative connections between two neurons in the Jonah crab. (Credit: ML Goeritz et al., PLoS One, 2013)
MARDER: It’s magical how brains can incorporate changes without destroying function. Just think about it. Every time you have a long-lived cell, you’re constantly replacing the components. This turnover allows for plasticity but it also has to be kept in check. That is at the cellular scale. At a larger scale, you don’t want to train a brain to do something better at the risk of losing its ability to do something else that’s really important.
SHATZ: We’re beginning to learn much more about how to tap into those stability mechanisms in the adult brain, including some of molecules that might be involved. Someday, one can imagine that might lead to a pill so I could, say, learn French without an American accent…
MARDER: I want that before you.
SHATZ: The thing is, I don’t think any of us want it right away, because we don’t want to lose other learned information that we have. This is part of this conversation, right? If you actually tap into that circuit and change it, what kind of readjustments will occur that might not be so positive?
TKF: That’s a fascinating question. What others would you still like to answer?
MERZENICH: At our companies, we’re trying our best to translate the science of neuroplasticity out into the world, for the benefit of children and adults who struggle. Our main targets are individuals who suffer from neurological problems. We’re also trying to keep brains healthy to an older age. We strongly believe that we can substantially extend our brain-healthy lives. We’re convinced that brain training tools are going to become a major part of the therapeutic repertoire available to medicine and society for improving the human condition.
MARDER: A very important piece of what Mike is saying, independent of his tools, is that we need to get the message out that after some kind of brain damage, there is much more capacity for recovery than people are often told. I saw this with my father, who had a very bad brain injury. So, I think the important message is that working really hard can achieve much more recovery than was ever thought possible years ago.
SHATZ: Hear, hear.
MARDER: Getting back to your question about our scientific goals, I am the antithesis of Mike in that I’m an adamant basic scientist. My goal is just to continue trying to understand the problem we’ve just been talking about: How do you allow change to a circuit, reversibly or irreversibly, without destroying its function?
SHATZ: In terms of my research on neuroplasticity, we’ve gotten to the point where we can manipulate molecules in mice to create new connections in the adult brain. We know these molecules are also important in mouse models of Alzheimer’s disease, and that they are present in the human brain. So we’d like to learn much, much more about how they work, and based on those discoveries, determine if it is possible to make drugs that could help people with learning, cognitive enhancement, and also possibly with Alzheimer’s.
There are so many unanswered questions that I could work for a bazillion years and enjoy every minute. I can’t tell you when I’m going to stop.