Sleep is universal on both the species and the individual level. Though there have been reports of individuals, both in humans and other species, who need almost no sleep, a truly sleepless individual has never been identified.

Whether it's necessary for survival or not, sleep is clearly necessary for health – not to mention decent functioning, as pretty much anyone can attest from personal experience. Poor sleep leads to immediate grogginess and, long term, to increased risk of multiple disorders.

Recently, studies have been delving into both the causes and the consequences of poor sleep. Genomewide association studies have identified new genetic risk factors for disrupted sleep. Two studies that are to be published in the March 2019, print issue of Nature Genetics used large-scale data to identify risk loci specifically for insomnia, the inability to fall asleep or stay asleep.

Using data from 23andme and the UK Biobank, the research teams – one led by VU Amsterdam's Danielle Posthuma and the other by Richa Saxena of Massachusetts General Hospital – identified hundreds of risk loci for insomnia. Interestingly, those risk loci showed little overlap with other sleep traits, but strong overlap with risk factors for several other disease categories, in particular psychiatric disorders, metabolic disorders and cardiovascular disorders.

Using the statistical method of Mendelian randomization, which can tease out the direction of cause and effect from association data, both teams identified a possible causal link between insomnia on the one hand and cardiovascular disease and depression on the other. Posthuma's team also found a causal link between insomnia and diabetes.

Guus Smit, professor of molecular neurobiology at VU Amsterdam and a co-author on the Posthuma study, argued in a prepared statement that the findings change the way that insomnia is conceptualized. "We have always searched for causes of insomnia in the brain circuits that regulate sleep," he said, but the new research shows that "we have to shift our attention to the circuits that regulate emotion, stress and tension."

Two other studies, meanwhile, have linked sleep to immune system functioning – one by showing that sleep deprivation's link to cardiovascular disease is via immune cells that enter atherosclerotic plaques, and another by identifying a protein that is simultaneously sleep-inducing and antimicrobial.

The two studies, as well as other recent insights, such as the identification of narcolepsy as an autoimmune disorder a few years ago, are part of a larger effort to understand the ways in which sleep and immunity are linked.

"Connecting those dots will be a major focus" going forward, Filip Swirski told BioWorld.

'A neuroimmune axis'

Swirski is an associate professor at Massachusetts General Hospital and Harvard Medical School, and the corresponding author of a paper in the Feb. 14, 2019, issue of Nature showing that the path from sleep to cardiovascular disease risk runs through the immune system.

The work amounts to the "identification of a neuroimmune axis – a direct communication pathway between a hormone, a neuropeptide... and the bone marrow which harbors stem cells that produce white blood cells," he said.

The neuropeptide in question is hypocretin, a wakefulness-promoting substance that is produced by cells in the hypothalamus. Belsomra (suvorexant, Merck & Co. Inc.), which was approved by the FDA in 2014 for the treatment of insomnia, works in part by targeting hypocretin receptors.

Belsomra is a more specific alternative to GABA agonist sleep drugs. (See BioWorld Today, April 12, 2013.)

The new work, however, once again reinforces the principle that true one-trick ponies are rare in the neurotransmitter world. In addition to promoting wakefulness, hypocretin also inhibits the production of monocytes and macrophages in the bone marrow. In mice, sleep deprivation disrupted hypocretin production and increased the numbers of white blood cells, which ultimately led to increased buildup of atherosclerotic plaques.

Swirski and his team conducted their studies in mice, but "there is reason to believe that our findings are relevant in humans," he said. And "if this axis is operational in humans, what we have really uncovered here is a mechanism by which a brain hormone controls the inflammatory cascade," which could potentially be exploited to treat inflammation.

Like the GWAS research looking at insomnia, Swirski and his team looked at sleep through the lens of its disruption. Another recent study screened fruit flies for sleep-promoting substances, and here, too, their findings pointed to a role of sleep for immune functioning.

Amita Sehgal, John Herr Musser professor of neuroscience at the University of Pennsylvania's Perelman School of Medicine, and her colleagues reported that through a screen of no fewer than 12,000 lines of drosophila, they identified a gene that increased the need for sleep. The protein coded for by that gene, nemuri, is an antimicrobial peptide.

The team showed that nemuri overexpression drove sleep, and that conditions that led to increased sleep – including infections – increased nemuri expression, thus "identifying a mechanism that accounts for increased sleep during sickness, and linking it to the immune system," Sehgal told BioWorld.

Sleep deprivation is another condition that increases the need for sleep, sometimes termed rebound sleep. "These immune molecules can turn on sleep during both conditions," she said.

Unlike Swirski, whose research team "takes a broad look at health and disease... through the prism of the immune system," Sehgal is primarily a sleep researcher. But, she said, "the immune system is now turning out to be involved in everything."

But why sleep?

Given its importance, whether sleep is truly necessary for life, and if so, why, has been surprisingly hard to tease out. Several studies have shown that sleep deprivation resulted in death, in species ranging from dogs to cockroaches.

But given the extremely stressful methods that have been used to keep animals awake, whether it was truly sleep deprivation rather than chronic stress that did them in is up for debate.

A recent study in fruit flies that used gentler methods to wake sleeping animals came to the conclusion that chronic sleep deprivation was not in fact lethal, as well as identifying animals that naturally slept for as little as 15 minutes in an average 24-hour period – though once again, there were no animals that truly did not sleep.

Another open question is why sleep is such a universal phenomenon. "The function of sleep has been a mystery," Sehgal said.

There is strong evidence, however, that sleep is necessary for the consolidation of memories, and in previous work, she and her team have addressed "what is happening during sleep that helps with the memories."

In work published in November 2018 in eLifesciences, Sehgal and her colleagues showed molecular movement across the blood-brain barrier. The function of that increased movement is not yet clear, but "what we think it's doing is clearing out metabolic waste that piles up during wakefulness," Sehgal said.

If that hypothesis is correct, it could explain what the point of sleep is. The immune system, after all, is active during sleep and wakefulness alike – though Swirski noted that energy demands for other metabolic processes are lower during sleep, making it a good time to stock up on leukocytes.

Sehgal's theory, though, is that the function of the blood-brain barrier is subtly different during the day and the night.

"When you are active and moving around, you are exposed to xenobiotics," she said, which are best kept out of the brain. But at the same time, the brain is generating metabolic waste that needs to be dealt with: Sleep may simply be a way to keep animals still long enough for "the restoration of metabolic homeostasis."