Cormac Taylor, School of Medicine & The Conway Institute, University College Dublin, Ireland

https://doi.org/10.36866/pn.112.34

A constant supply of molecular oxygen (O2) to every cell of our body is essential for the maintenance of health. However, we frequently encounter conditions where the oxygen demand by a tissue exceeds the supply, thereby leading to a dangerous state of oxygen deprivation (hypoxia). Because of our absolute reliance on oxygen, it is perhaps not surprising that we are equipped with multiple mechanisms which detect when oxygen levels drop and activate adaptive responses which help to increase oxygen supply and thereby overcome the hypoxic challenge.

The identification of the oxygen sensing mechanisms underpinning these mechanisms has proven to be a fertile ground for physiological research over the last quarter of a century and has recently identified a new class of therapeutic entities. The success of this rapidly growing field of research has depended heavily on the existence of a vibrant and well-structured multi-disciplinary international research community.

It is often said that we take for granted the air we breathe and the life-supporting oxygen which is contained within it. Indeed, a constant supply of molecular oxygen is essential for the maintenance of most multicellular life on Earth. However, this was not always the case. Early life on the planet, which was mostly composed of simple single-cell organisms, existed and thrived in an oxygen-free atmosphere. Indeed, when molecular oxygen (O2) first appeared in the Earth’s atmosphere it wiped out the vast majority of the planet’s biomass, which could not deal with its reactive chemistry (Taylor & McElwain, 2010).

However, during the course of evolution, some organisms developed the capacity to not only withstand the toxic effects of molecular oxygen (O2) but also to utilise its reactive chemistry for respiration (Taylor & McElwain, 2010). This represented a significant advance in the efficiency of metabolism. The step-up in bioenergetic efficiency and capacity that this enabled, provided the fuel to allow the development of multicellular animals (metazoans) and ultimately the expansion of higher organisms including vertebrates.

As such, the evolution of respiration as a metabolic strategy provided the fuel source to allow the development of complex life on earth. A payoff for this switch to respiration is that a constant supply of atmospheric O2 is essential simply for the maintenance of life in most higher organisms. This requirement renders cells, tissues, organs and consequently organisms susceptible to bioenergetic crisis under conditions where oxygen demand exceeds supply (hypoxia). However, hypoxia is a frequently encountered stress during a wide range of situations including ascension to high altitude and extreme exercise (Semenza, 2012). Furthermore, in a range of pathological conditions including ischemic disease (such as heart attack or stroke), inflammation and cancer, cells and tissues become exposed to hypoxia. Under these conditions, exposure of cells, tissues and organisms to hypoxia renders them at high risk of metabolic breakdown and death. Fortunately, we have also evolved mechanisms to detect when oxygen levels in the body begin to drop and to activate adaptive responses to promote survival during times of hypoxic stress. Because of our absolute reliance on oxygen, it is perhaps not surprising that much attention has been paid to studying the effects of this vital molecule on biological systems and how our systems adapt under hypoxia.

Two major breakthroughs mark our developing understanding of the biology of hypoxia. Firstly, the discovery and physiological understanding of the carotid bodies, two pea-sized organs located at the bifurcations of the carotid arteries which are responsible for monitoring blood oxygen levels and controlling the rate of and depth of breathing to keep them constant. The discovery of the physiologic role of the carotid bodies was recognised by the award of the Nobel prize in Physiology & Medicine to Corneille Heymans in 1939 (De Castro, 2009). Secondly, the discovery of the hypoxia-inducible factor, a ubiquitous master regulator of the transcriptional response to hypoxia, and the oxygen sensing mechanisms of the hypoxia-inducible factor (HIF) pathway opened up the field of cellular hypoxia. The latter was recently acknowledged by the award of the Lasker Award for basic medical research to Gregg Semenza, Peter Ratcliffe and William Kaelin in 2016 (Johnson, 2016).

A large part of the success of this field of research is fueled by the fact that interest in the mechanisms and consequences of oxygen sensing is shared by a diverse range of researchers including those interested in understanding the biology of high-altitude, comparative physiologists, sleep physicians, cancer biologists, physiologists, immunity researchers and clinicians. This diverse group has been well served by a strong sense of broad community as attested to a number of regularly convened high-level conferences around the topic of hypoxia which have
a strong history of being inclusive of researchers with diverse interests.

As is the case in much of life, in the field of hypoxia research, embracing diversity has been key to its success. Initial studies into why numbers of circulating red blood cells are induced in climbers ascending to high altitude through the induction of erythropoietin led to the identification of the hypoxia HIF as a ubiquitous regulator of the cellular response to hypoxia. Subsequent studies revealed a general role for HIF as a master regulator
of the cellular adaptive response to hypoxia and revealed roles for this pathway in cancer, ischemic disease and inflammation.

By developing our understanding of this pathway, a new class of pharmaceutical therapeutics (the HIF-hydroxylase inhibitors) are now in advanced clinical studies for the treatment of anaemia and other indications. It was through the presentation and discussion of the diverse aspects of the physiological response to hypoxia at regular international conferences that within 25 years of the first description of HIF, drugs will likely soon be approved for clinical use.

A key aspect to the success of this field of research has been a vibrant, active and well-organised community who meet regularly at dedicated international conferences such as Keystone symposia and the biannual Lake Louise hypoxia conference. At their most successful, the diverse interests of researchers in the field are well represented. This has promoted multidisciplinary studies involving clinical medicine, population genomics, cell biology, pharmacology and the application of state-of-the-art transgenic technologies to the field. Other funded initiatives, including two European Union funded COST actions, facilitated more dedicated conferences and provided support for lab placements and the promotion of international mobility for young scientists.

In a world where isolationist ideology appears to be on the rise in some countries, the success of the hypoxia research community represents a beacon of what can be achieved with goodwill, international cooperation and interdisciplinarity.

References

De Castro F (2009). The discovery of sensory nature of the carotid bodies – invited article. Adv Exp Med Biol 648, 1–18.

Johnson RS (2016). Profile of William Kaelin, Peter Ratcliffe, and Greg Semenza, 2016 Albert Lasker Basic Medical Research Awardees. Proc Natl Acad Sci USA 113(49), 13938–13940.

Semenza GL (2012). Hypoxia-inducible factors in physiology and medicine. Cell 148(3), 399–408.

Taylor CT, McElwain J (2010). Ancient atmospheres and the evolution of oxygen sensing in the HIF pathway. Physiology 25, 272–279.