NIH launches the next phase of its “human genome project” for the brain

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

Scientists from across the country are involved, from teams from 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 most complex organ in the body. What are all types of cells in the brain? How are they related to each other? How does brain functioning change during illness and what can we do about it?

So far, these questions have proved easier to ask than to answer, with researchers gleaning bits and pieces of information from individual studies, but the hope is that a large-scale effort could spark new revelations.

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

“I really consider it as the Human Genome Project. We now have the ability to define cells as we were able to define genes, “said Ed Lein, a neuroscientist at the Allen Institute in Seattle.” This is the basis for starting 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), 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 trillions of connections forming with each other.

“It’s probably the most sophisticated computer we know of,” said John Ngai, director of the BRAIN Initiative. “It is an extremely complex body whose connections and organizational principles we fail to understand and we realized that we needed better tools.”

Since then, BRAIN-related grants have funded approximately 1,200 studies and resulted in 5,000 research publications. Ngai also measures the success of the program in its life-changing impact on some patients. In 2021, researchers from the University of California, San Francisco, deciphered the brain signals of a paralyzed man who hadn’t spoken for over 15 years and used his attempts at speaking 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 electric shocks to stimulate brain circuits and has been shown to be useful for ailments 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”, seeks to capitalize on this advance. Eleven grants will go to groups that are building a complete atlas of the brain, some sort of parts list, and a 3D map of what cells there are and how they are organized. The Allen Institute will lead a key piece of this project: the mapping of the entire brains of humans, as well as marmosets and macaques, two species of apes often used in neuroscience research.

“We know the types of neurons in the front of the cerebral cortex [are] very different from those in the back of the brain stem, “said Hongkui Zeng, who will lead the Allen Institute’s efforts alongside Lein.” But we don’t know how They are different. Furthermore, we do not know the extent of the diversity. “

BRAIN-funded scientists have successfully mapped the mouse brain, Zheng says, and plan to publish those results 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 this, researchers first break down brain tissue, isolate cell nuclei, and use sequencing to figure out which genes are active in that cell. In this way, on many cells, scientists find clusters of cells that tend to use the same set of genes. They can then look at thin slices of brain tissue and look for the activation of those genes to find where certain cells are present.

It’s a bold task – our brains are about 3,000 times larger than a mouse’s, says Lein. To begin, her team will use the autopsy tissue of about six people to build an initial map, which they intend to make publicly available. This is enough to build a basic atlas, although understanding the person-to-person variation will require examining 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 could be responsible for a disease. For example, her group has already studied the brains of people with Alzheimer’s disease and identified the cell types that die during the disease and 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 about 30 samples from children to people between 70 and 80, according to Joseph Ecker, head of the effort led by Salk.

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 modifications of the DNA and changes in the way the genome is packaged and organized.

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

He adds that understanding the rules behind gene regulation in the brain could allow researchers to precisely target specific cell types. This is the goal of another aspect of BRAIN 2.0, with seven grants earmarked for the development of experimental tools capable of reaching 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 on the way. Ngai says a third pillar of BRAIN 2.0 won’t launch until early 2023: understanding the dizzying array of connections brain cells in one area make with cells in other distant regions.

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

“I think it will be our biggest challenge,” Zeng said. “It is not just about collecting data, but also about transmitting”.

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