‘Shall I continue for a while?’ asks the lab assistant, slicing the brain of a 19-year-old boy. It is not often that healthy people of that age die and donate their brains to science. That’s why neurobiologist Shawn Sorrells of the University of Pittsburgh knows: this is an opportunity. Sorrells is looking for areas where young brain cells sprout in the adult brain. He expects to find it, just like countless other research groups that preceded him over the past twenty years. Only: the newborn brain cells are nowhere to be seen, he says via video link.
Remarkable, because the production of new brain cells in adults seemed to be a certainty in neuroscience for years. Hundreds of studies have dealt with this so-called adult neurogenesis, which mainly takes place in the brain region called the hippocampus. It would be necessary to create memories, and Researchers hope that one day it will prevent diseases such as Alzheimer’s or even be cured. But since Sorrells’ conclusions in 2018 the whole story is under fire: can adults still make new brain cells at all?
That’s quite something, just removing the foundation from under a flourishing field of science. ‘Reputations are at stake, so the stakes are high,’ says Jos Prickaerts, professor of neuropsychopharmacology at Maastricht University. He has worked on neurogenesis for new drugs himself and is now following the discussion from the sidelines. It’s starting to look a bit like a soap opera. If someone publishes something, you know for sure that someone with the opposite point of view will comment on it.’
‘We were surprised that this one find would suddenly undermine all the previous work,’ says Paul Lucassen, professor of brain plasticity at the University of Amsterdam. He has been researching newborn brain cells in the hippocampus of mouse and human brains for years.
Dogma
The discussion is a reason for some researchers to warn against over-enthusiastic conclusions about rejuvenating the brain. ‘Misleading’, Yale University professor of neurobiology and hippocampus expert Pasko Rakic calls the many studies into brain cell production in adults at the beginning of this year in an opinion piece in Molecular Psychiatry.
Rakic especially warns doctors to protect patients of brain diseases from false hope. Patient association does that too Alzheimer Netherlandsfor example, that last year a message from the newspaper Fidelity nuanced how eating apples would promote the production of new brain cells – a premature conclusion.
‘Neurogenesis is very interesting and certainly exists’, says Elly Hol, professor of glial biology of brain diseases at UMC Utrecht, who studies cell growth in the brain. ‘But to what extent it is important in adults, let alone whether it will soon be possible to make a treatment, I think you have to be careful with that.’
The idea of researching neurogenesis exploded about the mid-1990s. Then scientists confirmed in several ways that adult mice do indeed make brand-new brain cells, which then settle in the olfactory organ and in the hippocampus.
At the time, that was a surprise, because neuroscientists had assumed for almost a century that a fully-grown brain could no longer make new cells. The old dogma was suddenly turned upside down. Since then, researchers have found solid signs of newborn brain cells in rats, sheep, monkeys, and yes, humans too.
There is also a catch with all that research: it is based on brain tissue from deceased people and laboratory animals. ‘You cannot immediately see whether new brain cells are being born somewhere,’ says Pickaerts. That is why researchers are mainly looking for other signs with which newborn brain cells could betray their presence, even after death.
This works well in laboratory animals and neurogenesis has even been demonstrated in adult mice, but it is more difficult in humans. Pickaerts: ‘The difference of opinion is very much about which of the methods really point to the development of new brain cells in adults.’
Sensitive
An example. In mice and embryos, very young brain cells, at most a few weeks old, go for a walk from their nursery to their future workplace in the brain. Such neurons are more mobile and agile, and are biochemically slightly different. Double cortin is one such flexibility molecule that researchers are looking at. And yes: especially near the hippocampus, human brain bank tissue abounds with the double cortin, according to a Spanish research team led by María Llorens-Martín.
However, when neuroscientist Sorrells searched for double cortin in the 19-year-old’s brain bank donation, and later in older human brains, he couldn’t find it. ‘We then started to doubt enormously: are we doing something wrong?’ The other research teams argue that they did: Sorrells’ team did not follow the correct protocol when cutting and chemically staining brain slices.
“Methods matter,” says Lucassen, who has written several responses to Sorrells’ studies. ‘We know that this coloring is very sensitive. If you do this research on tissue that has been waiting too long to prepare it neatly for storage, you lose the sensitivity to be able to detect double cortin.’
Sorrells has on it responded last year by doing new analyses with extra sensitive colorings according to the opposing party’s protocols, he thinks. Although his team sees a small sign of double cortin in adults, just like the previous studies, Sorrells doubts whether it really points to new brain cells, because double cortin also stains in other areas of the brain where no division takes place. Lucassen points out that Sorrell’s latest attempt deviates from proper protocol in other ways.
There seems to be a useless impasse, the neuroscientists fear. ‘That way they can go on for another five years and not get any further,’ says Prickaerts. “What I hope is that they will sit down and find out what they can agree on.”
brand new
More modern techniques promise to clear things up a bit further. By peeking into brain cells for molecular messages for cell division tools, researchers can see whether a cell has just finished dividing and to what extent the neurons are rejuvenating. More precisely, this concerns the so-called RNA sequencing, a technique that reads from RNA snippets which genes are active.
Sorrells has made a start on this and found few RNA fragments in the hippocampus that indicate cell division, but a brand new study from the University of Pennsylvania with a more extensive analysis found quite a few active cell division tools, also in adults, albeit less than in children.
UMCU neuroscientist Elly Hol recognizes that. ‘We have tried to grow new cells from adult neural stem cells. You can see that new brain cells can indeed arise from this, so it is possible and neurogenesis does take place there, but it is not much.’
That is a point on which both parties agree: most young brain cells mature around birth, later there are fewer. The question is therefore beginning to shift: it is not a question of whether adults can still make new brain cells in the same way as children and young mice, but especially what rejuvenation tricks the remaining immature brain cells in even an aging brain still have, says Evgenia Salta , neuroscientist at the Netherlands Brain Institute who studies the brain’s ability to recover for Alzheimer’s treatments.
According to Salta, it will be especially important for researchers and patients to understand what cells can and cannot do. ‘I don’t care what term scientists use to name that.’
snow under
Sorrells is also still enthusiastic about neurogenesis and repair work in the brain. ‘I started this research because I want to know how new brain cells are formed and how they integrate into existing brain circuits,’ he says. ‘We know that it is possible, because the brains of embryos and children do it anyway. That’s super exciting. This knowledge has an incredible amount of untapped potential for the treatment of brain disorders.’
Even though more brain cell births can be studied in young animals and humans, Salta thinks that adult research is important. ‘When a child develops and makes new brain cells, that is something completely different from what happens in adults.’ In children, the whole brain is in growth mode and there is still a lot of space, explains Salta, while in adults every new brain cell has to nestle itself between other neurons that have been in the same place for decades. ‘We are therefore also going to investigate in which soil a new cell ends up, as it were. It shouldn’t be too thin.’
For the time being, there is absolutely no question of a therapy in which Alzheimer’s patients miraculously recover all kinds of brain cells, Hol emphasizes. ‘Alzheimer eventually affects the whole brain and the areas that are now being investigated for neurogenesis are tiny. How should those cells populate the entire brain from there? There are still a few steps to take. I don’t know if that will ever work.’ In any case, Hol thinks that knowledge about dividing brain cells can be useful for other diseases, such as cancer.
Salta hopes to nip Alzheimer’s in the bud: after all, the disease starts close to the hippocampus and therefore also the possible nursery for new brain cells. ‘It is now becoming clear that immature brain cells in the hippocampus behave differently in patients with Alzheimer’s. If we understand how that works and can turn it around, you can start thinking about a new therapy. No magic bulletbut an extra treatment.’
Prickaerts, who also researches Alzheimer’s drugs himself, hopes the debate will start to cool down a bit. “The tone has been harmful, I think. Pharmaceutical investors may start thinking: it must be all wrong with those new brain cells. But its possible therapeutic value has not been discussed at all. Only the question of the extent to which new brain cells grow on their own in adults was a hot topic, but that is only a small part of how the brain retains its flexibility and stays healthy.’