By Guananí Gómez-Van Cortright

You can’t hear them ticking, but our bodies are full of tiny clocks—and scientists have just taken a major step toward understanding how they work. A collaboration of three University of California research labs has created a biological clock in a test tube.

“Understanding how these clocks work provides a powerful tool for future researchers to figure out–and perhaps one day even manipulate–the rhythms that govern our lives,” says Carrie Partch, a UCSC scientist who studies the biochemistry of biological clocks.

Biological clocks in our cells work together like an orchestra of timekeeping, controlling the circadian rhythms—the mental, physical and behavioral changes within a 24-hour cycle—that keep our bodies in sync with day and night. Circadian rhythms have a major influence on human health, from getting a good night’s sleep to improving chemotherapy treatments. Partch and other biological clock researchers hope that advancing our understanding of circadian rhythms will revolutionize medicine.

“There’s a growing awareness of the effect that time has on biology,” says Partch. “Understanding the environment that you live in and that you create for yourself can have a really powerful effect.”

WHAT ARE YOU SYNCING

Scientists know that circadian rhythms control sleep, metabolism and other systems crucial for our health and well-being. But until recently, they didn’t know how the biological clocks that control these rhythms work.

To learn what makes the clocks in our cells tick, researchers from UCSC, UC Merced and UC San Diego rebuilt a bacterial biological clock from scratch, and reported their findings in the scientific journal Science last fall. Now, researchers can watch the bacterial clock tick in real time.

“Biochemists are kind of like auto mechanics,” says Partch. “We like to pop open the hood and take a look at how the individual parts or pieces come together to make the thing work.”

Biological clocks have many parts, including proteins that change shape and interlock like gears to keep time. Human biological clocks are incredibly complex, interacting with so many different systems in every cell that scientists are still puzzling out just how many pieces are involved. To “pop the hood” on the basics of how biological clocks work, the UC research teams studied one of the simplest living things on Earth: bacteria. The researchers decided to recreate the biological clock of cyanobacteria, a type of bacteria that uses sunlight to make food.

Even stripping down this relatively simple clock to its basic parts was no easy feat. In 2005, a Japanese research team found that three key proteins in cyanobacteria could create a biological rhythm in a test tube. But they didn’t know how these gear proteins interact with the bacteria’s DNA to change what the bacteria cell does according to the time of day.

“There’s been this big gulf between what’s going on in the cell and what’s happening in the test tube system,” says Michael Rust, a circadian rhythm researcher at the University of Chicago who also studies biological clocks in cyanobacteria, but was not involved in the UC study.

Three teams of scientists spent four years crossing that gulf. Partch’s lab at UCSC—along with those of Susan Golden at UCSD and Andy LiWong at UCM—were used to create a more complete version of the bacterial clock in a tube. Their clock system includes a strand of DNA—which is important, because the gear proteins that mark time can only lead to changes in the bacterial cells if they change which parts of the DNA are being read according to the time of day. Creating a clock system that includes DNA for the clock proteins to interact with brings the test tube clock a significant step closer to matching how biological clocks control circadian rhythms in a real live bacteria.

“The real breakthrough in this paper is that it’s shown that it’s possible to start to extend that system of three proteins to get closer to the cell,” says Rust.

BAD TIMING

Modern life runs on alarms, time zones, daylight savings, caffeine and more, but we evolved with a different kind of timing—the timing set by the biological clocks in our cells that keep us in sync with the 24-hour cycle of day and night.

Biological clocks keep living things in sync with their surroundings, but a disrupted clock can wreak havoc. From flying across time zones to working night shifts and staying up too late staring at a screen, there seems to be no end to modern life’s disruptions of the 24-hour cycles we evolved to follow.

Across research disciplines, scientists are only beginning to understand how biological clocks set circadian rhythms and the consequences of disrupting those rhythms.

“It comes at a cost; we’re really perturbing all aspects of our biology,” says Michael Gorman, a researcher at UCSD’s Center for Circadian Biology. “We have all sorts of badly timed things. A culture that recognizes circadian health and well-being is fundamental.”

Unfortunately, that’s not the culture we live in.

Jetlag is a well-known example of the mayhem that disrupted circadian rhythms can cause. When we travel by plane and outrace the sun by flying across time zones, the biological clocks in our cells drag our old sense of time with them, leaving our bodies out of sync with the day and night cycle of our destination. This forces our biological clocks to reset themselves and throws our bodies out of whack.

Another common disruption of natural circadian rhythms is working night shifts. Night shift workers are chronically sleep deprived, and face a higher risk of heart disease, metabolic disorders, mental health problems and certain kinds of cancers. This suggests that when our circadian rhythms are constantly forced out of sync with our surroundings, our health and well-being suffer.

But as modern humans, we don’t even need to get on a plane or work a night shift to disrupt our circadian rhythms. In our quest to control time, humans invented electrical light, mechanical clocks, standardized timekeeping and, more recently, the internet. These inventions transformed day-to-day life and our sense of time, allowing us to rely less on the seasons and the sun, and making it easy to ignore natural light signals and be awake and working no matter what time it is.

With time zones and synchronized digital clocks, we can keep track of every hour and set detailed daily routines across society. Standardized transportation, work and school schedules keep the global economy working overtime all the time– but they don’t affect people equally. Social pressure to live according to standardized time pushes individuals to ignore their internal rhythms in order to keep up with everyone around them.

Suddenly changing standardized time is even harder on our internal rhythms. Twice a year, many places participate in the switch to and from daylight savings time, causing widespread circadian disruption across the population. This is especially detrimental in spring, when we switch our mechanical and social clocks an hour ahead, creating a similar effect to giving everyone mild jetlag all at the same time. This collective moment of circadian disruption and sleep deprivation results in higher rates of fatal car crashes and increased risk of heart attack, suicide and workplace accidents for about a week after the time change.

“By putting social pressure on people’s clocks, you do cause more disease,” says Rust. “It’s clear that our bodies are disturbed by not being able to follow a regular rhythm.”

While forcing ourselves to live by standardized time has mostly been accepted as a fact of modern life, some researchers and policymakers have been trying to change our timekeeping systems so that they are more in line with our bodies’ natural 24-hour cycles. This includes efforts to abolish daylight savings, as well as changing school start times so that they align better with the circadian rhythms of teenagers.

Teenagers’ circadian rhythms trend later than young children and adults, causing them to fall asleep later in the night and feel drowsy later into the morning. Getting up early for school despite internal rhythms leads to chronically disrupted circadian rhythms, which have been shown to cause ongoing harm to teens’ health and well-being.

Sleep deprivation in teenagers is associated with poorer school performance, higher risk for being overweight, symptoms of depression, and a higher risk of drowsy car crashes. In 2019, Gov. Newsom signed a bill requiring that California middle and high schools start no earlier than 8:30am in response to public health recommendations. But even though mandating later school start times may benefit students, the law faced fierce opposition due to requiring inconvenient schedule adjustments and controversy over community independence in how to govern local school systems.

Aligning standardized time and societal expectations with our circadian rhythms remains a major hurdle, but overlooking the consequences of ignoring our internal sense of time comes at a considerable cost.

NIGHT AND DAY

Even as policymakers consider changing school start times and researchers puzzle through the machinery of biological clocks, studying the effects of timing on our bodies is often neglected.

Time of day has a major influence on our bodies and how they respond to different medications, yet circadian rhythms are usually not part of the design of clinical trials for new treatments and drugs. 

“People are not walking around with the expectation that time of day is going to be an essential dimension, so they don’t pay attention to it,” says Gorman.

At different times of day, the biology of your body is like—well, night and day. Biological clocks in your cells cause your temperature to drop when it’s time for bed and release hormones that prepare your organs to digest food near mealtimes. Similarly, people’s bodies also respond to medications differently at different times of day.

For example, patients undergoing heart surgery have a higher risk for major heart damage if they undergo surgery in the afternoon rather than in the morning. Chemotherapy is better at killing cancer cells, and gives patients fewer side effects, when it is given at certain times of day.

In 2014, scientists found that circadian rhythms might affect how our bodies react to 56% of the best-selling drugs in the U.S., including all top seven. Drugs work by attaching to specific targets in your body, but circadian rhythm researchers are finding that how those targets receive drugs and how bodies respond to treatments depends on the circadian rhythms set by biological clocks. Drugs whose targets change according to the time of day include everything from Ritalin to asthma and high blood pressure medications. If clinical trials and medical treatments considered the effects of time on our biology, it could lead to a better understanding of when patients should take medicine or undergo surgery to benefit from the best outcome.

“I wish all biologists realized that circadian rhythms are happening in all of the processes that people are studying,” says Golden, one of the tube clock researchers and director of the UC San Diego Center for Circadian Biology. Golden hopes that one day, researchers across all of biology will keep track of time of day as an essential part of their experiments.

As researchers reveal just how important timing is for our health, some of them dream of understanding biological clocks well enough to manipulate them directly. Golden imagines a future where scientists develop drugs that can relieve shift workers from the harmful effects of being out of sync with the sun, or eliminate jetlag by resetting biological clocks upon arrival in a new time zone.

For any of that to happen, researchers will have to learn more about how our clocks work by taking them apart and putting them back together again, as Partch, Golden and their colleagues have done with the bacterial clock in a test tube. The rhythms set by biological clocks have a hand in everything we do, but science has a long way to go to fully understand these essential systems our way of life has disrupted so thoroughly.

The UC collaboration’s creation of the test tube clock opens the door for researchers to experiment on the biological clock itself– but gear proteins ticking inside a tube are just the beginning of understanding the timing that controls us all.