Every cell in our body contains a clock that helps the cell to adapt to the 24-hour circadian rhythm and changes in the environment. If the clocks go haywire and get out of sync, this can strongly affect our health. Joseph Bass, a researcher from the United States, is tracking down the molecular mechanism behind the cellular timepiece to create new and innovative therapies for such diseases and conditions as diabetes, obesity, autoimmunity and cancer.
In the past decade, two trends have shaken the world’s health systems. Today, more than one third of the global population is overweight or obese, and at least one third of the children born in 2000 or later will develop diabetes in their lifetime. Although the lack of physical exercise and inappropriate diet are important reasons for this epidemic, new research suggests that disorder in the body’s biological clock also plays a major role.
“Our circadian clocks collect the information that enables the body to regulate its systems in relation to when the sun rises and sets. We have shown that mice are better at switching on the genes that are important for optimizing their muscle function at night. Mice are nocturnal creatures, but we speculate that this applies to humans during the day. If we can learn to understand the mechanisms behind these clocks, we may also be able to learn to reset them if they malfunction,” explains Joseph Bass, Professor, Feinberg School of Medicine, Northwestern University, Chicago.
Scheduling malfunction
Joseph Bass has been a biology researcher for two decades since Ueli Schibler’s group discovered in 1997 that the circadian clock was not just located in the brain but throughout the body, even in skin cells. His search to understand how the body’s clocks synchronize resulted in 2005 in his group being able to connect a network of clocks directly to the body’s physiology. When the clocks were out of sync, the incidence of obesity and metabolic syndrome increased substantially.
“If we switched off the genes regulating the circadian clock in mice, this not only disturbed their sleep but also their entire physiology. They consumed much more food during the day, when they would usually have been less active. This led to a 35% increase in their stored fat. Their blood glucose regulation was similarly imbalanced, and they had classic signs of metabolic syndrome.”
Ever since, Joseph Bass and his colleagues have attempted to understand these biological clocks down to the molecular level. For example, clock mutant mice react inappropriately to specific neuropeptides such as ghrelin and orexin that control sleep and feeding. It has long been known that the body has a master clock located in the hypothalamus but not how this clock synchronizes with the various clocks in other cells in the body.
“When these clocks get out of sync with the master clock, several diseases such as diabetes clearly result. We have shown that pancreatic beta cells need to be regulated by a clock to produce insulin, and we have now also discovered the set of genes in the pancreas that the clock regulates. The next logical step is to learn how to influence how the clocks are controlled to perhaps normalize the secretion of insulin.”
Linked to ageing
Desynchronized clocks can thus result in human physiology not being regulated correctly in relation to light and dark. It is too early to determine whether this desynchronization is caused by poor diet, lack of exercise or too little sleep in modern society. Nevertheless, this new knowledge on the circadian clocks is very important for when we decide to eat and take medicine to combat the symptoms of disease, such as the time when insulin functions optimally to regulate the blood glucose of people with diabetes.
“This new knowledge on the circadian clocks has already helped to improve people’s health. Many current drugs work best when they are taken at the right time. For example, drugs to lower cholesterol work best at night because of the peak concentrations of the enzymes the drugs affect. The same applies to the use of aspirin to reduce blood clotting.”
The importance of these clocks for our health has led to the creation of a whole new discipline, chronopharmacology, which involves research into the importance of the clocks for treatment. Joseph Bass also thinks that we have currently only seen the tip of the iceberg. He has intensified his search for new molecular targets in the body’s many different clocks and hopes to discover possible targets for treating not only diabetes and obesity but also cancer and autoimmune diseases – and perhaps ageing.
“All living organisms contain the coenzyme nicotinamide adenine dinucleotide: NAD. Our experiments have shown that NAD is crucial for regulating the body’s clocks, for how food is metabolized and for how old we become. We are now attempting to understand this interaction between ageing, diet and the body’s clocks to determine whether there is a master key to understanding why and how we age and whether we can influence these processes,” concludes Joseph Bass.
Joseph Bass gave a presentation at the Copenhagen Bioscience Conferences in October 2017. The Copenhagen Bioscience Conferences are a Novo Nordisk Foundation initiative. “Circadian time signatures of fitness and disease” was published in Science in November 2016. “Circadian transcription from beta cell function to diabetes pathophysiology” was published in Journal of Biological Rhythms in August 2016.
