On the origin of cancer cells – part 2

Fifty years of intense research had passed from the year he received his doctorate in chemistry in 1906 to the year when On the Origin of Cancer Cells was published in 1956. The uniquely exceptional scientist that was Professor Otto Warburg was nominated for the Nobel Prize by his scientific peers a total of 46 times between 1923 and 1931, with 13 of these nominations in that last year. And in 1931, he was awarded the Nobel Prize for his seminal work on the essential role of iron in the biochemistry of cellular respiration published in 1928, and more generally for his work on the aerobic and anaerobic metabolic processes in cells. He was also, in that year, made director of the Kaiser Wilhelm Institute for Cell Physiology in Berlin (renamed Max Planck Society in 1948), and he maintained not only his post but also his scientific activity until his death in 1970 at the age of 86.

In fact, in 1969, just months before his passing, he published with one of his long-standing collaborators Dean Burk who translated the text (as he did for the 1956 paper), a revised and additionally prefaced version of the lecture he gave at the meeting of Novel Laureates at Lake Constance, Germany, in 1966 entitled The Prime Cause and Prevention of Cancer. The tone of this lecture, both for the first part of 1966 and the second of 1969, transpires frustration and even anger at the general lack of notice and acceptance of the crucial elements of the physiology of cancer cells that he had studied, understood, elucidated and clearly described in his publications over the course of more than 60 years of research.

Attempting to formulate a well-rounded and balanced explanation would require a lot of time and effort, not to mention a lot more words. But it is evident that then as now, financial interests have generally always been among the strongest driving forces both in research and in developing applications based on the understanding derived from this research. Hence, it is more than clear that eliminating the use of chemicals in all agricultural and industrial processes, stopping the consumption of simple and starchy carbohydrates and refined foods, and supplementing with iron, niacinamide and enzymes in general like Warburg recommended and did as a means to prevent and treat cancer is not only not at all lucrative, but it is highly financially detrimental to all chemical-based agricultural and industrial activities. I believe this is a most important part of the explanation, as it is for so many things.

What Warburg understood

Warburg had slowly, carefully, cautiously, diligently, painstakingly carried out experiment after experiment, trial after trial, studying every last detail of every aspect of the experimental process. He explained the cell’s most vital function, that of respiration, using oxygen to burn glucose or fats and produce energy, with a particular focus on the critical role of iron as a ‘respiratory enzyme’ carrying the oxygen molecule. He explained that the glucose molecule was ‘fermented’ (that it underwent glycolysis) in the cytosol of the cell, split into pyruvate molecules and fermented to lactic acid, and that this produced a small amount of adenosine triphosphate (ATP) without the need or use of oxygen. This process is termed anaerobic fermentation.

He explained that this process could either stop there, or be extended further by the pyruvate being taken up into mitochondria of the cell, and with the use of much oxygen, almost magically produce a lot more ATP without needing any additional glucose, but going through a series of steps and transformations relying primarily on clever recycling and reusing mechanisms of the niacin (B3) based molecule NAD (which stands for Nicotinamide Adenine Dinucleotide) within the mitochondria.

The ATP-generating process taking place inside the mitochondria was eventually described in detail by one of Warburg’s students, Krebs, who was awarded a Nobel Prize in 1953, and to which his name was given as the Krebs cycle also known as the citric acid cycle, as everyone who has studied some biology has heard (even if you never quite understood was this stuff was all about). Note that the Krebs cycle produces only 2 molecules of ATP, just as glycolysis does, and that it is what is called the electron transport chain, also taking place inside the mitochondria and using plenty of oxygen, that produces the bulk of the ATP with a potential of an additional 34 molecules, using products of the Krebs cycle, and in particular the 10 molecules of NADH.

Warburg was motivated to understand at the most fundamental level what was the difference between healthy cells and cancer cells. Naturally, as cancer was already a devastating disease in the 1930’s, he wasn’t the only scientist working and leading researchers in the study of the mysteries of cancer. He was, however, one of the most talented, dedicated and productive, together with the group of scientists he led at the Kaiser Wilhelm Institute and those with whom he collaborated.

The first major step was made in showing that tumours fermented glucose much more intensely than healthy tissues that normally hardly do so at all. This fact—that tumours ferment a lot more glucose than healthy mature tissues even in the presence of oxygen—is known as the Warburg Effect and is universally studied in physiology, medicine and oncology (cancer-ology). This fact is so fundamental to cancer metabolism as well as cancer research that it is the basis of the PET scan imaging technique in which radioactively labelled glucose is used to make detailed images of active tumours and their tendrils in our tissues. The reason why it works is that cancer cells take up glucose from the bloodstream far more efficiently than normal cells.

What is unfortunate but not surprising given how myopic scientists and we all in general tend to be, is that this has been consistently overlooked as being a critical aspect of the genesis of cancer, as Warburg’s research implied, and instead has been interpreted as a consequence of the dysfunctional cellular metabolism of these mutated cells that is unrelated to the actual development of the cancer.

This is pretty absurd. After all, if cancer cells derive a substantial fraction of their energy from fermenting sugar, wouldn’t the absence of sufficient glucose naturally halt the growth and proliferation, and thus the development of tumours? And even more fundamentally, because glucose can only be transported inside the cell by the action of insulin, and it is, in fact, to insulin—not glucose per se—that cancer cells are incredibly more sensitive than healthy cells, wouldn’t an important drop in circulating insulin levels be detrimental or even lethal to cancer cells? Of course it would! They would be starved of the only fuel they can use, and as a consequence, eventually become incapable of sustaining their activity.

How was this measured?

The way it was done was to measure oxygen consumption and lactic acid production either with plenty of oxygen or without any, for tumours and different tissues under physiological conditions of pH and temperature. This is the perfect trick because fermentation outside the mitochondria does not require any oxygen, whereas energy production by glucose oxidation inside the mitochondria depends entirely on the presence of ample amounts of oxygen, In fact, even a minute drop in oxygen concentration will negatively affect mitochondrial ATP production. Cancer cells don’t care much if there is oxygen or not: they don’t use much and therefore don’t depend on it. They ferment glucose anaerobically no matter what because this is the only way they can generate enough energy to survive.

It was understood a number of years later that tumours are rather heterogenous both in terms of the types of cells and tissues they are derived from, and in the concentration of cancer cells: tumours can grow extremely fast or extremely slowly; they can have a large proportion of cancer cells in relation to normal cells or a small one; and since different specialised tissues require different conditions and function differently, it is an obvious consequence that tumours developing in different tissues will have different characteristics.

Hence, the next step necessitated the isolation of cancer cells in order to avoid the problem of dealing with heterogeneous mixtures of cancer and healthy cells cohabiting in a solid tumour. It was this that Warburg presented in the 1956 paper, and what a difference this would make! These are his opening paragraphs:

Our principal experimental object for the measurement of the metabolism of cancer cells is today no longer the tumour but the ascites cancer cells living free in the abdominal cavity, which are almost pure cultures of cancer cells with which one can work quantitatively as in chemical analysis. Formerly, it could be said of tumours, with their varying cancer cell content, that they ferret more strongly the more cancer cells they contain, but today we can determine the absolute fermentation values of the cancer cells and find such high values that we come very close to the fermentation values of wildly proliferating Torula yeasts.

What was formerly only qualitative has now become quantitative. What was formerly only probable has now become certain. The ear in which the fermentation of cancer cells or its importance could be disputed is over, and no one today can doubt that we understand the origin of cancer cells if we know how their large fermentation originates, or, to express it more fully, if we know how the damaged respiration and the excessive fermentation of the cancer cells originate.

This was the programme that in the end led to the discovery that cancer cells produced 2-3 times (that’s 200-300%) more lactic acid than the most solid tumours. This meant that even those most solid tumours must have been composed of only about 1/3 active cancer cells, and thus 2/3 normal and inactive cancer cells.

This is necessary because cancer cells cannot do the things needed for the tumour to survive and grow, like making new blood vessels for example; only healthy cells can carry out such specialised activities. The wildly fermenting and proliferating cancer cells are dependent on healthy cells in the tissue where they are growing in order to survive. This makes good sense given that cancer cells gradually devolve, generation after generation, losing their function, their specialisation and their differentiated nature, and eventually cannot do much of anything but ferment glucose and replicate. For this reason, they rely on the healthy cells to maintain a viable environment for them.

Oxygen is crucial

Recall a key observation that was made in comparing the metabolic activity of cancer cells to normal cells: as the cell transitions from functioning normally and deriving virtually 100% of its energy needs by burning glucose (or fat) with oxygen inside the mitochondria, towards the defective cancerous cellular metabolism characterised by fermenting glucose without oxygen outside the mitochondria, they derive progressively more energy from fermentation and less from oxidation, independently of the amount of oxygen available.

You see, if oxygen in the cell drops, then ATP concentration drops because the mitochondria need the oxygen to make ATP. Immediately, fermentation outside the mitochondria will begin or increase in order to make up the energy deficit. This is normal and happens in all healthy cells whenever this situation occurs. However, the drop in available oxygen will also trigger heart rate and breathing to increase in order to make more available. This will very quickly correct the problem, allowing the cell to stop fermenting and return to the much preferred condition of generating ATP though oxidation in the little power plants that are the mitochondria. Once again, this is perfectly normal and happens in healthy, well-functioning cells every time we exercise.

Those cultured cells with which they were working did not have the support of the entire organism that we have, exquisitely fine tuned and orchestrated by countless specialised hormones, sensor cells, worker enzymes, etc., to react instantly to any kind of chance of condition. As oxygen concentration dropped, fermentation increased. But if oxygen levels weren’t replenished quickly enough, the damage to cellular respiration was found to be irreversible. Now, fermentation continued no matter if oxygen levels were raised to saturation following the period of hypoxia.

Not only did fermentation continue under oxygen saturation, but it increased over time. This is what was meant by irreversible in terms of the damage to respiration sustained by the period of deficient oxygen levels, and this is what showed very clearly how a cell can transition and devolve from normal and healthy to cancerous. The same observations were made irrespective of the means that were used to damage respiration: arsenic, urethane, hydrogen sulphide and its derivatives, hydrocyanic acid, methylcholanthrene and whatever else, whether oxygen was deficient or prevented from reaching the cell by a respiratory poison, the result was irreversible damage that always eventually resulted in cancer cells if the damage wasn’t too severe, because otherwise the cell would not survive at all.

The unavoidable consequence of this was immediately understood: it is the cumulative effect of chronic exposure to small amounts of carcinogenic respiratory poisons or low-oxygen that causes and leads to cancer within our tissues. Very unfortunately for us, the number, spread and quantity of such carcinogens grows with each passing day. Is it any wonder then, that cancer rates are soaring? That it is a modern plague in our highly industrialised, pesti-cised, herbi-cised, fungus-ised and globally chemi-cised countries?

Measuring cancer cell metabolism

Quantitative measures of cellular activity and metabolism of ascites cancer cells were done keeping the cells in their natural medium, ascites serum, that was ‘adjusted’ physiologically once they were removed from the abdominal cavity. Adjusted how? By adding glucose to feed them, but also bicarbonate to neutralise the lactic acid, because the fermentation rate was so strong that without the bicarbonate the pH would drop too quickly and too drastically, causing fermentation to be brought to a standstill and soon after the cells to die.

Under physiological conditions of pH and temperature, in units of cubic mm for 1 mg of tissue (dry weight) per hour at 38 C, they found the following:

• Oxygen consumption: 5 to 10,
• Lactic acid production with oxygen saturation: 25 to 35, and
• Lactic acid production without oxygen: 50 to 70.

Warburg and colleagues estimated that in anaerobic glucose fermentation, one mole of ATP was produced for every one mole of lactic acid. In contrast, even though the exact details were not yet known, measurements indicated that in cellular respiration, 7 moles of ATP could be produced for every mole of oxygen that was consumed. Based on these estimates, they compared ATP production form fermentation and oxidation in different types of cells.

Healthy liver and kidney cells showed identical metabolic values, consuming 15 cubic mm of oxygen per mg per hour, and in the absence of it, producing only 1 cubic mm of lactic acid. This means these cells were very poor at fermenting glucose; they could basically only derive energy from oxidation within the mitochondria. And this was made even more apparent by comparing, as they did, the amount of ATP that can be derived from fermentation or from oxidation. Using the 1:1 ratio of lactic acid to ATP under fermentation, and the 1:7 ratio of oxygen to ATP under oxidation, they found that these healthy liver and kidney cells could derive 105 (that’s 15 x 7) moles of ATP from oxidation versus only 1 from fermentation. As a fraction of the total, this is 105/106 or 99.1% from the normal mechanism reliant on the Krebs cycle and electron transport chain inside the mitochondria.

Next they looked at very young embryonic cells and found equal oxygen consumption of 15 cubic mm, but with a significantly greater—25 times greater—production of lactic acid when oxygen supply was cut. What this means is that these embryonic cells were much better adapted to surviving in anaerobic conditions without oxygen. This is quite natural given that the less evolved the cell, the more primitive and less specialised or differentiated, and therefore the closer to simpler cellular forms like yeasts. Doing the same as above in translating this metabolic function to compare the amount of ATP derived from either anaerobic or aerobic usage of glucose, we find that the same amount of 105 cubic mm of ATP from respiration, but in this case 25 moles of ATP from fermentation. And so, in this case the fraction is 105/130 or 80.8%, compared to the above 99.1% in normal liver and kidney cells.

The difference between these numbers and those calculated for the ascites cancer cells was large: they consumed less than half the oxygen, 7 cubic mm, but produced a whopping 60 cubic mm of lactic acid. That was 60 times more than the healthy mature liver/kidney cells! Here, ATP derived from respiration was therefore 49 (7 x 7) compared to 60 from fermentation. Hence, the fraction of the total that could be derived from oxidation was a mere 49/109 or 45%, implying that more than half the energy requirements could be derived from fermentation. This is how these quantitative measurements on the metabolism of healthy and cancer cells were done, and the result was indeed a remarkable finding.

What these results explained

So many things were understood or clarified through his efforts across these five long decades of intense research, and now with these latest results we understood different cell types have different propensity to become cancerous based solely on the cell’s inherent propensity towards fermentation: the higher the amount of ATP that could be derived from anaerobic fermentation, the easier it would be for the cell to become cancerous, and also the faster the tumour would grow.

The unfortunate but unavoidable implication is that embryos whose cells are all immature and therefore more primitive and naturally prone to greater fermentation, are the most susceptible to sustain damage to respiration whether from periods of low oxygen (think asthmatic mothers) or from exposure to respiratory poisons (think anything from pesticides, herbicides, food preservatives, to just supermarket household ‘cleaning’ and skin ‘care’ products, synthetic perfumes or substances they contain, and on and on…). Here again we can ask: is it any wonder that infantile cancer rates are also on a sharp rise?

We understand, for exactly the same reasoning, why cancer tumours in different tissues grow at different rates under the same physiological conditions, and easily explain why the increase in fermentation is gradual, requiring many cell divisions after the initial injury. As we know very well, it typically takes decades for adults to develop large cancer tumours that cause enough of an effect to get us to the hospital before it is diagnosed as such. Also, we know that tumours in or near the brain can develop and grow very quickly—within a year or two—whereas for the prostate they typically take an entire lifetime, sometimes completely unbeknownst to the host whose quality of life is not affected noticeably.

It was also understood why radiation therapy was generally effective at reducing the size of solid tumours by killing those already weakened and energy deficient cancer cells through a final blow to their injured and struggling mitochondria. By the same token, however, radiation will also always damage mitochondria of healthy cells, and thus set them on their way towards the process of devolution into dysfunctional fermenting cancer cells that the injury to respiration brings about.

And imagine this: 52 years following the publication of this landmark paper and a whole three quarters of a century after Warburg’s discovery of the fermentation of tumour cells even in the presence of oxygen, was published in the journal Nature a paper entitled The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. In this paper the authors describe how they were able to manipulate the expression of this enzyme in cancer cells, and doing so, decrease fermentation while increasing oxidation of glucose.

This enzyme, pyruvate kinase, is expressed in mammals in four different flavours (isoforms): L is expressed in liver cells, R in red blood cells, M1 is by far the most dominant and is expressed in most adult tissues, and M2, a variant of M1, is expressed during embryonic development. As it turns out, and as reported by two other groups of researchers in 2005 (refs 2 and 7 in the 2008 Nature paper), tumour tissues exclusively express the embryonic M2 form of pyruvate kinase.

Expressing these results as simply as we can, the situation appears to be as follows: once a glucose molecule enters the cell through one of the insulin-mediated entry ports, it is in the cytosol. There, through a series of 10 enzyme-mediated steps, it is split in two molecules of pyruvate. This requires 2 ATP but produces 4 ATP molecules; hence there is a net production of 2 ATP. At this stage pyruvate can either be converted to lactate which then turns to lactic acid, or to acetyl-CoA which is then transported to the mitochondria to enter the Krebs cycle and the electron transport chain. This transformation of pyruvate is performed by the enzyme that is the subject of these scientists’ investigation, pyruvate kinase. It would seem that the M1 form, the one that is active in healthy cells, takes pyruvate into acetyl-CoA and into the mitochondria, whereas the M2 form, the one that is expressed in embryos and cancer cells, takes it into lactic acid.

By some clever genetic manipulation, working with tumours in rats, they were able to switch off M2 expression and switch on M1 expression in cancer cells, and measured a decrease in lactic acid production and an increase in oxygen consumption that was associated with ATP production in the mitochondria through oxidative phosphorylation. This is the remarkable result that made the paper worthy of a publication in Nature magazine. And it is indeed amazing! This is why they write in the first paragraph that based on their research, the defect is not with the mitochondria as Warburg thought, but rather it is with the expression of the enzyme pyruvate kinase that goes from the healthy M1 to the embryonic M2 form. Why or how this happens is unknown.

This is indeed very encouraging! Just the idea of being able to force the expression of the healthy M1 and suppress the cancerous M2 form of pyruvate kinase is really amazing and has very important potential implications for cancer prevention and treatment. And this even if we don’t really yet know why or how it happens. But tell me, have you ever heard of this more than critically important result in cancer research on the news? Do you think your doctor has? Or his oncologist colleagues that cut, poison and burn cancer patients day in and day out?

Our basic cancer-fighting strategy?

What can we gather from this work that can help us not just understand Warburg’s research and his remarkable contribution to humanity though it, but also avoid cancer in this world where more than 1/3 of people currently succumb to it and where cancer rates keep rising every year?

Naturally, we want to minimise as much as possible our exposure to all manufactured chemicals, especially those confirmed as carcinogenic. We are all exposed to a greater or lesser extent through our being immersed in the environment in which we live, but we can go a long way by eating the cleanest, most natural and unprocessed food possible, drinking the cleanest water possible, using only natural cleaning and skin care products, and using regular or daily detoxification strategies such as taking sodium bicarbonate and magnesium chloride baths one to three times a week, drinking psyllium husks in water to cleanse the colon, and supplementing with iodine, chlorella and spirulina daily to flush out chlorine, fluorine, bromine and heavy metals like lead, mercury and arsenic on a continuous basis. These are, in a way, the simplest and easiest preventative measures we can take to reduce as much as we can our exposure to external sources of potentially carcinogenic and otherwise dangerous substances, as well as do what we can to flush them out to prevent accumulation in our tissues.

In consideration of the two fundamental characteristics of cancer cells—that they rely on glucose fermentation, and that they live and thrive in a milieu that his highly acidic and deprived of oxygen—it is just common sense to conclude that doing the opposite of what they need and prefer would be a good strategy. Doing the opposite means minimising glucose availability and especially insulin that is ultimately the agent responsible for transporting the glucose into the cell; remember that this is why cancer cells typically have 10 times the number of insulin receptors on their surface than normal cells. Doing the opposite also means preventing the accumulation of metabolic acids in their subsequent storage in tissues, preventing latent tissue acidosis, and ensuring a plentiful oxygen supply from a highly alkalising drinks, foods and lifestyle.

The first can be achieved by eliminating all simple and starchy carbohydrates, refined or not. Blood glucose levels will drop, and insulin levels will follow suit. This will shift the metabolism towards relying on fat as the primary source of cellular fuel throughout the day and night, day after day. The cool thing is that healthy cells function much more efficiently by burning fatty acids in the sense that they derive a lot more energy than they can do from burning glucose, even if the later is easier and enzymatically simpler: it is, after all, common to all living organisms, including the most primitive. The important difference is that all evolved and highly specialised animal cells can use fat, whereas primitive or devolved cancer cells simply cannot.

The second can be achieved by keeping the body hydrated and alkaline by drinking and eating to promote the alkalisation of the digestive tract, the blood, the other fluids of the body, and thus the tissues throughout: alkaline water and pressed lemon water, highly alkaline and alkalising freshly cold pressed green vegetables both juiced and whole, and magnesium chloride and sodium bicarbonate baths. Eating plenty of unrefined sea salt is also of the utmost importance in this. These are among the most important and effective means to first pull out and eliminate stored acids from the tissues and body, and then maintain alkalinity.

The only caveat is that digestion of concentrated protein in animal food, for example, require an acidic stomach for complete breakdown and digestion. Therefore,we should not combine alkalising water, lemon water or green juice when eating protein because this will cause poor digestion and absorption. Also, because protein is very important but also highly acid-forming, it is essential to not have excessive amounts, especially in a single serving, because this will cause excessive acidification and toxicity. Restrict your servings of animal protein to about 30-50 grams per serving, and try to restrict that to one main meal in the latter part of the day (afternoon or evening).

Pretty simple, aren’t they, these two strategies that we can draw from what we have learnt about cancer up to now. We will further explore cancer metabolism, prevention and treatment in the future, looking at methods that have been and continue to be successfully used to treat cancer patients and bring them back to health, as well as important nutrients and supplements with powerful cancer-fighting and health-promoting properties. But the fact is that these two basic points that address the most fundamental characteristics of cancer cells to ensure, on the one hand, that those that do emerge one way or another cannot sustain themselves or grow due to the lack of enough glucose and insulin for their needs, and on the other, cannot readily develop from being pushed towards fermentation because the environment of the body is everywhere alkaline and oxygen rich, are probably the most effective and important measures to grasp and apply in order to remain optimally healthy and cancer-free for as long as we are alive.

In closing

Before closing I want to briefly highlight that the vast majority of effective natural cancer healing treatments are based to a greater or lesser extent on the understanding of cancer as I have presented it in this and the previous article on the subject. However, there is a truly wide range of successful treatments that are used out there in various specialised cancer treatment centres. One important point to make in regards to the consumption of simple sugars from sweet root vegetables such as carrots and beets or fruit is that several treatment protocols include these and in sometimes large quantities still with great success in overcoming cancers of various kinds. This shows us that there is definitely more to preventing and treating cancer than just eliminating simple sugars.

There is lot of tremendously interesting material to explore about cancer, a disease that has been an important cause of suffering for at least a century. A lot of this exploration will be of historical research, experiments and discoveries that either have escaped the attention of the masses and medical establishment, or been actively suppressed by various agencies and individuals intent on nurturing as substantial population of ailing people for the purpose of profiting from the treatments they would require.

As awful as this may seem, it is unfortunately the sad truth. And even more unfortunately, this is not only historical as in the case of this well documented 1921 action plan by the US government, FDA and AMA for an influenza vaccination campaign to quickly and effectively spread disease across the country and greatly stimulate the need for medical attention and case as a means to generate profits from the associated expenses, but this continues to this day. The essential conclusion to draw from this is that it is we who must care for ourselves, our children, our family members, and our friends. And to do this, it is again we who must first learn and then teach our children and each other how to best do it. This is what I strive to do and what I strive to share with you.

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