̽��ֱ�� of Cambridge - Ewan St. John Smith

Ageing: can we add more life to our years?

jg533 — Wed, 20 Dec 2023 08:59:28 +0000

Research advances at the ̽��ֱ�� of Cambridge mean that the eternal quest to reverse the march of time may soon become a reality.

Mole-rats: meet the Ugly Naked Guys

jg533 — Tue, 06 Sep 2022 08:38:57 +0000

Understanding their weirdness could help prevent and better treat human illnesses like arthritis and cancer.

Nature’s epidural: Genetic variant may explain why some women don’t need pain relief during childbirth

cjb250 — Tue, 21 Jul 2020 15:00:21 +0000

Childbirth is widely recognised as a painful experience. However, every woman’s experience of labour and birth is unique, and the level of discomfort and pain experienced during labour varies substantially between women.

A collaboration between clinicians and scientists based at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH), and the ̽��ֱ�� of Cambridge sought to investigate why some mothers report less pain during labour.

A group of women was recruited and characterised by the team led by Dr Michael Lee from the ̽��ֱ��’s Division of Anaesthesia. All the women had carried their first-born to full term and did not request any pain relief during an uncomplicated vaginal delivery. Dr Lee and colleagues carried out a number of tests on the women, including applying heat and pressure to their arms and getting them to plunge their hands into icy water.

Compared to a control group of women that experienced similar births, but were given pain relief, the test group showed higher pain thresholds for heat, cold and mechanical pressure, consistent with them not requesting pain relief during childbirth. ̽��ֱ��researchers found no differences in the emotional and cognitive abilities of either group, suggesting an intrinsic difference in their ability to detect pain.

“It is unusual for women to not request gas and air, or epidural for pain relief during labour, particularly when delivering for the first time,” said Dr Lee, joint first author. “When we tested these women, it was clear their pain threshold was generally much higher than it was for other women.”

Next, senior co-author, Professor Geoff Woods, and his colleagues at the Cambridge Institute for Medical Research sequenced the genetic code of both groups of women and found that those in the test group had a higher-than-expected prevalence of a rare variant of the gene KCNG4. It’s estimated that one approximately 1 in 100 women carry this variant.

KCNG4 provides the code for the production of a protein that forms part of a ‘gate’, controlling the electric signal that flows along our nerve cells. As the joint first author Dr Van Lu showed, sensitivity of this gatekeeper to electric signals that had the ability to open the gate and turn nerves on was reduced by the rare variant.

This was confirmed in a study involving mice led by Dr Ewan St. John Smith from the Department of Pharmacology, who showed that the threshold at which the ‘defective’ gates open, and hence the nerve cell switches ‘on’, is higher – which may explain why women with this rare gene variant experience less pain during childbirth.

Dr St. John Smith, senior co-author, explained: “ ̽��ֱ��genetic variant that we found in women who feel less pain during childbirth leads to a ‘defect’ in the formation of the switch on the nerve cells. In fact, this defect acts like a natural epidural. It means it takes a much greater signal – in other words, stronger contractions during labour – to switch it on. This makes it less likely that pain signals can reach the brain.”

“Not only have we identified a genetic variant in a new player underlying different pain sensitivities,” added senior co-author Professor Frank Reimann, “but we hope this can open avenues to the development of new drugs to manage pain.”

“This approach of studying individuals who show unexpected extremes of pain experience also may find wider application in other contexts, helping us understand how we experience pain and develop new drugs to treat it,” said Professor David Menon, senior co-author.

̽��ֱ��research was support by the Addenbrooke’s Charitable Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome, Rosetrees Trust and the BBSRC.

Reference
Lee, M.C. et al (2020). Human labour pain is influenced by the voltage-gated potassium channel Kv6.4 subunit. Cell Reports; 21 July 2020; DOI: 10.1016/j.celrep.2020.107941

Women who do not need pain relief during childbirth may be carriers of a key genetic variant that acts a natural epidural, say scientists at the ̽��ֱ�� of Cambridge. In a study published today in the journal Cell Reports, the researchers explain how the variant limits the ability of nerve cells to send pain signals to the brain.

This [variant] acts like a natural epidural. It means it takes a much greater signal – in other words, stronger contractions during labour – to switch it on. This makes it less likely that pain signals can reach the brain

Ewan St. John Smith

u_njsabyvh

Mother and newborn baby

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Public Domain

Secrets of naked mole-rat cancer resistance unearthed

jg533 — Wed, 01 Jul 2020 15:00:00 +0000

Understanding how these remarkable animals are almost completely immune to cancer could improve our understanding of the early stages of the disease in people and lead to new ways to prevent or better treat it.

Until now, it was thought that naked mole-rats almost never got cancer because their healthy cells were resistant to being converted into cancer cells. However, researchers at the ̽��ֱ�� of Cambridge have shown for the first time that genes known to cause cancer in cells of other rodents can also lead naked mole-rat cells to become cancerous. ̽��ֱ��results are published today in the journal Nature.

This finding suggests that what sets naked mole-rats apart is the microenvironment - the complex system of cells and molecules surrounding a cell, including the immune system. ̽��ֱ��researchers believe interactions with this microenvironment are what stops the initial stages of cancer from developing into tumours, rather than a cancer resistance mechanism within healthy cells as previously thought.

Dr Walid Khaled, one of the senior authors of the study from the ̽��ֱ�� of Cambridge's Department of Pharmacology, said: “ ̽��ֱ��results were a surprise to us and have completely transformed our understanding of cancer resistance in naked mole-rats. If we can understand what’s special about these animals’ immune systems and how they protect them from cancer, we may be able to develop interventions to prevent the disease in people.”

Naked mole-rats (Heterocephalus glaber) are burrowing rodents native to East Africa. They can live for up to 37 years and are highly cancer resistant, with only a few cases ever observed in captive animals. Other unusual traits that have made them of interest to science include being the only cold-blooded mammal, lacking pain sensitivity to chemical stimuli in their skin and being able to withstand very low levels of oxygen (hypoxia).

In the study, the researchers analysed 79 different cell lines, grown from five different tissues (intestine, kidney, pancreas, lung and skin) of 11 individual naked mole-rats. They infected cells with modified viruses to introduce cancer causing genes. These genes are known to cause cancer in mice and rat cells, but were not expected to be able to transform naked mole-rat cells into cancer cells.

Fazal Hadi, lead researcher of the study from the Cancer Research UK Cambridge Centre, said: “To our surprise, the infected naked mole-rat cells began to multiply and rapidly form colonies in the lab. We knew from this accelerated growth that they had become cancerous.”

̽��ֱ��team then injected these cells into mice, and within weeks, the mice formed tumours. This striking result indicates that the environment of the naked mole-rat’s body prevents the cancer from developing, contradicting previous studies that suggested that an inherent feature of naked mole-rat cells stopped them turning cancerous in the first place.

̽��ֱ��scientists will now continue to investigate the mechanisms by which naked mole-rats stop cancer cells from developing into tumours. One avenue of particular interest is the unique immune system of naked mole-rats, as our immune systems play a critical role in protecting us from cancer and this power has already been effectively exploited in modern immunotherapy treatments.

Dr Ewan St. John Smith, one of the senior authors of the study from the ̽��ֱ�� of Cambridge's Department of Pharmacology said: “All our work with naked mole-rats, from studying their hypoxia resistance to pain insensitivity and cancer resistance, is aiming to leverage the extreme biology of this species to understand more about how our bodies work normally.”

This research was funded by Cancer Research UK.

Reference: Hadi, F. et al; 'Transformation of naked mole-rat cells,' Nature, July 2020. DOI: 10.1038/s41586-020-2410-x

Adapted from a press release by Cancer Research UK.

Naked mole-rats can live for an incredibly long time and have an exceptional resistance to cancer thanks to unique conditions in their bodies that stop cancer cells multiplying, according to new research.

If we can understand what’s special about these animals’ immune systems and how they protect them from cancer, we may be able to develop interventions to prevent the disease in people

Walid Khaled

Meghan Murphy, Smithsonian’s National Zoo, on Flickr

Naked mole rat

Yes

Licence type:

Attribution

Joint lubricating fluid plays key role in osteoarthritic pain, study finds

ta385 — Thu, 15 Aug 2019 06:00:00 +0000

Osteoarthritis is the most common form of arthritis. It causes joint pain and stiffness, and in some people swelling and tenderness of the joints. ̽��ֱ��condition affects an individual’s quality of life and costs millions to the global economy, both directly in terms of healthcare costs and indirectly due to impact on the individual’s working life.

Osteoarthritis tends to occur later in life and has been largely considered as a degenerative disorder in which pain is produced by damage and wear and tear to bone and cartilage. However, in recent years it has become clear that osteoarthritis is not restricted to cartilage damage, but is a failure of the entire joint, with inflammation – the body’s response to stress and injury – being a major contributor to the pain experienced by patients. A recent collaboration between the two pharmaceutical companies Pfizer and Eli Lilly has found that their anti-inflammatory drug, tanezumab, produced pain relief for osteoarthritic patients in a phase 3 clinical trial.

When inflammation occurs during osteoarthritis, the body produces an increased number of cells within and around the joint. These cells release inflammatory substances into the synovial fluid, the lubricant that allows joints to move smoothly. During osteoarthritis, synovial fluid becomes less viscous and these inflammatory substances come into direct contact with sensory nerve cells in the joint, producing the sensation of pain.

In a study published on 13 August 2019 in the journal Rheumatology, researchers at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals, examined whether synovial fluid produced during osteoarthritis is capable of directly exciting sensory nerves supplying knee joints – those nerves responsible for transmitting pain signals.

“Osteoarthritis can be a very painful condition, but we only know a little about what causes this pain,” says Sam Chakrabarti, a Gates Cambridge Scholar. “We wanted to investigate what was happening in the joint and to see whether it was the lubricant that ordinarily keeps these joints moving that was contributing to the pain. Studies such as these are important in helping us develop better treatments.”

̽��ֱ��researchers obtained synovial fluid from consenting osteoarthritis patients at Addenbrooke’s Hospital and from post-mortem donors with no known joint disease. They then incubated knee sensory nerves isolated from mice in either healthy or osteoarthritis synovial fluid and recorded the activity of these nerves.

̽��ֱ��team found that when incubated with osteoarthritic synovial fluid, the knee nerves were more excitable. ̽��ֱ��nerves also showed an increase in the function of TRPV1, a molecule that detects the hotness of chilli peppers (TRPV1 is also activated by heat, which is why chillis tastes hot). Although the presence of inflammatory chemicals in osteoarthritis synovial fluid has been known since 1959, this is the first evidence that synovial fluid can directly excite sensory nerves and hence is an important contributor to an individual’s experience of pain.

“This is the first time we have been able to use synovial fluid from human osteoarthritis patients to excite sensory nerve cells, making it more clinically-relevant than mouse studies alone, and so will hopefully help translating treatments from bench to bedside,” says Dr Ewan St John Smith from the Department of Pharmacology at the ̽��ֱ�� of Cambridge.

“In the future, this set up can be used to identify the specific components of synovial fluid that cause pain and then to test if and how a drug will be useful in arthritic pain. Since synovial fluid is regularly collected from arthritic patients as part of their treatment regime, our technique can be easily set up in laboratories throughout the world to understand and help to identify a cure for arthritic pain.”

Dr Deepak Jadon, Director of the Rheumatology Research Unit at Cambridge ̽��ֱ�� Hospitals, adds: “This study highlights how much we can learn with the help of our patients, as well as the importance of collaboration between clinicians and basic scientists.”

̽��ֱ��research was funded by Versus Arthritis and the Gates Cambridge Trust.

Reference

Chakrabarti, S et al. Human osteoarthritic synovial fluid increases excitability of mouse dorsal root ganglion sensory neurons: an in-vitro translational model to study arthritic pain. Rheumatology; 13 August 2019; DOI: 10.1093/rheumatology/kez331

A team at the ̽��ֱ�� of Cambridge has shown how, in osteoarthritis patients, the viscous lubricant that ordinarily allows our joints to move smoothly triggers a pain response from nerve cells similar to that caused by chilli peppers.

In the future, this set up can be used to identify the specific components of synovial fluid that cause pain

Ewan St John Smith

Courtesy for Jamelah e. under CC license

Researcher profile: Sampurna Chakrabarti

Around the time that Sam Chakrabarti graduated from the ̽��ֱ�� of Buffalo, the State ̽��ֱ�� of New York, the US was caught in the middle of the opioid crisis, in part because these addictive pain killers were being over-prescribed. Spurred on by the crisis, Sam joined the lab of Dr Ewan St John Smith at Cambridge as a Gates Cambridge Scholar, eager to improve the lives of other by furthering the understanding of pain pathways. “I want my research to contribute towards a world where pain relief is safe and affordable, a world where the reason people take time off work is to go on vacation, not because they are in excruciating pain,” she says.

Originally from Kolkata, India, Sam is interested in finding better ways of studying painful knee arthritis to help identify drug targets. Arthritis affects millions of people worldwide, but patients often receive inadequate pain relief. A major reason for this is the lack of understanding of the basic biology underlying the disease, but Sam recognizes that tackling arthritic pain will require a much broader approach than basic science.

“I hope my research will lead to an understanding of pain that crosses many disciplines and breaks down the language barrier between psychologists, biologists and computer scientists,” she says. “Pain is complex and manifests at multiple levels – a way to understand a phenomenon like this should also be multidisciplinary.”

Sam has been at Cambridge since 2016, during which time she says: “I have met more fascinating, inspiring and engaging people than in my entire life. At Cambridge I feel I am a part of the quest for knowledge that transcends grades and papers, but reflects our innate curiosity.”

Yes

Licence type:

Attribution-Noncommercial-ShareAlike

Pain in the machine: a Cambridge Shorts film

amb206 — Wed, 02 Nov 2016 08:00:00 +0000

Pain is vital: it is the mechanism that protects us from harming ourselves. If you put your finger into a flame, a signal travels up your nervous system to your brain which tells you to snatch your finger away. This response isn’t as simple as it sounds: the nervous system is complex and involves many areas of the brain.

We’re developing increasingly sophisticated machines to work for us. In the future, robots might live alongside us as companions or carers. If pain is an important part of being human, and often keeps us safe, could we create a robot that feels pain? These ideas are explored by Cambridge researchers Dr Ewan St John Smith and Dr Beth Singler in their 12-minute film Pain in the Machine.

Already we have technologies that respond to distances and touch. A car, for example, can detect and avoid an object; lift doors won’t shut on your fingers. But although this could be seen as a step towards a mechanical nervous system, it isn’t the same as pain. Pain involves emotion. Could we make machines which feel and show emotion – and would we want to?

Unpleasant though it is, pain has sometimes been described as the pinnacle of human consciousness. ̽��ֱ��human capacity for empathy is so great that when a robotics company showed film clips of robots being pushed over and kicked, views responded as if the robots were being bullied and abused. Pain is both felt and perceived.

Movies have imagined robots with their own personalities – sometimes cute but often evil. Perhaps the future will bring robots capable of a full range of emotions. These machines might share not only our capacity for pain but also for joy and excitement.

But what about the ethical implications? A new generation of emotionally-literate robots will, surely, have rights of their own

Pain in the Machine is one of four films made by Cambridge researchers for the 2016 Cambridge Shorts series, funded by Wellcome Trust ISSF. ̽��ֱ��scheme supports early career researchers to make professional quality short films with local artists and filmmakers. Researchers Beth Singler (Faculty of Divinity) and Ewan St John Smith (Department of Pharmacology) collaborated with Colin Ramsay and James Uren of Little Dragon Films.

̽��ֱ��pain we experience as humans has physical and emotional components. Could we develop a machine that feels pain a similar way – and would we want to? ̽��ֱ��first of four Cambridge Shorts looks at the possibilities and challenges.

Pain in the machine

Researchers: Beth Singler and Ewan St John Smith

Still from Pain in the Machine

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Naked Mole-Rats: are these rodents immune to cancer?

amb206 — Wed, 02 Sep 2015 09:00:00 +0000

Scroll to the end of the article to listen to the podcast.

‘Bizarre’ is a kinder word than ‘ugly’ and may be a more accurate description when it comes to a rodent with remarkable attributes. ̽��ֱ��naked mole-rat might look a bit like a raw sausage with protruding teeth but its behaviour and physiology are fascinating.

Zoologists first began to explore the unusual lifestyle of the naked mole-rat in the 1970s, identifying it as the only known mammal to be ‘eusocial’. Rather like bees, naked mole-rats live in colonies in which powerful ‘queens’ control groups of as many as 300 animals.

Researchers soon discovered that this small animal, which is native to East Africa and lives exclusively underground, packs a number of other surprises. It is unique among mammals in being poikilothermic (cold blooded) and is extremely efficient in its use of resources.

When the naked mole-rat finds a calorie-packed underground tuber, it eats what it needs and then covers the tuber with soil so that it can continue growing, meaning that the naked mole-rat, like humans, farms its crops.

Now neuroscientists and others are focusing on the ways in which the naked mole-rat differs from other rodents (such as mice) in other unique respects as a means of understanding conditions such as ageing, cancer and pain.

Dr Ewan St. John Smith, a researcher in the Department of Pharmacology, is one of only two scientists in the UK to hold a Home Office licence that allows his group to keep and study naked mole-rats in laboratory conditions.

Naked mole-rats are not hard to keep – but they are difficult to breed successfully. Smith describes them as surprisingly endearing. “If you hold a mouse in the palm of your hand, it will often try to escape or pee on you! Naked mole-rats are really playful.”

Smith has been studying the naked mole-rat for the past ten years, moving from a broad interest in the animal’s peripheral sensory system (e.g. how the animals detect noxious stimuli) to focus on molecular and cellular mechanisms that enable healthy brain function throughout their long lives.

By understanding the physiology of the naked mole-rat, and its differences with that of mice, Smith and colleagues are helping to pinpoint mechanisms that might, in the future, help clinicians to treat human conditions.

Just one of the significant differences between naked mole-rats and other small rodents is their long and healthy life span: typically they live for 30 years against an average of two to three years for mice.

“Naked mole-rats age quickly right at the end of their lives – and the females remain fertile right to the end, sometimes producing as many as 20 offspring in a single litter,” said Smith.

An apparent resistance to the cancers which shorten the average lives of most mammals is likely to be a key reason for this longevity. “At this point in time, it might be an overstatement to suggest that naked mole-rats don’t get cancer,” says Smith.

“What we can say is that none of the animals examined in the course of autopsy studies in both zoos and research institutes has been shown to have a tumour. We can’t be completely sure they don’t develop cancer, but it’s certainly true that they are resistant to change on a cellular level.”

Another claim often made about naked mole-rats is that they don’t feel pain. Again, this is only partly true.

“Naked mole-rats do feel pain in response to stimuli such as heat and mechanical threats just as mice do,” says Smith. “But, unlike most other mammals, they do not react to acid-induced pain such as lemon juice, nor do they experience the burning sensation induced by capsaicin – the chemical found in chillies that produces their hotness.”

̽��ֱ��naked mole-rat’s resistance to acid-induced pain is thought to stem from its underground life style: the labyrinths of burrows in which colonies live are high in carbon dioxide and low in oxygen. Carbon dioxide produces acid when it mixes with bodily fluids and naked mole-rats have developed an insensitivity to acid-induced pain, which enables them to live in a habitat that to many other mammals would be toxic.

In a study published in 2011, Smith and colleagues discovered that the acid-insensitivity is likely to be the result of a variation in a protein that is responsible for sending electric signals in nerves from the periphery to the spinal cord. ̽��ֱ��naked mole-rat version of this protein is switched off by acid, which, like a local anaesthetic at the dentist, then prevents painful signals reaching the central nervous system.

“Identification of the differences between how the nervous system functions on a molecular level between species is the key to understanding more about the incredibly complex ways in which the human nervous system functions – and may, in the long term, help us to set targets for the development of new therapies for treatment of conditions such as chronic pain,” said Smith.

Next in the Cambridge Animal Alphabet: O is for a bird that is inspiring physicists to make wind turbines that are more efficient and less noisy.

Have you missed the series so far? Catch up on Medium here.

Inset images: Naked mole-rats (Ewan St. John Smith).

The Cambridge Animal Alphabet series celebrates Cambridge's connections with animals through literature, art, science and society. Here, N is for Naked Mole-Rats, which won't win any beauty contests, but can live for 30 years and may be able to help in the development of new therapies for chronic pain.

It’s certainly true that they are resistant to change on a cellular level

Ewan St. John Smith

Playful naked mole-rats

Ewan St. John Smith

Naked Mole-rat

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes