The Wild Type is a weekly look at the most interesting thing happening in biotech, written for the curious rather than the credentialed. I am Riya, a biology student, and each issue is one idea, explained properly, in about three minutes. No background required.
This week: a kennel of Dobermans, and the reason people are awake.
The Lead
From the mid-1970s the sleep lab at Stanford kept a kennel. The dogs in it had inherited something nobody could explain: they would be perfectly well, get excited about food or a visitor at the door, and go down mid-stride, awake the entire time and unable to move a muscle.
A French researcher called Emmanuel Mignot took the colony on at the end of the 1980s. He spent ten years feeding, watching and breeding dogs while hunting for the one gene behind it. This was in the years before you could sequence an animal and simply look, which meant narrowing the search by inheritance alone.
He published in August 1999. The dogs could not respond to a molecule called orexin, which happens to be the signal keeping you conscious while you read this.
The Big Picture
A good number of people I know take something to sleep. The pills people take have been built on a single idea since barbiturates arrived in 1903, running through Valium and Ambien: press on the brain's general-purpose brake and hold it down until consciousness stops.
That produces sedation, and the difference between sedation and sleep is not a matter of opinion. Put someone on a benzodiazepine and their deep sleep and the dreaming stage both shrink. A night has a shape, cycling between light sleep, deep sleep and dreaming, and these drugs flatten it while leaving the person unconscious for the right number of hours. You wake up having been switched off rather than having slept. Everybody who has taken one knows the feeling and nobody has been able to say what to do about it.
Melatonin is not the exception people think it is. It is a darkness signal, which makes it a clock, useful for jet lag and shift work and no help at all with the actual mechanism.
The Gap
What the dogs gave up in 1999 was a system nobody had known was there. Being awake is something your brain does deliberately, every second, using a cluster of about seventy thousand cells near the base of it. Orexin is what they make, and it is what holds the switch on the waking side. Sleep is not a hole that opens when the brain gets tired. Sleep is what happens when that cluster lets go.
You can see the consequences most clearly in people whose cells are gone. Total daily sleep in narcolepsy stays roughly normal, so the problem was never quantity. What goes is the holding. Sleep arrives in pieces, at the wrong hour, and the pieces turn up separately. When you dream, your brain switches your muscles off so you cannot act out whatever is happening in your head, which is why you can dream of running without moving an inch. In narcolepsy that shutdown escapes into the daytime. Somebody tells a joke, the body goes, and the person ends up on the floor fully awake, hearing every word in the room. The dogs had been doing the same thing at the sound of dinner.
Startup Spotlight
Once you know something is being actively held open, you can let go of it instead of knocking it down. The drugs that do this are called orexin blockers.
Idorsia, the Swiss company spun out of Actelion when Johnson & Johnson bought it in 2017, has a sleeping pill that does exactly that, and the interesting bit is how they chose it. Instead of the strongest blocker, they picked on timing: a compound that works for about eight hours at the starting dose and clears fast enough that what is left by morning does not keep you drowsy. Designing a drug around when it stops is only available to you if you are letting go of one specific signal rather than sitting on an entire brain. The trials that got it approved were run by Emmanuel Mignot. The man who spent a decade in the kennel ran the studies for the drug the kennel produced.
Two results matter more than the rest. A rival in the same class was tested head to head against Ambien in a thousand older adults and came out ahead on both getting to sleep and staying asleep. And across three months of Mignot's trials, the proportions of light, deep and dreaming sleep came out no different from placebo. The old pills buy unconsciousness by deforming the night. These ones leave the shape of it alone.
Regardless of this, I would still not oversell it. They are expensive, and the case for them rests on what happens over months rather than on any single night.
On the Radar
The same switch, in reverse. If narcolepsy is a missing signal you can supply it rather than block it, and Takeda has built a drug that does. The mid-stage results are in the New England Journal with Mignot among the authors, both large trials hit every target, and an American decision is due this quarter.
Pills should remain the second option. Talking therapy for insomnia is what sleep specialists reach for first, and it is the only option that keeps working after you stop doing it. Nothing here is a reason to change a prescription on your own.
Twenty-seven years. There are people reading this who are older than the explanation for why they are awake.
Nobody has worked out how to install sleep, and on the evidence nobody needs to, because the only thing standing between you and it is a signal your own brain is choosing to send. A century of chemistry went into overpowering a brain that was never fighting you. The drugs that finally worked do the one thing the dogs did by accident: it takes the signal away for eight hours, on a timer, and gives it back before you wake. You are essentially dosing yourself with narcolepsy, just at the correct time.