In 1928, Santiago Ramón y Cajal, the father of modern neuroscience, proclaimed that the brains of adult humans never make new neurons. “Once development was ended,” he wrote, “the founts of growth and regeneration ... dried up irrevocably. In the adult centers the nerve paths are something fixed, ended and immutable. Everything must die, nothing may be regenerated.”
Ninety years later, it’s still unclear if his statement is true.
For decades, scientists believed that neurogenesis—the creation of new neurons—whirs along nicely in the brains of embryos and infants, but grinds to a halt by adulthood. But from the 1980s onward, this dogma started to falter. Researchers showed that neurogenesis does occur in the brains of various adult animals, and eventually found signs of newly formed neurons in the adult human brain. Hundreds of these cells are supposedly added every day to the hippocampus—a comma-shaped structure involved in learning and memory. The concept of adult neurogenesis is now so widely accepted that you can find diets and exercise regimens that purportedly boost it. Predictably, there’s even a TED talk about it.
The trouble is: This stream of fresh neurons might not actually exist.
In a new study, and one of the biggest yet, a team led by Arturo Alvarez-Buylla at the University of California at San Francisco completely failed to find any trace of young neurons in dozens of hippocampus samples, collected from adult humans. “If neurogenesis continues in adult humans, it’s extremely rare,” says Alvarez-Buylla. “It’s not as robust as what people have said, where you could go running and pump up the number of neurons.”
Needless to say, that’s a highly contentious claim. “There is a long history of concluding that adult neurogenesis doesn’t exist in a given species based on difficulty in identifying new neurons,” says Heather Cameron from the National Institutes of Mental Health. “This happened in rats and then in nonhuman primates, both of which are now universally acknowledged as showing adult hippocampal neurogenesis.”
Fernando Nottebohm from Rockefeller University sees things differently. He was one of the first scientists to conclusively show that adult neurogenesis occurs, by studying the brains of canaries. Alvarez-Buylla was one of his students, and Nottebohm speaks effusively about his former protégé—and his latest study. “It’s first class,” he says.
After Alvarez-Buylla left Nottebohm’s team and started his own, he showed that rodents continually add new neurons to the olfactory bulb—a region devoted to smell. But in humans, this river of olfactory neurons is finite: It’s there in infants, but dries up in adults. The same is true for the frontal lobe—the front-most part of the brain that governs our most important mental abilities. Floods of fresh neurons migrate there during early childhood, but they stop as we mature.
Next, Alvarez-Buylla turned his attention to the hippocampus—the region that’s the center of most research into adult neurogenesis. His colleagues Shawn Sorrells and Mercedes Paredes analyzed the brains of 17 adult humans who had died and donated their bodies to research. The duo searched for telltale molecules that are specifically made in young neurons, or in the stem cells that produce such neurons. To their surprise, they found nothing. “Even in our best-preserved samples, we didn’t see any evidence of neurogenesis,” Paredes says.
The same wasn’t true for children, infants, and fetuses. In 19 of these much younger brains, Sorrells and Paredes found clear signs of new neurons in the hippocampus. But even then, humans differ from even closely related animals. In macaque monkeys, neural stem cells in the hippocampus coalesce into a beautiful ribbon that pumps out new neurons. This structure breaks up in early life, and it’s mostly gone in adulthood. But in humans, the ribbon doesn’t seem to form at all.
We’re not alone in this. Another study recently suggested that whales and dolphins don’t have adult neurogenesis either. It’s tempting to point at our shared intelligence, and wonder if that has something to do with the lack of new neurons. But whales and dolphins have another trait in common with us: For mammals, we have pretty poor senses of smell. “Maybe adult neurogenesis in the hippocampus is related to smell, and smell in humans just isn’t that important,” Alvarez-Buylla says.
But it’s always hard to prove a negative, and other researchers aren’t convinced by the team’s work. “They’re not really measuring adult neurogenesis,” says Fred Gage from the Salk Institute. Instead, they’re looking at postmortem brains for proteins that are markers of young neurons and dividing cells. That’s “notoriously difficult,” Gage adds, because those same proteins could degrade after death.
Paredes counters that she analyzed two brain samples that had been perfused with fixatives, to prevent their contents from decaying. She also analyzed samples from 22 living patients—12 adults, seven children, and three infants—whose brains were being surgically resected in an attempt to treat severe epilepsy. These brains were most certainly not postmortem, and they didn’t show signs of adult neurogenesis either. And crucially, Paredes notes that they succeeded in finding neurogenesis in infant and fetal brains. It’s not that their techniques didn’t detect anything; it’s more that there’s nothing to detect in adults.
Gage adds that adult neurogenesis is affected by the state of the individual; running increases it and stress decreases it. “It would be good to know the state of the individual before they died,” he says. Nottebohm sympathizes with this critique; “negative results under some conditions do not preclude the possibility that under others the outcome might differ,” he says. Still, he notes that earlier studies which supported claims of neurogenesis didn’t talk about the state of the subjects either; it seems like a double standard to request such information now in the face of contradictory evidence.
Finally, Gage and others say that several other lines of evidence suggest that adult neurogenesis in humans is real. For example, in 1998, he and his colleagues studied the brains of five cancer patients who had been injected with BrdU—a chemical that gets incorporated into newly created DNA. They found traces of this substance in the hippocampus, which they took as a sign that the cells there are dividing and creating new neurons.
Perhaps the most evocative evidence comes, inadvertently, from the Cold War. The nuclear bomb tests of the 1950s and 1960s released large amounts of carbon-14—a harmless but mildly radioactive form of carbon—into the atmosphere. It was taken up by plants and made its way into the food chain, ending up in the cells of people who were alive at the time. Jonas Frisén from the Karolinska Institute has exploited this radioactive legacy to essentially carbon date living tissues, and work out how old they are. And in 2013, he concluded that the adult hippocampus does make new neurons—around 700 every day.
Meanwhile, others have tried the same kinds of experiments that Alvarez-Buylla’s team did—labeling marker molecules produced by young neurons and dividing cells—and found positive results. “It is very difficult to draw reliable and strong conclusions about the absence of an entire phenomenon based on the failure to replicate one method that has worked in the hand of others,” says Gerd Kempermann from TU Dresden.
But Sorrells and Paredes say that these previous studies have their own problems. BrdU, for example, can sometimes label dying cells instead of dividing ones, creating fake signals of neurogenesis. Other markers might accidentally label different kinds of brain cells called glia instead of neurons. And the study of carbon-14 is “complicated and prone to contamination,” says Alvarez-Buylla. To pull it off, you need to accurately identify neurons and collect their DNA; if you pick a different kind of cell by mistake, you’ll get a misleading answer.
Greg Sutherland from the University of Sydney agrees. In 2016, he came to similar conclusions as Alvarez-Buylla’s team, using similar methods. “Depending on your inherent biases, two scientists can look at sparse events in the adult brain and come to different conclusions,” he says. “But when faced with the stark difference between infant and adult human brains, we can only conclude that [neurogenesis] is a vestigial process in the latter.”
“I imagine this debate will go on for a while and will likely be resolved only by the development of techniques that allow for imaging new neurons in the brains of living humans,” adds Elizabeth Gould from Princeton University, who has studied neurogenesis in rodents.
Alvarez-Buylla agrees that there’s still plenty of work to do. Even if neurogenesis is a fiction in adult humans, it’s real in infants, and in other animals. If we really don’t make any new neurons as adults, how do we learn new things? And is there any way of restoring that lost ability to create new neurons in cases of stroke, Alzheimer’s, or other degenerative diseases? “Neurogenesis is precisely what we want to induce in cases of brain damage,” Alvarez-Buylla says. “If it isn’t there to begin with, how might you induce it?”