September 24, 2021

BRAIN Initiative’s first director sets sights on clinical tools

Brittany Hosea-Small/University of California, Berkeley

Since its launch in 2013, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has doled out about $1.3 billion in grants to develop tools that map and manipulate the brain. Until now, it has operated with no formal director. But last week, the National Institutes of Health (NIH), which manages the initiative and is a key funder, announced that neurobiologist John Ngai would take the helm starting in March.

Ngai, whose lab at the University of California, Berkeley, focuses on the neural underpinnings of the sense of smell, has helped lead BRAIN-funded efforts to classify the brain’s dizzying array of cell types with RNA sequencing. Ngai told ScienceInsider about how the initiative is evolving and how he hopes to influence it.

The interview has been edited for clarity and brevity.

Q: Why is the BRAIN Initiative getting a director now?

A: The initiative has been run day to day by a terrific team of senior program directors and staff with oversight from the 10 NIH institutes and centers that are involved in BRAIN. Walter Koroshetz [director of the National Institute of Neurological Disorders and Stroke] and Josh Gordon [director of the National Institute of Mental Health] have been overseeing the activities of BRAIN … kind of in addition to their “day jobs.”

I think as enterprises emerge from their startup phase, which is typically the first 5 years, the question is how do you translate this into a sustainable enterprise, and yet maintain this cutting-edge innovation? … How do we leverage all the accomplishments that have been made, not just within BRAIN, but in molecular biology, in engineering, in chemistry and computer science, in data science. The initiative really will benefit from somebody thinking about this 24/7.

Q: What distinguishes this second phase of BRAIN from the first?

A: In the first phase, there was a very intentional and concentrated focus on tool development: How do we come up with better and more methodical ways of defining a cell type? [How do we] develop tools for measuring neuronal activity—and nonneuronal cells’ activity—at scale? How do we better devise ways of interfacing with the nervous system in living animals, to develop brain-machine interfaces?

As we learn more about how neural circuits drive behavior … we can start implementing that knowledge, in terms of treating human diseases. We’re seeing progress already in the treatment of certain blinding diseases of the retina. There’s at least the amelioration of symptoms of movement disorders. There’s a big win in the treatment of spinal muscular atrophy. The therapies right now are extremely expensive, because the patient pool is small, and the risk and investment to develop these tools has been extremely high. I am hopeful that BRAIN, with other efforts in NIH and in partnership with industry, [can] significantly derisk the enterprise and make it more accessible by creating technology platforms that could be applied across multiple disease applications.

Q: What would that look like?

A: For example: a toolkit of different types of viral delivery vectors [for gene therapy] that could be applied to different parts of the brain, different cell types in the brain, and so on. Another shelf in the toolkit [could have] say, different payloads—enzymes or ion channels that could be used to alter activity, or gene-editing enzymes that would correct a mutation.

Q: This sounds like a real shift from the basic research tools BRAIN has typically focused on.

A: Many people bristle a little bit when they hear me talking about clinical applications. They say, “John, you’re a basic scientist, don’t forget who you are.” And of course, it’s not an either/or proposition. … Many of these tools have been developed in animal models, and they’ve been great for discovery-based science there as well. It all kind of goes along together.

The mission of BRAIN is not to cure specific diseases. We have 27 institutes and centers at NIH, and each has a specific disease mission. I see BRAIN as enabling the other institutes and the field in general to use tools in a mission-specific way. If we develop tools that can be used across multiple cell types, multiple disease states, multiple genes, it’s all for the good. I don’t want to get totally out over my skis here, but I really do see potential.

Q: What do you see as the shortcomings of the BRAIN Initiative so far?

A: We have a lot of figuring out to do in terms of how to balance the unique potential of individual investigator-initiated research versus the power of large-scale projects. How do we preserve the creativity and innovation in these large projects? How do we encourage and enable people to get into these large projects? Once you get on a team of 50 people, how do you claim or get credit for what you’ve done in order to go on to the next steps?

I don’t think this is necessarily particular to BRAIN, but BRAIN may have some demographic issues … in terms of the applicants, as well as the funded investigators. There is a diversity issue in terms of ethnic diversity as well as gender diversity. It’s not a criticism of BRAIN, per se. It’s just a hard problem that’s facing the scientific enterprise in general. And I’m certainly committed to doing our level best to make it better, not just for reasons of social justice, but it just kills me that we’re leaving all this talent on the table.

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