Scientists on Thursday unveiled the most detailed and complex portrait yet of the human brain in a dazzling catalogue of more than 3,000 types of brain cells that collectively give rise to emotion, thought, memory and disease.
The painstaking work is part of the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) initiative, a $3 billion government-funded effort to develop tools and technology to understand and map the human brain. The results, published in 21 papers across multiple journals, are starting to open up the black box of the brain by providing an initial parts list for the most complex organ scientists have ever studied.
“Each part of the brain is as complex as another organ,” said Ed Lein, a neuroscientist at the Allen Institute for Brain Science, a research nonprofit based in Seattle, and a leader of several of the new studies. “This is the first really sort of comprehensive description of this,” he said. “If we don’t understand it at that kind of level of granularity, I don’t know how we’re ever going to understand brain diseases.”
The papers reveal that the cell types that make up a human brain are similar to those that make up other primate brains. That suggests it is differences in how those cell types are combined, and in the activity of just a few hundred genes, that helps to explain the sophisticated cognitive abilities that humans have. The papers also provide a glimpse of how these techniques could be used to detail how the human brain changes over time, how much typical adult brains are different from each other and how the developing brain becomes vulnerable to complex disorders such as autism and schizophrenia.
Henry Greely, a law professor at Stanford University who specializes in the ethics of biomedical technologies and was previously involved in a council that helped guide the project, likened it to sending a spaceship to circle another planet and take photos. “You see where there are mountains and valleys, and you see the ice caps, and that is what the work on the brain has done,” he said.
“It has shown a really complicated object, maybe the most complex physical object we know of in the universe so far,” Greely added. He noted that the new raft of papers is in many ways not a final product but an interim report on a project that will take many years to complete. “You need to be on the ground, to do the hard work acre by acre.”
A DAUNTINGLY VAST ORGAN
Over a century ago, Spanish neuroscientist Santiago Ramón y Cajal made some of the first intricate sketches of different kinds of brain cells. But the human brain is dauntingly vast, an intricate assemblage of 86 billion neurons and roughly the same number of glial cells. The brain initiative, announced a decade ago, supercharged the classification scheme by using the newly developed ability to classify different cell types by their precise molecular characteristics, including which genes are active.
In a paper published in the journal Science, researchers used that technique to study three brains from human donors and identify more than 3,000 types of cells. It is not a final count, but it marks the most detailed draft yet. To put that number in perspective, Trygve Bakken, another neuroscientist at the Allen Institute, said there might be 100 cell types that make up the lung. Identifying the constituent parts of a typical human brain is just one part of the quest.
Scientists also need to understand how they are connected, what the circuits do, how they change as the brain develops and what happens during neurological disease. In one study, scientists examined the brains of children who had died of various causes to see if those who suffered inflammation showed signs of it affecting their brains at the cellular level. They found two key types of neurons, Golgi and Purkinje neurons, were altered. And now they are examining the brains of adults diagnosed with schizophrenia and autism to see if similar changes exist.
Other projects are examining the brains of people with Parkinson’s and Alzheimer’s disease, disorders whose onset and precise mechanisms still remain largely mysterious. “The challenge with many neurological and neuropsychiatric disorders is we don’t know what portion of the brain is functioning non-optimally,” said John Ngai, the director of the brain initiative. “The cool thing here is this gives us a way in.”
Other parts of the brain initiative are still unfolding. The National Institutes of Health has funded over 1,300 projects. It is one of those scientific quests that could, in theory, never end because each layer of complexity reveals new questions. Even scientists who were impatient to get through cataloguing so they could start asking more specific questions have found themselves taken aback by what has already been discovered.
“When it started five years ago, I was thinking, ‘We are just going to get through this atlasing phase. It’s not the interesting stuff,'” said Seth Ament, a researcher with the Institute for Genome Sciences at the University of Maryland School of Medicine who worked on the inflammation study. “The longer we’ve been in it, it’s amazing to me our genome is able to produce such a diversity of cells across the brain. It’s fundamental to how our brain works.”
CHEMISTRY OF THE THE PAINT
Researchers have already embarked on the next stage of the project, where they are trying to create even more complete atlases with more brains. The ultimate hope is that they get a fine-grained understanding of what goes wrong in human brain diseases that have stubbornly resisted much progress. Many drugs that are promising in laboratory experiments ultimately fail when people use them. The work will help inform scientists trying to understand when an animal model, or even a simplified brain organoid grown in a dish, might be a reasonable approximation of a brain and when it falls short.
“This is going to be a stepwise process, whereby we first need to understand the building blocks of the human brain, gaining understanding of its myriad of cell types,” Paola Arlotta, chair of the stem cell and regenerative biology department at Harvard University who was not involved in the new studies, said in an email. “Eventually, what we’d really like to understand is how these cells and their interaction produce specialized function.”
Thomas Insel, a former director of the National Institute of Mental Health, was a chair of the brain initiative until 2015. He has focused his work since not on neuroscience but on innovating new ways to care for mental illness. In his book, “Healing: Our Path from Mental Illness to Mental Health,” he recalled the parent of a young patient who argued that neuroscience was too focused on the details of biology while people suffered. “Our house is on fire, and you are focused on the chemistry of the paint,” the parent told him.
Insel said that despite his recent focus on mental health, he views the details gained from work like the new brain atlas as critical. “I’m excited to see this trove of new data on the brain,” he wrote in an email. “It may be the chemistry of the paint, but we need to know more, even when knowing more seems to suggest that the chemistry of the paint is even more complicated than we thought.”
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