NIH launches next stage of its ‘Human Genome Project’ for the brain

Jhe National Institutes of Health on Thursday announced more than $600 million in new funding for an expansive and ongoing campaign to unravel the mysteries of the human brain, fund efforts to create a detailed map of the entire brain, and design new ways to target therapies and other molecules to specific populations of brain cells.

Scientists from across the country are involved, from teams from the Salk Institute at Duke University to the Broad Institute at MIT and Harvard, among others. 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 each other? How does brain function change during illness, and what can we do about it?

So far, these questions have proven easier to ask than answer, with researchers gleaning insights from individual studies, but the hope is that a widespread effort will spark new revelations.

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The new funding is in addition to the $2.4 billion the NIH has already invested in related projects. By 2026, the agency will have spent $5 billion. The scientists who will lead the research openly compare its scale and scope to the drive to sequence the first human genome in the 1990s and early 2000s.

“I really see this as the human genome project. We now have the ability to define cells like we were able to define genes,” said Ed Lein, a neuroscientist at the Allen Institute in Seattle. “It’s the basis for beginning to understand many other aspects of biology and disease.”

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The latest announcement is part of an ongoing effort known as Brain Research Through Advancing Innovative Neurotechnologies (BRAIN), which was unveiled by the Obama administration in 2013 and launched in 2014. Its goal: to better understand the 86 billion cells that populate the brain. and the billions of connections they form with each other.

“It’s arguably the most sophisticated computer we know of,” said John Ngai, director of the BRAIN Initiative. “It’s a very complex organ whose connections and organizing principles we are far from understanding, and we realized that we needed better tools.”

Since then, BRAIN-related grants have funded approximately 1,200 studies and led to 5,000 research publications. Ngai also measures the success of the program in its impact on the lives of some patients. In 2021, researchers at the University of California, San Francisco deciphered the brain signals of a paralyzed man who hadn’t spoken in over 15 years and used his attempts to speak 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 circuitry that has been shown to useful 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 funding round, dubbed “BRAIN 2.0”, aims to build on this progress. Eleven grants are going to groups that are building a comprehensive atlas of the brain, a kind of parts list and a 3D map of the cells in it and how they are organized. The Allen Institute will lead a key component of this project: mapping the entire brain of humans as well as marmosets and macaques, two species of monkeys often used in neuroscience research.

“We know that the types of neurons at the front of the cerebral cortex [are] very different from those at the back of the brainstem,” said Hongkui Zeng, who will lead the Allen Institute’s efforts with Lein. “But we don’t know How? ‘Or’ What they are different. We also don’t know the extent of the diversity.

Scientists funded by BRAIN have successfully mapped the mouse brain, Zheng says, and plan to publish these findings soon. And researchers will draw on many of the same state-of-the-art experimental tools to study primates and humans.

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

It’s a daunting task — our brains are about 3,000 times bigger than a mouse’s, Lein says. To begin, her team will use autopsy tissue from about six people to construct an initial map, which she plans to make publicly available. This is enough to build a basic atlas, although understanding the variation from person to person will require looking at many more samples in the future.

Lein says 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 example, his group has previously studied the brains of people with Alzheimer’s disease and identified cell types that die during the disease as well as others that become more abundant.

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

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

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

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

And there is more work to come. Ngai says 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, distant areas.

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

“I think that’s going to be our biggest challenge,” Zeng said. “It’s not just a matter of data collection, it’s also a matter of transmission.”

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