Metabolic Theory of Cancer and Common Misconceptions

Metabolic theory of cancer and common misconceptions

Oncology as a field is very resistant to change, so much so that the vast majority of research scientists and oncologists working in this area still believe in a notion that has been soundly disproven several times during the last century.

I am talking about the Somatic Mutation Theory of Cancer (SMT), which reached its heyday in 1976.  This was a time that various research efforts had arrived at common conclusions and then convinced the world of a dogma that has taken stubborn hold ever since.  That dogma says this: 

Cancer is caused by damage to DNA, which leads to damaged genes.  Those genes, oncogenes, are responsible for the reproduction of cancer cell lines (which one could think of as multi-generation families), which grow unchecked to the point of being a tumor.  Those tumors can be tested for damaged genes and will allegedly show those genes.

Not only has this particular dogma been proven to be false, or at most only true a tiny percentage of the time in a tiny percentage of the cells of a tumor, but this particular dogma has launched the confetti of pink ribbons all over the Western world and billions of dollars chasing those ribbons in pursuit of research for a now-failed theory.

Why is the SMT wrong?  Don’t you get cancer when your DNA is damaged or when you inherited bad genes?  Here is the problem:  The genetic machinery is in the nucleus of a cell.  Studies have shown that if you transplant a cancer nucleus into a normal cell, the cell stays normal.  But if you transplant the mitochondria, the power plant so to speak, of a cancer cell into a normal cell, then you get a cancer cell as a result. 

In other words, the mitochondria (energy supplier) is decisive.  The nucleus (genetic library) is not decisive in creating or maintaining a cancer cell.

Therefore, it is NOT the genetic machinery, not the nucleus, which creates cancer.  It is damage to the mitochondria that creates the cancer.   Two groups working independently of each other found this to be the case.  One was at the University of Vermont, and the other at the University of Texas, Southwestern Medical Center in Dallas.  Both research teams confirmed in repeated experiments that putting a cancer nucleus into normal cells results in normal cells, but putting cancerous cytoplasm (which contain the cells’ mitochondria) into normal cells results in cancerous cells nearly every time.  These results were independently verified to be the same nearly every time.i ii iii iv

The implications of this research are enormous:  It means that the determining factor in creating cancer is not in the nucleus where the genetic material is.  Rather, the decisive factor in creating cancer is in the cytoplasm where the mitochondria are.  Cancer arises from this and this alone: impaired cellular respiration.  Cellular respiration is known to occur in the mitochondria. 

The genetic damage that happens to a cell is simply one of the results of the original cause, which is damaged mitochondria.  Later I will discuss damaged mitochondria.

Many billions of dollars of research money went into the Cancer Genome Atlas (TGCA) Project funded by the National Cancer Institute (NCI), which purported to identify the cancerous genes in tumors.  It is a multi-national project so ambitious in scope that writer Travis Christofferson calls it the Manhattan Project of cancer.v  But something went terribly wrong.  The genetic makeup of one part of a tumor is different almost every time from the genetic make-up of another part of even the same tumor! vi

In other words, any pursuit of a genetic signature or genetic identification of a tumor is a waste of time, because it only relates to a small part of that tumor.  There is no single, coherent genetic characterization of a person’s cancer, and almost every type of genetic variation can be found within the cancerous tissue of one person.  That is, there is no reliable or consistent genetic signature to a person’s cancer.  vii viii ix  In other words, all that money collected for cancer research has been donated, and is still being donated, to a now disproven theory.

There are scientists involved in the TCGA project who now realize its failure, and are acknowledging the “sobering realization” that “maybe it is just too hard to figure out.”  Of the roughly 700 drugs to come out of the TCGA, none were helpful to patients, except perhaps Gleevec, which actually seems to be something of a metabolic drug, rather than a SMT-type drug.  The drugs that came out of these research efforts generally offer the patient no greater duration of life and certainly no greater quality of life.

This particular realization, though it has now become apparent to some cancer researchers, is not the headline-making news that it ought to be, because the embarrassment and financial loss of the funding of the gene theory / SMT would be devastating to pink ribboners and the like.  The disgrace also of having to admit that decades of work were a complete mistake, and that all the money donated in that direction had been an utter waste, would be a bit hard for anyone to take, not to mention would stir up the pitchfork temperaments of the public who has donated so generously over the years, and may very well feel that a refund is in order.  So, sparing all that anguish, the status quo does not get disrupted.  The bigger loss of course is the lives of cancer patients who were sold the bill of goods that later betrayed them and cost them their lives.

As a result of finding different genetic signatures in different parts of the same tumor, researchers who subscribe relentlessly to the SMT have then concluded this:  That cancer is such a complex array of diseases that we are further from understanding cancer than at any time in the past. The assumption then is that cancer is not one disease but many different diseases in a complex array, but that it must – because they have always been told it must – be related to and caused by genetic aberrations.  This results in a further assumption, that the complexity of cancer makes it almost unknowable.  This is a faulty premise, and an unnecessary one, if the majority of cancer researchers had not been so eager to dismiss Nobel prize-winning biochemist Otto Warburg’s findings, which have been verified throughout the world and over the 90 years since he announced them, and which I will discuss below.

The fact is, and I am by no means the first to say it, is that the genetic paradigm is deeply flawed.  Groupthink sclerosed over a long-cherished dogma, and hardened so relentlessly that it is still considered blasphemy to question the idea of the genetic origins of cancer.  Yet this insistence on the familiar dogma prevents new information – as well as new confirmation of very old information – from coming to the fore and getting a fair hearing.

Let’s start at the beginning:  The scientist who first understood cancer well was Otto Warburg, the world’s leading biochemist and a Nobel laureate.  In 1924 he figured out the essential nature of cancer:

“Cancer, above all other diseases, has countless secondary causes.  But, even for cancer, there is only one prime cause.  Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar.”x

Because of the many secondary causes, and also because cancer could take root in any tissue of the body, Warburg concluded what should be obvious to all, that cancer is not a peripheral problem. 

Rather cancer is a very fundamental problem.  Therefore, it is a problem of the basic mechanism of the body: metabolism.  What is metabolism?  It is an economy so to speak in which the currency is units of energy, molecules and macromolecules or nutrients.  Warburg hit on the true nature of cancer: a disorder that is at the very essence of how we function.  Forget genetic changes; those come afterward, and are not decisive, not helpful to the basic understanding of cancer nor to its cure.

Otto Warburg’s thesis did not find much favor in his time, and even less after his death in 1970.  If it weren’t for research scientists Pete Pedersen and Young Hee Ko of Johns Hopkins University School of Medicine taking an interest in and testing Warburg’s theory xi through the 1970’s and 1980’s, Warburg’s findings may well have been completely forgotten.  Yet through the work of Pedersen, Ko and then Thomas Seyfried, whose book Cancer as a Metabolic Diseasexii, establishes and gathers the empirical studies that proved Warburg correct, we now have a substantial body of proof in favor of Warburg’s theory.

Another very helpful work, especially to laypeople wanting to sort through the science is Travis Christofferson’s Tripping Over The Truth.xiii

Seyfried in particular was able to show evidence confirming Warburg’s metabolic theory, that damage to the mitochondria, the engines of the cell, rather than the nucleus where the genetic material lies, was the decisive factor in whether a cell turned cancerous or not.   He was able to show that the genetic damage that we see in cancer cells is not the cause of the cancer, but rather one of the secondary effects of this damage to the mitochondria.

When mitochondria are damaged, they send distress signals to the nucleus of the cell, and it is only then that we see the hallmark features of cancer: genetic instability, uncontrolled growth, cell immortality, etc.  But these are only downstream effects, the very effects that the multi-billion dollar cancer research industry assumed were causative, which wasted an enormous amount of resources, and delayed what could have been life-saving understanding of cancer for generations of cancer patients.

Back in the 1920’s, Otto Warburg reasoned that cancer must be fundamentally different from most other diseases.  Whereas other diseases damage a predictable part of the body or body system, cancer on the other hand, could arise just about anywhere.  Therefore, he reasoned it must be a more fundamental disease, not having to do with a function of a part of the body, as the other diseases.  But rather it had to do with something much more basic, as we said before: that is, metabolism. 

First, let’s talk about cells.  Cells are a basic operational unit in living things.  They take in nutrients, and perform work, with division of labor, in various cell parts, called organelles, and produce and discharge waste.  They take signals and information and direction from inside and outside the cell.  Mitochondria are of particular interest here, because the hundreds of mitochondria in each cell are the furnaces or energy plants of the cell.  Oxygen is essential to mitochondrial health and function.  Lack of oxygen disrupts them, and prolonged lack of oxygen causes permanent damage and death to mitochondria.  Okay, let’s store that away, because Otto Warburg did not yet know all of that as a medical student, but he learned much that moved the world closer to that understanding.

When Warburg studied embryonic growth as a medical student, he noted fast, uncontrolled growth of cells, as we would expect of embryos.  Later, he compared cancer growth to this fast growth.  However, whereas embryos used six times the oxygen of normal cells in their energy metabolism, cancer would default to anaerobic growth (that is growth that occurs without oxygen). 

The preferred mechanism of cancer growth is fermentation.  This is a very inefficient way of living and growing, and a feature that is very important for us to note, because it is cancer’s Achilles’ heel, and the key to our strength against it.  Fermentation is inefficient because it produces only 2 units of energy (ATP) per energy cycle (a metabolic stroll through the citric acid cycle, which is our basic biochemical engine, or at least a large part of it, and which is a bit too detailed for our discussion here). 

Whereas our normal cells use aerobic metabolism, a highly efficient mechanism, which produces 38 ATP per cycle, cancer is only about 5% as productive. So it produces only 2 ATP per cycle.   Even when cancer exists in an oxygen-rich environment, it defaults or seems to prefer, the inefficient fermentation.

So what is the nature of an inefficient system?  One might even say, to study cancer, let’s study this particular form of incompetence. 

An inefficient machine consumes lots of fuel and produces little output.  Warburg observed consumption of glucose in cancer, with relatively little output of ATP.  This is known as the Warburg Effect.  It is an effect that normal cells do not exhibit.  In the presence of oxygen, normal cells do not ferment, but cancer cells do.  Despite an oxygen-rich or oxygen-poor environment, cancer cells ferment as if oxygen were not present, and as in other fermentation systems, cancer cells produce a lot of lactic acid.

In fact, there is a principle in chemistry and biochemistry that if you want to stop a particular chemical process, you add a lot of the end-product to the system.  In this case, since lactic acid is the result of fermentation in general, including when we pickle cucumbers in the kitchen, it has been proposed to urge the consumption of fermented foods to cancer patients, in order to discourage the cancer machine from using the lactic-acid producing mechanism that it favors.  In essence, a feedback inhibition, or negative feedback loop.

There is another thing that Warburg learned from cancer, and that is this:  Normal cells, as mentioned above, will not ferment in the presence of oxygen.  However, in less than ideal circumstances, say anaerobic conditions in muscles, after strenuous exertion, the fermentative production of lactic acid will occur.  So this begs the question: If normal cells will only ferment as last resort, and only as a back-up, inefficient, poor-choice energy system, then is the following possible?  Is it possible that cancer cells are originally normal cells that lost their ability to metabolize normally, and that this loss made them default permanently to the less efficient system of fermentation?

And if that is the case, then it raises a really interesting question:  What exactly was it that happened to the cell to damage it so that it became cancerous?  And it gets even more interesting, when the conventionally accepted answer to the question, that is DNA damage, is not adequate or true.  That is, genetic damage did not create the cancer cell.  So what did?

This question was destined to be lost to distraction, due to a very compelling event occurring in 1953.  Molecular biologists James Watson of the US and Francis Crick of England, announced that they had discovered the form of the molecule at the core of life: the double-helix (twisting ladder) DNA molecule.  Their discovery was so dazzling, because of the beauty of the form and because every rung of the ladder was found to code for instructions for everything from eye color to height to predilection for certain diseases, across all plant and animal species.  The universally applicable finding was so impressive that other scientists, who had contributed much to the discovery, got kicked down off that ladder on the rise of the much-celebrated Watson and Crick. 

Rosalind Franklin was not acknowledged by the pair, but was the first to have discovered the essential structure by her unprecedented quality and precision x-ray diffraction photos of the DNA molecule in January 1953.  She had also deduced the double helix structure from mathematical modeling.  Only later, in the spring of 1953 did Watson and Crick see Franklin’s photograph, without her permission, and published the double helix structure of DNA themselves. xiv 

American chemist Linus Pauling had also been in a tight race with the pair, and was close to discovering the molecular structure himself.

Scientists had now found the key to unlocking so many of the mysteries of nature.  If we could find genetic programming in this beautiful new but ancient double helix, then we could explain not only inherited traits from one generation to the next, but also we could learn more about hereditary diseases: hemophilia, sickle cell anemia, Tay Sachs.  Perhaps all non-infectious diseases really had a genetic origin, perhaps even the biggest mystery: cancer.  So in the following decades, medical research investment was off to the races, enthusiastically pursuing genetic explanations for as much of the human condition as possible.

There was one problem with that when it came to cancer, by far the largest target of all of this effort, money and study:  Otto Warburg had proven such pursuits of a genetic origin of cancer baseless and unwarranted a full two to three decades before Watson and Crick’s famous discovery.  But Warburg was neither as famous as he deserved, nor one who had successfully persuaded others to look deeply enough at his work, even after his Nobel Prize.  From there on, Warburg, very confident that he was correct, but not so talented at enlightening others, languished in obscurity.

This turn of events effectively postponed for decades the most essential and urgent question regarding cancer, one that could have saved hundreds of thousands of lives:  If the cause of cancer is not genetic, then what does cause cancer?

Warburg’s experiments with normal cell lines and oxygen deprivation showed this:  Take normal cells and deprive them of oxygen, and at first, they will ferment.  But if you deprive them of oxygen for hours, even with no other influence, no toxin, no other damage, they will turn cancerous, without returning to normal state.  This was the evidence Warburg needed to convince himself that the first carcinogenic event was oxygen deprivation, which disrupted the most basic function of the cell: creating energy for its survival.  If you deprive a cell of oxygen, you damage its energy-producing apparatus, now known as the mitochondria, and it is at that point that the cell turns cancerous.

Warburg the Nobel scientist was convinced of this as the fundamental cause of cancer for the rest of his life, yet it would take decades before he was again taken seriously.  Warburg had shown how very simple the mechanism of cancer is.  Yet much infrastructure and vast fortunes have been built on the notion that cancer is almost hopelessly complex.


i Israel B, Schaeffer W. Cytoplasmic suppression of malignancy. In Vitro Cell Dev Biol. 1987; 23:627-32.  https://link.springer.com/article/10.1007/BF02621071

ii Israel B, Schaeffer W. Cytoplasmic mediation of malignancy. In Vitro Cell Dev Biol. 1988; 24:487-90.  https://www.ncbi.nlm.nih.gov/pubmed/3372452

iii Shay J, Werbin H. Cytoplasmic suppression of tumorigenicity in reconstructed mouse cells. Cancer Res. 1988; 48: 830-33.  http://cancerres.aacrjournals.org/content/canres/48/4/830.full.pdf

iv Shay, J, Liu Y, Werbin H.  Cytoplasmic suppression of tumor progression in reconstituted cells. Somat Cell Mol Genet.  1988; 14:345-50.

v Christofferson T. Tripping Over The Truth.  Create Space Independent Publishing Platform. 2014.

vi Salk J, Fox E, et al.  Mutational heterogenicity in human cancers: origin and consequences.  Annu Rev Pathol. 2010; 5:51-75.  https://www.ncbi.nlm.nih.gov/pubmed/19743960

vii Wu J, Fackler M, et al.  Heterogeneity of breast cancer metastases: comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases.  Clin Cancer Res.  2008; 14:1938-46.  https://www.ncbi.nlm.nih.gov/pubmed/18381931

viii Campbell P, Yachida S. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer.  Nature: 2010; 467: 1109-13.  https://www.ncbi.nlm.nih.gov/pubmed/20981101

ix Ohgaki H, Kleiheus P.  Genetic alterations and signaling pathways in the evolution of gliomas.  Cancer Sci.  2009; 100:2235-41.  https://www.ncbi.nlm.nih.gov/pubmed/19737147

x Warburg O.  On respiratory impairment in cancer cells.  Science. 1956, 124(3215): 269-70.

xi Christofferson T. Tripping Over The Truth. Op cit.

xii Seyfried T.  Cancer as a Metabolic Disease.  Wiley.  2012.

xiii Christofferson T.  op cit.

xiv US National Library of Medicine.  The Rosalind Franklin papers.  Profiles in Science.  National Institutes of Health, Bethesda, MD. www.profiles.nlm.nih.gov.

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