On February 24 1956 was published in the journal Science a remarkable and exceptional paper by an equally remarkable and exceptional scientist. The paper was entitled On the Origin of Cancer Cells, and the author was the winner of the 1931 Nobel prize for Physiology or Medicine, Professor Otto Warburg.
After more than 50 years of research on cellular respiration, metabolism and physiology, Warburg had identified, understood, demonstrated and now explained the mechanisms by which cancer cells develop, survive, spread and proliferate, and what, at the most fundamental level, distinguishes them from normal cells.
It is my intention to relate the essence of these results, together with the necessary background, as clearly as it is possible for me to do with the hope that you will remember it well. This is without any doubt one of the most important and far-reaching results of medical science in its entirety. Such is the importance of this work, that it may well be the most important bit of medical science I will ever write about and that you will ever read about. But although this is so, it can be stated in a single sentence.
The truth about the origin of cancer is that despite the numerous carcinogenic agents, those identified as such and those still unknown, and despite the numberless forms and tissues in which cancer can manifest itself, there is only one fundamental cause of cancer at the cellular level: injury to respiration by damage to mitochondria.
The mitochondria, independent micro-organisms with their own metabolic and reproductive systems living symbiotically with the other organelles inside the cell, could be considered as the most important of the organelles because it is the mitochondria that normally produce the energy (in the form of adenosine triphosphate or ATP) on which each cell, and therefore also the entire organism, rely for function and survival.
Each cell must produce the energy it needs to sustain its activity and maintain its structure, and each cell cares only about itself: it knows only what it must do and what it needs in order to keep itself alive in the best possible condition and health that it can manage through continual adaptation. The way it knows anything else outside of itself is by sensing its environment, its immediate surroundings, through the various sensors (biochemical receptors) and doorways (ionic channels) in its walls (the cell’s outer double-layered membrane).
Cells can produce energy using glucose (from carbohydrates), amino acids (from protein) or fatty acids (from fat). By far the most effective way to do it is through burning fatty acids. This produces the most energy and no acidic byproducts. This is therefore a normal cell’s preferred fuel.
There are two intervening factors, however, that make it rather rare for humans to function primarily on energy derived from fat. And although this is true today, it wasn’t for the bulk of our evolutionary history during which all species of homo must have derived most, and probably often even all, of their energy from fat. The first and most important of these factors is that today, we tend to get most of our calories from carbohydrates.
Because it is easier for cells to breakdown and use the much smaller and simpler glucose molecules than it is to use the longer and more complex fatty acids, while there is enough glucose in the bloodstream, it will always be used preferentially, and eventually almost exclusively, as the cells grow insulin-resistant and become unable to use fatty acids almost completely. In such a metabolic state, because protein can relatively easily be converted into glucose, this is what the body does when it runs out of glucose, because, from the lack of practice, it cannot access the fat stores. Therefore, due to insulin resistance, fat just keeps accumulating, stock piled in ever larger and distended fat cells throughout the body, and never used to make energy for the now struggling, energy-starved cells.
The second factor is strictly physiological, and relates to the fact that it takes longer to oxidise fat than to oxidise glucose, and even for glucose, it takes about 100 times longer to oxidise inside the mitochondria than it does to process it anaerobically (without oxygen) in the protoplasm, the general space within the cell, outside the mitochondria. For this reason, in circumstances where the cell needs ATP quickly (in lifting weights or sprinting, for example), it will need to use this super fast energy production mechanism in addition to the slower oxidation in the mitochondria, with proportions that depends on the energy demand.
All ATP production using glucose begins with its breakdown into something called pyruvate. This is called glycolysis (or substrate level phosphorylation). It takes place whether there is oxygen available or not, and does not involve the mitochondria because it takes place in the protoplasm. Glycolysis involves 10 steps each of which requires the action of specialised worker proteins (respiratory enzymes). From this process the cell derives two molecules of ATP. Pyruvate is the main product, but the process also leads to the production of lactic acid and hydrogen ions.
At this point, the pyruvate can be carried to the mitochondria where through a much lengthier and vastly different process (oxidative phosphorylation), which in this case relies on an ample supply of oxygen, the mitochondria can produce up to an additional 34 ATP molecules (this is the case in aerobic yeasts), for a total of 36 counting the first two from glycolysis.
In practice, factoring in some metabolic inefficiencies in the process, the result is probably somewhere around 28-30 molecules of ATP for our cells. This is nonetheless a lot of energy—15 times more than from glycolysis alone—that can be derived from a single molecule of glucose. Bear in mind, however, that gram for gram, fat can produce six times more energy than glucose, raising the total to around 200 molecules of ATP, and this without producing acidic byproducts.
Aside on the use of words and names as symbols
Before going any further, I want to bring your attention to something important, generally unrecognised, but essential to our understanding and perception of the world and everything we come into contact with. It is language, complex language, symbolic language, that allowed a small subgroup of Homo Sapiens to first distinguish themselves from all other animals and also from all other species of Homo, and then spread across the continents and come to dominate almost every ecosystem on the planet.
The more language is refined and the more thorough is its mastery, the more complex cognitive processes become and the more subtleties of understanding can be both expressed and discerned. There is a major problem, however, that comes about in every language-using person, and this is that the symbol used to refer to something, the word, is unconsciously taken to be the same as the object to which it refers. Furthermore, not only is the object treated as an entity on its own, a thing that does not depend on anything else to be what it is (which, of course, it does), but the word also becomes a thing unrelated to other words that are different in appearance and sound.
This is a serious problem for understanding complex processes. And it is particularly relevant in this discussion here. We must remember that even if we are talking about all sorts of different things like glucose, amino acids, fats, pyruvate, enzymes, mitochondria, organelles, and on and on, that these are all words, symbols that we use to identify molecules and little beings like mitochondria that do not possess language, and further, that do not care at all what we call them.
It is best to view this whole business of processes at the cellular level as a ceaseless dance where atoms mostly of carbon, hydrogen, oxygen and nitrogen with a few others here and there, combine into molecules that are manipulated by proteins into other molecules, sometimes simpler and sometimes more complex, the change sometimes being unidirectional and sometimes a reversible state change going back and forth, everything depending everywhere on the characteristics of the environment, the stage, in which this dance is taking place. And that all of this takes place totally unaffected and independently from any of the names we have for any of its characters and dancers.
So don’t be fooled by the words and names in thinking that because the names are so different they are referring to inherently different things. This is not so. Words and names are just words and names. We use them to express ourselves, but must not be moved to believe that they are referring to entities having a life of their own, interacting in a world of things where every thing bounces against every other thing. This is just wrong, and it is highly misleading: clearly misleading in the realm of cellular biology, which is our immediate concern in this article, but also misleading in our everyday, which should definitely be of concern.
Back to cellular respiration
Cellular respiration (oxidation in the mitochondria) requires oxygen. If for any reason there is not enough, the cell uses a backup method to sustain its energy needs. This happens when the energy demand is so great that the cell cannot wait for the mitochondria to produce the additional ATP (as mentioned above under extreme exertion), but also if there is simply a lack of oxygen for any other reason, whether it is acute, like from exposure to a large enough amount of a respiratory (mitochondrial) poison or during an asthma attack, or chronic, like when we spend our days in an office building with recycled air where levels of oxygen are lower and carbon dioxide higher than they should ideally be, but not quite enough to become a problem noticeable by a critical number of people. In such cases, instead of being brought to the mitochondria, the pyruvate can be used as the oxidative agent by the respiratory enzymes to ferment the lactic acid, and recondition the NAD so that it can engage again in the breakdown of another molecule of glucose into pyruvate. (We’ll come back to the details of this another time.)
Essential to remember is that for a normal cell this is the solution of last resort when there is not enough oxygen, and that animal tissues suffer serious damage when deprived of oxygen for an extended time, where ‘extended’ here is on the timescale of cellular processes, which for us is very short—on the order of minutes.
Anyone who has done all out sprints with high resistance on a bike, or bench pressed a heavy weight to muscular failure, knows the feeling associated with the muscles being unable to respond to the load. This is because the cells are starved of oxygen and overloaded with acid. Under extreme exertion, lactic acid fermentation for ATP production dominates from about 10 to 30 seconds, and muscular failure follows within 30 to 60 seconds.
Struggling to survive
As we’ve seen, there are two major differences between these processes of using glucose for energy production. The first is that for one molecule of glucose, complete oxidation produces around thirty molecules of ATP, whereas glycolysis or fermentation produces only two. The second is that oxidation occurs inside the mitochondria, whereas fermentation, sustained by respiration enzymes, takes place outside the mitochondria. Therefore, it is both the quantity and quality of the energy that is degraded.
Also as we’ve seen, a normal cell under normal circumstances sustains itself—both in function and structure—by relying on the energy produced by the mitochondria, whether by oxidation of glucose (pyruvate) or fatty acids, and only ever use fermentation for energy balance adjustments in exceptional circumstances. If, however, for any reason at all, even a small number of the mitochondria in the cell get damaged, a serious problem arises because the injury makes the cell incapable of producing the energy it needs for proper function, maintenance and repair.
If the damage is severe, the cell will die, and will, if things are running relatively smoothly, be broken down, cleaned up, excreted and replaced by a new one that will take its place. If the damage to the mitochondria is not so severe, the cell will not die, but will be crippled in its energy-producing capacity, the mitochondria will not be able to produce all of the ATP the cell needs, and this will force it to use fermentation to top up its energy requirements.
Unfortunately, the injury to the mitochondria’s genetic code will not only be passed down from the damaged parent to the next generation, but will lead to an irreversible degradation of mitochondrial function with each transcription and reproduction into each successive generation of these vital organelles. With each generation, the mitochondrial function is degraded further and the energy deficit grows.
As a consequence, the growing energy deficit is compensated by increasing ATP production from fermentation. But the energy from fermentation is not just less plentiful, it is also of a much lesser quality compared to that resulting from proper aerobic respiration involving the mitochondria, and it simply cannot maintain the structure and function of the cell. Thus, the cell degrades. Everything about the cell degrades as it struggles for survival.
The evolution in the ratio of energy produced by respiration to that produced by fermentation, initiated by the damage to the mitochondria and driven by the cell’s striving to maintain energy balance, is in fact a devolution from a finely tuned energy production system of a highly refined and specialised cellular structure and function, to a primitive energy producing mechanism and a coarse and severely degraded cellular structure and function akin to what we see in yeasts and fungi.
The birth of a cancer cell
Degradation and devolution continue until fermentation energy is enough to fully compensate the loss of respiration. It is at this point that we witness the emergence of a cancer cell. And it is now a perfectly functional and healthy cancer cell that has lost enough of its original characteristics, both structural and functional, to begin a programme of its own, intended to increase as much as possible survival probability in its new and partially self-generated environment that should ideally be high in glucose—as high as possible, low in oxygen—this is preferred but not critical, and highly acidic—cellular pH as low as 6 or even less and extracellular pH potentially significantly lower.
Although these terms, birth and emergence, are powerful and very useful in conveying a vivid imagery of a developing process that eventually reaches and overcomes a critical threshold as it is the case here, it is not really a birth or an emergence as much as it is a metamorphosis, gradual and typically very slow, taking place over decades if not over most of a person’s lifetime, with a continual and intimate dependence on the biochemical makeup of the environment surrounding the cell, and surrounding each and every cell throughout the body, from hair, scalp and skin, to fingers, fingernails, toes and toenails, from mouth to colon, from brain to liver, from breast to uterus, from throat to prostate, and from and to everything else that constitutes the entire human organism inside and out.
Over this long struggle for survival, because this is truly what it is, the cell is at first forced to generate supplemental energy from fermentation to make up the small difference that the slightly damaged mitochondria cannot. This increases the level of acid inside the cell. Because every enzyme-mediated biochemical process that takes place—and that indeed has to take place—is sensitively pH-dependent, all are instantaneously affected negatively by this acidification and drop in pH.
Moreover, increased acid translates directly into lack of oxygen, which further stresses the mitochondria, making their oxidation of glucose and fatty acids more difficult and less efficient. This in turn leads to a further degradation of the mitochondria, cell structure and function, an increased reliance on fermentation energy, a rise in acid levels, and a drop in oxygen availability: clearly a vicious cycle—a very vicious cycle.
Because ATP production is so much less efficient through fermentation than through respiration, the cell needs much greater amounts of glucose. This forces it to develop a greater sensitivity to it, which forces the formation of more insulin receptors because it is insulin that carries the glucose through the cell wall. And it is, in fact, the case that cancer cells typically have about ten time more insulin receptors than normal cells, and that this makes them ten times more capable of grabbing hold of circulating glucose to sustain themselves. But again, remember that this is yet another adaptation in a struggle for survival without which the cell would die.
Questions, questions and more questions
There is quite a lot more that needs to be addressed and explained. General questions like: How did Warburg figure all this stuff out? And what else did he discover? Specific questions like: Are cancer cells weaker or stronger, more fragile or more resilient? What is it that fundamentally distinguishes them from normal cells? And why does it sometimes take an entire lifetime but at other times just a few years to grow a cancerous tumour? Epidemiological questions like: Why is cancer spreading? Why does it appear more and more in young people? And why does it tend to not only develop but intensify with each generation along family lines? Finally, from all of this detailed information and knowledge, wouldn’t we like to know if there is something to do to prevent or cure cancer? Wouldn’t we like to know what that is: what we can do to prevent and cure it? Of course! That’s our main goal, isn’t it?
We will look at all of these issues and more together, but now I can’t help wonder if the following question, this multi-billion dollar question, might have popped up in your mind while you were reading, as it did for me when I read Warburg’s paper: If he, and by extension, we, as the community of thinking human beings, had understood, explained and demonstrated how cancer arises and then develops in 1956 already, why is it that today, almost 60 years later, cancer rates continue to rise every year, cancer cases appear in people at an increasingly younger age every year, and cancer claims the lives of more people every year than it has ever done? How can this be, and why is it so? Hasn’t anybody else looked at his research and reproduced the results? Haven’t we got today much better instruments and technical means of verifying everything he presented throughout his long career? Don’t worry. We’ll definitely look at that too.
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