UCSD Center for Brain Activity Mapping: Interview with Director Ralph Greenspan

A new Center for Brain Activity Mapping (CBAM) has been established at the University of California at San Diego. Under the aegis of the interdisciplinary Kavli Institute for Brain and Mind (KIBM) at UC San Diego, the new Center will tackle the technological and biological challenge of developing a new generation of tools to enable recording of neuronal activity throughout the brain. It will also conduct brain-mapping experiments and analyze the collected data.

CBAM will focus on developing new technologies necessary for global brain-mapping at the resolution level of single cells and the timescale of a millisecond, participate in brain mapping experiments, and develop the necessary support mechanisms for handling and analyzing the enormous datasets that such efforts will produce.

Brain-mapping discoveries made by CBAM may shed light on such brain disorders as autism, traumatic brain injury and Alzheimer’s – and could potentially point the way to new treatments. The technologies developed and advances in understanding brain networks will also likely have industrial applications outside of medicine.

CBAM will bring together researchers from neuroscience (including cognitive science, psychology, neurology and psychiatry), engineering, nanoscience, radiology, chemistry, physics, computer science and mathematics.

The new Center will be directed by Ralph Greenspan, one of the original architects of a proposal that eventually led to President Obama’s Brain Research through Advancing Innovative Neurotechnologies Initiative (BRAIN Initiative). Greenspan, who also serves as associate director of KIBM, studies the role of network level activity in the nervous system and among genes, and for years he has studied the genetic and neurological basis of behavior in the fruit fly.

In addition to Greenspan, prominent neuroscientists involved in CBAM include Nick Spitzer, distinguished professor of neurobiology and director of KIBM, and Terry Sejnowski, director of UC San Diego’s Institute for Neural Computation and member of KIBM, who holds joint appointments with UC San Diego and The Salk Institute. Both Spitzer and Sejnowski authored the proposal for CBAM with Greenspan.

The Kavli Foundation spoke recently with Greenspan about the genesis of the new Center, its goals and ambitions.

THE KAVLI FOUNDATION: First, let’s talk about the BRAIN Initiative itself. What was your reaction when you heard the announcement and what do you hope will be achieved through this Initiative?

RALPH GREENSPAN: I was shocked and delighted. During the State of the Union address, the President quoted a passage from a 2011 report by the Battelle Memorial Institute, which discussed the return on investment from the Human Genome Project. I had included that report in our very first white paper that proposed the Brain Activity Map Project to the White House. So when the President cited the Battelle report, this told me unequivocally they had chosen the Brain Activity Map project – or what would ultimately become the BRAIN Initiative – for funding, and I was tremendously excited. What I think can come out of it is nothing less than a revolution in neuroscience and in our understanding of the human brain and who we are.

TKF: Did the idea for the Center come directly from UCSD’s involvement in the development of the Initiative?

GREENSPAN: Not so much in official terms, but in the past federal research initiatives have offered grants to form academic research centers. So scientists have assembled a group of people on their campus or even across multiple sites, then applied for a large grant to do a coordinated project. In this case, after the announcement in Washington, the Chancellor of UCSD, Pradeep Khosla, told my colleague Nick Spitzer, who is director of the Kavli Institute for Brain and Mind at UCSD, and myself that he really wanted to do something at the University, to have some kind of center or institute working on the goals outlined by the national BRAIN Initiative. So the morning after we came back from Washington, we had a meeting with the Chancellor, his Executive Vice Chancellor, and people from KIBM. We then talked with several people on campus, and we had an overwhelmingly positive response. The Chancellor encouraged us to submit a proposal to the Vice Chancellor of Research Affairs and it was ultimately approved.

TKF: Can you discuss in greater depth the mission of the Center and what you envision when it’s fully in place?

GREENSPAN: The original impetus for the federal Brain Activity Map Project was to push technology forward to handle the huge amounts of data generated by mapping brain activity, and to develop theoretical formulations for how large-scale measurements of brain-wide activity could be made. But the BRAIN Initiative has broadened its goals.

As Director of the new Center at UCSD, I’ve been clear that I want it to focus on the initiative’s initial goals, which included the creation of new technological tools to enable global detection of activity in the brain at the resolution of the cell and at the millisecond timescale. We have the kind of talent in engineering, physics, chemistry, and computer science – as well as one of the strongest neuroscience communities in the whole world – to pursue the goals of the BMI as originally envisioned.

We can put together real working teams of people to carry this off, and we've been encouraged by some people in technology development that we have the potential to raise a significant amount of private philanthropy and money from industry for that effort. Nick and I have now been going around to talk to nanoengineers, chemical engineers, bioengineers, computer engineers and electrical engineers to see what they're interested in and what they can do. We’re also organizing working groups and getting people to really do the hard intellectual work up front, so they will be primed for when the calls for grants come out by the government later this year. Having these groups will also help us as we try to raise money around here for specific projects.

Down the road, we’ll give out seed grants – as KIBM has done here – to help people get started on something that they could never get funded otherwise. The money may be needed to buy a piece of equipment or pay a graduate student to begin a project. We will choose projects that fit our mission, and we’ll try to get them to be collaborative projects. In time, if we can raise additional money we hope to support bigger projects as well.

Ultimately, we would like to be able to have a place to house all of this, to bring together people from these different disciplines so they can all work under one roof. These are grandiose ideas but ones that we are very enthusiastic about.

TKF: The new Center emphasizes drawing upon the broader San Diego research community. Can you elaborate?

GREENSPAN: San Diego has not just premier biomedical sciences but also a premier start-up community of biotech and high-tech companies. The original longest-standing organization that's in the business of trying to bring those sectors together is CONNECT, and its leadership is very interested in bringing people together for the new Center’s work.

I think there will be spinoffs that undoubtedly come out of new research, but there may technologies that companies already have today that can facilitate some of the work. Some of these companies may want to do joint projects. Those are the kinds of things we're hoping to explore. Any of the scientists in the area who want to participate in the Center’s projects are certainly welcome to, as long as they're willing to take part in this mission as we are defining it.

TKF: Can you discuss a bit more the kind of projects you envision and what do you hope will be the outcomes?

GREENSPAN: I can tell you generally what kinds of things I expect to see happen. On one level there are people who are trying to develop novel optical techniques for being able to see further into tissues, and in some cases for developing things that can actually penetrate and report out from tissues beyond the range of visibility.

There are also people who have been developing nanosensors of various sorts. Most of them have been thus far aimed at either targeting a drug to a tissue or measuring the level of a particular chemical inside a cell. But much of the same technology can be adapted to making the kinds of measurements in the nervous system that we are very interested in having the capability to do.

Roger Tsien, a Nobel Laureate in chemistry at UCSD, has spent his career developing novel tools for reporting functions out of cells, including those that would be relevant to the nervous system.

People are also working on enhancing the capabilities of existing human brain imaging techniques, to make them more direct than, for example, functional magnetic resonance imaging, or fMRI, which measures blood flow as an indirect consequence of neuronal activity. So it might be possible to figure out agents that could be administered benignly to people that would enhance the MRI’s ability to detect activity in the brain. That would be a major advance.

There are people who have been developing enhanced analytical techniques for getting better localization information out of existing imaging techniques, such as electroencephalography. These are things where you can sort of already see progress and I'm sure they will move further.

Finally, we have high hopes for new things to come along that we do not now envision.

TKF: Do you anticipate the new Center will collaborate with other brain mapping projects such as the Human Connectome Project, or projects outside the realm of the BRAIN Initiative, and what might they look like?

GREENSPAN: For sure, when such things become relevant to do. After we have the ability to look at lots of neurons, it will become more important to know what their connection patterns are. We do not intend to keep the center’s work limited to the San Diego area. If we can make a team that is more powerful because we’ve gotten together with researchers outside San Diego, then we’ll do that. Some of these outside collaborations may be with other Kavli institutes.

TKF: To what extent do you think advances in neuroscience will be propelled by reaching across disciplines?

GREENSPAN: I think there's no question that bringing together people with very different perspectives to attack a problem is a recipe for breakthroughs. To achieve dramatic advances, as opposed to incremental progress, a novel perspective is often needed. In the life sciences, you see this happening over and over again with people coming together from different areas.

TKF: Mapping brain networks is expected to drive novel treatments for brain disorders such as autism, traumatic brain injury and Alzheimer’s. But there could also be benefits outside of medicine. What do you anticipate might be a spinoff benefit in technology that the new Center could be involved in?

GREENSPAN: Many of the technological advances are going to be in sensors. Sensor technology is by no means limited to neurobiology. It's going to have widespread uses in medicine and many other fields. The federal Defense Advanced Research Projects agency, or DARPA, spends a lot of effort developing sensors – especially for national security since 9/11 and the anthrax scares that followed. Sensor technology developed for neuroscience will have very broad applications.

TKF: Another advance that might be applied outside medicine is our increased knowledge of brain networks – the intricate connections between brain cells that serve particular purposes, such as memory, movement, vision, and so on. What spinoff do you envision here that the new Center may contribute to?

There are two related parts to this. First, the neuroscience studies that we’re planning at the Center generate enormous amounts of data, and so we need to find new ways of handling, analyzing and making sense of it. What we learn in information science will be broadly applicable to many fields.

Secondly, understanding how brains solve problems through the activity of complex networks is going to give us some novel strategies for how machines solve problems. And it will be quite different from how computers currently solve problems. Many computerized devices can’t cope with changes in the environment around them and ultimately crash. One of the problems with engineered devices is that you have to build in a lot of safeguards to be able to allow them to function as conditions change. The brain doesn’t have to be preprogrammed to cope with all possibilities it can think of in advance. Brains are designed to solve problems that are new. Having devices that can handle things like that would make them enormously more resilient and effective.

TKF: What other outcomes do you see for the Center?

GREENSPAN: Our hope for this center is it can be the kind of incubator for developing novel technologies that will open up all kinds of breakthroughs in medicine for brain disorders and for our understanding of how the brain does things in health as well as in disease. Also, we want to be able to take the strategies that we learn from the brain and make them work for us in the way we design networks, devices, computers and other machines in our society at large.

And we think this new center will innovate in ways that will allow new technologies to spark new industries. Our center is situated in a place that has a history of doing all of those things.