When John Ngai (PhD ’87) became director of the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative at the National Institutes of Health in 2020, he took the helm of one of the most ambitious undertakings in science: to map, understand, and ultimately heal the human brain. Launched in 2014 with bipartisan Congressional support and additional funding from the 21st Century Cures Act, the program’s annual appropriations have increased dramatically, to a peak of $680 million in 2023. So far, the money has funded over 1,600 grants to nearly 2,000 principal investigators spanning some 250 institutions—a unique collaboration of federal and non-federal partners that aims not just to decode the brain’s structure and function, but to create the tools and knowledge base needed to treat neurological and psychiatric disorders at the cellular level.
Raised in New Jersey and New York by parents who were professors at Columbia University medical school, Ngai’s path to neuroscience was forged at Pomona College, where he majored in biology and chemistry; at Caltech, where he thrived in an environment of “remarkable intellectual freedom” while earning his PhD in biology; and at Columbia, where he pursued postdoctoral work in the lab of Nobel laureate Richard Axel. “Axel had this insight,” Ngai recalls, “that in order to understand something as complex as the brain, one really needed to use the tools of modern molecular biology. And that’s how I got into neuroscience.”
Ngai speaks of the brain with reverence and urgency. “It’s the most powerful computer known to humankind,” he says, “yet it consumes only about 15 to 20 watts of energy. It’s composed of 86 billion neurons and probably twice as many non-neuronal cells, and together they make hundreds of trillions of connections.” Those connections give rise to everything from emotion and cognition to memory and movement. But with that complexity comes vulnerability: Roughly one in three people worldwide live with some form of brain-related disorder, such as Alzheimer’s, Parkinson’s, epilepsy, depression, and PTSD. “We really don’t know what’s going on in the circuits of the brain to cause these issues,” Ngai says.
That’s where the BRAIN Initiative steps in. Ngai’s role is twofold: to set the Initiative’s long-term strategic vision and to ensure its effective day-to-day implementation. Unlike other NIH programs, the BRAIN Initiative is “disease-agnostic” and multidisciplinary. It spans 10 of the NIH’s 27 institutes, each of which offers “a different perspective on the nervous system and what goes wrong with it,” Ngai says, noting that most of the research is conducted by extramural investigators. “It’s very rewarding to learn so much from all these folks and come up with a cohesive vision about what kinds of tools and resources we can develop.”
As director, Ngai has launched three “BRAIN transformative projects,” each tackling a core area of the Initiative’s mission. The first is the Cell Census Network, which Ngai likens to a “parts list” of the mammalian brain. Researchers began their work on the mouse brain because of its many similarities to the human brain, identifying over 5,000 distinct cell types classified by location, morphology, and connectivity. Since building such an immense atlas “was beyond the capabilities of even the most effective labs,” Ngai coordinated a groundbreaking global collaboration involving some 200 scientists across various disciplines on three continents.
The second project seeks to map the connectivity of the brain—or, as Ngai calls it, “a wiring diagram.” This is no small task. A complete high-resolution map of a mouse brain’s synaptic connections would consume about an exabyte of data, or a thousand petabytes, each of which is a thousand terabytes. A human brain would require a zettabyte, or a thousand exabytes—roughly equivalent to all the global internet traffic in a year. (“I didn’t know what a zettabyte was until we started going through the numbers,” laughs Ngai.) Yet progress is being made.
“In 2024, researchers completed a full wiring diagram of a fruit fly—the first such model of any brain, and a technological breakthrough that has paved the way for maps of more complex brains.”
The third transformative project, known as the Armamentarium for Precision Brain Cell Access, develops molecular tools to target brain cells and circuits with extraordinary accuracy, allowing researchers to track how specific cell types behave in models of human disease—and opening the door to new gene therapies to treat those diseases.
All of this work is yielding tangible results. In early-stage trials of neuromodulation therapy, for instance, scientists use electrodes implanted in the brain to identify biomarkers of abnormal brain activity, which lets them stimulate specific circuits to potentially treat disorders like depression, OCD, PTSD, and chronic pain. “It’s starting to show great promise for multiple conditions,” says Ngai. “The advances have been breathtaking.” Also seeing rapid growth are brain-computer interfaces (BCIs), in which electrodes enable patients with ALS, stroke, or paralysis to use their thoughts to control robotic arms, generate text, and even produce speech. “This is stuff that was science fiction 10 years ago,” Ngai reflects.
Ngai envisions even more precise interventions in the years ahead, fueled in part by the recently launched Brain Behavior Quantification and Synchronization program, which seeks to develop new tools in support of a more comprehensive mechanistic understanding of the neural basis of behavior. Some BRAIN-funded investigators are also thinking about how to advance the emerging field of NeuroAI—artificial intelligence systems that learn and adapt like the human brain. These efforts could lead not only to better technology but to deeper insights into the very nature of human cognition. “The future could come to us sooner than we think,” Ngai says, “if we keep at it.”