A Surprise about Our Body Clock

July 5, 2006

The first gene known to control the internal clock of humans and other mammals works much differently than previously believed, according to a study by Utah and Michigan researchers.

The surprising discovery means scientists must change their approach to designing new drugs to treat jet lag, insomnia, some forms of depression, sleep problems in shift workers and other circadian rhythm disorders, according to researchers at the University of Utah's Huntsman Cancer Institute and the University of Michigan, Ann Arbor.

The study – which involved the so-called tau mutation that causes hamsters to have a 20-hour day instead of a 24-hour day – will be published online the week of July 3 in the journal Proceedings of the National Academy of Sciences.

The researchers discovered that what was previously believed about the tau mutation – that a decrease in gene activity sped up a mammal's internal clock – was incorrect. Instead, the mutation caused an increase in gene activity to speed up the clock, making the day two to four hours shorter for affected animals.

Previous work had indicated that the tau mutation occurred in a gene called casein kinase 1 epsilon (CK1) and that the mutation caused an 85 percent loss of gene activity. This, it was thought, explained why the hamster had a short day. But as it turns out, this idea was wrong.

"The key to developing treatments for problems like depression and insomnia – disorders influenced by circadian rhythm – is being able to predict how the body"s internal clock can be controlled,” says David Virshup, M.D., co-principal investigator on the project and a Huntsman Cancer Institute investigator. “If the working model is wrong, drugs will have the opposite effect.”

The new study involved the collaboration between University of Michigan mathematician Daniel Forger, Ph.D., assistant professor of mathematics, who had developed a computer simulation of the biological clock, and Virshup, who had previously done research on CK1’s effect on circadian rhythm and its role in cancer development. Disruption of circadian rhythms has been linked to cancer and diabetes as well as depression and sleep disorders.

Forger ran computer simulations of how the tau mutation influenced the mammalian body clock. The tau mutant hamster has a short day. When a simulation used the prevailing theory that the mutation decreased CK1 gene activity, the simulation predicted that the day for the hamster got longer. But when Forger ran a simulation based on the controversial idea that the tau mutation increased activity of the CK1 gene, the day did get shorter, just as it does in real hamsters with the tau mutation.

“So he concluded that the tau mutation must increase, not decrease, the activity of the CK1 gene,” contrary to the accepted wisdom, Virshup says.

Few people working in circadian rhythm were convinced that Forger’s mathematical model was correct. But the Huntsman Cancer Institute researchers were interested because their experiments also suggested the tau mutation increased rather than decreased activity of the CK1 gene.

Virshup, with members of his lab Monica Gallego, Ph.D.; Erik Eide, Ph.D.; and Margaret Woolf, had used a drug that inhibited CK1 on cultured rat cells. According to the published research, they expected the cells to have a shorter day, just like the mutant hamster. Instead, the cells had a longer day. They were ready to believe that Forger’s simulation could be proved.

A simple experiment showed them why the cells’ day got longer and why Forger’s simulation was correct.

The Virshup lab had already established a way to measure how quickly PER, one of the proteins responsible for running the biological clock, degraded. It is the disappearance of PER and a related protein from cells that resets the body’s internal clock to start a new day.

Forger’s simulation said the tau mutation would cause PER to go away more quickly. The old model said the mutation caused PER to build up more quickly. Virshup explains: “The mutation can’t do both. We put either the normal or the mutant CK1 gene into mouse cells, and then we watched what happened to PER stability.”

The results proved Forger’s prediction: the circadian rhythm within the mouse cells sped up because the mutant CK1 gene was more active, making the PER protein disappear more quickly. That would explain why a day for an animal with the tau mutation would last only 20 hours.

Virshup says his team has begun development of a mouse model so they can begin to test ways to regulate circadian rhythm based on their findings. That will be a necessary step before new drugs can be developed for disorders related to circadian rhythms.

Source: University of Utah

Explore further: Early Alzheimer's gene spells tragedy for patients, opportunity for science

Related Stories

Early Alzheimer's gene spells tragedy for patients, opportunity for science

January 10, 2017
Rosemary Navarro was living in Mexico when her brother called from California. Something wasn't right with their mom, then in her early 40s. She was having trouble paying bills and keeping jobs as a food preparer in convalescent ...

Researchers harness targeted delivery of microRNAs to primary tumors in mice to block the movement of cancer

September 19, 2016
A new Tel Aviv University study finds that combining genetic therapy with chemotherapy delivered to a primary tumor site is extremely effective in preventing breast cancer metastasis.

Crowdfunding helps solve rare disease mystery

February 10, 2015
Rare diseases—those that affect fewer than one in 200,000 people—are often identified early in life. Some 30 percent of children afflicted by these "orphan diseases" do not live to see their fifth birthday. While the ...

The medical odyssey of an undiagnosed child

July 21, 2015
Children born with ADNP-related autism syndrome suffer from a heart-breaking combination of ambiguous developmental problems injurious to both their physical health and cognitive functioning. For parents, the mystery surrounding ...

New Alzheimer's drug studies offer patients hope (Update)

December 3, 2012
For Alzheimer's patients and their families, desperate for an effective treatment for the epidemic disease, there's hope from new studies starting up and insights from recent ones that didn't quite pan out.

Family found with unusually heritable Alzheimer's risk

February 17, 2016
More than a decade ago, a woman in her early 70s came to see neurologist Allan Levey for an evaluation. She was experiencing progressive memory decline and was there with her children.

Recommended for you

One in 4 women and 1 in 6 men aged 65+ will be physically disabled in Europe by 2047

October 23, 2017
By 2047 one in four women and one in six men aged 65 and above is expected to be living with a physical disability that will severely restrict everyday activities, reveals an analysis published in the online journal BMJ Open.

Major study of genetics of breast cancer provides clues to mechanisms behind the disease

October 23, 2017
Seventy-two new genetic variants that contribute to the risk of developing breast cancer have been identified by a major international collaboration involving hundreds of researchers worldwide.

Exploring disease predisposition to deliver personalized medicine

October 23, 2017
Geneticists from the University of Geneva have taken an important step towards true predictive medicine. Exploring the links between diseases and tissue-specific gene activity, they have been able to build a model that constitutes ...

Protein regulates vitamin A metabolic pathways, prevents inflammation

October 23, 2017
A team of researchers from Case Western Reserve University School of Medicine have discovered how uncontrolled vitamin A metabolism in the gut can cause harmful inflammation. The discovery links diet to inflammatory diseases, ...

Running on autopilot: Scientists find important new role for 'daydreaming' network

October 23, 2017
A brain network previously associated with daydreaming has been found to play an important role in allowing us to perform tasks on autopilot. Scientists at the University of Cambridge showed that far from being just 'background ...

Long-lasting blood vessel repair in animals via stem cells

October 23, 2017
Stem cell researchers at Emory University School of Medicine have made an advance toward having a long-lasting "repair caulk" for blood vessels. The research could form the basis of a treatment for peripheral artery disease, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.