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For seven years, molecular biologist Ionut Dumitru and his colleagues played what felt like the world’s most exhausting game of hide-and-seek.
Yet instead of peeking around doors or under beds, they were examining brain tissue in a lab at the Karolinska Institute in Sweden, looking for something that had long evaded neuroscientists: concrete proof that the adult brain can form new neurons via a process called neurogenesis. Scientists have spent decades debating whether this is possible. As soon as one paper turned up positive clues, another would yield nothing at all.
But it seems the search may finally be over. A slew of new findings, including those from Dumitru and his team, have revealed near-certain evidence that adult neurogenesis occurs in the human hippocampus, part of the brain central to learning and memory. The discovery is forcing us to rethink long-held assumptions about our most indispensable organ, from how it functions to how it changes with age.
Even more exciting is the potential neurogenesis holds for brain regeneration. Some of our most devastating medical conditions, including Alzheimer’s, stroke and amyotrophic lateral sclerosis (ALS), involve neurons dying at massive scale. If the brain is capable of replacing some of those lost neurons, we may be able to harness and enhance that ability, stimulating neurogenesis to help treat neurological conditions that are currently incurable.
“To many of us, we think the question is no longer whether it exists or not,” says neuroscientist Hongjun Song at the University of Pennsylvania. “It’s, how can we take advantage of that?”
Neurons are the brain’s key messengers, transmitting the signals that underpin our most basic functions, from moving and talking to thinking and dreaming. They form when a stem cell – which can morph into other cell types – transforms into a “parent” progenitor cell, which then births an immature neuron that eventually matures.
Scientists long believed this process played out only during development in the womb and, to a lesser degree, during childhood and adolescence. In other words, humans were born with essentially all the neurons they would ever have. The brain would change in many ways over one’s lifetime – forming new connections between neurons and pruning away those that were no longer necessary – but it wasn’t going to get a windfall of new neurons. Or at least, so we thought.
In the early 1960s, Joseph Altman, a biologist at the Massachusetts Institute of Technology, went against the grain by looking for signs of neurogenesis in adult rats. He injected the animals with a radioactive tracer used to track cell division, then identified cells bearing it in the rodents’ brains, revealing what appeared to be freshly generated neurons.
But the finding was widely panned by the neuroscience community. The idea that adult neurogenesis was impossible “had really been embedded within the scientific literature”, says Fred “Rusty” Gage, a neuroscientist at the Salk Institute for Biological Studies in California.
Altman was apparently undeterred, replicating his findings in the brains of additional rats and then cats. Other researchers eventually joined in, finding adult neurogenesis in species such as canaries and monkeys, and discovering that it seemed to play a role in learning and memory – helping birds learn new songs, for instance.
But whether human brains also pump out new neurons remained an open question. You can’t ethically crack open a living person’s skull and dig around in their brain tissue.
Gage and his colleagues found an ingenious workaround to that problem. In the 1990s, some people being treated for cancer received injections of a chemical called BrdU, which flagged dividing cells so that doctors could monitor disease spread. When five such patients had died, Gage and his colleagues were able to autopsy their brains. Lo and behold, they found BrdU in hippocampal cells – a sign of neurogenesis.
The trouble is that BrdU can sometimes flag cells undergoing repair, not necessarily division. And subsequent studies that used different markers yielded results all over the map. Some showed next to no neurogenesis in the adult brain; others, that the adult hippocampus adds 700 new neurons every single day, on a par with that of a much younger brain.
So, Song and his colleagues pioneered a different approach. Instead of looking for immature neurons with just one or two markers, they analysed the full genetic profile of individual brain cells, searching for the genetic characteristics of freshly generated cells. They discovered immature neurons in people who had died across all stages of life, even up to age 92.
But spotting a young neuron still isn’t enough to prove the adult brain is generating new ones. Neurons can linger in an immature state for a long time, perhaps even an entire lifespan. These Peter Pans of the brain aren’t necessarily created in adulthood; they just aren’t growing up.
The real challenge in proving adult neurogenesis occurs was to capture each stage of the process – and one remained elusive. “Nobody had identified the proliferating progenitors,” says Dumitru. “They could identify immature neurons, they could identify maybe stem cells – so the cells that are at the beginning and end of the trajectory – but nobody identified the proliferating ones.”
To identify these cells, which actually birth new neurons, Dumitru and his colleagues genetically analysed roughly 400,000 brain cells from the hippocampi of people who had died between infancy and adulthood. They used a machine learning model – a type of artificial intelligence – to pinpoint genetic patterns that resembled those seen in progenitors from animals and developing infants.
The researchers almost couldn’t believe it when they spotted the first few progenitors. “It was so difficult to convince ourselves,” says team member Marta Paterlini, a molecular biologist also at the Karolinska Institute.
But after years of testing and re-testing, they finally felt confident their search was over. They found only about 350 progenitor cells – and they weren’t present in all the brains sampled. But by finding any at all, “we showed that there is active neurogenesis” in the hippocampus, says Dumitru. “That cannot be contested.”
Except that, well, some scientists still do. Developmental neurobiologist Arturo Alvarez-Buylla at the University of California, San Francisco, isn’t convinced that machine learning models can reliably categorise cell types. He says the only way to know for certain that adult neurogenesis happens would be to track a stem cell as it transforms into a neuron – a nearly impossible task to do in a living human.
But sceptics like Alvarez-Buylla are increasingly finding themselves outside a coalescing consensus. At least 38 clinical trials related to adult neurogenesis are now under way. “It’s there,” says Sandrine Thuret, a neuroscientist at King’s College London. “The new debate is, what is it for?”
One of the first clues to answering that question comes from the fact that adult neurogenesis appears almost exclusive to the hippocampus, the brain’s headquarters of learning and memory. This region is highly plastic, meaning it can easily reorganise itself and form new connections, helping us to take in and remember new information.
In a study from earlier this year, neuroscientist Orly Lazarov at the University of Illinois College of Medicine and her colleagues found that neurogenesis may play a role in this process. They examined post-mortem hippocampus samples from adults who had Alzheimer’s and adults without cognitive impairments, including “superagers” – people in their eighties or older who had outperformed younger adults on a memory test. On average, superagers had roughly twice as many immature neurons in their hippocampus as adults without cognitive impairments. People with Alzheimer’s had almost none at all.
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