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Wanted: Better tools to study the brain

Federal agencies look for ways to involve more chemists in President Obama’s BRAIN initiative

by Andrea Widener
May 30, 2016 | A version of this story appeared in Volume 94, Issue 22

Woman in a lab holding a small piece of electrical equipment.
Credit: Julie Russell/Lawrence Livermore National Laboratory
Tolosa examines a flexible probe used to record brain activity in rodents that she designed with neuroscience collaborators at the University of California, San Francisco, through a BRAIN Initiative grant.

Five years ago, Vanessa Tolosa wasn’t sure how she would get funding to support her brain research.

The chemical engineer at Lawrence Livermore National Laboratory had finished an artificial retina research project but had no prospects for more funding. “On the technology side, it’s actually difficult to get funded” by the federal government, she says.

Chemists and the BRAIN Initiative

What is the initiative?

Proposed by President Barack Obama in 2013, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative aims to better understand the brain through the development of new technologies.

Why recruit more chemists?

Neuroscientists don’t know all of the chemicals that are active in the brain. There is room for chemists to identify important players and figure out what they do. There is also an opportunity for chemists to create new tools or drugs that will help neuroscientists understand the brain.

How much money is available?

Five federal agencies—the Defense Advanced Research Projects Agency, National Institutes of Health, National Science Foundation, Intelligence Advanced Research Projects Activity, and Food & Drug Administration—will spend a combined $300 million in 2016.

The Obama Administration proposed an increase to $434 million in fiscal 2017.

That is until the White House announced the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative in 2013. Now Tolosa works on a half-dozen projects that use her chemical engineering skills toward the initiative’s goal of creating tools to better study the brain.

The National Institutes of Health and the National Science Foundation say they want to bring more chemists and chemical engineers like Tolosa into the BRAIN Initiative. The goal is to move beyond those who traditionally work on neuroscience problems to attract new researchers who can make a contribution.

“The issue for us is finding the people who know about the kind of chemistry that could help us,” explains Walter J. Koroshetz, director the NIH’s National Institute of Neurological Disorders & Stroke. “How do they know they could help us?”

No one knows how many chemists and chemical engineers are currently involved in the BRAIN Initiative, but they are few and far between, Tolosa says. She is excited to hear that the agencies are reaching out. “I think we have a unique contribution we can provide to the community,” she explains.

The White House formally launched the BRAIN Initiative in 2013 with the goal of revolutionizing understanding of the brain by funding the development of new technologies. That is necessary because scientists know very little about how neural circuits work, including what chemicals are active in the brain. “An inability to interrogate these circuits is what is holding us back,” Koroshetz explains.

The project provides money—$300 million at five agencies in 2016—for scientists to build tools to better observe what is happening in the brain. That will be the first step toward understanding complicated processes such as memory and emotion. Once they know what normal circuits look like, they can figure out how circuit dysfunctions result in problems such as Parkinson’s Disease, schizophrenia, or drug addiction.

Federal agencies are right to turn to chemistry, which has created some of the important tools neuroscientists use now, says Jonathan Sweedler, a chemistry professor and neuroscience researcher at the University of Illinois, Urbana-Champaign.

“New tools start in many ways in the chemical sciences and move toward the biological sciences as they get refined,” Sweedler says. “The question is, ‘What is the next set of tools that we need and are they chemical in nature?’ ”

The BRAIN Initiative came out of a series of workshops hosted by The Kavli Foundation about how to start mapping important brain activities. “I felt there was a really important aspect missing to the goals,” remembers Anne Andrews, a professor of psychiatry and behavioral sciences and of chemistry and biochemistry at the University of California, Los Angeles, who attended some of those early meetings. “Most of the effort looked like it was going to be focused on mapping electrical activity.”

Andrews, who studies the neurotransmitter serotonin, pushed for the initiative to include chemical signaling between neurons, which is diverse and not well understood. Unraveling what she calls the “chemical connectome” is vital to knowing how our brain works and what goes wrong in disease, she says. “Without understanding chemical neurotransmission, we won’t have that fundamental understanding” of the brain.

Chemists have the expertise that is needed for the BRAIN Initiative to be successful, says chemist James H. Eberwine, a professor of pharmacology at the University of Pennsylvania’s Perelman School of Medicine. “Every molecule in a cell is modified in some way—RNAs are modified; proteins are modified. All of these are chemical reactions.”

Eberwine is a member of the NIH panel that ensures the mix of BRAIN Initiative grants helps push technology development forward. The initiative’s leadership wants to fund early-career scientists and seasoned investigators, individual researchers and large teams, and companies and academics.

“I think one of the hallmarks of the BRAIN Initiative is that they recognize it requires the expertise of people in multiple fields,” Eberwine explains. “There are certainly people coming into the field who were not doing brain science before.”

More chemists are becoming interested in the brain, Eberwine says, but using neurons as a model system “is not something that traditional chemists would think about.”

That’s one reason NIH and NSF are attempting to reach out to more chemists. Greg Farber, a chemist and director of the Office of Technology Development & Coordination at NIH’s National Institute of Mental Health, says he sees a good fit for analytical chemists, nanotechnology researchers, materials scientists, and organic or inorganic chemists interested in developing new brain research tools.

“New tool development can be a hard thing to get funded for a variety of reasons,” Farber explains. The BRAIN Initiative “really does provide a home for this type of ‘high-risk’ work to happen.”

In the past, NSF’s chemistry division has funded only a handful of neuroscience proposals. But its budget for brain-related research has risen from $3.6 million in 2015 to $4.9 million in 2016. With those extra funds, it plans to support more individual or collaborative proposals on brain research. The division would also like to see more brain research proposals as part of major grants that are open to any area, such as undergraduate research, instrumentation grants, or NSF’s Centers for Chemical Innovation program.

“We think chemists can fit quite nicely into the BRAIN Initiative,” says the division’s director, Angela Wilson.

UCLA’s Andrews is co-organizing a BRAIN Initiative session at the fall American Chemical Society meeting in Philadelphia that she hopes will help more chemists and chemical engineers understand what the project is about and how they can get involved. If someone is brand new to neuroscience, “I think it does pay for chemists to collaborate,” Andrews says.

That’s been the strategy of Massachusetts Institute of Technology chemistry professor Stephen J. Lippard. He spent decades building a successful bioinorganic chemistry research program before pursuing his long-standing interest in the brain in the late 1990s. “I did not try to become a card-carrying neuroscientist,” he explains.

Lippard started by reading the literature to identify problems to work on. Then he did a sabbatical in the lab of colleague, and eventual Nobel Prize winner, Roger Tsien at the University of California, San Diego. That’s when he launched a program in his own lab studying mobile zinc and nitric oxide signaling in the brain, which he terms metalloneurochemistry. He teamed up with what he calls “spectacular” neuroscience collaborators.

His lab has built fluorescent sensors that measure zinc and nitric oxide in neural systems and chelating agents to intercept the zinc. He has also worked with collaborators to examine how mobile zinc functions in the hippocampus and, more recently, in sensory processing such as hearing, odor, and vision. Lippard suspects many of the brain’s problems result from metal mismanagement of some sort.

Chemists have an important role to play in brain research, Lippard says. “The brain is just replete with interesting problems that chemists can help us understand.”

Credit: Theodore Goodson III
University of Michigan postdoc Sung Hei Yau uses laser spectroscopic experiments to examine the physical chemistry of amyloid aggregation.
Scientist examining table filled with lasers.
Credit: Theodore Goodson III
University of Michigan postdoc Sung Hei Yau uses laser spectroscopic experiments to examine the physical chemistry of amyloid aggregation.

Theodore Goodson III, from the University of Michigan agrees that chemists can contribute a lot to brain research. He is a physical chemist who uses spectroscopy to study large molecules. His lab started working on brain research a decade ago when a postdoc noticed that the organic aggregates they were studying were similar to the amyloid plaques found in the brains of Alzheimer’s disease patients.

Chemists “are really trained to understand mechanisms,” Goodson says. Designing diagnostics is where he thinks chemists can add the most to brain research.

LLNL’s Tolosa believes finding the right collaborator is vital. Some neuroscientists “are used to taking tools off the shelf” and having them work, she explains. But that’s not how it goes when you’re designing a new tool from scratch.

At her first Society for Neuroscience meeting just before the BRAIN Initiative was announced, Tolosa sought out scientists who she thought would share her interests. That’s where she met University of California, San Francisco, neuroscientist Loren Frank, who now works with her to develop tools to observe the brains of living animals.

Frank agrees many neuroscientists are not used to being involved with the back-and-forth required to build new tools. “It is important to recognize that this is a process that takes years,” he says.

But neuroscience has an advantage over other biological disciplines because it is a “multiple personality field” that has long attracted people from many different research fields, including chemistry, Frank says.

Tolosa particularly loves being on a team of people who are working toward understanding the brain, including the people who will actually use the tools that she makes. “Neuroscientists are really starting to see that new technologies are needed to push the field forward,” she says.

“It really feels different with these BRAIN Initiative grants.”  


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