Cause area: Short-sleeper genes
There is decent evidence that there are “short sleeper genes”: individual genetic mutations that cause a human to naturally get only 4-6.5 hours of sleep per night (instead of ~8) while remaining healthy, happy, and productive. There don’t seem to be any negative side effects, although there might be positive ones.
So far, 5 short-sleeper mutations across 4 genes have been identified. Probably at least one of these is a good candidate for developing a drug to mimic the effects of the gene.
Such a drug would be enormously valuable. If it worked, presumably it would give people at least one extra waking hour per day, and maybe the “higher resilience and productivity” side effects would be real too. If you care about overall utility, then consider the value of 1 extra waking hour per day, times 365 days per year, and imagine that 100 million people ended up taking the drug; if we say each hour is worth at least $1 (a lowball), then that’s $36 billion per year.
Just to illustrate the point, if an investment yielding 3% returns were that profitable, the investment would be $1 trillion. Even if you assume the probability of success were as low as 1%, that’d be worth $10 billion. Such an opportunity is clearly worth looking into.
I’ve skimmed several of the papers on the subject of familial natural short sleepers (FNSS), most of which were written by UCSF professor Ying-Hui Fu and colleagues. (Disclosure: I’ve emailed Ying-Hui, video chatted with her, and consider her something of a friend.) As I understand it, what they’ve done is collect people who might be natural short sleepers, validate that they are, look among family members, find candidate short-sleeper genes, and test those genes in mice or similar organisms, and publish papers if an effect is demonstrated in the mice.
The DEC2 mutation reduced sleep in mice by about an hour. The ADRB1 mutation reduced by 55 minutes. NPSR1 by 71 minutes, and the two GRM1 mutations (roughly equivalent to each other) by 25 minutes. Ying-Hui says it’s expected that the effects in mice are smaller than in humans.
All the genes in question are known to affect wakefulness. For example, the DEC2 protein suppresses expression of a neuropeptide called orexin, and mutant DEC2 suppresses it less; orexin is known to promote wakefulness (e.g. people who can’t produce orexin are narcoleptic). This part of the mechanism seems reasonably clear.
What’s less clear is how these genes accelerate the repairs/maintenance the body performs during sleep. (If they did not do any such acceleration, then you’d expect these people to be miserable, unhealthy insomniacs.) But there is at least one experiment that seems to show that they do accelerate some type of repair:
They took mice that were engineered to generate amyloid plaques and tau protein tangles—pathologies that seem associated with Alzheimer’s disease (though the causality seems unclear and you should take such research with a grain of salt). Anyway, they gave some of them the DEC2 and others the NPSR1 mutations, and found that both genes significantly reduced those Alzheimer-correlated pathologies.
I’ll just directly quote this summary article:
[Short sleepers] report greater flexibility around sleep timing and less subjective deficit after sleep deprivation. They often deny experiencing jetlag (unpublished data). However, it is not just sleep duration that characterizes this group of individuals. There is a high behavioral drive among those with FNSS, and individuals report a need to always be mentally active resulting commonly in high profile, high pressure jobs or holding multiple jobs. FNSS individuals also appear to have high pain thresholds and relative resilience to life stressors (unpublished data). Thus, the phenotype does not only encompass a sleep pattern but also daytime behavior. Individuals with short sleep and increased behavioral drive have been described in the literature as early as 1972 when Hartmann et al., while studying sleep need variation, described those who sleep less than 6 h as “smooth [and] efficient” and with greater tolerance and flexibility and less depression compared with long sleepers . It is possible that DEC2, ADRB1 and other causative mutations all lead to a higher behavioral drive, which allows those with FNSS to overcome increased homeostatic sleep pressure though much work needs to be done to test this hypothesis.
And, from a 2015 BBC article profiling a short sleeper:
A positive outlook is common among all of the short-sleepers that Fu has studied. “Anecdotally,” she says, “they are all very energetic, very optimistic. It’s very common for them to feel like they want to cram as much into life as they can, but we’re not sure how or whether this is related to their mutations.”
More from the summary article:
FNSS is defined as a stable trait of sleeping 4–6.5 h/night without daytime sleepiness or clear impairments (Table 1). These individuals are sometimes seen in sleep clinics because they are told they “need” more sleep—they are sometimes considered insomniacs. However, when these individuals are asked how they feel after sleeping 4–6.5 h, they often report feeling “great” and “well rested.” [...]
Individuals with FNSS report decreased sleep need throughout adult life, some dating to childhood. They report sleep durations ranging from 4 to 6.5 h per night without daytime sleepiness or reported deficits from sleep deprivation. FNSS individuals are in part distinguished from facultative short sleepers by their lack of catch-up sleep on weekends and free days.
Ying-Hui says, in private communication: “From our observation on those natural short sleepers during past 15 years, there is really no one negative thing that we can put our fingers on.” Also: “We have carefully characterized more than 100 (somewhere around 160) FNSS and have not seen major negative problem. However, it’s not impossible that we have missed some very subtle negative effect.”
If there were long-term negative consequences from the lack of sleep, I think we’d expect them to accumulate over time (and therefore be worst in older people). Ying-Hui likes to mention an over-80-year-old triathlon competitor and some other impressive old people, and says “Many of the FNSS individuals have remarkable memory and cognitive capacities (unpublished data)”. I believe her opinion is that, if anything, FNSS people are healthier on average because they’re better at self-repair through sleep.
I do suspect there are selection effects: people who would go visit a sleep clinic despite feeling fine (and therefore be discovered as FNSS) seem likely to have more disposable cash, and perhaps be more medically conscientious (or scientifically curious) than average, which probably correlates with various advantages; one should bear this in mind if comparing against the general population. This would extend, less strongly, to the FNSS relatives one discovers from the first one—but equally to their non-FNSS relatives, who are an ideal comparison group. I don’t know if that comparison has been made.
Overall, I suspect that, if there are any negative side effects, they are (a) small to very-small and (b) outweighed by the positive side effects. (This is where “having a drug you can start and stop taking when you like” may be superior to actually having the gene.)
Speculation and doubts
Common wisdom is that some essential maintenance and repair processes occur during sleep; also that if you don’t get “enough” sleep (and <6 hours is usually not “enough”), it causes misery and cognitive underperformance in the short term, and there’s good reason to expect longer-term negative mental and physical consequences. (Some have expressed contrarian views.)
Wakefulness-promoting chemicals, which the mutations seem involved with, could probably suppress the “short-term misery and cognitive underperformance”, but it’s unclear how they would accelerate the repair processes. And since some of the mutations are only a single base pair, it would have to be the very same protein that caused both the reduced tiredness and the accelerated repair. Once could be a coincidence, but four times on different genes suggests something more fundamental. Does wakefulness promotion inherently accelerate repair? How?
A few possibilities come to mind:
Perhaps misery itself causes long-term health problems (e.g. via cortisol or other stress hormones), or the tiredness mechanism suppresses repairs or accelerates damage or something. (Test: are other ways of suppressing tiredness, say with stimulants that had no other side effects, also a long-term healthy way to reduce sleep? I’m skeptical of this but don’t know.)
Perhaps the wakefulness chemicals also stimulate, say, increased blood flow, or increased production of something that’s generally useful in repairs. (Test: is there a difference in e.g. heart rate or nutrient consumption among short sleepers?)
Perhaps the most relevant repair is akin to taking out the trash, where it all gets taken out at once, no matter how much there is; and the mutations let you endure a higher level of trash before negative consequences happen (like having a bigger trash can). This wouldn’t explain the “FNSS mutations help mice prevent Alzheimer plaques” result.
Or maybe the genes don’t accelerate repair. This is contraindicated by the Alzheimer mice result, but let’s say we dismiss that. Possibilities that come to mind:
“Null” hypothesis: the short sleepers are actually suffering negative effects, and the research has just failed to notice this. Ying-Hui seems pretty confident this isn’t so, and she has seen plenty of data that I don’t think has been published; nevertheless, I can’t completely rule it out. (Tests: interrogate the short sleepers more closely; compare them to their relatives to defeat selection effects; find others with the genes in the population and see if they’re unhealthy insomniacs.)
Alexey Guzey is right: common wisdom about mild lack of sleep is overblown/placebo/correlated with but not causing other problems. (Tests are fairly obvious, though probably hard to recruit volunteers for a RCT.)
The short sleepers in Ying-Hui’s sample also happen to have different mutations that accelerate repairs. This isn’t too unlikely because the human sample sizes are really small: Ying-Hui mentioned ~160 FNSS individuals, and I counted 16 with the identified mutations (DEC2, ADRB1, NPSR1, and GRM1)—and many of these individuals are related. Now, if this were true, it seems decently likely that there’d be overlap in which repair-accelerating genes they had (Test: compare their other genes), and we’d love to find those genes.
Readers may form their own probability estimates. I think I give at least 50% that the genes work as advertised—and I stand by my conclusion that it’s well worth investigating.
There are several things one can follow up on. For those who want to validate the premise that short-sleeper genes work as advertised, I mentioned a few tests and readers can probably think of more (if one can gain access to population-wide genome databases and get data about others with the known mutations, that could be very nice).
For those who want to work towards developing a drug, there are various paths of advancement. For example, with DEC2, one could check (first in mice) if administering orexin (which can be done with nasal spray) at the right dose and schedule has the same effect as having mutant DEC2; if so, that could be the drug. If not, then you look for something that sensitizes the orexin receptor—or something, this isn’t my field. Ying-Hui and her team have plenty of ideas about how to proceed; that’s not the bottleneck here (though it is fun to think of ideas).
The big problem is funding. Ying-Hui was saying on Reddit in 2015 that funding was insufficient, and it seems to have gotten worse since then; she has said she’s “pretty much given up on trying to get NIH to fund my research” and she’s had to lay people off from her sleep lab. The cost to run the lab is in the low millions per year. Compared to the expected value of the research, the cost is laughable—but unfortunately it would drain my personal savings pretty quickly, and I must appeal to others.
So. I’m trying to tell people about this trillion-dollar bill lying on the sidewalk. Who’s going to pick it up?
FNSS in general (search page for FNSS): “Genetics of the human circadian clock and sleep homeostat” (2020): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879540/
DEC2: “The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals” (2009): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884988/
”DEC2 modulates orexin expression and regulates sleep” (2018): https://www.pnas.org/doi/10.1073/pnas.1801693115
ADRB1: “A Rare Mutation of β1-Adrenergic Receptor Affects Sleep/Wake Behaviors” (2019): https://www.sciencedirect.com/science/article/pii/S089662731930652X
NPSR1: “Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation” (2019): https://www.science.org/doi/abs/10.1126/scitranslmed.aax2014
GRM1: “Mutations in Metabotropic Glutamate Receptor 1 Contribute to Natural Short Sleep Trait” (2021): https://www.cell.com/current-biology/pdfExtended/S0960-9822(20)31441-X
Alzheimer mice + FNSS experiment: “Familial natural short sleep mutations reduce Alzheimer pathology in mice” (2022): https://www.cell.com/iscience/pdf/S2589-0042(22)00234-6.pdf
Press release: https://www.ucsf.edu/news/2022/03/422416/when-it-comes-sleep-its-quality-over-quantity
2015 BBC article that profiled a short sleeper, plus quotes from Ying-Hui: https://www.bbc.com/future/article/20150706-the-woman-who-barely-sleeps
2015 Reddit AMA with Ying-Hui: https://old.reddit.com/r/science/comments/3kj669/science_ama_series_im_yinghui_fu_i_study_the/
Nasal spray orexin: “Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates” (2007): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673447/
For those who care only about research projects such as AI safety, I’d still say it’s pretty valuable. Imagine if all your current and potential researchers had an extra hour per day, and were resilient to sleep deprivation, and had “a need to always be mentally active resulting commonly in high profile, high pressure jobs or holding multiple jobs”-tier motivation.
A more precise model, which I suspect does describe some sleep functions, would be: During wakefulness, some trash (metabolites, toxins, whatever) accumulates at rate R. During sleep, the body pumps in clear liquid and pumps out the impure liquid, which, assuming perfect mixing, means the metabolites drain at rate K*M, where M is the current level of metabolites. As calculus students learn, implies : exponential decay. But the takeaway is that delaying this type of repair makes it more efficient.
Of course, there are other possibilities. The straight linear model is: “During wakefulness, resource X (e.g. cell glycogen) is depleted at a fixed rate, and during sleep, it’s replenished at a fixed rate.” Probably this describes some other repairs.
Finally, there’s the unpleasant model where if you put off the repair for a long time, it becomes harder to repair, and in the worst case might become unrepairable by normal means; examples include scarring and dental plaque accumulation. I do fear that some sleep repairs are like this, that being extremely sleep-deprived for some number of days could cause permanent damage.
Even if these short-sleeper genes fail us, I strongly suspect that some dedicated effort could find out some of the bottleneck sleep repair processes (e.g. tissue repair is thought to occur during deep sleep, partly because that’s when growth hormone is secreted); and either speed them up, or make them occur during other sleep phases, or even when resting but awake; and probably buy us at least 2 hours per day at no cost to health. These short-sleeper genes just seem to be the most convenient, already-prototyped way to do it.
There’s a fascinating 2007 study where they administered orexin-A to sleep-deprived rhesus monkeys, and found that it masked the symptoms of sleep deprivation on a memory test.