By Dr Niels Haan
Recently, the debate about adult human neurogenesis seems to be just a dame short of a panto. Do adult humans form new neurons? Oh no, they don’t! Oh yes, they do! There are not many fields where people debate the very existence of the phenomenon they are studying. What do nuclear bombs have to do with it? We’ll come to that later.
What is the big deal?
For many decades, neuroscience dogma was that once the brain was formed after childhood, that was it. All you could do was lose cells. This was first challenged by Robert Altman in the 1960s, when he showed new neurons were forms in adult rodents, but his work was largely ignored at the time. A second wave of evidence came along in the late 1980s and 90s, first starting in songbirds, and later on the conformation that adult neurogenesis does take place in rodents.
In the years that followed, it has been shown that rodent adult neurogenesis takes place in two main areas of the brain, the wall of the lateral ventricles, and the hippocampus. The real importance is the function of these new neurons. In rodents, these cells are involved in things like discrimination of similar memories, spatial navigation, and certain forms of fear and anxiety.
Obviously, the search for adult neurogenesis in humans started pretty much immediately, but decades years later we still haven’t really reached a conclusion.
Why is there so much controversy?
To definitively show adult neurogenesis, you need to be able to show that any given neuron was born in the adult animal or human, rather than in the womb or during childhood. This means using a way to show cell division, as birth of a neuron requires a stem cell to divide and produces at least one daughter cell that ends up being a neuron.
In animals, this is straightforward. Cell division requires the copying of a cell’s DNA. You inject a substance that gets built into new DNA, detect this later once the new neuron has matured, and say “this cell was born after the injection”. To test what these cells are used for, we tend to reduce the numbers the stem cells with chemicals or genetic tricks, and see what the effect on the behaviour of the animal is.
However, injecting chemicals into the brains of humans tends to be frowned upon. Similarly, killing off all their stem cells and doing behavioural tests doesn’t tend to go down well with volunteers. So, we can’t use our standard methods. What we’re left with then is to detect certain proteins that are only found in stem cells or newly born neurons, to show they are present in the adult brain. However, that’s easier said than done.
Although there are proteins that mark mainly things like dividing cells, stem cells, or newly born neurons, those are not necessarily always only found in those cells. All these markers have been found time and again in the human hippocampus. However, because they are not always unique to stem cells and newly born neurons, there is endless debate on which proteins – or indeed which combinations of proteins – to look at, and what it means when cells have them.
What is the evidence?
Dozens, if not hundreds of papers have tried to address this question, and I don’t have the space – or the energy – to discuss all of them. Let’s look at some influential and recent studies that made the headlines, to show how radically different some people are thinking about this subject.
One of the major influential studies in the field came from the lab of Jonas Frisen in 2015. They used a way to get round the problem of detecting dividing cells. When DNA is copied to make a new cell, a lot of carbon is used. Nuclear bomb testing in the 50s and 60s introduced small amounts of (harmless) radioactive carbon into the atmosphere, and so eventually into the DNA of cells born during that time. The end of nuclear testing has lead to a slow decline of that radioactive carbon. So, by measuring how much radioactive carbon is in a cells DNA, you can determine when it was born. Frisen and his group did just this, and showed that people had neurons born throughout their lives in their hippocampus, with about 700 cells being born per day.
This didn’t convince everyone though. This was shown earlier this year when a widely publicised paper came out in Nature. This group did not do any birthdating of cells, but looked for the characteristic markers of stem cells and immature neurons in brains from people of a wide range or ages. According to them, the only way to reliably detect a newly born neuron is to look for two different markers on the same cell. They could only find one of the markers in adults, so by this measure, they found no new neurons after childhood.
The very next month, a very similar paper came out, using essential identical methods, and showed the exact opposite. They did find the new neurons in brains of a wide range of ages, and when counting them, found very similar rates of neurogenesis as Frisen did with his completely different methods.
So, who is right?
That depends on who you ask, and it depends on the question you’re asking (isn’t science fun?). The majority of studies have shown evidence for some neurogenesis in one form or another. How convincing this evidence is comes down to seemingly petty technical arguments, and biases of who you’re asking. The biggest questions are about which markers to use to find the cells, as shown by the two studies mentioned above, and nobody agrees on this yet.
Barring some spectacular technical breakthrough that gives us the same sorts of tools in humans as we have in animals, this debate will undoubtedly keep going for some years yet. The bigger question, which we haven’t addressed at all yet, is whether these adult born cells actually do anything in humans. That’s the next big debate to have…..