Something is Very Wrong

For over 50 years researchers have been hunting down, cataloging, and developing drugs to combat the genetic mutations thought to cause cancer –  with remarkably little success.  Enormous amounts of time and money have been spent on cancer research yet contradictions, confusion, and frustration continue to dominate the landscape of the field.

What is The Metabolic Theory of Cancer?

Put simply, the metabolic theory states that cancer originates from damage to the cell’s capacity to generate energy with oxygen (oxidative energy production), with a concurrent increase in energy generation without oxygen.

The metabolic theory of cancer is not a new theory.  It was first proposed by Nobel Prize winning German biochemist Otto Warburg in 1924.  The theory was subsequently discarded when it was discovered that cancer cells had mutations to DNA, the profound new molecule Watson and Crick had just reveled to the world.

A healthy cell produces 89% of its energy using oxygen, and 11% through non-oxidative metabolism (non-oxidative metabolism is also known as “fermentation”).  Oxidative energy production is far more efficient than fermentation.  Almost 20 times more energy is released when glucose is completely oxidized, as opposed to when it is fermented.

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Healthy Mitochondria. Note the abundant looping structures inside the mitochondria (cristae), this is where all energy is produced through oxidative pathways.

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Image of a mitochondria from a cancer cell. Note the almost compete absence of cristae.

Oxidative energy production takes place in a cellular organelle called the mitochondria.  The mitochondria are known as the cellular “power plant.”  The metabolic theory of cancer contends that cancer begins with damage to the mitochondria.  The cell is then forced to shift energy production to fermentation in order to survive.  It is telling that this one feature of cancer, damaged mitochondria and

PET scan showing widespread metastasis

PET scan showing widespread metastasis

increased fermentation is present in all cancer types.  Also telling is the fact that the greater the degree of fermentation displayed by a given cancer, the more aggressive the cancer. Because a tumor cell’s mitochondria are damaged, and are therefore forced to generate energy by such an inefficient pathway, they have to consume much more glucose to remain viable.  A glance at a PET scan, which uses a radioactive labeled glucose analog to image cancer, provides stunning visual evidence of the voracious appetite tumor cells have for glucose compared to normal tissue.

Emerging evidence suggests that all of the hallmarks of cancer can be explained by mitochondrial damage followed by a shift to non-oxidative energy metabolism.  Once the oxidative energy generating capacity of the cell is impaired, the cell undergoes a dramatic transformation; important oncogenes (cancer causing genes) are switched on, initiating the uncontrolled proliferation that is the hallmark of the disease.

Some degree of metabolic dysfunction has been shown to be present in every type of cancer, regardless of tissue of origin. 

Confusion Reigns

The latest push by the NCI is called the Cancer Genome Atlas Project.  Its stated mission: “To systematically explore the entire spectrum of genomic changes involved in more than 20 types of human cancer.”  The goal of this ambitious project is to once and for all, find and sequence all of the genetic mutations responsible for cancer. But so far the search for causative mutations has remained elusive – in fact, to date, the data suggests that mutations may not be involved in ways previously assumed.  The genetic mutational profile of any given cancer type looks different from person to person, rendering it impossible to claim mutations are definitely responsible for the origin of the disease. To be sure, some genes are mutated more frequently than others, but it appears that no single gene, or even any combination of genes, is absolutely necessary for the development of a tumor within a person.  And to make things even more confusing, the mutational profile is different from cell to cell within the same tumor, rendering development of drugs that target mutations next to impossible.  The drug targets not only change from person to person, but even within the tumor of a single individual.

One Single Comprehensive Theory

It is well established that once a cell has an impaired ability to produce energy through oxidative pathways, the genomic instability (increased potential for DNA mutations to occur) that accompanies tumor development, inevitable follows.  While the genetic mutations acquired following mitochondrial impairment unquestionably contribute to the tumor cell’s qualitative features and aggressiveness, experimental evidence is unable to unequivocally assign them as the origin of the disease.  The metabolic theory contends that mutations to DNA are of secondary consequence, or an epiphenomenon to the true cause, metabolic dysfunction.  While it’s true that most of the agents known to cause cancer; chemical carcinogens, viruses, radiation, and inflammation can cause mutations to DNA, it is also true these provocative agents damage the mitochondria. The metabolic theory of cancer states that once the mitochondria of a given cell acquire a threshold degree of damage, and the cell reverts to fermentation to obtain energy, cancer has begun.

Progressionofcancer

Diagram showing the progression of cancer. Once a threshold degree of mitochondrial damage occurs uncontrolled proliferation begins. The different colors depict cells with different mutational profiles within the same tumor. If a drug is developed targeting a specific mutation, the presence of sub clonal populations with different mutations will most likely render it ineffectual.

Inherited Cancer Risk fits the Metabolic Theory

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An electron microscope image showing the location of BRCA1 within the mitochondria.

Many of you have probably heard of BRCA1.  An inherited version of BRCA1 can increase a women’s risk of developing breast cancer by up to 60%.  Even though genes like BRCA1 receive a lot of press and evoke fears of the inevitability of cancer, only 5 to 7% of all cancers are attributed to the genes inherited from your mother and father – most cancers arise spontaneously.  An inherited predisposition to develop cancer has been historically cited as evidence that cancer is a genetic disease – and it certainly appears that way at first glance.  However, an exhaustive look at these rare inherited mutations reveal that all of them also increase the propensity of the cell to incur mitochondrial damage – leading to impaired oxidative energy production – the hallmark of the metabolic theory.

Strong Evidence

It is certainly true that all scientific endeavors are not created equal, and some experiments provide a more profound understanding of the physical world compared to others.  An elegant series of nuclear/cytoplasm transfer experiments fall into this esteemed category, and are exceptionally important in revealing important qualities of the disease.  In brief, the experiments consist of transferring the nucleus (this is where the DNA resides) of a cancer cell into a healthy cell that has had its nucleus removed prior.  The newly created hybrid cell has the genetic material of a cancer cell, with all of its defects, but now has the healthy mitochondria of a normal cell.  Intuitively, if the origin of cancer stems solely from mutations to DNA, the newly created hybrid cells, that still retain all of the mutations, should be tumorigenic.  But they are not.  They are perfectly healthy. These experiments were carefully executed, with strict controls, and were found to be very reproducible.  Experiments like these provide strong evidence that damaged mitochondria appear to be the driving force behind malignancy.

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A diagram summarizing a series of experiments conclusively determining that it is the mitochondria, and not nuclear DNA, that causes cancer.

Just getting started

The therapeutic implications of the metabolic theory of cancer are enormous.  It opens up profound possibilities for new avenues of treatment.  Without question the metabolic therapeutic approaches explored so far have exhibited tremendous promise.  The first and most obvious place to start is by implementing a ketogenic diet, starving the cancer cells of the glucose they so heavily rely on for survival.  The preclinical results have been remarkably consistent.  In virtually every experiment in which the ketogenic diet has been tested in mice, tumor growth rates have slowed dramatically.  The results of the diet stand alone, but the results get really exciting when the diet is utilized in addition to other therapies.  It appears that the ketogenic diet is able to put cancer cells under significant metabolic stress allowing addition therapies, like cisplatin, radiation, and hyperbaric -oxygen to push the cells over the edge, increasing their efficacy exponentially.  And this is just scratching the surface.  So much remains to be done.

We don’t want to sit on our hands waiting any longer.