Tumour necrosis factor makes you sleepy…

How we fall asleep isn’t widely understood. Of the fifty or so peer-reviewed papers I have sitting on my desk, about 45 conclude that sleep is complicated. The other five conclude that it’s really complicated. That’s because we can only look at the activity of the human brain through snapshots of its metabolism or its electrical charge at the surface.

Genetics, too, is what we non-geneticists like to call ‘fucking loopy.’ For example, among those papers I mentioned, there are several that look at a gene that helps to determine whether or not it’s time to go to sleep. That gene – and the protein that it makes – is called TNFα. So far so acronym-y. But TNFα is short for tumor necrosis factor alpha. That’s what it was first spotted doing somewhere else in the body so the name stuck. But now we know that it also suppresses appetite, increases insulin resistance, and regulates how bitter things taste. But we’re stuck with the name; because history.  

Model of TNF-alpha, produced by common mouse. Baeyens, KJ et al. (1999).
Model of TNF-alpha, produced by common mouse. Baeyens, KJ et al. (1999).

But because I care for you, dear reader, more than I care for my sanity, I’ve autopsied this mangled body of research, and here’s what I’ve found. 

We now know that TNFα expresses a protein inside star-shaped cells in the brain called astrocytes. These cells support neurons both physically and metabolically – they’re a scaffold and a glycogen supply mechanism. But it was recently discovered that glial cells don’t just support neurons, they have signalling duties of their own. Astrocytes accumulate TNFα throughout the day, and then release it into the adjacent neurons, where it binds with receptors, which then contributes to the drive to go to sleep. (Vanderheyden et al. 2018)

But again, neither messing around with human genes, or surveying the entire population to find some very rare mutants, is going to get the science done. Results of previous research had shown that both sleep deprivation and high levels of neuronal activity makes humans and other animals produce more of the TNFα protein. It also showed that injecting TNFα into rabbits makes them go to sleep. So rather than tinkering with humans or searching for mutants, Professor William Vanderheyden and his team at Washington State University bred a population of fruit flies that lacked a very similar gene. 

‘Fruit flies happen to have a molecule that is very similar to TNFα  that is called Eiger, and the receptor to which it binds is called Wengen,’ says Professor Vanderheyden. ‘What we tried to identify through this research were mechanisms by which Eiger and Wengen could be regulating sleep in the fruit fly.’

When the team knocked out the flies’ ability to produce Eiger in their astrocytes, the flies became insomniac, sleeping less and sleeping irregularly. But when they injected the flies with the human TNFα protein, the flies went back to typical levels and patterns of sleep. So far so good:  TNFα sends a ‘sleep’ message. 

Next, they bred flies that lacked the Wengen receptor in their neurons. This time, injecting the flies with TNFα did nothing to fix their sleep. What’s more, the flies with no Wenger receptor proteins were incapable of recovering from sleep deprivation. You may be wondering how you deprive flies of sleep. In the old days you did it by depriving researchers of sleep. They would stay up all night tapping the flies’ jars, or gently moving them around. But this is one of the jobs that has fallen prey to automation: the Sleep Nullifying Apparatus (or SNAP) was invented at the machine shop at Washington University in Saint Louis. It tilts back and forth, moving the flies ten times a minute and preventing them from catching any shut eye for twelve hours or so.

So the next time you’re feeling sleepy, blame your astrocytes. But don;t be too quick to sign up for gene modification… In a future post I’ll explain why lack of sleep is super bad for you!

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