Oxygen: a Double-Edged Sword

One of the great scientific ironies is that in a system as finely-tuned as an organism, an explosively reactive element like oxygen is the key to so many processes. Pure oxygen as the fuel for any sort of fire yields truly spectacular results. An out-of-control blaze does not seem conducive to biology does it?

But, as it turns out, the oxygenation of the atmosphere around 2.3 billion years ago was the beginning of life as we know it. Once photosynthesis began and oxygen filled the atmosphere, we started to see multicellular organisms take advantage of the excess O2 and use it as a cellular energy source. Oxygen now forms the basis of heterotrophic energy production through respiration.

Oxygen is so universal that it is even the main energy source, as a gas, underwater! Dissolved O2 forms the basis of cellular respiration underwater just as it does on land. While this does not apply to marine mammals because they breathe air, it is obvious in fish and invertebrates that oxygen is central to energy production just as it is above water.

It's role in the cellular energy process is as the crucial final electron acceptor in the electron transport chain that drives ATP synthesis, making it vital to cell survival. In fact, hypoxic conditions can lead to cell death faster than nearly every other danger. For example, the human brain can not be without oxygen for more than 4 minutes without suffering permanent damage and brain death follows closely.

While humans certainly can not handle more than a few minutes without oxygen, there are other mammals, including some of those in this image from a blog called Whale Scientists, that can hold their breath for an hour or more. How can we reconcile two mammal species having such a massive difference in hypoxia tolerance?

We as a team have used several approaches to try and answer this question. One of which has been treating cultured whale skin cells in hypoxia and observing the difference in several key genes and pathways to see if the cells are fundamentally different in their hypoxia tolerance. Another approach has been to transplant whale mitochondria into terrestrial mammal cells and test them in hypoxia to see if the mitochondria are the difference. A third approach we are taking is to use those whale skin cells to create pluripotent stem cells (able to turn into many call types) and differentiate those cells into heart, lung, or nervous tissue. This organoid creation process will allow us to test our hypotheses on hypoxia more directly, on more representative test subjects.

Ironically, we have found that, based on the 2009 article in Cell written by Yoshida et al., that hypoxia is extremely useful in inducing stem cell character. The very experimental test we want to use, when applied to cells of a different state, is the stimulus for de-differentiation. Why is this? Why does a deadly condition push cells to become their most versatile? The answer lies in the pathways that are activated in order to induce stem cell character, specifically Oct3/4 and NANOG. Mild hypoxia, around 5%, allowed those pathways to push the cells away from their differentiated form and towards stem cells.

Hypoxia kills, hypoxia creates flexible life. This ironic juxtaposition is the kind of idea that keeps us, as molecular biologists, connected to the larger picture. Biology will never fail to surprise us.

Citations:

WATWOOD, S.L., MILLER, P.J.O., JOHNSON, M., MADSEN, P.T. and TYACK, P.L. (2006), Deep-diving foraging behaviour of sperm whales (Physeter macrocephalus). Journal of Animal Ecology, 75: 814-825. https://doi.org/10.1111/j.1365-2656.2006.01101.x

Hal Whitehead, Sperm Whale: Physeter macrocephalus, Editor(s): Bernd Würsig, J.G.M. Thewissen, Kit M. Kovacs, Encyclopedia of Marine Mammals (Third Edition), Academic Press, 2018, Pages 919-925, ISBN 9780128043271, https://doi.org/10.1016/B978-0-12-804327-1.00242-9. (https://www.sciencedirect.com/science/article/pii/B9780128043271002429)

Nicola J. Quick, William R. Cioffi, Jeanne M. Shearer, Andreas Fahlman, Andrew J. Read; Extreme diving in mammals: first estimates of behavioural aerobic dive limits in Cuvier's beaked whales. J Exp Biol 15 September 2020; 223 (18): jeb222109. doi: https://doi.org/10.1242/jeb.222109