Tag Archives: science

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.

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.)

Early Career Conference: Join us in December!

Want to run a two-day early career physiology conference? This valuable experience will give you leadership experience and boost your CV! Any Affiliate and/or Undergraduate Members of The Society may apply. Read testimonials from our first Future Physiology conference in 2017 below. 

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Jose L. Areta, Norwegian School of Sport Sciences, Oslo, Norway:

Attending the Future Physiology meeting in Leeds in December 2017, coming all the way from Oslo, Norway, was a privilege I had thanks to a Physiological Society travel grant. I am a post-doctoral researcher in the early stages of what, I think, might turn into a long academic career. I signed up for this conference specifically to get a better overview and insights on what a researcher at my stage could do to make the right choices for his future career. The conference did not fail to provide valuable food for thought.

The attendees included a wide range of representatives of the academic career continuum, from undergraduates to professors. A majority of these were, seemingly, early career researchers (ECRs) and they belonged to a reasonably wide range of areas within the field of physiology. This showed that the purpose of the conference was to go beyond delving into their specific areas of expertise. A dominant topic of interest seemed to be commonalities irrespective of the specific area of expertise, meaning the ins and outs of working in and growing through academia.

Several of the sessions provided examples of more established researchers showcasing how they built their own academic careers in the context of research in physiology. The take-home message for me was that there is no one way to become an established researcher in any given area. The impression that I got is that love for the work you do followed by dedication and a solid network play a key role, immediately followed by serendipity. This seemed to provide some support to the saying ‘the harder you work, the luckier you get’, that I sometimes remind myself of.

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On that note, it was also nice to feel supported by other researchers going through similar difficulties in a research system that seems to very often put high-pressure on individuals and can lead to sub-optimal life quality and, in many cases, burnout. Uncertainty seems to be a common denominator for many researchers in different stages of their careers (more so ECRs). Making this explicit is important to find a solution for it. I think this conference was a good first step to bridge the gap between ECRs who have a lot of questions on how to progress through the ranks, while making meaningful contributions to science and more experienced researchers talking about their specific experiences or professionals providing advice.

Personally, one of my favourite events was a small grant-writing workshop I had the chance to attend that also turned into a bit of a career advice workshop. Transitioning towards being an independent researcher is very significant milestone for anyone in research, I think. Gathering some tools to do so in the context finding one’s place in the field was a nice addition to the experience of the conference.

In conclusion, I think this conference was a good first step to put the uncertainties that ECRs face throughout their development as researchers in the spotlight, and provide them (us!) with tools and networks for better tackling these.

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Dan Brayson, King’s College London, London, UK:

As a member of the Affiliate Working Group of The Society, I was privileged to have the opportunity to help with the planning and execution of the Future Physiology meeting, an early career researcher (ECR) focussed meeting held at the University of Leeds last month. The meeting was ‘by ECRs for ECRs’. This meant that the Affiliate Working Group was placed at forefront of the brainstorming process to come up with a plan for a meeting which facilitated an engaging experience for early career scientists.

What we hoped for was an opportunity for ECR’s to shed their inferiority complex baggage (we all have it), and to feel invigorated by the conference experience rather than being overwhelmed. To this end 20 ECRs were selected for oral presentations whilst five talks were given by senior scientists (for balance, of course). Of these, three were young PIs and shining examples that we don’t have to wait around for professors to retire in order to make significant progress in our careers. We hoped that this would add a motivational slant for attendees. If they can do it, why can’t we?

On a personal note it was a red letter day. I was charged with sharing the chairing and presentation-marking duties with my fellow Affiliate Working Group members, a first for me, and with this, I got to experience the joy of facilitating meeting proceedings rather than merely taking part. At least this was my perception of it, and I would definitely do it again.

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Reflecting now on the meeting I feel that it was a good first crack at a meeting for ECRs. However, I also feel that there is further scope to create the most engaging and immersive experience for young scientists. One idea would be to have facilitated debate workshops on general topics (neuroscience, cardiovascular physiology, gastrointestinal physiology etc.). This would engage people in a relaxed environment to talk more generally about the big issues/questions facing their chosen fields.

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.

The First Mars Marathon: Part 3

Martian nutrition: How runners will fuel

Carb-loading for the Red Planet marathon might prove more difficult than simply gorging on a pre-race pasta dinner. Since they will be shivering and burning a lot more calories not only during, but before the race, runners will simply have to eat more on Mars during the pre-race period to fully saturate their muscles with glycogen.

Just getting plates of pasta to Mars will be a major issue. After years in transit, many of the nutrients in any food shipped to Mars will have been lost, and deep-space radiation will have degraded much of a food’s chemical and physical structure. Preparing and shipping food to Mars for the runners to eat requires special methods. Anyone care for high-pressure processed, microwave sterilized, freeze-dried spaghetti and meatballs…anyone?

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Use of critical fuels such as carbohydrate and fat will drastically increase on mars due to the extreme cold

Mid-race nutrition is equally important. As stated earlier, the drastically cold temperatures will result in a higher rate of glucose use and glycogen depletion, so the runners will need to fuel more often to keep glucose stores elevated in the face of increased use of these from shivering, coupled with the metabolic demand of running. Marathoners, who rely heavily on their glycogen stores into the later miles of the race will need to ingest glucose during the race at a rate exponentially higher than the recommended 25-60 grams per hour to avoid hitting the dreaded wall around mile 20 of the Red Planet marathon. This drink will likely have to be specially formulated with a higher glucose content.

Authors of a 1998 paper in Experimental Physiology provide evidence that providing a drink containing 15% carbohydrate was able to maintain blood glucose levels better than one containing just 2% during a cycling test to exhaustion (1). For this reason, Martian aid stations will need to occur at regular intervals and provide runners with carbohydrate-rich gels, drinks, or tasty freeze-dried space snacks.

What they’ll wear

Until we evolve into actual Martians, humans won’t get away with running unprotected on the surface of Mars. For now, technology will prove vital to success as runners on this new planet. Newly minted Martian sports scientists and gear technologists will be recruited to design a top of the line marathon-specific spacesuit.

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Theoretical concept of the Mars runner suit. Source: News.mit.edu

This suit will provide a sealed, pressure-controlled environment, help maintain some warmth and control body temperature, riding a fine line between protection and optimal range of motion. A protective suit is necessary: in the low atmospheric pressure environment of Mars, bodily fluids would boil. This is known as the Armstrong limit of pressure, which Mars sits well below.

Additionally, runners will develop severe impairments in blood pressure maintenance due to the reduced atmospheric pressure. This drastic reduction in blood pressure was demonstrated in a Journal of Physiology study from 2015 (2). Studying astronauts on the International Space Station, researchers noted a reduction in blood pressure of 8-10 mmHg, mainly due to central volume expansion.  The marathon gear will resemble something of a wet suit– a design which is able to solve the low-pressure problem by using super tight wrapping  (instead of gas-pressurization, it uses mechanical counter-pressure) (3). This leaves the body mobile. Wrapping the lower limbs in this counter pressure “fabric” will allow full range of motion at the ankles, knees, and hips,

The suit will require an enclosed helmet with breathing apparatus for runners to get their oxygen which is lacking in the Martian environment and dispense of the large amount of atmospheric as well as metabolically produced CO2. But don’t even think about attempting a snot-rocket.

Additionally, features of the suit crucial to completing our space-race might include an airtight hole in the mask so that runners can ingest their mid-race fluids and gel packs.

One final, and perhaps most vital feature will be the shoes. Just as elite runners have custom shoes designed to their unique gait pattern and foot size, Mars marathoners will need footwear tailored with the same precision and comfort in mind. As it turns out, the painful condition of onycholysis (separation of the finger/toe nail from the nail bed) is not just a problem among ultra-endurance athletes, but astronauts too. Ill fitting gloves combined with the intra-suit pressure can spell disaster (and pain) for anyone carrying out activities in space, and this would surely apply to the feet as well. After 26 miles of running in cramped space-boots, it can only be expected that runners might lose one or more toenails. To prevent this, it will be necessary for runners to have Mars boots fit to their particular foot size, strike, and biomechanics.

Can They Do It?

Just as Opportunity Rover completed its own Red Planet marathon, so too will humans eventually cover 26.2 miles on foot over the dusty red surface of the fourth planet from the Sun.

Will it be fast? Probably not – but let’s hope we break the current standing record of 11 years, 2 months. Evolving a new, skipping gait required for efficient running on Mars will take some time, just as did the adaptation of lower limbs and body structure of Australopithecus to that of the modern Homo erectus, a body ideally formed for endurance running. Tendons and ligaments will have to adjust to the new microgravity environment, and it will take time for muscle fibers to regain their strength and capacity. The deconditioning of the cardiovascular system (due to fewer hemoglobin molecules, reduced ability to both supply and utilize oxygen, and decline in heart and lung function) will take some time to adapt to. Along with the various environmental factors (extreme cold, hypoxia, and dangerous levels of radiation), runners will certainly have a slow marathon debut.

We will eventually design equipment and training protocols that allow us to traverse 26.2 in record times on Mars. Remember, the first marathon run by Pheidippides resulted in his keeling over in death upon arrival. Since then, we have perfected running tactics, advanced our knowledge of performance, and unlocked human physiology such that it is now possible for man to run 26.2 miles at an astonishing 4 minutes and 41 seconds per mile, something once thought impossible.

Perhaps, some day, the elusive 2-hour barrier will be broken, not on a curated and well-paced course in Italy, but near Endeavor crater, some 54.6 million kilometers away.

References:

  1. Galloway et al. The effects of substrate and fluid provision on thermoregulatory, cardiorespiratory, and metabolic responses to prolonged exercise in a cold environment in man. Experimental Physiology. 81 (1998); 419-430
  2. Norsk et al. Fluid shifts, vasodilatation, and ambulatory blood pressure reduction during long duration spaceflight. The Journal of Physiology 593.3 (2015); 573-584
  3. Shrink-wrapping spacesuits. Jennifer Chu, MIT News Office. September 18, 2014. http://news.mit.edu/2014/second-skin-spacesuits-0918

 

The First Mars Marathon: Part 2

By Brady J. Holmer, @B_Holmer

Unlikely or not, it is interesting to ponder the physiological and technical challenges of a Martian marathon. Read our post from last week to learn why runners will be moving in giant leaps. Stride aside, how will the freezing cold, lack of oxygen, calorie requirements, and protective clothing affect the runners?

Cons of the Mars environment:

Temperature: beyond chilly

Race day conditions can be quite unpredictable even on Earth, and Mars will be no exception. Temperatures can vary from a moderate 70˚ F (20˚ C) around noon to an unbearable -195˚ F (125˚ C) at night. For the sake of this thought experiment, let’s assume that race day temperatures hover around the average of -67˚ F (-55˚ C).

At this temperature the blood vessels in many organs and leading to the skin will undergo profound constriction, reducing blood flow to areas where the runners don’t need it (that is, everything but the legs, brain, lungs, and heart). This conserves heat and maintains core body temperature as close to normal as possible.

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Average race day temperatures at select endurance races.

Authors of a classic 1998 paper in Experimental Physiology demonstrated that this constriction can occur even at a “mild” temperature of 45˚F (7˚C) for just 90 minutes (1).

Exaggeration of this physiological response in instances of extreme cold (i.e. Mars) would occur due to a condition called non-freezing cold injury (2). Symptoms include damage to vascular tissue and heightened constriction of blood vessels. This means runners will have trouble providing oxygen-rich blood to their working muscles which will be in competition with the core to maintain a survivable temperature. Frostbite on Mars sounds disproportionally painful.

Another main concern of extreme cold exposure will be the detrimental effects of shivering thermogenesis, the body’s involuntary quivering of muscles to produce heat in an attempt to maintain core body temperature. To do this, the body must use fuel sources such as carbohydrate and fat. This also occurs at even relatively “mild” cold temperatures.

A study appearing in a 2005 issue of The Journal of Physiology exposed a group of men to a temperature of 41˚F (5˚C) for just 90 minutes and showed that utilization of glucose and glycogen increased five-fold from normal resting conditions (3). Muscle glycogen, our stored form of carbohydrate, contributed up to 60% of the total increase in heat production during just moderate-level shivering.

Exposure to Mars level cold would exacerbate these effects in runners and lead to a sacrifice of valuable fuel stores in an attempt to stay warm, leaving little for the marathon effort. In a race over 2 hours such as the marathon, fuel partitioning is key, and glycogen stores become important late into the race. Without fuel to provide energy for muscle contractions, performance will inevitably suffer, even if proper nutrition and “carbo-loading” are implemented.

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Solar particle events will lead to a destruction of valuable red blood cells in space.

Oxygen deprivation in the air

Given the vast difference in the composition of the air, breathing on Mars will also be difficult.  The atmosphere of Mars is 95% carbon dioxide (CO2), meaning there is very little oxygen. Normally, CO2 is produced during high intensity exercise such as marathon running, but is counteracted by expiration, preventing accumulation of acidifying ions and the ensuing unpleasant burning feeling in the lungs and legs. In this regard, Mar’s atmospheric gas composition presents an ideal situation for the lung-torching turmoil that all runners fear late into the end miles of a marathon, although now, this will occur from the start. Even the most rigorous altitude training regimen won’t prepare Martian runners for the low-oxygen conditions they will experience. Well-designed spacesuits will need to be implemented to allow runners to inhale a gas composition that resembles one on Earth, while simultaneously helping to expire CO2 at a higher rate than usual.

Wreaking havoc with red blood cells

Let’s not forget about the radiation. Mars’ atmosphere is less dense than the Earth (approximately 100-fold less so), and radiation from the sun is much more potent. Spontaneous and largely unpredictable solar flares that decide to pop up during the marathon will send charged helium nuclei, neutrons, protons, and other dangerous and highly energetic particles coursing through the runner’s bodies. Exposure to one of these solar particle events during the Mars marathon would lead to the destruction of red blood cells (hemolysis) and along with it, the all-important, oxygen carrying hemoglobin molecules, oxidative stress, and damage to muscle fibers.

Runners will likely fall victim to a condition we might call “space anemia”. A study in Physiological Reports from 2017 investigated the response of the circulation to a head down tilt bed rest condition – used to simulate microgravity encountered in space – and found that it resulted in a loss of hemoglobin  (4)! Hemoglobin is necessary to carry oxygen to sites of active muscle during running, and a reduction  is associated with a lower exercise capacity.

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Aerobic capacity and power will both decline after just 15 days in space.

Reduced circulation

Circulatory changes may be further exacerbated by the well-known detrimental effects that microgravity has on aerobic capacity. Indeed, researchers have used a model of sustained bed rest further compounded by low-oxygen space environments such as Mars, to investigate the effects on cardiovascular capacity.

Keramidas et al. demonstrated in a 2017 Experimental Physiology paper that just 10 days in this space-simulating condition impaired whole-body peak oxygen uptake (VO2peak) by 8% with an accompanying reduction in peak power output during an exercise test (5).

Furthermore, in 2018, Salvadego et al demonstrated in The Journal of Physiology that 21 days of hypoxic bed rest led to an 8% reduction in V02peak, a reduction in thigh muscle volume, and impairments in the body’s production of energy (mitochondrial respiration and aerobic metabolism) and an ability to match oxygen supply to demand during leg exercise (6).

These changes lead to a reduction in aerobic performance – and Mars runners will fight against all of these pathological changes as they try and complete the race as they find themselves starved of the ability to get crucial, oxygen rich blood to their working muscles during the race. This means that runners will be less capable of performing at their max capacity on race day.

So far, the prospects are looking quite grim for the runners. Will nutrition or protective suits be their saving grace? Find out on Friday in the final blog of our series.

References

  1. Weller et al. Physiological responses to moderate cold stress in man and the influence of prior prolonged exhaustive exercise. Experimental Physiology. 83 (1998); 679-695
  2. Tipton M.J. Environmental extremes: origins, consequences, and amelioration in humans. Experimental Physiology 101.1 (2016); 1-4
  3. Haman et al. Partitioning oxidative fuels during cold exposure in humans: muscle glycogen becomes dominant as shivering intensifies. The Journal of Physiology 566.1 (2005); 247-256
  4. Trudel et al. Hemolysis during and after 21 days of head-down-tilt bed rest. Physiological Reports. 5.24 (2017)
  5. Keramidas et al. LunHab: interactive effects of a 10-day sustained exposure to hypoxia and bedrest on aerobic exercise capacity in male lowlanders. Experimental Physiology 102.6 (2017); 694-710
  6. Salvadego et al. PlanHab: hypoxia does not worsen the impairment of skeletal muscle oxidative function induced by bed rest alone. The Journal of Physiology 000.00 (2018); 1-15

The First Mars Marathon: Part 1

By Brady J. Holmer, @B_Holmer

Humans have successfully conquered herculean feats of endurance in some of the most unbearable conditions on Earth. Such conquests as the Badwater Ultramarathon, 135 miles (217 km) through Death Valley, where temperatures can reach 130˚ F (54˚ C), or the 100k Antarctic Ice Marathon (average wind-chill -4˚F (-20˚ C)) not only require a certain amount of mental fortitude (some might call it insanity), but also careful consideration of human physiology and its inherent limits. Unpreparedness for such harsh climates can spell disaster; Mother Nature isn’t merciful to those who are ill-prepared. In tests of extreme endurance, environmental conditions, and the body’s response to those conditions, can be the dividing line between successful completion of the race and  a certain meltdown.

It is unlikely that humans will ever lose their aspiration to push the limits of human physiology through feats of endurance. Given humanity’s recent interest in colonizing planets other than our own, it seems likely that our sporting and recreation habits will make their way out into the cosmos.

mars1

Images from http://alpacaengine.com/mars-landscape/ ; https://runningmagazine.ca/elite-qa/eliud-kipchoge-loves-running/ Photo: Nike 2018, Bejo Creative Theme 2018.

Indeed, Tesla CEO and Mars colonization proponent Elon Musk thinks that exploring new planets isn’t just a choice we have, but a necessity, and projects that the first manned trip to Mars will leave no later than the year 2020 (1).  Should we colonize Mars, humans will have stay active to prevent muscular atrophy, deconditioning, and boredom. Eventually, someone will have the crazy idea to try a marathon on the newly colonized Red Planet.

However sci-fi this situation may seem, it is interesting to ask what physiological and technical challenges a Martian marathon would provide. Will the vast climactic differences between Mars’ atmosphere and our own prove insurmountable? Will the elite road runners of our modern time be reduced to hobby joggers in the extreme climate? Or, perhaps even more tantalizing, will this novel atmosphere allow us to finally run a marathon under two hours? Let’s explore the physiology of humankind’s first marathon on Mars.

It may be important to note that the first Mars marathon has been completed, although not by a human. On Tuesday, March 24, 2015, Mars exploration Rover “Opportunity” completed the 26.219-mile (42.195k) journey across the Red Planet’s surface (2). Opportunity’s performance was quite mediocre, finishing in approximately 11 years and 2 months (a speedy pace of 222,000 minutes per mile). Let’s hope humans can improve on the current record.

mars2.jpg

The first marathon route completed on Mars. Source: Mars.nasa.gov, Nasa 2015

Fortunately, thanks to Opportunity, we have a perfectly measured course, and the Red Planet marathon will follow the same route, putting the finish tape at the rim of Endeavor crater. On this journey, how will environmental conditions be different, and what adjustments will be required to nutrition and protective clothing? Stay tuned to find out.

The Martian environment

Will the environment on Mars be conducive enough to run, much less perform well in, a marathon, even for the most battle-hardened endurance veterans? Various factors about the climate, both positive and negative, affect physical capacity and physiological response.

Pros: A giant leap for mankind

One benefit, taking nothing else into account, is that runners will be lighter on Mars. Martian gravity is a little less than one third that of the Earth, so a man or woman weighing 154 pounds (70 kilograms) on Earth will weigh a mere 51 pounds (23 kilograms) on Mars. Many of the top-100 world class marathon runners typically weight around 123 pounds (56 kg) – so if we forget about the danger of “floating away” for a moment– this puts Martian runners way below the “elite” weight class.

Weight reduction will dramatically increase V02max (maximum oxygen use, which measures exercise capacity) relative to body weight without any training required! The transition to partial gravity will cause an immediate 67% increase in relative V02max. Compared to changes seen in an Experimental Physiology study in which V02max increased only around 9% after 6 weeks of aerobic exercise training (3), this is quite the shortcut.

Wopmay_in_Endurance_Crater_(PIA06920).jpg

Source: Wikimedia Commons, NASA/JPL/Cornell

 

Another beneficial change upon arrival to Mars will have to do with the biomechanics of running.  Even if we design aerodynamic spacesuits which provide ample range of motion and reduce mass as much as possible, human locomotion will differ substantially; our running will look more like skipping, in fact. Apollo astronauts discovered the benefits of skipping on the Moon. A bouncing gait in the low-gravity conditions on Mars will also be preferred to walking and running since it leads to a threefold reduction in cost of movement. In addition to reducing work, skipping enhances grip control, which will be helpful on Mars’ surface. Covered by in “lunar dust”, it provides little in the way of friction.

Stride rate, typically 150-160 steps per minute for a marathon runner, will dramatically fall on Mars. This is mainly due to the large vertical displacement and increased time spent in the “flight” phase while skipping. Airborne time while running will be 80% longer in duration than on Earth, and stride length approximately 3 times as long. On Earth, the average stride length is 54 and 74 inches (1.3 to 1.8 meters) for men and women, respectively. This means that Martian marathoners will travel around 13.5 to 18.5 FEET (4 to 5.5 meters) per stride. Compare that to Usain Bolt, who has a stride length of about 7 feet (2 m). Talk about a “giant leap for mankind.”

The above changes, resulting in only a decrease in work and slight increase in biomechanical efficiency, may be the only beneficial alterations in running physiology on Mars – and it might look quite funny. Indeed, where gravity gives runners a benefit, the other environmental factors on Mars will all work against running a fast marathon.

Check back next week to learn how the freezing temperatures, and lack of oxygen impact the marathoners, as well as how they’ll fuel up and what they will wear.

References

  1. Elon Musk Has a New Timeline for Humans Living on Mars. June Javelosa. February 19, 2017. https://futurism.com/elon-musk-has-a-new-timeline-for-humans-living-on-mars/
  2. NASA’s Opportunity Mars Rover Finishes Marathon, Clocks in at Just Over 11 years. NASA release 15-049. March 24, 2015. https://www.nasa.gov/press/2015/march/nasas-opportunity-mars-rover-finishes-marathon-clocks-in-at-just-over-11-year
  3. Montero et al. Haematological rather than skeletal muscle adaptations contribute to the increase in peak oxygen uptake induced by moderate endurance training. The Journal of Physiology. 593.20 (2015); 4677-4688