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The Miraculous World of Oxygen
Jul 1, 2004

All living organisms require oxygen to live. As humans, we breathe to take in oxygen; if we were not to do this we would die as we would not be able to meet our energy needs. Eighteen times more energy is extracted from glucose, a basic carbohydrate, in the presence of oxygen than without it. Just as we tend to underestimate the beauty and miracles found around us everyday, so we take oxygen and the breathing process for granted. In this article, we will illustrate several aspects of the miraculous world of oxygen.

The air that we breathe consists of 78% nitrogen, 21% oxygen and 1% other gases, such as water, carbon dioxide, and carbon monoxide. First of all, the level of oxygen in the air is of extreme importance; that is, if the air were to contain 40% oxygen instead of the normal 21%, then there would be no life on Earth. Most living organisms, if not all, would die due to oxygen poisoning. Their proteins and DNA would be oxidized and become non-functional. Metals would be corroded and trees would burn at slightly higher temperatures than normal.

Vertebrates have been equipped with two principal mechanisms to supply their cells with an adequate and continuous flow of oxygen. The first one is the circulatory system and the second one is oxygen-carrying molecules; hemoglobin in the red blood cells and myoglobin in the muscles. The air we breathe is filtered even before it reaches our lungs. Then, it dissolves in the mucus, a highly viscous material, which coats the inside of our lungs. Next, the dissolved oxygen diffuses into the blood through alveolar cells and the walls of the capillary vessels. Finally, the oxygen is picked up by the red blood cells; these are what make our blood red. The red color is due to a molecule called heme that is present in hemoglobin and myoglobin. Every heme molecule in hemoglobin can bind four oxygen molecules together. Every oxygen molecule bound to hemoglobin increases the affinity of hemoglobin to bind to another oxygen molecule. The hemoglobin becomes saturated if the dissolved oxygen is above a certain level; this can be seen in the lungs. If the level of dissolved oxygen drops below a certain level, as can be seen in tissues like the muscles, brain, and liver, then the oxygen molecules start to dissociate from the hemoglobin. Likewise, every dissociating oxygen molecule facilitates the dissociation of another oxygen molecule from the hemoglobin. This is one miraculous design that is known to us: a molecule devoid of any wisdom and intelligence grasps a very crucial cargo where it is abundant, carries it to a place where the cargo is most needed and less abundant, and releases it. The myoglobin in the muscle tissue then binds the oxygen and serves as an oxygen backup resource for times when there is inadequate oxygen supply during exertion.

Fetuses have their own specific hemoglobin, called hemoglobin-F, which is different from that of adult hemoglobin, hemoglobin-A. Before birth, the fetus gets its oxygen from the mother’s blood through the placenta. The higher affinity of hemoglobin-F than hemoglobin-A to oxygen makes the oxygen exchange between the maternal and fetal blood possible. It is interesting to note that right around the time of birth the fetus switches the production of hemoglobin-F to hemoglobin-A, as this is more efficient under normal breathing conditions. Our current knowledge is insufficient to completely understand how this switch-over occurs and how it is regulated. Future studies will shed light on this complex but magnificent mechanism of regulation and this superb design.

Why are we so dependent on oxygen? In fact, our energy metabolism is completely dependent on oxygen. The chemical breakdown of nutrients by a dozen enzymes releases energy, which as is cannot be stored or transferred to the places where it is required. We are equipped with a second mechanism, which involves another set of different proteins that converts the released chemical energy to a more useful and transferable molecular form, called ATP. ATP, which we can think of as small packages of energy, is the main form of energy within our cells that can be readily used by all reactions that require energy. The first set of enzymes abstracts electrons from the nutrients during their chemical breakdown. These so called high-energy electrons are transferred from one protein to the next by the second set of proteins that form the electron transport chain. The final acceptor of these electrons is molecular oxygen. If oxygen were not there to pick up the electrons at the end of this chain, the last protein (cytochrome oxidase) would lead to a dead end, as it would be rendered inactive with the electrons that it is carrying. This would make this superb design of complex mechanism useless and wasteful; the synthesis of every new and active cytochrome oxidase would require more energy than is produced in one cycle of an electron transfer in the absence of oxygen.

It has been known for some time that cells can sense the level of oxygen in their environment. They are equipped not only with a sensing mechanism, but also with a response mechanism, by which they can survive for a short period of time. In 1995, a protein called HIF (Hypoxia Inducible Factor) was identified and was shown to regulate cellular response to hypoxia, i.e., a reduced oxygen level. HIF is a transcription factor, which induces the expression of a set of genes that are required for survival under hypoxia. Several genes encoding glycolytic enzymes are regulated under hypoxia; this allows cells to produce ATP even without oxygen. Nevertheless, oxygen-independent energy generation is very inefficient and the yield is insufficient. Another set of genes induce angiogenesis (vascularization), or the making of new capillary vessels. VEGF (vascular endothelial growth factor) is one of the best known HIF target genes that induces the formation of new vessels where expressed.

One of the most remarkable aspects of HIF-based oxygen sensing is that under normal oxygen levels the HIF protein is simultaneously synthesized and degraded. Only under low levels of oxygen does HIF accumulate and induce its target genes. At first sight, this continuous production and degradation of HIF may look wasteful, whereas in reality it is a very well designed precautionary mechanism. The HIF protein is marked and sent for degradation by a class of enzymes called HPH/PHD. These enzymes also use the oxygen molecule to tag the HIF protein. If there were not enough oxygen around, HPH/PHD enzymes would not be able to tag HIF. As a result HIF accumulates and induces its target genes to ensure the adequate supply of oxygen. With this mechanism cells can quickly adapt and survive. Therefore, continuous production and degradation of HIF turns out to be a necessary precautionary measure which is taken against the risk of death arising from a low oxygen level.

This article is by no means a complete picture of the miraculous world of oxygen, perhaps it is no more than a brush stroke on the entire picture. Yet, even this incomplete glimpse is enough to help us realize how perfectly we have been created, and how well we are taken care of. We do not have even the slightest control over any of these aforementioned mechanisms. We breathe day and night, and every breath should be taken in gratitude to God, who created us as this masterpiece.