Introduction
Why do some critically ill patients survive physiological insults that apparently similar patients do not?
It is one of the enduring questions of intensive-care medicine.
Two patients may be of similar age. They may have similar diagnoses, comparable arterial oxygenation, similar haemoglobin concentrations and apparently comparable haemodynamic parameters. Both may receive sophisticated organ support.
Yet their outcomes can be dramatically different.
One recovers.
The other develops progressive multi-organ failure.
Medicine understandably searches for explanations in disease severity, comorbidity, treatment and timing. But the research arising from the Caudwell Xtreme Everest programme introduced another intriguing possibility:
Could some human beings simply be biologically better equipped to survive hypoxia than others?
The idea is sometimes reduced to the appealing phrase “the survival gene.”
The reality is considerably more interesting.
There is no known single gene determining survival from critical illness. What researchers have discovered instead is evidence for genetically influenced differences in oxygen sensing, metabolism, microcirculation and cellular energetics.
To investigate this, researchers turned to a population that has undergone thousands of years of natural selection in one of the most hypoxic inhabited environments on Earth.
The Sherpa.
And in Xtreme Everest 2, Everest again became a laboratory for intensive-care medicine.
From Caudwell Xtreme Everest to Xtreme Everest 2
The original 2007 Caudwell Xtreme Everest expedition investigated how healthy lowlanders adapted as atmospheric oxygen availability progressively declined.
The results demonstrated extraordinary human tolerance of hypoxia.
They also revealed something equally important:
people did not respond identically.
Some individuals acclimatised remarkably well.
Others struggled at considerably lower altitude.
This variation raised an obvious scientific question.
If lowlanders differed substantially in their ability to tolerate hypoxia, what would happen if researchers compared them with humans whose ancestors had been exposed to severe hypobaric hypoxia for hundreds of generations?
That question became central to Xtreme Everest 2 (XE2).
The investigators explicitly recognised that oxygen availability falls both during ascent to altitude and during many forms of critical illness. Studying healthy humans exposed to environmental hypoxia could therefore help identify beneficial adaptations potentially relevant to pathological hypoxia in intensive-care patients.[1,2]
The Sherpa provided an extraordinary comparison population.
Why Study the Sherpa?
Sherpas are descended from populations with a long history of residence at high altitude on the Tibetan plateau.
For generations their ancestors lived, reproduced and worked in an environment containing dramatically less available oxygen than at sea level.
This creates evolutionary pressure.
Individuals whose physiology functioned effectively under chronic hypoxia were more likely to survive and successfully reproduce.
Over many generations:
Environmental hypoxia
↓
Natural selection
↓
Advantageous genetic variants become more common
↓
Physiological phenotype changes
↓
Population becomes increasingly adapted to hypoxia
The result is not immunity to altitude.
Sherpas can still develop altitude illness.
But as a population they demonstrate extraordinary capacity to live and perform physical work under conditions that severely compromise unacclimatised lowlanders.
Genomic studies subsequently identified strong evidence of positive selection involving several genes concerned with the response to hypoxia, particularly EPAS1, EGLN1 and PPARA.[3]
The question for critical-care researchers became irresistible:
What exactly is different about Sherpa physiology?
And perhaps more importantly:
Could understanding those differences help explain why some critically ill patients survive hypoxia while others do not?
Xtreme Everest 2
Xtreme Everest 2 was conducted during 2012–2013 by the Xtreme Everest Oxygen Research Consortium.
It represented a considerably more sophisticated investigation than simply comparing oxygen saturations.
Of the 180 healthy volunteers who departed Kathmandu for the high-altitude investigations:
64 were Sherpas
and
116 were lowlanders.
The participants followed controlled ascent profiles through Nepal, with research laboratories established at locations including:
Kathmandu – 1,300 m
Namche Bazaar – 3,500 m
Everest Base Camp – 5,300 m.
Researchers collected physiological, biochemical, genetic and epigenetic data.
Core investigations examined:
microcirculatory blood flow,
nitric-oxide metabolism,
exercise performance,
mitochondrial function,
cellular metabolism,
ventilatory responses,
and
cardiovascular function.
Forty-four separate study protocols were successfully undertaken.[1]
The experiment therefore examined oxygen physiology from the whole organism down towards the cellular level.
The Search for a Survival Gene
The phrase “survival gene” is attractive because it suggests a simple explanation.
Perhaps Sherpas possess a gene that allows them to survive hypoxia.
Perhaps critically ill patients who possess a similar genetic advantage survive while others do not.
Human biology is rarely that simple.
What research has identified instead is a group of genetic adaptations affecting different components of oxygen physiology.
Three genes are particularly interesting:
EPAS1
EGLN1
and
PPARA.
All have shown evidence of positive selection in Tibetan/Sherpa high-altitude populations.[3]
Rather than constituting one survival switch, these genes influence the body’s response to oxygen availability.
The result is better described as a:
hypoxia-survival phenotype.
EPAS1: Sensing Oxygen
EPAS1 encodes hypoxia-inducible factor 2-alpha — HIF-2α.
The hypoxia-inducible-factor system is one of the body’s fundamental mechanisms for detecting and responding to reduced oxygen availability.
When oxygen falls, HIF signalling influences numerous biological processes including:
erythropoiesis,
vascular responses,
metabolism,
and
cellular adaptation to hypoxia.
One might assume that successful adaptation to altitude requires producing enormous quantities of haemoglobin.
Interestingly, Tibetan high-altitude populations frequently demonstrate a more restrained erythropoietic response than acclimatising lowlanders.
This matters.
Excessively increasing red-cell concentration increases blood viscosity.
There is therefore a physiological trade-off.
More haemoglobin potentially carries more oxygen.
But excessively viscous blood becomes increasingly difficult to circulate through small vessels.
Sherpa/Tibetan adaptation appears to involve a more sophisticated solution than simply:
less oxygen → produce more haemoglobin.
EGLN1: Regulating the Hypoxic Response
Another gene showing evidence of selection is EGLN1.
EGLN1 encodes prolyl hydroxylase domain protein 2, an important regulator of the HIF pathway.
Together, variations involving EPAS1 and EGLN1 demonstrate something fundamental.
Evolution has acted upon the machinery responsible for sensing oxygen and coordinating the response to oxygen deficiency.
This begins to explain why two humans exposed to identical oxygen environments may not necessarily respond identically.
Their biological response to hypoxia may differ before any clinician measures a blood gas.
PPARA: The Metabolic Clue
Perhaps the most intriguing finding from the perspective of intensive-care medicine concerns PPARA.
PPARA encodes peroxisome proliferator-activated receptor alpha, an important regulator of fatty-acid metabolism.
Xtreme Everest researchers examined skeletal muscle metabolism in Sherpas and lowlanders.
The findings were fascinating.
Sherpa muscle demonstrated a metabolic phenotype favouring greater reliance upon carbohydrate metabolism and reduced fatty-acid oxidation.[4]
Why should that matter?
Because glucose is a more oxygen-efficient fuel.
Oxidising fatty acids can produce large quantities of ATP, but doing so requires relatively more oxygen for a given amount of ATP than carbohydrate metabolism.
When oxygen is plentiful this difference may not be particularly important.
When oxygen becomes critically scarce, it matters considerably.
Sherpa metabolism therefore appears to follow an elegant evolutionary principle:
Do not simply obtain more oxygen.
Extract more useful energy from the oxygen that is available.
Cellular Efficiency
This fundamentally changes how we think about hypoxia.
Imagine two cells receiving the same limited quantity of oxygen.
Cell A requires relatively more oxygen to maintain ATP production.
Cell B produces the required ATP more efficiently from the oxygen available.
Their arterial oxygen saturation could be identical.
Their PaO₂ could be identical.
Their oxygen delivery could theoretically be similar.
Yet their ability to maintain cellular function could be different.
The question therefore moves beyond:
How much oxygen reaches the patient?
towards:
How efficiently does the patient use the oxygen that arrives?
This is where Sherpa physiology becomes particularly relevant to intensive care.
The Mitochondrial Connection
Oxygen ultimately matters because mitochondria use it during oxidative phosphorylation to generate ATP.
The complete pathway is therefore:
Atmospheric oxygen
↓
Pulmonary oxygen uptake
↓
Arterial oxygen
↓
Haemoglobin transport
↓
Cardiac output
↓
Microcirculation
↓
Cellular oxygen delivery
↓
Mitochondria
↓
ATP
Conventional intensive-care monitoring concentrates heavily on the upper half of this pathway.
We measure:
SpO₂,
PaO₂,
haemoglobin,
blood pressure,
cardiac output,
and lactate.
But survival ultimately depends upon the entire chain.
Xtreme Everest research demonstrated that adaptation to prolonged hypoxia involves alterations in mitochondrial and metabolic biology.
The Sherpa comparison suggested that evolution had already influenced these mechanisms before exposure to the experimental ascent.
The Microcirculation
The second important component concerns the microcirculation.
Large arteries deliver blood towards tissues.
But oxygen reaches individual cells through microscopic capillary networks.
A patient can therefore theoretically have:
normal arterial pressure
- ●
adequate cardiac output
- ●
reasonable arterial oxygen content
while still experiencing:
inadequate regional cellular oxygen delivery.
Xtreme Everest research has demonstrated differences in microcirculatory responses between Sherpas and lowlanders.
Sherpas appear particularly capable of maintaining microvascular oxygen delivery and tissue oxygen handling during hypoxic exposure.
This means that successful adaptation potentially occurs at both ends of the oxygen pathway:
oxygen is effectively delivered
and
oxygen is efficiently utilised.
That combination is extremely important.
Nitric Oxide
Nitric oxide represents another component of this system.
NO plays an important role in regulating vascular tone and therefore blood flow.
High-altitude populations demonstrate distinctive nitric-oxide physiology, and XE2 specifically investigated NO metabolism alongside microcirculatory function.[1]
Again, the physiological objective appears not simply to increase oxygen in the blood.
It is to ensure that limited oxygen reaches the places where it is required.
The challenge is therefore one of distribution as well as supply.
This has obvious parallels with critical illness.
The Intensive-Care Patient
Consider two patients admitted with severe pneumonia complicated by sepsis.
Both develop significant hypoxaemia.
Both receive appropriate respiratory support.
Both have similar haemoglobin concentrations.
Both achieve comparable arterial pressures.
Their cardiac outputs may be similar.
Their SpO₂ readings may even be identical.
Yet one improves.
The other develops renal failure, cardiovascular instability and progressive multiple-organ dysfunction.
Why?
The conventional explanation might focus upon disease severity.
Often that will be correct.
But cellular physiology introduces additional possibilities.
Perhaps Patient A:
maintains microvascular perfusion,
extracts oxygen effectively,
maintains mitochondrial function,
and
efficiently generates ATP despite reduced oxygen availability.
While Patient B develops:
microvascular dysfunction,
impaired oxygen extraction,
mitochondrial dysfunction,
oxidative injury,
and
progressive cellular energetic failure.
Their monitor readings could initially appear surprisingly similar.
Their cellular environments might not be.
Sepsis and Cellular Hypoxia
This is particularly relevant to sepsis.
Septic shock is not simply a state of low blood pressure.
The disease can involve profound abnormalities in:
endothelial function,
microcirculatory blood flow,
oxygen extraction,
inflammation,
metabolism,
and potentially
mitochondrial function.
Consequently, restoring arterial pressure does not necessarily prove that normal tissue oxygenation has been restored.
Likewise, correcting arterial oxygen saturation does not demonstrate normal mitochondrial function.
The patient may have oxygen in the bloodstream yet remain unable to distribute or utilise it optimally.
The concept has sometimes been discussed in terms of cytopathic hypoxia — impaired cellular utilisation of oxygen despite its availability.
Sherpa physiology presents an intriguing opposite condition.
Oxygen availability is profoundly restricted.
Yet cellular physiology is exceptionally well adapted to function within that limitation.
Evolution Has Already Conducted the Experiment
This is perhaps the most elegant aspect of studying Sherpas.
Medical research normally asks:
What treatment can we give to make humans tolerate hypoxia better?
Evolution approached the problem differently.
For hundreds of generations, high-altitude populations were exposed continuously to an environment in which successful oxygen physiology offered a biological advantage.
Natural selection effectively conducted an enormous experiment.
Variants associated with successful reproduction and survival under chronic hypoxia became more prevalent.
The result was not one miraculous mutation.
It was a collection of interacting adaptations affecting:
oxygen sensing,
haemoglobin regulation,
vascular function,
microcirculation,
substrate utilisation,
and
cellular energetics.
Xtreme Everest 2 attempted to understand that experiment.[1,2]
Genes Are Not Destiny
There is, however, an important distinction.
No evidence demonstrates the existence of a single “ICU survival gene.”
Possessing EPAS1, EGLN1 or PPARA variants does not determine whether an individual will survive sepsis, ARDS or another critical illness.
Outcome from critical illness depends upon enormous numbers of interacting variables:
age,
underlying disease,
physiological reserve,
severity of illness,
immune response,
timing of treatment,
organ function,
microbiology,
environment,
and
genetics.
Furthermore, Sherpa physiology represents adaptation to chronic environmental hypoxia, whereas critically ill patients frequently experience acute pathological hypoxia combined with inflammation and organ dysfunction.
The two situations cannot simply be equated.
What XE2 establishes is something more defensible:
genetically influenced human physiological variation can substantially alter the response to hypoxia.
That makes the possibility that similar variation contributes to critical-illness outcomes biologically plausible.
It does not yet make it clinically proven.
The Survival Phenotype
The term survival phenotype may therefore be more useful than survival gene.
Imagine a physiological phenotype characterised by:
efficient oxygen sensing
↓
effective vascular adaptation
↓
preserved microcirculation
↓
efficient oxygen unloading
↓
oxygen-efficient substrate metabolism
↓
preserved mitochondrial ATP production
↓
reduced cellular injury during hypoxia
↓
greater physiological tolerance
No individual component guarantees survival.
Together, however, they could provide a substantial advantage when oxygen becomes scarce.
Sherpas appear to possess several elements of precisely such a phenotype.
Could ICU Patients Have Different Hypoxia Phenotypes?
This raises perhaps the most important translational question.
Modern intensive care generally classifies patients according to disease:
ARDS
septic shock
cardiogenic shock
haemorrhage
respiratory failure
But patients could potentially also be classified according to how their physiology responds to oxygen deprivation.
Some patients might tolerate reductions in oxygen delivery remarkably well.
Others might develop cellular energetic failure considerably earlier.
If reliable biomarkers could identify these differences, intensive-care treatment could potentially become more individualised.
Rather than prescribing essentially identical oxygen targets to broad populations of patients, future clinicians might conceivably identify the oxygen-delivery requirements of individual physiological phenotypes.
That remains a research aspiration rather than current clinical practice.
But the concept is important.
From Population Medicine to Precision Medicine
The implications extend beyond simply understanding why Sherpas climb well.
Suppose biomarkers could identify whether a critically ill patient’s cells were successfully adapting to reduced oxygen availability.
Treatment might then eventually distinguish between:
compensated hypoxia
and
cellular energetic failure.
That distinction could potentially be more meaningful than arterial oxygen saturation alone.
It might also help answer a question that repeatedly confronts intensive-care clinicians:
When should we intervene, and when is the patient’s physiology successfully compensating?
The ultimate objective would not necessarily be normal physiology.
It would be adequate cellular physiology for that individual patient.
What Xtreme Everest 2 Actually Demonstrated
It is important to distinguish the evidence from the hypothesis.
XE2 demonstrated that:
1. Sherpas and lowlanders respond differently to progressive hypobaric hypoxia.
2. Sherpas possess a distinctive metabolic phenotype relevant to oxygen efficiency.
3. Skeletal-muscle metabolism in Sherpas shows reduced reliance on fatty-acid oxidation and greater oxygen-efficient carbohydrate utilisation.
4. Differences exist in microcirculatory and nitric-oxide-related physiology.
5. Genetic selection has occurred in pathways associated with the human response to hypoxia.
6. Important candidate genes include EPAS1, EGLN1 and PPARA.
7. Human adaptation to hypoxia therefore extends far beyond simply increasing haemoglobin concentration.
What XE2 did not demonstrate is that any one of these genes determines survival from critical illness.
Nor did it establish that Sherpa-associated genetic variants could be used to predict ICU mortality.
That remains an important distinction.
The Question Xtreme Everest Leaves Behind
The progression of the research is nevertheless extraordinary.
The original Caudwell Xtreme Everest expedition asked:
How can humans survive extreme hypoxia?
The results demonstrated remarkable adaptation and substantial variation between individuals.
Xtreme Everest 2 then asked:
What happens when ordinary lowlanders are compared with humans whose ancestors have undergone generations of natural selection under hypoxia?
The answer revealed differences extending from genetics to metabolism and the microcirculation.
That inevitably leads to a third question:
Could the same biological pathways help explain differences in survival among critically ill patients?
That question remains open.
But it may ultimately prove more important than any summit reached during the expeditions.
Conclusion
The concept of a “survival gene” is compelling because it offers a simple explanation for an extraordinarily complicated biological problem.
Science suggests something more sophisticated.
There is probably no single genetic switch determining whether a human being survives hypoxia.
Instead, Sherpa physiology demonstrates what might more accurately be called a hypoxia-survival phenotype.
Thousands of years of natural selection appear to have influenced multiple interacting systems governing:
oxygen sensing,
vascular regulation,
microcirculation,
haemoglobin response,
cellular metabolism,
and
mitochondrial energetics.
The result is not an organism that does not require oxygen.
It is an organism remarkably efficient at functioning when oxygen becomes scarce.
That distinction has profound implications for intensive-care medicine.
The arterial blood gas tells us how much oxygen has reached the arterial circulation.
The pulse oximeter tells us how much haemoglobin is saturated.
Neither tells us precisely what is happening inside the mitochondrion.
Two critically ill patients may therefore have apparently similar conventional physiological measurements while possessing very different capacities to maintain cellular energy production during hypoxia.
One may compensate.
The other may progress towards energetic failure and organ dysfunction.
Xtreme Everest does not yet allow clinicians to identify those patients reliably.
Nor has it discovered a gene that predicts who will survive intensive care.
What it has demonstrated is that the human response to oxygen deprivation is profoundly variable, partly genetically influenced and measurable at metabolic and cellular levels.
Evolution has already demonstrated, through the Sherpa population, that human physiology can be remodelled to function remarkably efficiently in chronic hypoxia.
The challenge for intensive-care research is to understand those mechanisms sufficiently well to determine whether any can eventually be translated into diagnosis, prognosis or treatment.
Perhaps, therefore, the search for the survival gene began with the wrong question.
The question is not:
“Which gene allows a human to survive?”
It is:
“Which combination of genetic, vascular, metabolic and mitochondrial characteristics allows one human being to tolerate cellular hypoxia better than another?”
The Sherpa may already carry part of the answer.
The task now is to determine whether that answer can ever be translated from Everest to the intensive-care bed.
References
1. Gilbert-Kawai E, Sheperdigian A, Adams T, et al. Design and conduct of Xtreme Everest 2: an observational cohort study of Sherpa and lowlander responses to graduated hypobaric hypoxia. F1000Research. 2015;4:90. doi:10.12688/f1000research.6297.1.
2. Martin DS, Gilbert-Kawai E, Levett DZH, Mitchell K, Kumar BCR, Mythen MG, Grocott MPW. Xtreme Everest 2: unlocking the secrets of the Sherpa phenotype? Extreme Physiology & Medicine. 2013;2:30.
3. Bhandari S, Zhang X, Cui C, et al. Sherpa high-altitude adaptation and population history. Genomic studies of high-altitude populations have identified evidence of positive selection involving hypoxia-related pathways including EPAS1, EGLN1 and PPARA. See also: Population History and Altitude-Related Adaptation in the Sherpa. Frontiers in Physiology. 2019;10:1116.
4. Horscroft JA, Kotwica AO, Laner V, et al. Metabolic basis to Sherpa altitude adaptation. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(24):6382–6387. doi:10.1073/pnas.1700527114.
5. Gilbert-Kawai E, Coppel J, Court J, et al. Sublingual microcirculatory blood flow and oxygen transport in Sherpas and lowlanders during exposure to hypobaric hypoxia. Research arising from the Xtreme Everest 2 programme.
6. Grocott MPW, Martin DS, Levett DZH, McMorrow R, Windsor J, Montgomery HE; Caudwell Xtreme Everest Research Group. Arterial blood gases and oxygen content in climbers on Mount Everest. New England Journal of Medicine. 2009;360:140–149. doi:10.1056/NEJMoa0801581.
7. Levett DZH, Radford EJ, Menassa DA, et al. Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB Journal. 2012;26:1431–1441.
8. Fink MP. Bench-to-bedside review: cytopathic hypoxia. Critical Care. 2002;6:491–499.
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