Lessons from sleep-deprived fruit flies

At Nobel Prize time, journalists tend to celebrate the ingenuity of scientists. This year, let’s show some appreciation for the ingenuity of evolution and the human body instead.

The 2017 Nobel for medicine went to three researchers who uncovered the workings of tiny clocks inside your cells — clocks that tell you when to eat, when to stop eating, and when to shut off that computer and get some sleep. The prize-winning work was done on fruit flies, but its findings are relevant to us humans, since once evolution invents something useful, it often spreads far and wide. In humans, mice, insects and a multitude of other creatures, circadian clocks use chemical reactions and feedback loops to keep time and connect living things to the astronomical world — a pas de deux between our planet and the sun.

Like almost any Nobel finding, this work — conducted by Jeffrey C Hall, Michael Rosbash and Michael W Young — was not done from scratch. Back in the 1970s, Caltech biologist Seymour Benzer set the groundwork for their discoveries. He had been exploring the connections between genes and behaviour in fruit flies, using chemicals to create mutant flies. He would observe ones with abnormal behaviour patterns, and then figure out which genes had been altered. 

Sleep — or at least some form of cyclical periods of rest — is one of the most universal of animal behaviours. Fruit flies snooze at night and also tend to take a siesta in the day, said University of Pennsylvania biologist Amita Sehgal, who studies sleep and circadian rhythms. Among Benzer’s mutant flies, she said, there were some with sleep disorders — short cyclers who slept every 19 hours, long cyclers who slept every 29 hours, and a few that seemed to sleep and wake at random.

Benzer discovered that these out-of-sync flies all had mutations in a gene called PER on the X chromosome, she said. Humans and other animals also have a PER gene, and people with mutations in PER sometimes suffer from a syndrome called familial advanced sleep phase syndrome, which makes them want to go to sleep early in the evening and wake up around 3 am or so.

Sehgal said she and other researchers use infrared motion sensors to track flies at rest, although until recently, biologists weren’t sure they could really call it “sleep.” She helped change that by showing that if you disturb flies with light or by vibrating their enclosures, they get sleep-deprived, just like we do, and try to make up the missing slumber. Researchers at Caltech recently carried out similar experiments to show that even the humble, literally brainless jellyfish cycles between activity and sleep.

What the trio of Nobel Prize winners did was pinpoint the PER gene, make copies of it, and figure out how it works to keep time — or at least figure it out part-way.

So how does it work? Patrick Emery, a neurobiologist who studies circadian clocks at the University of Massachusetts, explains that PER holds the code for a protein — the PER protein, whose production rises and falls in a negative feedback loop. Once it builds up to a threshold, it interferes with its own production, and the existing PER protein degrades. The cycle starts over every 24 hours — or approximately so. If you put fruit flies or people in perpetual light or darkness, their sleep-wake cycles continue, though they will gradually get out of sync with one another and with the real day-night cycle.

The system didn’t quite work with just one gene, however, and other researchers started to wonder of there was another part to the clock. Penn’s Sehgal in collaboration with Young (one of the new Nobel winners) found that second part — a gene and associated protein dubbed “timeless,” because flies with damage to this gene don’t appear to sleep at all. Timeless binds to the PER protein at some point in the cycle, and then degrades when cells are exposed to sunlight, thus allowing the sun to reset our circadian clocks.

This leaves open the question of why these little clocks in our cells evolved in the first place. Why not just have sensors that react to changes in light, letting the Earth’s rotation keep time for us?

It’s all about foresight and anticipation, said Emery. Internal clocks allow our bodies to be proactive rather than reactive, preparing in advance to shut things down during sleep and gear them up before we awaken. It’s not just sleep that’s controlled by these clocks — it’s also metabolism, body temperature, hormone secretion, liver function and other workings of your body. About half of your genes are connected to the basic biological clock mechanism, said Emery.  The biological clock genes are activated at some point in cells all over the body, he said. “This makes sense because your whole body needs to be synchronised — optimised for the time of day.” In other words, timing really is everything.

Even some scientists don’t fully appreciate the importance of circadian rhythms, said Sehgal. Many conduct experiments on humans or other animals, then try to repeat the same experiment at a different time of day and wonder why they don’t get the same result. Medical researchers are just beginning to appreciate that the time of day changes the efficacy and side-effect risk of some drugs. Others are finding hints that it’s not just what you eat but when you eat that influences risks of obesity and diabetes.

A handful of worrisome studies have pointed to health hazards of working night shifts or flipping back and forth from day to night, including connections to metabolic disorders, depression and even cancer. But society needs people to work at night — from hospital nurses to security guards to firefighters — and this Nobel prize should remind us to put a high priority on research into keeping them healthy. Beyond that, it’s a reminder of who we are, and what we are: Fantastic machines tuned to motion of the heavens.

Bloomberg