NIH launches next stage of its ‘human genome project’ for the brain

The National Institutes of Health on Thursday announced more than $600 million in fresh funding for an expansive and ongoing push to unravel the mysteries of the human brain, bankrolling efforts to create a detailed map of the whole brain, and devise new ways to target therapeutics and other molecules to specific brain cell populations.

Scientists across the country are involved, from teams at the Salk Institute to Duke University to the Broad Institute of MIT and Harvard, among other places. If successful, they will help answer fundamental questions about the body’s most complex organ. What are all the cell types in the brain? How are they connected to one another? How do the workings of the brain change during disease, and what can we do about that?

So far, those questions have proven easier to ask than to answer, with researchers gleaning bits of information from individual studies, but the hope is that a broad-based effort will jump-start new revelations.

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The fresh funding adds to $2.4 billion that the NIH has already invested in related projects. By 2026, the agency will have spent $5 billion. The scientists who will be spearheading the research openly compare its scale and scope to the push to sequence the first human genome in the 1990s and early 2000s.

“I really do view this as like the Human Genome Project. We have the ability now to define cells like we were able to define genes,” said Ed Lein, a neuroscientist at the Allen Institute in Seattle. “This is the foundation to start to understand a lot of other aspects of biology and disease.”

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The latest announcement is part of a continuing effort known as Brain Research Through Advancing Innovative Neurotechnologies (BRAIN), which was unveiled by the Obama administration in 2013 and kicked off in 2014. Its goal: to better understand the 86 billion cells that populate the brain and the trillions of connections they form with one another.

“It’s arguably the most sophisticated computer that we know,” said John Ngai, director of the BRAIN Initiative. “It’s a highly complex organ whose connections and organizational principles we do not come close to understanding, and there was a realization that we needed better tools.”

Since then, BRAIN-related grants have funded around 1,200 studies and led to 5,000 research publications. Ngai also measures the program’s success in its life-changing impact on some patients. In 2021, researchers at the University of California, San Francisco deciphered brain signals from a paralyzed man who hadn’t spoken in over 15 years and used his attempts to talk to generate words that appeared on a screen. Last November, researchers at Baylor College of Medicine launched a clinical trial for patients with depression that is testing the benefits of deep brain stimulation, an approach that uses electrical jolts to stimulate brain circuits and which has proven helpful for disorders such as Parkinson’s disease.

“These were experiments based on concepts that were literally science fiction 10 years ago — maybe even five years ago,” Ngai said.

The new round of funding, dubbed “BRAIN 2.0,” seeks to build on this progress. Eleven grants are going to groups that are building a comprehensive atlas of the brain, a sort of parts list and 3D map of what cells are there and how they are organized. The Allen Institute will lead one key piece of this project: Mapping the whole brains of humans as well as marmosets and macaques, two monkey species often used in neuroscience research.

“We know that the neuron types in the front of the brain cortex [are] very different from the ones in the back of the brainstem,” said Hongkui Zeng, who will be leading the Allen Institute’s efforts along with Lein. “But we don’t know how they’re different. We also don’t know the extent of the diversity.”

BRAIN-funded scientists have successfully mapped the mouse brain, Zheng says, and plan to publish those findings soon. And researchers will rely on many of the same cutting-edge experimental tools to study primates and people.

One technique, known as spatial transcriptomics, allows researchers to understand where different cells are located. To do so, researchers first break up brain tissue, isolate cell nuclei, and use sequencing to understand what genes are active in that cell. By doing this across many cells, scientists find groups of cells that tend to use the same set of genes. They can then look at thin slices of brain tissue and search for activation of those genes to find where certain cells are present.

It’s an audacious task — our brains are about 3,000 times bigger than a mouse’s, Lein says. To start, his team will use autopsy tissue from roughly six people to build an initial map, which they plan to make publicly available. That’s enough to build a basic atlas, though understanding person-to-person variation will require looking at many more samples in the future.

Lein says that even a preliminary map could help researchers find cell types that are damaged by a certain neurological disorder — or that may be responsible for a disease. For instance, his group has already been studying the brains of people with Alzheimer’s disease and has identified cell types that die off during disease as well as others that become more abundant.

Researchers at the Salk Institute in San Diego will focus on 50 brain regions to understand how they change with age. The plan is to use roughly 30 samples from infants all the way to people in their 70s and 80s, according to Joseph Ecker, head of the Salk-led effort.

The team will focus on so-called epigenetic changes. These are changes that don’t alter a cell’s genetic code but control the activation of genes in other ways, often through small chemical modifications of DNA and changes in how the genome is packed and organized.

“At each one of these stages during the lifespan, there are diseases that probably impact those cell types,” Ecker said. “We want to be able to understand how the normal brain develops so we can compare it to various disease states.

He adds that understanding the rules behind gene regulation in the brain could allow researchers to precisely target specific cell types. That’s the aim of another aspect of BRAIN 2.0, with seven grants going to developing experimental tools that can reach specific regions of the brain. Many of these efforts are focused on adeno-associated viruses, a class of viruses that are already popular in gene therapy.

And there’s more work to come. Ngai says that a third pillar of BRAIN 2.0 won’t launch until early 2023: Understanding the dizzying array of connections that brain cells in one area make with cells in other far-flung regions.

One of the basic challenges facing researchers will be how to process and present their findings in a clear, intelligible way to the public. Case in point: The Salk group alone will likely generate 11 petabytes of data, which is enough to fill up nearly 172,000 USB drives.

“I think that’s going to be our greatest challenge,” Zeng said. “It’s not just a matter of collecting data — it’s also the matter of conveying.”

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