Category Archives: Science news

Supporting breathing in muscular dystrophy

By David P Burns and Ken D O’Halloran, Department of Physiology, University College Cork, Ireland

The respiratory system plays a very important role in maintaining oxygen levels within our blood. The supply of oxygen to our body is necessary to allow the cells in our body to make and use energy (a process called metabolism).

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Respiratory muscle from mdx mice displays signs of muscle damage. When dystrophin is absent from muscle, muscle fibres become damaged during normal cycles of muscle contraction and relaxation. Over time, damaged muscle becomes replaced by fat cells and there is an accumulation of connective tissue resulting in further muscle weakness and hardening of the tissue.

The respiratory system is an integrated organ system that relies on input from our central nervous system (brain and spinal cord). Motor nerves project from our central nervous system and send electrical signals, called action potentials, to our respiratory muscles. These signals activate our respiratory muscles, including the diaphragm (the main pump muscle of breathing) and intercostal muscles, resulting in contraction of these important muscles. The diaphragm and external intercostal muscles contract during inspiration, allowing a negative pressure to be generated within the respiratory system. This negative inspiratory pressure draws air from the atmosphere into our lungs. In our lungs, oxygen that has entered from the atmosphere enters our blood and is transported around our body to our cells. The same system is crucial for the excretion of carbon dioxide, a by-product of cellular metabolism, during expiration.

Poor performance or weakness of our respiratory muscles can result in impaired respiratory function, limiting how much air enters and leaves our lungs. Respiratory muscle weakness can occur due to a loss of muscle mass, such as in cancer cachexia and age-related sarcopenia.

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Recording of the electrical activity of diaphragm muscle (electromyogram) in an anaesthetised mouse.

Breathing with neuromuscular disease

Researchers at University College Cork in Ireland are focusing on respiratory muscles and how they are controlled by the central nervous system in neuromuscular diseases such as muscular dystrophy. Duchenne muscular dystrophy (DMD) is a genetic disease that causes severe muscle weakness in boys. The diaphragm has reduced strength in DMD due to the absence of an important structural protein found in muscle, called dystrophin. As boys with DMD grow older they have difficulty with their breathing. Initially, this occurs during sleep with the development of sleep-disordered breathing and later problems also present during wakefulness.

Studies led by researchers David Burns and Ken O’Halloran aim to understand the effects of a weakened diaphragm (due to a lack of dystrophin) on respiratory system performance in animal models of muscular dystrophy. Currently, the group is trying to understand ways in which the body can compensate for a mechanically weakened diaphragm muscle, with the aim of enhancing or at least protecting these compensatory mechanisms that support normal breathing.

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Healthy diaphragm muscle is composed of a blend of different types of muscle fibres (shown above as blue, red, black and green muscle fibres). Each muscle fibre type has its own unique characteristics. The blue muscle fibres (Type I) can generate small amounts of force when they contract and are resistant to fatigue. The green fibres (Type IIB) can generate large forces such as those required during coughing or clearing of our airways. Type IIB are not resistant to fatigue. Top left traces show diaphragm electromyogram activity. Bottom right shows diaphragm muscle contractions in response to increasing stimulation frequency.

New research published by the group in The Journal of Physiology (1) has revealed that the capacity of the respiratory system to increase breathing when challenged is preserved in an animal model of muscular dystrophy, the mdx mouse. This is an interesting finding given the diaphragm muscle of mdx mice can generate only half the force of a non-diseased diaphragm.

Compensation to support breathing

To understand how mdx mice can breathe at levels similar to the control group of mice, the group measured the inspiratory pressure generated by the system during normal and near maximal breathing. In order to examine how the central nervous system controls weakened respiratory muscles, the group measured the electrical signals in the diaphragm and intercostal muscles (which were sent along motor nerves from the central nervous system). These unique studies have revealed that although the diaphragm muscle of mdx mice is weakened and displays less electrical activity than the control group of mice, the mdx mice can generate inspiratory pressures similar to control mice. These novel findings reveal a form of compensation that supports breathing in young mdx mice.

Retaining the capacity to generate peak inspiratory pressure during the course of aging and in disease states such as DMD is essential during periods of increased demand on our respiratory systems. Current studies by Burns and O’Halloran aim to understand the specific mechanisms responsible for this compensatory support in young mdx mice and to determine if this compensation is preserved or lost over the course of this progressive disease. Therapeutic and rehabilitative strategies that promote compensatory support of breathing in muscular dystrophy may provide support for maintaining respiratory function in patients as the disease progresses.

References:

  1. Burns DP, Murphy KH, Lucking EF, O’Halloran KD (2019) Inspiratory pressure-generating capacity is preserved during ventilator and non-ventilatory behaviours in young dystrophic mdx mice despite profound diaphragm muscle weakness. The Journal of Physiology 597(3):831-848.

Treating autism spectrum disorders by targeting connections in the brain

By David A. Menassa, @DavidMenassa1, University of Southampton, Neuroscience Theme Lead of The Physiological Society

The United Kingdom has seen a rise in the number of people diagnosed with autism spectrum disorders (ASDs). More recently, some trusts in Northern Ireland have reported a three-fold increase in diagnoses since 2011. Some cases of ASD are linked to a genetic mutation but most of the time, we do not actually know why they occur.

ASD is an umbrella term for disorders characterised by impairments in social interaction and language acquisition, sensory and motor problems and stereotypical behaviours of variable severity according to the Diagnostic and Statistical Manual of Mental Disorders.

Multiple studies report that the physiology and structure of synapses (the gaps between our neurons) are affected in ASDs (1, 2) and that addressing these changes could offer clues for therapy.

The genetic mutations giving rise to different ASDs are predominantly involved in synaptic function. A large-scale analysis of 2000 human brains from individuals with ASDs, schizophrenia and bipolar disorder showed that genes involved in controlling the release of neurotransmitters into the synapse are least active in ASDs (3, 4).

An attempt using the CRISPR/Cas9 gene editing method in a genetic form of ASD known as Fragile-X syndrome (FXS) showed some promise (5). When the researchers turned on a gene that is turned off in this condition, this changed the cells derived from affected individuals from diseased to normal.

Because the number of synapses in ASD post-mortem brains is altered (1), microglia (the brain’s resident immune cells) are thought to be directly involved (as these cells can determine whether synapses stick around) (6-8). Minocycline, which inhibits these microglia, has been used in trials on FXS individuals with promising outcomes including improvements in language, attention and focus as well as an alleviation of core symptoms (9, 10). Furthermore, novel approaches involving inducing microglia to self-destruct (11) or shielding synapses from microglia (12) are being explored. At least in terms of symptom alleviation, addressing synaptic dysfunction and microglia seem to be promising avenues for treatment.

Environmental factors such as changes during pregnancy could contribute to ASD such as the transfer of maternal antibodies against fetal synapses (13) or maternal immune activation (14) or lack of oxygen to the mum or the baby (15). Ways to reduce the risk of injury to the brain with low oxygen in the mum for example have involved delivering antioxidants to the placenta (16). Furthermore, in the early life of the newborn when low oxygen is detected, inhalation of xenon gas combined with cooling also seem to provide promising results that improve neurological outcome (17).

The impact of altered brain development extends beyond the individual influencing their family, carers and the healthcare system. More funding is needed to support this research in order to elucidate the underlying physiology and identify effective treatments.

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This figure illustrates how connections can occur in the ASD brain. Neurons in various colours (black, green and blue) make connections with each other through synapses and some connections are interrupted. Microglia (pink) are near the synapses which we can see in the highlighted squares: in a) a part of the neuron called a dendrite with very few dots on it means there are less synapses than in b) where there are more black dots on the dendrite which means more synapses. These changes represent what we tend to see in post-mortem brain tissue in ASD. Microglia are thought to be involved here by either not clearing away black dots in which case we get more synapses (e.g. typical autism) or by overclearing in which case we have less synapses (e.g. Rett’s syndrome). ASD is otherwise known as a disorder of how connections are established in the brain or a connectivity disorder.

References

  1. Penzes P, Cahill ME, Jones KA, Van Leeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci. 2011;14(3):285-93.
  2. Lima Caldeira G, Peça J, Carvalho AL. New insights on synaptic dysfunction in neuropsychiatric disorders. Curr Opin Neurobiol. 2019;57:62-70.
  3. Zhu Y, Sousa AMM, Gao T, Skarica M, Li M, Santpere G, et al. Spatiotemporal transcriptomic divergence across human and macaque brain development. Science. 2018;362(6420).
  4. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362(6420).
  5. Liu XS, Wu H, Krzisch M, Wu X, Graef J, Muffat J, et al. Rescue of Fragile X Syndrome Neurons by DNA Methylation Editing of the FMR1 Gene. Cell. 2018;172(5):979-92.e6.
  6. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691-705.
  7. Schafer DP, Heller CT, Gunner G, Heller M, Gordon C, Hammond T, et al. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. Elife. 2016;5.
  8. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):1456-8.
  9. Utari A, Chonchaiya W, Rivera SM, Schneider A, Hagerman RJ, Faradz SM, et al. Side effects of minocycline treatment in patients with fragile X syndrome and exploration of outcome measures. Am J Intellect Dev Disabil. 2010;115(5):433-43.
  10. Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell IM, et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 2010;10:91.
  11. Kim HJ, Cho MH, Shim WH, Kim JK, Jeon EY, Kim DH, et al. Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol Psychiatry. 2017;22(11):1576-84.
  12. Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST, Frouin A, et al. CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development. Neuron. 2018;100(1):120-34.e6.
  13. Coutinho E, Menassa DA, Jacobson L, West SJ, Domingos J, Moloney TC, et al. Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero. Acta Neuropathol. 2017;134(4):567-83.
  14. Careaga M, Murai T, Bauman MD. Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol Psychiatry. 2017;81(5):391-401.
  15. Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med. 2007;161(4):326-33.
  16. Phillips TJ, Scott H, Menassa DA, Bignell AL, Sood A, Morton JS, et al. Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development. Sci Rep. 2017;7(1):9079.
  17. Mayor S. Xenon shows promise to prevent brain injury from lack of oxygen in newborns. BMJ. 2010;340:c2005.

Learning a research career is within my reach: Undergraduate Summer Studentship Scheme

By Sara Rayhan, University of Southampton

I received a Summer Studentship in 2017 for a project at the University of Southampton, under the supervision of Felino Cagampang. My project examined the effects of maternal obesity in pregnancy on the placenta, an organ that supplies the foetus with oxygen and nutrients, in mice. More specifically, we measured placental expression of two growth-related genes in obese pregnant mice. One gene is responsible for blood vessel formation (VGEF) and the other (RAPTOR) for the response to nutrient and insulin levels.

Both have been linked to cardiovascular disease. We also examined the effect of maternal metformin treatment in obese pregnancy on the expression levels of these genes in the placenta. Metformin is a drug used to treat gestational diabetes but its effect on the placenta and the developing foetus is unknown. Maternal high fat diet (HFD) during pregnancy reduced VEGF mRNA expression in the placenta depending on MET treatment, while placental RAPTOR expression increases with maternal HFD. These changes in gene expression could alter placental function and foetal development, and have long-term consequences on cardiometabolic health of the offspring. It further suggests that metformin should be prescribed with caution to pregnant women.

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Due to the great deal of guidance given, the project was far less daunting and the workload was more than manageable. I learnt that research is coordinated within a specific lab group, with individual each conducting their own research projects, and feeding back to the team to provide a more holistic understanding. Also, numerous different departments liaise with each other and I had the privilege of being able to attend to these meetings along with conferences held within the hospital. This showed me how a research environment is very much interdisciplinary and relies on understanding how the work presented by others may impact your own research.

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This studentship has given me the opportunity to experience what it means to be a part of a research group and the fundamental impact your work could have and this is something that has very much resonated with me. It’s allowed me to be challenged, but also to gain a greater insight and grow in confidence in my laboratory techniques. Because of this, I now realise that a research-intensive career is not beyond my reach and that it is far less intimidating than I perceived it to be. I am now in the process of considering pursuing a Masters in Biomedical Sciences, and would very much like to pursue a technical laboratory focused career, perhaps in a hospital setting.

(This article was originally published in Physiology News 110, page 43.)

Obesity: hamsters may hold the clue to beating it

Apply by 28 February for our Research Grants of up to £10,000 (over a 12 to 18-month period). This scheme supports physiologists in their first permanent academic position or returning to a permanent position after a career break, to provide support for their research or to provide seed-funding to start a new project. Gisela Helfer was a 2017 awardee of this grant, and you can read about her research below:

The global obesity crisis shows no signs of abating, and we urgently need new ways to tackle it. Consuming fewer calories and burning more energy through physical activity is a proven way to lose weight, but it’s clearly easier said than done. The problem with eating less and moving more is that people feel hungry after exercise and they have to fight the biologically programmed urge to eat. To develop effective ways to lose weight, we need a better understanding of how these biological urges work. We believe hamsters hold some clues.

Hamsters and other seasonal animals change their body and behaviour according to the time of year, such as growing a thick coat in winter or only giving birth in spring. Some seasonal animals can also adjust their appetite so that they aren’t hungry when less food is available. For example, the Siberian hamster loses almost half its body weight in time for winter, so they don’t need to eat as much to survive the winter months. Understanding the underlying physiological processes that drive this change may help us to understand our own physiology and may help us develop new treatments.

How hungry we feel is controlled by a part of the brain called the hypothalamus. The hypothalamus helps to regulate appetite and body weight, not only in seasonal animals but also in humans.

Tanycytes (meaning “long cells”) are the key cells in the hypothalamus and, amazingly, they can change size and shape depending on the season. In summer, when there is a lot of daylight and animals eat more, tanycytes are long and they reach into areas of the brain that control appetite. In winter, when days are shorter, the cells are very short and few.

These cells are important because they regulate hormones in the brain that change the seasonal physiology of animals, such as hamsters and seasonal rats.

Growth signals

We don’t fully understand how all these hormones in the hypothalamus interact to change appetite and weight loss, but our recent research has shown that growth signals could be important.

One way that growth signals are increased in the brain is through exercise. Siberian hamsters don’t hibernate; they stay active during the winter months. If hamsters have access to a running wheel, they will exercise more than usual. When they are exercising on their wheel, they gain weight and eat more. This is true especially during a time when they would normally be small and adapted for winter. Importantly, the increased body weight in exercising hamsters is not just made up of increased muscle, but also increased fat.

We know that the hamsters interpret the length of day properly in winter, or, at least, in a simulated winter day (the lights being on for a shorter duration), because they still have a white winter coat despite being overweight. We now understand that in hamsters the exercise-stimulated weight gain has to do with hormones that usually regulate growth, because when we block these hormones the weight gain can be reversed.

When people take up exercise, they sometimes gain weight, and this may be similar to what happens in hamsters when appetite is increased to make up for the increased energy being burned during exercise. This doesn’t mean that people shouldn’t exercise during the winter, because we don’t naturally lose weight like Siberian hamsters, but it does explain why, for some people, taking up exercise might make them feel hungrier and so they might need extra help to lose weight.

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We need to find ways to overcome appetite. Lucky Business/Shutterstock.com

What we have learned from studying hamsters so far has already given us plenty of ideas about which cells and systems we need to look at in humans to understand how weight regulation works. This will create new opportunities to identify possible targets for anti-obesity drugs and maybe even tell us how to avoid obesity in the first place.

By Gisela Helfer@gi_helfer and Rebecca Dumbell

(This blog was originally published on The Conversation.)

Life Sciences 2019: Post-translational modification and cell signalling

Submit your abstract by 21 January 2019 for this exciting meeting on 17-18 March 2019 in Nottingham, UK. 

By Gary Stephens, member of the Organising Committee

Even after proteins are built via transcription and translation, post-translational modifications (PTMs) can change their function. As this has implications throughout the body – such as neuronal signalling, cardiac function, circadian rhythms and in diseases including cancer and psychiatric disorders – post translational modulations are an expanding area of scientific research. All physiologists looking to innovate their science by networking across disciplines should attend Life Science 2019, brought to you by The Physiological Society, the British Pharmacological Society and the Biochemical Society.

In addition to symposia and plenary lectures, the meeting will have training events and an early career researcher (ECR) networking event. If you’re keen to present your research orally, you’re in luck, as a good number of submitted abstracts will be elevated to oral presentations, in particular from ECRs.

PTMs increase the diversity of the protein function, primarily by adding functional groups to proteins, but can also involve the modification of regulatory subunits, or degradation of proteins to terminate effects. PTMs include numerous biologically vital processes such as phosphorylation, glycosylation, ubiquitination, SUMOylation, nitrosylation, methylation, acetylation, lipidation and proteolysis. Identifying and understanding PTMs within major body systems including neuronal, cardiovascular and immune systems is critical in the study of normal physiological function and disease treatment.

As a researcher interested in synaptic function, one symposium that has immediate personal appeal is “PTMs in the regulation of neuronal synapses” will include how PTMs on both sides of the synapse are fundamental to forms of synaptic plasticity. Matt Gold (University College London, UK) will speak on targeting of the calcium/calmodulin-dependent protein phosphatase calcineurin in postsynaptic spines. Moitrayee Bhattacharyya (University of California, Berkeley, USA) will present about the postsynapse, specifically the role of calcium/calmodulin-dependent protein kinase II in driving synaptic long-term potentiation via modifications in postsynaptic spines. For the ion channel aficionados, Annette Dolphin (University College London, UK) will discuss the role of post-translational proteolytic cleavage of α2δ voltage-gated calcium channel subunits in synaptic function.

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Protein methylation in health and disease will feature a presentation from Steven Clarke, (University of California Los Angeles, USA) on cross-talk between methyltransferases to affect the final degree of protein modification and epigenetic control. Kusum Kharbanda (University of Nebraska, USA) will present about how external stimuli such as the consumption of alcohol has important cellular consequences for methyltransferase activity and the development of disease. Pedro Beltran-Alvarez (University of Hull) will detail the combination of biochemical, cell biology, bioinformatics and proteomics methods used to identify the arginine methylome in tissues including platelets and the heart. This has clear functional importance in physiological cardiovascular function.

We hope to see you in Nottingham!

Friends in high places: Researchers go global for answers at high altitude (Part 2)

By Alexandra Williams, @AlexM_Williams

This blog is the second and final part of a series that began here.

Experience

1 July 2018, Day 2 at altitude

The viscometer is being set up in the bloods room and is a key weapon in our arsenal for primary outcome measures in multiple studies. Due to voltage differences (compared to Canada) the unit needs to be connected to a step-down. We connect the viscometer, water bath and the step-down, and at first all seems to be functioning well. A few minutes later, an odd scent emerges. Ah, the step-down is smoking, not good! This unfortunately is not the first fire hazard we’ve encountered. In Nepal, one of our technicians had to rewire most of the outlets to ensure they wouldn’t catch flame. A few days ago, an outlet connected to a locally-made space heater went alight. We are constantly having to double- and triple-check that our equipment doesn’t melt due to poor electrical wiring, or mismatched voltage inputs/ outputs. At the same time, though, we more often find ourselves very thankful that we have electricity to power the large volume of studies being conducted in these remote locations.

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Views from the valleys: descent through Lobuche Pass, Nepal 2016 (top) and Ticlio Pass, Peru 2018 (bottom), both ~4800-5000 m altitude.

These expeditions provide comprehensive research experience and encourage growth amongst the team and its individuals. Things are not always sunshine, rainbows and unicorns, though the many logistical hurdles provide an opportunity for learning and developing our problem-solving abilities.

We often must think outside of the box and utilise our creative capacities to circumvent roadblocks, technical difficulties and unexpected challenges.

Aside from common technical conundrums, there are often cultural barriers that are both interesting and of course region-dependent. One obvious challenge is language – in Nepal, this was less obvious because many of the porters and Sherpa required some English for their work in tourism. Surprisingly to us, Peru has proved much more difficult, as virtually no one in Cerro de Pasco speaks a language other than Spanish. In fact, the local residents have an accent that is ‘poquito’ difficult for our translators to understand, so trying to explain protocols can be tricky. For example, measurements of total blood volume using the carbon monoxide rebreathe technique require the participant to complete a few steps: fully empty the lungs; attach to the spirometer mouthpiece; turn the valve; rapidly fill the lungs and hold for ten seconds; breathe normally for two minutes into the spirometer; then empty the lungs and turn the valve to close the system… all without breaking the glass spirometer (Fig. 2). Simple, right? Not so much. Despite our efforts to perform practice runs and explain the protocol several times over with physical demonstrations and translators, this is notably challenging.

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Members of the Global REACH team, in 2016 at the Ev-K2-CNR Laboratory (5050m) in Khumjung region, Nepal (top) and recently in 2018 at the Institutio de Investigaciones de la Altura (4350m) in Cerro de Pasco, Peru (bottom).

While these international expeditions allow us to become immersed in a different geographical and cultural environment, certain local traditions or values unbeknownst to us can provide unexpected barriers. In Nepal, the Sherpa were incredibly kind, and almost always smiling. They would seldom show negativity or utter complaints. One of our prime focuses on these expeditions is to examine blood markers of inflammation, blood gases and hematocrit concentration. In Nepal we collected serial arterial and venous blood samples at every stop during our ascent, but in Pheriche, one stop before the Pyramid, the Sherpa began to show concern, some requesting to skip the blood draws. We would find out the Sherpa perceived blood as their lifeforce, and that once lost, blood could not be replaced. They believed the loss of blood would weaken them and impair their state of being.

One translator mentioned the word ‘vampire’ and explained the concern that their blood might be sold. Luckily, with the help of our lead Sherpa and a few of the elders, we were able to convey that the bloods were solely used for research purposes and that we would never take more than necessary for study.

1 July 2018, day 2 at altitude; 16:05 h

I look over after completing one great blood volume test on the fourth Andean participant today (we’re getting more effective at translating) and the viscometer is now working, with a step-down that isn’t smoking! Turns out the previous step-down was pulled off the shelves of the Cerro lab. We’ve found one of our own from Canada and it has worked like a charm. With a bit of flexibility and a sprinkle of luck, these things often happen to work out.

Despite the aforementioned challenges, these expeditions provide overwhelmingly positive experiences, opportunities for personal growth and adventure. As researchers, we gain incredible organisational skills: much like a game of Tetris, we learn to schedule participants amongst multiple studies, ensuring a fine balance between efficiency and crossover i.e. that no measures conflict with other studies. Our communication skills grow as we continually coordinate between our local contacts, the P.I.s and the rest of the team. Even when things go completely off-plan, we learn to utilise flexibility and make the best of challenging situations. This field-based research teaches us quick thinking, adaptability (no pun intended) and resourcefulness. The challenges themselves provide strong learning experiences to be applied moving forward.

Perhaps the most obvious and enticing draw of these expeditions is the element of adventure. Not surprisingly, team leader Phil Ainslie’s initial involvement in altitude research was borne from his job as a mountain guide before attending university. ‘The first (trip) was when I was 22 or 23… I was running a trip in northwest India to some peaks at 6,000 m or 7,000 m. Damian (Bailey) was my instructor and he asked, ‘would you collect some blood samples’? And I said, ‘sure’. I spun samples down with a hand-crank centrifuge at 5,000 m on 25 people and took (saturation) measures, just me. And brought it all back. I’ve gone back (to altitude) every few years since.’ Following Phil’s lead, these expeditions allow us to explore incredible regions and share awe-inspiring experiences with our international collaborators. Visiting Everest Base Camp or climbing a (slightly dangerous) hill to look out at the Andes creates a bond of friendship and provides the foundation for long-lasting international collaborations that define Global REACH.

Team

9 July 2018; 21:53 h

Phil Ainslie (University of British Columbia), Mike Stembridge (Cardiff Metropolitan University), Craig Steinback (University of Alberta) and Jonathan Moore (Bangor University) and I are sat in the lobby of our hotel, chatting over a few Cusqueña beers. While discussing the 2016 Nepal Expedition, I explained how impressed I was that a group of 37 individuals had worked so well together, with no obvious dramas despite living in a harsh environment.

‘It’s similar to the New Zealand All Blacks values… basically the ‘no dickheads’ rule’, one of us said. We all laughed, then nodded in agreement. ‘Well, much like in mountaineering leadership, a mantra of the All Blacks rugby team is that they ‘sweep the sheds’, meaning that it doesn’t matter if you’re the star player – everyone on the team cleans the dressing room. If you’re a dickhead, if you’re not a team player, you’re not part of the All Blacks.

Phil has explicitly provided permission to include this conversation in the article, because while blunt, this type of value characterises the core of our collaborations and ensures the success of the expeditions. When everyone works together, dismisses ego and shares positive energy, the team thrives. Sixteen-hour testing days become relatively easy when you’re having fun.

Our team is at the heart of our success. We embrace collaborators with infectious personalities that border on the sides of eclectic and hyperactive: those with a genuine passion for research and zest for life. Team members remind each other to look beyond the academic pressures of funding and publication for the sake of career progression and light a fire and excitement for discovery.

Our peers drive us to new heights, literally and figuratively, in our academic prowess. We find less pride in our individual successes than in those of our teammates.

Our leaders – Phil Ainslie, Mike Stembridge and the late Christopher Willie – continue to inspire us. Their energy brings the continents together to create impressively cohesive and brilliant multidisciplinary collaborations. Their teams will continue to go global and reach for answers to important health-related questions at Earth’s highest altitudes.

(You can read the full article in its original version in Physiology News magazine.)

Friends in high places: Researchers go global for answers at high altitude (Part 1)

By Alexandra Williams, @AlexM_Williams

Global Research Expedition on Altitude Related Chronic Health (or Global REACH) is an international collaboration of academics and physicians from 14 institutions across Canada, the UK, the US, Peru and Nepal. While the “Global REACH” title is relatively new, its leaders have conducted a multitude of expeditions over the last decade to Nepal’s Himalaya, California’s White Mountains and now Peru’s Andes. With a collective interest in heart, lung and vascular health and altitude medicine, Global REACH’s collaborations ultimately aim to understand how the human body adapts, or maladapts, chronically to the low oxygen environments of earth’s highest altitudes.

I am writing this from 4,300 m, at the Laboratorio de Cerro de Pasco and Institutio de Investigaciones de la Altura in Peru. Our team of over 40 researchers, trainees, principal investigators and physicians are currently conducting approximately 20 studies examining heart, lung and brain physiology in lowlanders (us) and Andean highlanders with and without chronic mountain sickness.

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Example of a centrifuged blood sample from an Andean participant with chronic mountain sickness. A normal, healthy lowlander’s hematocrit (i.e. fraction of red cells in the blood) is ~40%; several Andean participants including this one had hematocrit values of 75-80%.

This series of blogs, however, does not intend to outline our experiments or specific scientific findings (which was described in a recent issue of Physiology News). Instead, you will get a raw, behind-the-scenes look at what transpires on these expeditions: the challenges we face, the experiences we gain, and most importantly the team values that drive the success of these international collaborations.

30 June 2018: Day 1 at altitude

Yesterday, the last of three groups of the Global REACH team drove from sea level in Lima up to 4,300 m in Cerro de Pasco, Peru. Amongst the team, some individuals are feeling “okay” (say, a rating of 7/10), while others have been in bed with splitting headaches for more than 24 hours. We would later discover that one, in fact, had a bout of pneumonia. Nevertheless, one thing remains constant across the team – the excitement. It is palpable. Seven lab bays are set up, participants are being scheduled in, the equipment is (mostly) accounted for and working. Data collection has already begun today, and our first Andean participants are coming in tomorrow morning. This is what we came for, and we’re ready for the fun to begin.

For those who haven’t experienced the thin air of Earth’s highest mountain ranges, a 7-hour jump from sea level to over 4,300 m altitude is significant, one which often leaves individuals feeling much worse than “not great.” Yet, with advanced knowledge of the side effects of altitude and hypoxic exposure, Global REACH members have joined forces to answer a plethora of physiological questions. For many, this will mark more than four expeditions to high altitude, a select few even in the double digits. In the first few days, most – including our team leaders – will have headaches, nausea, sleep disturbances and apnoeas. The inter-individual variability of these symptoms is quite high, as a select few may feel fine, most will feel some magnitude and combination of the list, and others will be periodically out of commission.

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Performing a carbon monoxide rebeathe test to measure red cell volume and total blood volume with an Andean participant in Cerro de Pasco. This method is technically challenging, and is made more difficult with a significant language barrier.

So, why do we do it? Why do we involve ourselves with the potential suffering at altitude and any additional risks (i.e. transport, illness) kindred to these trips? From my experience, three fundamental elements outweigh the risks and define the success of expeditions and collaborations like Global REACH: the science, the experience, and the team.

Science

1 July 2018: Day 2 at altitude

“MAS FUERTE, MAS FUERTE, yeah Johnny!” Johnny, our first Andean participant is laying on the bed of testing Bay 1, currently practising a handgrip protocol for a vascular study. Johnny already has a venous catheter placed in his forearm and will be shuttled through a screening circuit: ultrasound imaging (cardiac, ocular and vascular), a maximal exercise test and assessment of total blood volume. Our Spanish skills are currently dismal, but we’re managing to compliment the amazing work of our translators to collect a large cardiovascular dataset on approximately 50 Andean participants.

3 July 2018: Day 4 at altitude

Four of us are working in the bloods room to measure total blood volume, hematocrit and viscosity. We knew from previous reports that Andeans would have augmented total blood volumes and hematocrit levels compared to us lowlanders but seeing those bloods ourselves was staggering. ‘A hematocrit of SEVENTY-EIGHT per cent!’ a colleague yelled, astounded. For reference, a lowlander’s normal hematocrit is ~40%. (Fig. 1) An undeniable passion for physiology underpins collaborations like Global REACH.

The energy amongst the group drives impressive productivity and allows us to complete multiple studies in relatively restricted time periods. During the 2016 Nepal Expedition our team conducted 18 major studies, including a total of 335 study sessions in just three weeks at 5,050 m (further to multiple sea level and ascent testing sessions). This high-density data collection is relatively uncommon outside of field work and is only made possible by the vast breadth of technical fluency, specific expertise and research experience amongst the team. The expeditions allow us to not only answer our current questions but further breed a multitude of ideas for future study.

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‘We could answer that one next, Ethiopia 2020? Another Nepal expedition?’ Of course, these expeditions allow us as trainees and investigators to be productive, and to present and publish high-quality data and exciting findings. They strongly contribute to our development and career progression in academia. But what is undoubtedly most important is the greater aim of Global REACH: to understand altitude health on a ‘global’ scale. This collaboration and research ultimately aims to understand why chronic mountain sickness occurs, how different high-altitude communities have adapted (or maladapted) to low oxygen, and what might ultimately be done to improve the health of individuals exposed to acute or chronic hypoxia.

Stay tuned for Part 2 next week, or read the full article in its original version in Physiology News magazine.