The citation for the Nobel Prize for Physiology or Medicine awarded recently reads, “The Nobel Prize in Physiology or Medicine for 2019 is awarded to William Kaelin, Jr., Sir Peter Ratcliffe, and Gregg Semenza. The need for oxygen to sustain life has been understood since the onset of modern biology; but the molecular mechanisms underlying how cells adapt to variations in oxygen supply were unknown until the prize-winning work described here.“
The very first sentence after the awardees’ names took my breath away. It is so wrong. “The need for oxygen to sustain life”? Hardly. Given the relative size of the habitats where oxygen is absent vs. present, there are probably vastly more anaerobic organisms that metabolize in the absence of oxygen than there are aerobes that use oxygen. It seems the Nobel Committee conflated aerobes with life in the sentence. Egregious as the mistake is, let’s move on.
Pondering the next topic for this “Endless Forms Most Beautiful” series I thought, why not look at what essential elements like oxygen, magnesium and iron do in living organisms and the many forms of metabolic adjustments by which they adapt to their environments. Further, even before writing this article, I was pondering the topic of wintering bee clusters, because I am amazed how bees can cluster so tightly and yet produce core temperatures of a balmy 70oF (21.3oC). The two ideas converged in this article with respect to oxygen. I will tease out the ways by which animals deal with high and low oxygen levels, and the many biochemical molecules that have evolved for coping with this task.
Oxygen was not present in the atmosphere when life in bacterial form first evolved on Earth, a little after 4,000 million years ago. Descendants of those ancient Archaebacteria still thrive today in places where oxygen is absent: in hot springs, in very deep water and, surprisingly, in animals’ digestive systems where there is little to no oxygen. Methanogens, a type of anaerobic Archaebacteria in cows’ guts, release significant amounts of the greenhouse gas methane. But around 3,500 million years ago, something extraordinary happened. Bacteria with the ability to do photosynthesis evolved. Photosynthesis is a chemical reaction that stores energy in organic molecules, releasing oxygen as waste; this oxygen accumulated in the atmosphere driving the concentrations up and up and up in what is known today as the Great Oxidation Event and stayed high ever since. But chemical reactions are reversible, and this is the key to understand why oxygen is so valuable to living organisms – it does the opposite of photosynthesis by releasing the energy stored in organic molecules and making it available to cells. This took the waste product of photosynthesis and made it the key to effectively releasing stored energy in organic molecules. The equation for photosynthesis in simple form is:
carbon dioxide + water + energy ßà energy stored in organic molecules + oxygen
The way that aerobic cells like plants, animals, fungi and some protists evolved is that an anaerobic Archaebacterium engulfed one of these energy-releasing bacterial cells and aerobic “Eukaryotic” cells – cells that can use oxygen – were born. Those bacteria today live inside eukaryotic cells and are called mitochondria. So the thing to understand is that the key reason oxygen is needed is help with extracting the stored energy of organic molecules – food.
To explain how oxygen helps to release energy, I need to set the stage with a simple biochemical concept. The concept is that electrons carry different amounts of energy: there are high-energy electrons and low-energy electrons. You have to keep cycling in high-energy electrons from food into the body, and taking low-energy electrons out by adding them to oxygen to make water. Food and oxygen work just like the two wires in the charger cord that you plug into the wall to charge your phone: food brings in fresh high-energy electrons, and oxygen takes out spent, low-energy electrons.
But funneling enough oxygen to provide a steady supply to every cell is not a trivial problem for aerobes that live where there is very little of it: in the water, in the gut, deep in the soil, or where there are so many bodies there is little oxygen to go around such as in wintering bee clusters. Rather than make bodies so thin that every cell is in contact with air, life evolved solutions to move oxygen along with stored organic molecules to every cell. Some animals, such as flatworms, use the digestive system to move both oxygen and digested food to cells. Others use dedicated circulatory systems with oxygen binding pigments like hemoglobin, hemocyanin, hemeythrin, chlorohemoglobin, pinnaglobin, Vanadium, molpadin, and echinochrome. All of these pigments have the ability to bind oxygen by virtue of their metal cores, and to carry oxygen to cells. What the Nobel Laureates last year accomplished is discovering ways by which individual cells monitor the amount of oxygen that gets to them.
If either food or oxygen become difficult to obtain, there are other ways to stretch the energy stores. One is by using less energy. Analogous to substituting a 100 Watt bulb with a 1 Watt bulb which will run a hundred times longer, metabolism can be slowed down by hibernation and torpor. Some animals even have a suspended-animation-like diapause, that keeps fertilized embryos from implanting!
Can this be extended to whole animals like bees, to make energy with low, or even no, oxygen while clustered tightly in winter? There is, and it’s how anaerobes, aerobes that can tolerate short spells of oxygen deprivation, and even obligate aerobes survive in the absence or paucity of oxygen.
If food is plentiful but oxygen is hard to come by, the cell can get rid of the depleted electrons by using them in anaerobic glycolysis – literally the breaking of glucose – to make lactate. Otto Warburg received a Nobel Prize in 1931 for elucidating this pathway. Humans do this when they sprint, with lactate accumulating in the muscles. Cancer cells preferentially use anaerobic glycolysis to grow quickly. Lactate can be converted back to glucose by the liver and get cycled back into the circulation again for energy production. A related mechanism used by naked mole rats to survive up to 18 minutes without using any oxygen at all uses a sugar related to glucose, called fructose, to provide their high-energy electrons. Fructose is an even better substrate than glucose for anaerobic glycolysis.
Bees operate two thermal mechanisms during the winter. These are ectothermy, reducing the temperature of the body by torpor to match the lower temperatures of the surroundings. The second is endothermy, where heat is produced but which requires large amounts of both food and oxygen. Endothermy releases water as a byproduct. Water draws heat towards it, and this can be a huge problem for wintering bees as they may freeze or chill. So any water that is produced by this process has to be directed to the outside of the cluster.
I will expand on this in the next month’s article, and describe how wintering bees cope with plummeting temperatures, providing a little more biochemical detail.
