Author Archives: The Physiological Society

About The Physiological Society

The Physiological Society brings together over 3,500 scientists from over 60 countries. Since its foundation in 1876, its Members have made significant contributions to our knowledge of biological systems and the treatment of disease. We promote physiology and support those working in the field by organising world-class scientific meetings, offering grants for research, collaboration and international travel, and by publishing the latest developments in our leading scientific journals, The Journal of Physiology, Experimental Physiology and Physiological Reports.

Wikipedia, women, and science

Every second, 6000 people across the world access Wikipedia. The opportunity to reach humans of the world is enormous. Perhaps unsurprisingly, many eminent scientists, especially eminent female scientists, don’t have pages!

Melissa Highton is on a mission to fix this. Her first step was bringing together a group of students and librarians for an Edit-a-thon to update the page of the first female students matriculated in the UK, who started studying medicine at the University of Edinburgh. They’re known as the Edinburgh Seven.

Not only do Edit-a-thons provide information for the world, the Edinburgh Seven serve as role models for current students studying medicine at the University of Edinburgh.

Melissa shines light on Wikipedia being skewed towards men, and also on structural inequalities that lead to so few women having pages. Women are often written out of history; they are the wives of famous someones who get recognised instead, they get lost in records because they change their last name, or they juggle raising a family, meaning they don’t work for as long or publish as much.

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Having a forum to talk openly and transparently about these inequalities is one of the steps to closing the gap. Our event for Physiology Friday 2017 did just that, and we hope participants will continue the conversation. Listen to Melissa’s talk here.

 

Diet, exercise or drugs – how do we cure obesity?

by Simon Cork, Imperial College London, @simon_c_c

October 11th is officially “World Obesity Day”, a day observed internationally to promote practical solutions to end the obesity crisis. The term “obesity crisis” or “obesity epidemic” is often repeated by the media, but how big is the problem? Today, over 1.9 billion adults worldwide are overweight or obese. By 2025, this is projected to increase to 2.7 billion with an estimated annual cost of 1.2 trillion USD. Of particular concern is that 124 million children and adolescents worldwide are overweight or obese. In the UK, this equates to 1 in 10 children and adolescents and is projected to increase to 3.8 million by 2025. We know that obesity significantly raises the risk of developing 11 different types of cancer, stroke, type 2 diabetes, heart disease and non-alcoholic fatty liver disease, but worryingly, we now know that once someone becomes obese, physiological changes to the body’s metabolism make long-term weight loss challenging.

Our understanding of the physiology of food intake and metabolism and the pathophysiology of obesity has grown considerably over the past few decades. Obesity was seen, and often still is seen, as a social problem, rather than a medical issue: a lack of self-control and willpower. We now know that physiological changes occur in how our bodies respond to food intake. For example, hormones which are released from the gut following food intake and signal to the brain via the vagus nerve normally reduce food intake. However, in obesity, the secretion of these hormones is reduced, as is the sensitivity of the vagus nerve. The consequence of this is a reduced sensation of feeling full.

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Imaging of the hypothalamus (a key region for keeping food intake at a balanced level) shows a reduction in activity following food intake in lean men, an effect which was absent in obesity. This effect may relate to a reduction in the body’s responses observed following food intake in obesity, such as balancing blood sugar and signalling that you are full. Furthermore, numerous studies have shown that obese individuals have a reduced availability of dopamine receptors, the structures on cells that respond to the pleasure chemical dopamine, in key brain regions associated with reward. Whether the reduction in dopamine receptor availability is a cause or consequence of obesity remains to be fully explored, but it is likely to be a combination of both of these factors. Individuals with a gene called the Taq1 A1, associated with a decreased availability of dopamine receptors, are more likely to become obese, suggesting that decreased responsiveness to high calorie foods leads to increased consumption in order to achieve the same level of reward. (Interestingly, this same gene is also associated with an increased risk of drug addiction). However, much like drug addiction, hyper-stimulation of the dopamine system (i.e. by consuming large quantities of dopamine-secreting, high calorie foods) can in turn lead to a reduction in dopamine receptor levels, thus creating a situation where more high calorie foods are required to stimulate the same level of reward.

It is therefore clear that obesity is not simply a manifestation of choice, but underpinned by complex changes in physiology which promote a surplus of food consumption, called positive energy balance. From an evolutionary standpoint, this makes sense, as maintaining a positive energy balance in times of abundant food would protect an individual in times of famine. However, evolution has failed to keep up with modern society, where 24-hour access to high calorie foods removes the threat of starvation. The good news is that we know that weight loss as small as 5% can yield significant improvements in health, and can often be managed without significant modification to lifestyle.

 

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Presently, treatment options for obesity are limited. The first line treatment is still diet and exercise; but as the above examples of how our physiology changes show, maintaining long term weight loss through self-control alone is almost always impossible. However, the future does look bright, with new classes of drugs either recently licenced, or in production. Saxenda (a once-daily injectable drug which mimics the gut hormone GLP-1 made by Novo Nordisk) has recently been licenced for weight loss in patients with a BMI greater than 30. However, after 56 weeks treatment, average weight loss was a modest 8kg. Likewise Orlistat (which inhibits absorption of dietary fat, made by Roche) has been on the market for a number of years and shows average weight loss of around 10%. However, it is associated with unpleasant side effects, such as flatulence and oily stools. Presently, bariatric surgery is the only treatment that shows significant, long term weight loss (around 30%, depending on the surgical method used) and is also associated with long-term increases in gut hormone secretion and vagus nerve sensitivity.  Research is currently underway to assess whether the profile of gut hormones observed post-surgery can be mimicked pharmacologically. Studies have shown that administering select gut hormones in combination results in a reduction in body weight and food intake greater than the sum of either hormone when administered in isolation. This observed synergy between gut hormones will undoubtedly form the basis for future pharmacotherapies with improved efficacy, with various combinations currently in both clinical and pre-clinical trials.

For healthcare policy makers, the future obesity landscape does not make for happy reading. A combination of better therapies and improved public health messages are undoubtedly needed to stem the rising tide. However, both policy makers and society as a whole should be mindful that changes in ones physiology mean maintaining long-term weight loss through diet and exercise alone are unlikely to be the whole answer.

Nobel Prize 2017: Our 24 hour body clock

By Professor Hugh Piggins
Professor of Neuroscience, The University of Manchester

The winner of the Nobel Prize in Physiology or Medicine was announced today (Monday 2nd October). Physiologist Hugh Piggins of the University of Manchester explains why the research is vital to understanding how our bodies respond to health and disease.

The Nobel Prize winning research by Jeffrey Hall, Michael Rosbash and Michael Young has transformed our understanding of how our bodies work.

In simple terms, they have discovered that molecules in our body have a clock that represents a 24 hour day. They first found this in fruit flies in the 1980s and then later other researchers showed that these fundamental components were also present in cells and tissues of mammals, including humans.

All mammals have a master clock in the brain that receives input from the eye that synchronises it to day and night. We now know that, having evolved on a planet with changing conditions across roughly a 24 hour cycle, our bodies are designed to anticipate when these changes should happen. Thus the 24 hour cycle is called our circadian rhythm and we all feel the impact of this, for example, when our bodies signal to us in the morning and we find ourselves awake just before our alarm clock.

As so much of our brain and body relies on this 24 hour rhythm, it needs to be kept in good order to ensure optimum health. As our bodies are programmed to operate in 24 hour periods then deviation from this can cause problems.

This is felt by shift workers or those suffering from jet lag. The result of forcing our body to operate abnormally means our internal clock clashes with external signals. This means the body is not ready and we see the sometimes tragic consequences of this with industrial accidents more likely to occur with those working long shifts.

Longer term, this disruption in the body clock causes health issues such as obesity or heart disease. There is lots of evidence to show that night shift workers are at greater risk of developing obesity, partly due to the fact that night shift patterns disrupt the metabolism and sleep cycles of employees.

This research also points the way towards new treatment routes. Now that we know the disruption of these clocks can cause illness, it opens the door to targeting particular components of the clock to stop the development of disease. There is also evidence that the body can be more sensitive to certain drugs at specific times of the day, which could help us deliver more effective treatments.

Finally, our internal clock changes over time, which means a teenager’s clock runs differently to that of an older person. By recognising this biological reality and, for example, changing school start times, there is increasing evidence that the performance of school pupils will improve.

This is an exciting and important area of scientific research. It highlights why an understanding our daily physiology –the science of biological timekeeping – is vital to understanding how our bodies respond to health and disease.

More information about this year’s Nobel Prize in Physiology or Medicine is available on the Nobel Prize website.

Watchers on the wall: Microglia and Alzheimer’s Disease

By Laura Thei, University of Reading, UK

The watch, worn by years of use, sits ticking on our table for the first time in two years. It has a simple ivory face and is the last memorabilia my partner has from Grandad Percy. Percy passed from us after a long personal battle with dementia, specifically Alzheimer’s disease. It is in his name that my partner and I will take to the beautiful winding pathways beside the Thames, to raise money for the Alzheimer’s Society.

We will be taking part in a 7 km Memory Walk, with thousands of others, some my colleagues from the University, each sponsored generously by friends and families, each who has had their life touched by this disease in some way. Last year nearly 80,000 people took part in 31 walks, raising a record £6.6 million. As a researcher in Alzheimer’s disease, I am acutely aware of every penny’s impact in helping to solve the riddle of dementia.

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Alzheimer’s Society Memory Walk

Alzheimer’s disease is ridiculously complicated. Oh, the premise is simple enough: two proteins, amyloid beta and phosphorylated tau, become overproduced in the brain and start to clog up the cells like hair down a plug. This causes these cells to be deprived of nutrients, oxygen and other vital factors that keep them alive. This eventually causes regional loss in areas specific to memory and personality. It’s simple in theory, but the reality is that we still have much to learn.

Current, extensive research is starting to answer these questions and whilst there is a growing list of risk factors – genetic (APOE4, clusterin, presenilin 1 and 2) and environmental (age, exercise, blood pressure) – confirmation only occurs when a brain scan shows the loss of brain region volume in addition to the presence of amyloid beta and tau. This means that by the time someone knows they have the disease, it’s possible that it’s already been chugging away at their brains for some time.

So we need to push diagnoses earlier. To do that we need to look at the very early stages of the disease, down to a cellular level, to find out how we can prevent the build-up of amyloid and tau in the first place. This is what I, the group I’m in, and many other researchers nationally and globally are striving to do.

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In a non-active state, microglia lie quietly surveying their local area of the brain. ©HBO

I am specifically focusing on the immune cells of the brain, microglia, and their contribution. Microglia are the most numerous cells in the brain. They act as the first line of defence, so their involvement and activation is often seen as an early sign of disease progression. Like all good defences, they tend to be alerted to damage before it becomes deadly. But, like the neurons (the basic building blocks of the brain), microglia are also susceptible to the disease. If they die, does that leave the brain more vulnerable to further insult? That is what I would like to know too!

In a non-active state, microglia lie quietly surveying their local area of the brain. When activated by a threat to the brain, they cluster around the targeted area, changing shape in the process. They then enter one of two states. The pro-inflammatory state releases molecules that attack the harmful pathogens directly, and the anti-inflammatory state releases ones that promote healing and protection of the area.

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Microglia can change shape to either attack pathogens or protect the area. ©Nickelodeon

With Alzheimer’s, microglia are activated by the accumulation of amyloid, not damage. They absorb the amyloid beta, and in the process, trigger the pro-inflammatory response. This then increases the permeability of the brain’s blood supply, allowing immune cells into the brain to assist removal of the excess protein. However, in the brain of Alzheimer’s patients, the amyloid beta production outdoes the microglia’s ability to remove it. This creates a perpetual cycle of pro-inflammatory response, releasing molecules that can kill cells in the brain. It is unclear whether there is a threshold between beneficial or detrimental in the microglial response.

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Microglial response to fight Alzheimer’s Disease can become detrimental. ©2011 Scott Maynard

Given the importance of microglia in neurodegenerative diseases, a new field of microglial therapeutics has recently emerged, ranging from pharmacologically manipulating existing microglia by switching their response status, to inhibiting microglial activation altogether. Continued research and clinical efforts in the future will help us to improve our understanding of microglial physiology and their roles in neurological diseases.

We’re making progress, but there’s still a long way to go, which is why every penny counts!