Technological leaps in neuroscience are enabling researchers to study the brain in unprecedented detail. With the launch last month of the NeuroTechnology Center (NTC), Columbia University has officially joined the neurotechnology race.
The NTC brings together Columbia’s technical innovators from a broad spectrum of sciences to create new tools and technologies for brain research. In particular, it will focus on the development of optical, electrical and computational technologies. It will do this by funding interdisciplinary research projects, training a new generation of tool makers and connecting these tool makers with tool users.
The stakes associated with developing new tools for brain research are high: These technologies stand to accelerate the pace of discovery, giving us insight into how the brain works and how to intervene when it doesn’t.
The Kavli Foundation recently spoke with Rafael Yuste about the NTC’s goals and the future of neurotechnology. Yuste is director of the new center and co-director of the Kavli Institute for Brain Science at Columbia. He is also one of the researchers who spearheaded the Brain Activity Map Project, a precursor to the U.S. Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative—a national effort to develop tools that can be used to create a dynamic picture of the brain in health and disease.
THE KAVLI FOUNDATION: How did the NeuroTechnology Center (NTC) come about?
RAFAEL YUSTE: It started maybe five years ago when a group of faculty from Columbia moved together to a new building for interdisciplinary science. Some of us were working on building new tools for neuroscience, and we started a discussion with our administration about creating a center or institute. Then, after the BRAIN Initiative happened, it became much clearer to Columbia that it was important to have a center that could bring together all the different groups working on tools for neuroscience. At that point, we generated a proposal for the Provost and he approved it.
TKF: Why is it important to Columbia to have such a center?
YUSTE: Our vision is to serve as a conduit for physical scientists, who otherwise would never be working in the field, to branch into neuroscience and for neuroscientists to engage them. The NTC will serve as the bridge between the combined talent that we have at Columbia in the physical sciences and engineering and in the neurosciences, which is represented by the Kavli Institute for Brain Science and the Zuckerman Mind Brain Behavior Institute.
That combination is important: to have on the one hand, the neuroscientists, who are the tool users, and on the other hand, the physical scientists and people doing interdisciplinary research — like my team, who are the tool builders.
TKF: The federal BRAIN Initiative recently handed out $46 million in grants. In light of that, what role can the NTC play in advancing the discovery of new research tools?
YUSTE: I don’t want to diminish what’s going on with the BRAIN Initiative. I think it’s fantastic. But what it is missing right now is the critical-mass effect, where a high density of people work together to solve problems that cannot be tackled in individual laboratories. We want to start to build a critical mass of people at Columbia. If you add together neurotechnology builders and users, in a couple of years Columbia could have a group of 100 labs working very closely. Then some of those big challenges, which are technological bottlenecks for neuroscience, may yield.
TKF: Let’s talk about the scope of the challenge facing neuroscientists today. The 19th-century neuroanatomist Ramon y Cajal talked about “impenetrable jungles” of the brain. Would you still describe the brain this way? And how will novel neurotechnologies help resolve that picture?
YUSTE: I think the picture Cajal painted is still pretty prevalent. If you stop neuroscientists on the street and ask them, "Why don’t we understand how the brain works?" nine times out of 10, they’re going to tell you it’s because it’s very complicated. What is complicated are actually the neural circuits, how the different types of neurons are connected.
So the brain could be a big jungle. But that is speaking from ignorance because we still don’t really know how the circuits are connected. We don’t know how complicated they are or are not.
I’ve argued that this “jungle” idea prevails because the techniques neuroscientists have been using traditionally look at neurons one at the time. If you’re in a jungle and you look at trees one at a time, well, it’s going to look impenetrable. But if you can lift yourself above the canopy, then you may see how it’s organized. That viewpoint is what’s missing from neuroscience because we don’t have the tools to lift ourselves up from the canopy. My intuition is that those impenetrable jungles of the brain may be actually quite simple, but we’ve just been looking at them the wrong way.
TKF: That’s a great analogy. So what emerging technologies will help us see the brain in new ways?
YUSTE: I’d say that one of the technologies on the table right now that is starting to deliver is calcium imaging. That’s the use of fluorescent dyes that respond to calcium to monitor the activity of groups of neurons. The first publication on this technique was 1991, so it has a little bit of history, but now it’s starting to be used in a very creative and large-scale fashion. There are certain simple organisms like the larvae of zebrafish in which we can now monitor the activity of pretty much every neuron in the brain. That’s pretty exciting.
In the near future, maybe in five years, voltage imaging could displace calcium imaging as a dominant technology. With calcium imaging, you can only measure action potentials, the output of neurons when they fire. But with voltage imaging, you can also measure the input to neurons. So it gives you a more complete picture of what going on in a neural circuit.
On an even longer timeframe, there may be technologies emerging now from nanoscience that will allow us to electrically record from millions of neurons or have wireless reporters of neural activity that could work through the skull of an animal. There are many creative people taking on this challenge, so it’s not completely crazy to think that in 10 years we might have the ability to record the activity of individual neurons non-invasively.
TKF: How will the NTC help to speed the development of new tools for brain research?
YUSTE: We don’t want to build a new laboratory but rather harness our existing laboratories, to tape them together essentially to work on particular projects. We’ll provide the funding resources so they can jointly hire students and post-docs and maybe also buy equipment. Training is also important. It’s critical for this type of interdisciplinary research in general and for the BRAIN Initiative to have students that are trained both in neuroscience and in the physical sciences. This is precisely why the first thing we did was to send an application for a training grant, so we can start recruiting students to train in this mixed discipline.
TKF: Is there a successful example of interdisciplinary research that you hope to emulate with the NTC?
YUSTE: My dream is to recreate Bell Laboratories, perhaps the paradigm for interdisciplinary research in the 20th century, albeit at a smaller scale. I was lucky enough to work there for four years and I still miss the exciting lunchtime conversations I had with scientists from different disciplines, which eventually changed my career path.
Also, we’re taking very seriously what happened with the Human Genome Project, which had an enormous economic payoff 15 years later. It’s been estimated that every dollar invested by the U.S. led to an economic return of 140 dollars through the creation of the genomics or bioinformatics industry. You can appreciate that when you drive around Cambridge, Mass., or Palo Alto, Calif. Something like this could happen as a result of the BRAIN Initiative.
So we’ve made it part of our mission to develop strong links between New York technology labs and New York tech companies so that this critical mass translates into success not just to research, but also to local industry and the economy.
TKF: I didn’t realize the return on investment from the Human Genome Project had been quite that large.
YUSTE: Yes. We think neurotechnology could be a similar opportunity for New York. The greater New York City area has by far the largest concentration of neuroscientists in the world. It’s just phenomenal. Then of course we have big pharma companies, a huge concentration of hospitals and a lot of capital downtown on Wall Street. Plus, there’s a culture of young entrepreneurs interested in tool building, in particular in Brooklyn. They’re not working on neuroscience tools but they have a similar type of attitude, a desire to find fresh approaches to technology.
TKF: The goal of the NTC is to drive innovation in three specific areas: optical, electrical and computational technologies. Can you tell me about them?
YUSTE: At this point, mapping brain activity is a two-horse race between imaging and nano. Both tools enable the large-scale recording and large-scale manipulation of neural activity. It’s not clear which will the winning horse. So it makes sense to have both represented in the Center.
Then the third field is computation. It’s very different. It’s an overarching tool that you need no matter what. At the end of the day, you’re going to need computational neuroscientists to harness the data, and mine the data, and put it to good use. And those tools need to be developed, too.
TKF: What kind of research is currently underway at the Center?
YUSTE: There is a group of seven labs at Columbia that are part of a multidisciplinary grant from the Department of Defense that I lead. We’re trying to develop better methods for recording neural activity in single neurons, using a spectrum of techniques from atomic force microscopy to calcium imaging of mouse brains in vivo. The goal is to understand how a neuron computes.
Another existing collaborative project aims to develop nanodiamonds to image neural activity. These tiny diamonds are built by chemists and used by physicists interested in quantum computing. So this is coming out of left field for neuroscience! It’s not only coming from physics. It’s coming from quantum computing and quantum optics. But it turns out that they have ideal properties for imaging brain activity.
Another project is the development of very, very small electrodes. Traditional electrodes in neuroscience have tips of about a micron, or one millionth of a meter. Two labs here are collaborating to build electrodes with a tip of about 10 nanometers, which is 100 times smaller. We’re trying to use these nano-size electrodes to record electrical signals from parts of the neuron that are so small that you cannot stick a traditional electrode into them.
Then there’s a collaboration called the 3D Imaging Project to develop smart algorithms to analyze imaging data from volumes of tissue and mathematically extract the activity of neurons located at different depths of the brain. This is a very challenging problem but if we solve it, we’ll be able to build movies of the activity of a piece of brain in three dimensions.
TKF: Do you expect the NTC to have benefits outside basic research, for example, to human health?
YUSTE: Absolutely. While the major objective of the Center is not to cure mental or neurological diseases, the activities and the tools generated by the Center will definitely have an impact on some of them. For example, there are projects going on already in our labs to develop tools for better measuring of epileptic seizures, better control of epilepsy, and better diagnosis of schizophrenia.
TKF: In 10 or 20 years time, how will you know if the NTC has been a success?
YUSTE: I’d say a key measure of success will be in the younger people. Will being associated with the Center have positively impacted the careers of our younger colleagues? Will we have inspired a younger generation to work on new tools for brain research? My mentor, Sydney Brenner, once told me that what made him confident that he had spent his life usefully was to see the excited look in the eyes of a 14-year-old that he had inspired when discussing science. So that’s an important metric of success for me.
In more practical ways, we could look at startup companies. I wouldn’t say that we want to redo Silicon Valley, but it’s interesting to consider how Silicon Valley started with spin-off companies from Stanford. If we achieve a little bit of that, then that would be a major success.