American Travis Christofferson’s Tripping Over the Truth describes the development and growing adoption of the Metabolic Theory of Cancer. Here he outlines how it offers a more accurate understanding of how cancer develops and why a ketogenic diet can be effective
First, one needs to understand what the ketogenic diet is and why and how it works. Your body, like a hybrid car, can burn two types of fuel; it has been designed that way by millions of years of evolution.
The fuel we all know about is sugar/glucose, which comes from carbohydrates. The other, much less-familiar type is called ketones or ketone bodies – small, energy-dense molecules that the body makes in the liver from fat. It is a sort of back-up system that automatically kicks in when carbohydrate/glucose supplies run low. So, a ketogenic diet involves eating almost no carbohydrates and replacing them with fat.
What has this got to do with cancer? Healthy cells can make energy in small ‘power plants’ called mitochondria using either glucose or ketones. Some athletes claim that ketones are a better source of fuel for long distances. Crucially, the mitochondria in cancer cells do not work very well, if at all, so the cells have to switch to a cruder and less efficient system called glycolysis, which needs much larger glucose supplies than the mitochondrial route.
Remove cancer’s preferred source of fuel
Going ketogenic can weaken cancer cells because, not only are they getting less glucose in the blood, but their faulty mitochondria cannot use ketones. So, the logic behind the ketogenic diet as a cancer therapy is seductively intuitive: remove the cancer cells’ preferred source of fuel and replace it with a fuel it has difficulty burning. Simple.
Given this very plausible scenario, it is a big mistake to categorically claim the ketogenic diet is a ‘cancer treatment myth’, as some have done, especially if your life is at stake. Critics have challenged the scenario by saying that changing diet is flawed from the very start because cancer is caused by mutations to DNA – and therefore any dietary intervention cannot affect cancerous cells. The dogmatic assumption that cancer is exclusively a genetic disease, however, is a position that is becoming harder and harder to defend.
A massive US Government effort to understand the genetic underpinning of cancer, called The Cancer Genome Atlas (TCGA) project, that kicked off in 2006 and concluded in January, 2015, has left many cancer researchers scratching their heads. Its findings have shaken the very foundation of the standard theory of cancer.
TCGA shows cancer not exclusively caused by DNA mutations
The model we all know about says that cancer is the result of a relatively small number of ’driving’ mutations turning a healthy cell cancerous and causing it to grow uncontrollably. This would allow them to be targeted with drugs. However, this is not what the Atlas shows; the most defining feature of the cancer cell genome as revealed by TCGA is that it is completely chaotic.
The TCGA sequenced the entire genomes from 10,000 malignant tissue samples and reportedly discovered 10,000,000 cancer related mutations but there was no clear pattern. Some cancers had 20 or more mutations; others might have just one mutation or even none at all. The conclusion: cancer is not exclusively caused by mutations to DNA. It cannot be. Something else must be causing and driving it. TCGA was intended to be our last battle with cancer; we would finally know it in its entirety but, rather, it left us with a murky, muddled mess. A 2015 Nature article titled, End of cancer-genome project prompts rethink, highlighted the confusion: ‘Also a problem was the complexity of the data. Although a few ‘drivers’ (genes that, when mutated, cause or ‘drive’ cancer) stood out as likely contributors to the development of cancer, most of the mutations formed a bewildering hodgepodge of genetic oddities, with little commonality between tumors.’
This is what James Watson, the Nobel Prize-winning, co-discover of the structure of DNA, said of TCGA: ‘We can carry on and sequence every piece of DNA that ever existed, but I don’t think we will find any Achilles’ heels. We’ve had about 10 years. It’s not the story I wanted to hear. I would have hoped for a lot more success.’
If mutations to DNA are not the entire picture, then what is the ultimate cause of cancer?
The role of epigenetics
What we do know is that something called epigenetics – the turning on and off of genes – is involved in transforming a normal cell into a cancerous one. Dr Jean Pierre Issa, of MD Anderson Cancer Center, a tremendously respected cancer researcher, said in an interview for NOVA, a division of Public Broadcasting:
‘Up until recently the idea was that cancer is a disease of genetic changes. The genes themselves, their structures, become abnormal. Over the past few years we have come to realize that there might be more than one way to skin the cat – that there might be changes other than genetic changes that would account for the bizarre behaviour of cancer cells. And these relate to epigenetics.’
Epigenetic changes – the turning on and off of genes without changing the underlying sequence of DNA – are responsible for a striking metabolic shift within the cancer cell, which involves a major change in the way cancer cells make energy.
This dates back to 1924 when the great German biochemist, Dr Otto Warburg, discovered that cancer cells were doing something strange. Unlike normal cells, they were making most of their energy via a method called ‘aerobic fermentation’. Also known as glycolysis, it involves burning glucose (sugar) very fast and making lactic acid in the process. Today this metabolic quirk of the cancer cell is called the Warburg effect.
Cell turns into a sugar-consuming machine
Normal cells make 90 percent of their energy in the tiny power plants found in almost every cell in the body called mitochondria. They use oxygen but do not produce lactic acid. We now know how cancer cells switch to the Warburg effect but the reason why is still hotly debated.
They do it by changing the amount of protein produced by a gene called hexokinase II. The gene does not change, it just becomes more active – this is epigenetics. The result is the cell turns into a sugar consuming machine.
So, I would challenge anyone to show a single mutation that is a cause of the Warburg effect, rather than a trigger of the epigenetic shift to hexokinase II. The reason why it matters whether the energy production switch is due to a mutation or to epigenetics is because an epigenetic change can be reversed, unlike a mutation.
If you have seen a PET scan, you have seen a visual image of the Warburg effect. A PET scan is done by injecting radio-labelled glucose into the patient. The ‘hot spots’ that then appear are a dramatic visualisation of cancer’s voracious appetite for sugar. This is the basis of a PET scan. Without the ability of sugar to ‘gravitate’ and become concentrated inside cancer cells, the PET scan would not work. In fact, there is no argument about cancer’s love of sugar, which leaves the basic idea behind the ketogenic diet – reducing energy for the cancer cell – unaffected.
Ketogenic effect on cancer cells
Turning cancerous has the effect of re-wiring a cell’s energy production system so it becomes more demanding and less efficient. And that opens up many new ways of tackling tumours.
For instance, it is already leading to a less gruelling way of delivering chemotherapy (CT), which comes with a raft of side effects because it damages fast-growing, cancer cells and fast-growing, healthy cells alike. By focusing on the way that cancer makes energy, treatments can be developed that damage cancer cells but not healthy ones.
The original idea behind the ketogenic diet was that it provided the body with an alternative source of energy – one that healthy cells can use but cancer cells cannot because of the changes to their energy production system.
But it turns out that ketones can do much more than supply energy; they are also potent, epigenetic, signalling molecules – that is, they can turn gene activity up or down. And for reasons not yet understood, they ‘turn own’ about a dozen – maybe many more – cancer-related genes (oncogenes). They do this by changing the chemical ‘tags’ on the proteins that package the DNA.
Ketones slow tumour growth in the lab
Ketones engage cancer cells in a sort of epigenetic diplomacy. Certain beneficial genes get exposed and so become more active, while a host of oncogenes (cancer-driving genes) get turned down, causing the cancer cells to behave more like normal cells. Far from being unable to affect genes, it now seems that a ketogenic diet could be having an impressive range of very specific, genetic effects.
A simple experiment highlights this signalling action of ketone bodies: picture two petri dishes with cancer cells. Both dishes have the same concentration of sugar for the cells to use as fuel. When ketones are added to one of the dishes the cancer growth dramatically slows. This is one way we know ketones are affecting cancer cells in ways that go beyond energy restriction.
The ketogenic diet is unique among cancer therapies in that it affects healthy cells and cancer cells very differently. The biochemical details of each one are too complex to discuss here, so I will only list them:
■ Cancer cells are put under energetic stress because they have difficulty burning ketones.
■ Normal cells are actually energised by the ketogenic diet. Per unit of oxygen burned, ketones generate more energy than sugar.
■ Cancer cells show many important oncogenes are turned down.
■ Normal cells show beneficial genes are turned on (many of the same ‘housekeeping’ genes are turned on by caloric restriction).
■ Cancer cells have a diminished ability to generate glutathione – the ‘master’ antioxidant.
■ Normal cells trigger an increase in glutathione.
Diet cuts damaging chemotherapy side effects
So, how does all this lead to new approaches to clinical treatment? Leading researcher, Valter Longo, of UCLA, calls this strange ability of ketones to make healthy cells healthier and cancer cells weaker ‘Differential Stress Resistance’ (DSR). Longo convinced oncologists to allow their patients to enter ketosis by fasting (cutting calories right down automatically cuts carbohydrates) for 48-140 hours before CT and a 5- to 56-hour fast
after CT. He then measured side effects. Every one of the 14 most common CT-related side effects was diminished. Of particular note: the fasted patients did not vomit at all and had no diarrhoea – two of the most debilitating side effects. So, it appears that the ketogenic diet and its ability to create DSR can diminish side effects; but can it increase the efficacy of other treatments? This seems to be where the diet truly shines.
For instance, a substantial and growing block of evidence suggests the ketogenic diet can enhance traditional, standard-of care treatments such as CT and radiation, by combining them with still unconventional therapies such as hyperbaric oxygen and drugs that affect glucose levels in the blood.
Diet makes CT and hyperbaric oxygen more effective
The ketogenic diet weakens cancer cells by physically throttling back their energy, while simultaneously decreasing the damage done by oxidants by turning up the genes that produce natural antioxidants, such as glutathione. This then makes conventional treatments more effective.
The ketogenic diet (or ketosis via fasting) has been shown in animal models to increase the efficacy of: radiation, CT, hyperbaric oxygen (cancer cells normally thrive at lower oxygen levels than healthy ones), drugs that reduce the ability of cancer cells to make energy from glucose) and giving supplements of ketone synthesised in the lab.
If the benefits of the diet really were a myth, then it is odd that the ketogenic diet is currently being investigated as a cancer therapy in at least 26 clinical trials in the US and around the world, including at the University of Liverpool.
Istanbul clinic shows remarkable results
Just recently we are finally getting glimpses of real clinical data. At the ChemoThermia clinic in Istanbul, Turkey, oncologists are giving their patients a protocol they call metabolically supported CT (MSCT), whose goal is to enhance standard of care by exploiting the metabolic derangement of the cancer cell. This is the protocol:
- Ketogenic diet
- 14-hour fast immediately before CT
- 2-deoxyyglucose (this is what is called a glycolytic inhibitor – it makes energy production via glycolysis less effective)
- Dichloroacetate (DCA) – cheap chemical compound that also interferes with glycolysis. (Crucially, neither affect the different method of energy production in healthy cells)
- Hyperbaric oxygen
■ Standard care: median survival: 8.6 months
■ MSCT: median survival: 43.4 months! (over 600% increase and climbing since many patients are still alive)8
Note: the patients getting MSCT were sicker (all stage 4) than those getting standard care, a group that included patients with stages 3 and 4.
Credible supporting results
Promising as all this is, one criticism – a lack of overall credible data – is correct. At present there are no double-blind, placebo-controlled, phase 3 trials to support the ketogenic diet as an adjunctive cancer therapy. This is the so-called gold standard of proof and the reflex reaction of most mainstream oncologists faced with a possible cancer treatment is to dismiss it out of hand unless it comes with a full Randomized Controlled Trial, which costs millions.
So, the question becomes just how high should the bar of burden-of proof be set? A growing number of oncologists and researchers now believe it is insanely high. Highly respected oncologists – such as the original pioneers of combining CT drugs, Vincent DeVita and Emil Freireich – have been railing against the absurd criteria that the FDA has arbitrarily established for years as a threshold to approve a new therapy. They point out that good therapies – potentially lifesaving therapies – sit on the side line because they will never get the billion-dollar backing necessary to shepherd them through a massive phase-3 trial.
Promising treatments side-lined
Listen to Dr Vincent DeVita (former director of the National Cancer Institute), pioneer of MOPP CT, author or co-author of more than 450 scientific articles, editor-in-chief of The Cancer Journal and author of The Death of Cancer):
‘At this date, we are not limited by the science; we are limited by our ability to make good use of the information and treatments we already have. Too often, lives are tragically ended not by cancer but by the bureaucracy that came with the nation’s investment in the war on cancer, by review boards, by the FDA, and by doctors who won’t stand by their patients or who are afraid to take a chance.’
And this is what Dr Emil Freireich thinks about the current standard of evidence (he currently holds the positions of: the Ruth Harriet Ainsworth Chair, Distinguished Teaching Professor, Director of Adult Leukemia Research Program, and Director of Special Medical Education Programs at the University of Texas, MD Anderson Cancer Center in Houston, Texas):
‘It’s so obvious that if the FDA allowed us to be rational about treating cancer patients we could move the ball 100 times faster…[Do] you have to do a phase 3 randomized trial? No. If you have evidence that’s clear. If you have an objective response. Objective, progression-free survival. That’s it.’
The debate generally centres around drugs rather than non-drugs but it seems that there is substantial evidence that the ketogenic diet is a good, perhaps great, adjunctive therapy. So maybe the ‘lack of overall credible data’ is not as fatal as it sounds.
It appears to enhance the outcome of other treatments while mitigating side effects. It is also completely safe, something most physicians do not appreciate. It has been used for nearly 100 years as a treatment for childhood epilepsy and is currently approved for that use on the NHS.
From my perspective, it seems difficult to make the case against it. It seems to demand the multimillion- dollar trial that is never going to happen. Dr Freireich’s view seems more sane and humane. The ketogenic diet can clearly tick his boxes: ‘clear evidence, an objective response and objective, progression free survival’. So, the question for orthodox oncology is: why not?
 Christofferson T. Tripping Over The Truth. How the Metabolic Theory of Cancer Is Overturning One of Medicine’s Most Entrenched Paradigms. Chelsea Green Publishing, White River Junction, VA, USA, 2017.
 Ledford H. End of Cancer-Genome Project prompts rethink, Nature 2015;517(7533):Jan 5.
 Wagstaff A. Jim Watson: DNA revealed the causes, it may never reveal a cure, Cancerworld 2013;56:1 Sept.
 Safdie FM Longo V et al. Fasting and cancer treatment in humans: A case series report. Aging 2009;1(12):988-1007.
 Lyikesici M, Slocum AK and A, Seyfried TN et al. Efficacy of metabolically supported chemotherapy combined with ketogenic diet, hyperthermia and hyperbaric oxygen therapy for stage IV triple negative breast cancer. Cureus 2017;9(7):e1445. Doi. 10.7754=9/cureus.1445.
 Christofferson C. op cit, Ch 6.
 Unpublished internal data from ChemoThermia Oncology Center, Istanbul, Turkey.
 DeVita V. The Death of Cancer. Sarah Crighton Books, McMillan, London, 2016.