Oxygen: A ‘Nobel’ gas
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Those of you who remember the tedious hours expended in learning chemistry on the pathway to a medical degree may recall the noble gases from the periodic table — helium, argon, krypton, xenon, neon and radon — which were long believed to be totally unreactive.
That said, in the interest of chemical accuracy, you should be aware that compounds of xenon, krypton and radon are now known ... someone had better alert Superman!
In a hematology/oncology publication, you might expect me to direct this discussion toward radon and lung cancer, given the emphasis of my latest editorials, but instead we will go in another direction today.
The 2019 Nobel Prize in Medicine was recently awarded to Sir Peter J. Ratcliffe, FRS, FMedSci,Gregg L. Semenza, MD, PhD, and William G. Kaelin Jr., MD, for an extraordinary series of experiments that have explained some of the processes of cellular adaptation to changes in oxygen tension (see related article). Thus, I wish to summarize work focused on this “Nobel” gas.
Long history for O2
The relationship between the Nobel Prize committee and oxygen dates to 1931, when Otto Warburg, MD, PhD, received this distinguished accolade for his work that elucidated the enzymatic mechanisms by which oxygen is used as an energy source within mitochondria by normal and malignant cells. Warburg hypothesized that metabolic changes associated with hypoxia were responsible for initiating carcinogenesis. Interestingly, Warburg received the Iron Cross in Germany for his role in the cavalry in World War I, and he was proposed for a second Nobel Prize for other studies.
Oxygen was the subject of yet another Nobel Prize when Corneille Jean François Heymans, MD, received the prize in 1938 for identifying the mechanisms by which the carotid body regulates blood oxygenation, altering the respiratory rate in response to hypoxia, thus preserving cerebral function.
Let’s fast-forward to the present era, ignoring a tremendous amount of elegant science that did not receive this prize. But, before leaving the 20th century, let us not forget Paul Carnot, who proposed the existence of a hormonal regulator (“hemopoietin”) of blood cell production in 1905 — he did not receive a Nobel Prize, but he was elected to the French Academy of Medicine. We also should not forget Bonsdorff, Jalavisto and others, who coined the term “erythropoietin,” and Reissman and Erslev, who showed that erythropoietin is present in the blood and can stimulate red blood cell production. No less important was the work of Goldwasser and Kung, who purified the substance, although none of them secured the grand prize.
Physiological response to hypoxia
With the advent of the molecular revolution, attention has been focused on the genetic regulation of the physiological response to hypoxia, both in the context of hemopoiesis and in the domain of carcinogenesis (given Warburg’s original postulate).
In a series of seminal experiments, Semenza and Ratcliffe focused on erythropoietin and its oxygen-dependent control. Semenza and colleagues studied the interplay of erythropoietin and oxygen tension in genetically modified mice, showing the specific sequences of DNA near the erythropoietin gene control the response to hypoxia. They also identified hypoxia-inducible factor (HIF), a composite of two protein transcription factors that bind to these DNA sequences. His team showed that these factors, which are normally labile and rapidly degraded in normal, oxic conditions, appear to be protected in the hypoxic environment.
In 2004, Aaron J. Ciechanover, MD, DSc, Avram Hershko, MD, PhD, and Irwin Rose, PhD, received the Nobel Prize for demonstrating that the proteasome degrades HIF-1-alpha in the presence of normal oxygen tensions, but that degradation is averted by ubiquitination in the hypoxic state. Ratcliffe extended these observations, showing that most tissues have oxygen tension sensitivity and inducing oxygen-sensing capacity in other tissues via delivery of a relevant messenger RNA.
Around the same time, Kaelin and colleagues studied von Hippel-Lindau (VHL) disease — an inherited disorder with a high frequency of cancers, most particularly renal cell carcinoma — and noted that VHL mutations are associated with increased incidence of certain cancers. They showed that the VHL gene encodes a protein that interferes somehow with carcinogenesis, but also that cancer cells lacking a functioning VHL gene express very high levels of hypoxia-regulated genes.
At this point, team science came into play, and the 2019 prize-winning team and colleagues collaborated to show that VHL interacts with HIF-1-alpha, that specific hydroxylation of HIF allows VHL to recognize and bind to HIF, and that this hydroxylation process is oxygen dependent.
This mechanistic explanation of how oxygen sensing occurs and allows cells to adapt to the level of oxygenation in their environment is fundamentally important and potentially has broad applications — for example, the regulation of renal failure-associated anemia, the control of cancer-induced angiogenesis, and the development of targeted therapeutic strategies for a protean set of vascular- and anemia-related disorders, such as cancer, cerebrovascular disease and anemia.
Importance of collaboration, redoubled efforts
This set of four Nobel Prizes should be encouraging to the yeomen who labor in their labs and clinics every day.
Particularly pleasing to me was the public distribution of a copy of a letter from a very august scientific magazine to one of the laureates, rejecting a key proffered manuscript as being scientifically invalid. Those of us who have suffered that indignity, albeit for work of less fundamental importance, should take heart and redouble our efforts without being chastened by small thinkers on scientific review panels.
That reminds me of the time in about 1993 when a young colleague and I submitted a grant to the NCI, proposing the development of a site-agnostic clinical trial focused on tumor tissue expression of dipyridamole dehydrogenase and thymidylate synthase as determinants of fluoropyrimidine use; we eventually recovered from the study section’s assault on our intellect and ethics, and the castigation associated with considering that a tumor pathologist’s surgical pathology report might not even be needed. I guess we should just have ignored them and pressed on with the plan. Maybe we could have added a measurement of pO2 in the tissues, compared it with outcome and booked our flights to Stockholm.
However, the key point of this commentary is simply to congratulate Kaelin, Ratcliffe and Semenza for their work that will continue to shape our understanding of cancer biology well into the future, and to salute them for understanding that collaboration in science often is so much more productive than working in isolation.
References:
Bonsdorff E and Jalavisto E. Acta Physiol Scand. 1948;16:150-170.
Carnot P and Deflandre C. C R Acad Sci Paris. 1906;143:384-386.
Erslev A. Blood. 1953;8:349-357.
Goldwasser E and Kung CKH. Ann N Y Acad Sci. 1968;49:49-53.
Reissmann KR. Blood. 1950;5:372-380.
For more information:
Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Atrium Health. He can be reached at derek.raghavan@atriumhealth.org.
Disclosure: Raghavan reports no relevant financial disclosures.