What Is The Origin of Cancer?

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Written by: Travis M Christofferson

It is cancer biology’s Most Fundamental question:  What is the origin of cancer?

 

The symbols are everywhere.  Pink ribbons, Yellow LIVESTRONG bracelets, billboards advertising Race’s for Cures, T-shirts, and media reports hinting at blockbuster new drugs that are always just around the corner.  All of them, taken together, give the impression we are surely winning the war against cancer.

Hidden from the hope and optimism, the feel-good industry of cancer, is the battlefield – where a simple body count will tell a far different story.  This year almost 600,000 Americans will die from cancer – the equivalent of one world trade center collapsing on society every day.  But beyond the raw numbers are the survival statistics, and they all lead to an uncomfortable conclusion – we are not winning the war against cancer; we are no closer to cures than when Nixon declared the war on cancer in 1971 – in fact, we may be further away.

This is surprising considering, my generation, following in the wake of the irascible baby-boomers, has reaped the benefits of a class-action suit that their demographical-bulge seemed to have filed against aging itself – compiling a resume of success against almost every conceivable malady – except cancer.

Something has gone terribly wrong.

Everybody should be asking the question –what has gone wrong in our generational war against cancer?  As a country, we spend more on cancer research that any other disease – 200 billion since 1971 – with tremendously little to show for it.  (Not even considering the fact cancer is under constant investigation at every major pharmaceutical company around the world.)

Many have suggested answers to this question that seem to just skim the surface — but the real answer may be much deeper.  This situation couldn’t exist unless there was a profound and fundamental flaw in the way we’re thinking about cancer — This article is an attempt to shine light on exactly what the flaw might be.

 Image from Wikipedia

Cancer is a genetic disease – right?

Cancer is a disease of DNA.  If you’ve had a biology 101 class you know this. One hundred years of slow and painstaking detective work has firmly established the primacy of DNA as the critical macromolecule responsible for cancer.  The link between DNA and cancer is through genes called oncogenes, genes that when mutated result in the formation of cancer.  Textbooks tell us we all carry oncogenes within our DNA — the seeds for cancer are already baked into each and every one of us, just waiting for activation.  The established theory on the genesis and progression of cancer is called the ‘Somatic Mutation Theory of Cancer’, and it contends that exogenous agents like cigarette smoke, chemical carcinogens, radiation, and so forth, eventually damage, and activate (by mutations) the critical oncogenes responsible for keeping cellular growth organized – unleashing  aggressive and uncontrolled proliferation – the hallmark of cancer.  The Somatic Mutation Theory of Cancer is to cancer researchers what gravity is to physicists — It is scientific dogma, it is learned early by all students and never questioned again.

Because cancer is a disease of DNA, in order to completely understand it, providing the foundation for potential cures, researchers would have to identify and catalog all the mutations that cause the disease, the drugs then developed to target these ‘driver’ mutations would be quick to follow.

When the war on cancer was declared in 1971 the idea of sequencing the entire genome of multiple types of cancers was still science fiction, existing only in the imagination.  As is often the case, technology eventually transforms imagination into reality, and right now laboratories throughout the world are churning out the genomic sequence of multiple types of cancer with inconceivable speed and efficiency.  This technologically ambitious, NCI-funded project is called the Cancer Genome Atlas Project — it is the Manhattan project of cancer, it is an outcome based endeavor and its sole reason for existence is to win the war against cancer.

The Cancer Genome Atlas Project (TCGA) which began in 2005 will compare the sequence of normal DNA to that of 9 different types of human cancer in order to determine the exact mutations responsible for the origination and progression of the malignancies.  Researchers would finally know cancer in its entirety – they would be staring the relentless shape-shifting enemy directly in the face, with nowhere for it to hide.  Make no mistake, everything has led to this – If you could fast forward over 100 years of cancer research every intellectual avenue would lead to the Cancer Genome Atlas Project  as the flagship endeavor required for a cure.  Almost every cancer researcher on the planet will tell you cancer is through and through a genetic disease, and the TCGA is the culmination of lifetimes spent trying to reveal the elusive details of this insidious foe – the details necessary to develop real and enduring cures.  This was to be the final battle in a protracted war.  This one project would vindicate the generations that have fought and succumbed to the disease.

That was how it was supposed to happen.  What was supposed to be the decisive battle in the war against cancer has turned into Custer’s Last Stand…..We have to step back to see what happened.

 

Know Thy Enemy

In the summer of 2009 Nobel Prize winner and co-discoverer of DNA (the molecule at the center of the cancer universe), James Watson, was full of optimism. So much so that he decided to pen an op-ed for the New York Times calling for a “refocusing of efforts in the war on cancer” – even going as far to call for “lifelong cures within a decade.”  He declared, “Beating cancer now is a realistic ambition….we shall soon know all the genetic changes that underlie the major cancers that plague us.”

“Beating cancer now is a realistic ambition….we shall soon know all the genetic changes that underlie the major cancers that plague us.” James Watson

James Watson, after his world-changing discovery of the structure of DNA, shifted his focus to cancer.  And like so many before him, he lived through the stops and starts, the fleeting victories and the crushing defeats – but overwhelmingly a pervasive feeling of frustration on the progress of cancer research was as ambient as air itself.  He was there when Nixon declared the war against cancer.  Americans were full of hubris and optimism at the time, fresh off the moon landing it was widely believed the disease would be cured in a handful of years.

The discovery of oncogenes was to come shortly, the genes that when mutated were thought to result in cancer.  It was not a bold-leap of imagination to envision a smart-war from here– a war that utilized drugs targeted to the products of oncogenes, specifically honing in on cancer cells, sparing normal cells.  The days of toxic chemotherapy and radiation would soon be gone, relics of an era of medieval medicine, akin to bloodletting and leaches.  But that fleeting moment of optimism, I’m sure Watson would attest, was followed by decades of excruciatingly slow progress.

Clifton Leaf, cancer survivor, New York Times guest editor, and acclaimed author, has spent the last decade trying to identify the reasons we appear to be losing the war against cancer.  His search has uncovered a fountain of statistics, that when taken together, reveals just how agonizing slow progress has been since Nixon declared his ambitious war.  For sure the once imagined targeted smart drugs have come, over 700 of them to date, and only one, Gleevec, a drug that targets chronic myelogenous leukemia has had any meaningful impact.  Clifton will also tell you if you’re a woman you have a 1 in 3 chance of acquiring cancer in your lifetime – if you’re a man 1 in 2.  He will tell you that within the next decade, cancer is likely to replace heart disease as the leading cause of U.S. deaths, according to forecasts by the NCI and the Centers for Disease Control and Prevention.  It is already the biggest killer of those under 75. Among those ages 45 to 64, cancer is responsible for more deaths than the next three causes (heart disease, accidents, and stroke) put together. It is also the leading disease killer of children, thirtysomethings–and everyone in between.  But the most important  statistic Clifton leaf will tell you, the one that exposes what an abysmal failure the war on cancer has been it this:  the death rates from cancer today, are the same today as they were in 1950.

The one statistic that EXPOSES what an abysmal failure the war on cancer has been is this:  the death rates from cancer today, are the SAME as they were in 1950.

But James Watson knew all the statistics when he penned his op-ed in the New York Times – he had a brand new reason for optimism.  To be sure he had experienced a lifetime of transcendental moments of hope in the war against cancer, moments when it seemed the tide might be shifting – all of them decisively crushed by the seemingly impenetrable force of the disease – so he probably wasn’t predisposed to optimism; he probably chose it carefully.  The title of Watson’s op-ed was “To Defeat Cancer – Know Thy Enemy.” The title was certainly appropriate because the Human Genome Atlas Project was underway.  All the gaps in understanding that prevented cures, all the dead ends that Watson had viscerally experienced through his career on the front line in the war on cancer, would soon be filled in.  Watson knew as he wrote, thanks to the cancer genome atlas project, he would soon finally- truly, ‘know thy enemy.’

 

A Sardonic Sense of Humor

Nobody saw this coming.  Between the spring of 2009 (when Watson penned his op-ed), and now, mountains of sequencing data has come in, reveling the mutational profile of many cancers, including ovarian, pancreatic, lung, melanoma, brain, breast, and several forms of leukemia, and the data is anything other than what was expected.  Rather, The Cancer Genome Atlas Project had revealed something completely unexpected.  The mutations that were always thought to sequentially sabotage critical cellular machinery – marching a cell, step by step, toward a chaotic, aggressive, uncontrolled, and invasive killer – simply made no sense.

Researchers believed the sequencing data would reveal a nice and orderly sequence of maybe 3 to 8 oncogenes that when mutated, manifested in a specific type of cancer – an identifying signature like a fingerprint – and they would work off this mutational signature with cures to follow, as Watson suggested.  But what they found instead was an almost random collection of mutations – not a single one, or any combination for that matter, being absolutely responsible for initiating the disease.  In 1976, after an arduous six decade long search for oncogenes –commenting on the vicissitudes, complexities, and surprises of cancer biology, renowned scientist Peyton Rous said, “Nature has a sardonic sense of humor”.  He had no idea how hauntingly prophetic that statement was to be.

IF cancer researchers ever HAD a collective “STAND-with-your-MOUTH-WIDE-OPEN in SHOCK” moment, it is RIGHT NOW.

You won’t read about this in the newspapers yet, about the confusing data coming out of the TCGA.  Mostly because the data is still being collected, and right now the entire field of cancer biology is collectively in the middle of a hasty and massive reorganization.  If cancer researchers have ever had a collective “stand-with-your-mouth-wide-open in shock” moment, it is right now.  Some researchers are transfixed, sort of staring at each other in disbelief – looking to each other for clues as to what to do next.  Others, clinging onto a lifelong investment in the somatic mutation theory of cancer, are desperately trying to make the data work – modifying the current theory to account for the seemingly random data.  And yet others have moved on – embracing different theories to explain the obtuse sequence data.  But to be sure, if cancer biology was marching in a straight orderly line a short time ago, it has now converged into a cloud of chaos, with everyone running in different directions, picking new teams.  Not yet mainstream, this phase of the battle is still being fought in scientific journals – It’s true you can’t read a review of the data from the TCGA without encountering the words, “sobering”, “incredibly complex”, or “Immense therapeutic implications.”  Most mainstream publications seem to avoid the topic altogether.

Including Siddhartha Mukherjee’s 2010 book on cancer, “The Emperor of all Maladies.”  Time magazine called it one of the 100 most influential books of the last 100 years.  It is a wonderfully written, rich historical journey of cancer, from its distant past all the way to the present.  The book portrays the excruciatingly difficult journey scientists have encountered in their efforts to understand and combat this disease, and it culminates with the Cancer Genome Atlas Project – a subject Mukherjee gives remarkably little attention.  In the previous chapters of Mukherjee’s book he brings the characters to light in delightfully colorful detail and vivid texture, weaving an inspired and imaginative narrative. The progression of scientific discovery, in Mukherjee’s book, all leads to the TCGA as the one tool needed to coalesce the randomly scattered pixels of data into a complete image of understanding.  Generations of effort culminating in one final unveiling, lifetimes of struggle, disappointment, and frustration would not have been in vain because the TCGA would completely reveal our foe.  It is strange because Mukherjee seems to just sort of gloss over it – only introducing a single scientist, Bert Vogelstein, to walk the readers through the data.  The one project destined to finally make a cure realistic seemed like it deserved so much more in such a comprehensive work on the story of cancer – but there is a good reason Mukherjee gives little attention to the TCGA – the data is virtually incomprehensible.

In fact, the grim details of the data from the TCGA are absent from many narratives – it’s as if the cancer community is desperately waiting with their breath held for the data to make sense.  The most striking feature of the journal articles and reviews is what is not there, as if omitting something will just make it go away.

To truly appreciate the situation cancer biology is in, you have to take a brief walk through the data from the TCGA– it seems remarkably few have, and even fewer fully realize the implications and consequences of the data.

The unsettling data came in slowly at first. Between 2002 and 2003 the first large-scale efforts to systematically screen individual tumors from colon cancer samples for somatic mutations contained the first surprise for cancer researchers — remarkably few previously unknown oncogenes were identified.  It was sort of assumed that new key oncogenes would be identified – genes that would be implicated as causative when mutated.  But that was not to be the case – maybe the decades of work teasing out oncogenes had been more thorough than researchers realized.

The initial studies were also relatively limited – limited in the fact they did not sequence the entire 20,000 genes contained within the human genome.   The more comprehensive studies to come would surely reveal more.  The next cancers in line to be sequenced were breast and colon.  These studies would delve further into the genomes of these cancers than the previous work, hopefully culling out the handful of genes that cause these two types of common cancers.  But like before, when the results were published between 2006 and 2007 – that was not the case.

Again no new oncogenes were found, but far more unsettling than that, was the beginning realization that none of the mutations found were conclusively determined to be responsible for the origin of the disease.  In order for the somatic mutation theory to work, mutational patterns must be found that explain the origin of a given type of cancer – cause must precede, and explain effect.  Critically, the mutations determined to start and drive the disease were different from person to person – vastly different.  No single mutation could be identified that was required for the disease to start, no combination of mutations, for that matter, could be found that initiated the disease.  Other than a few commonly mutated oncogenes, the mutational pattern appeared to be largely random.  These studies sequenced the tumors from 11 different individuals with breast cancer, and 11 different individuals with colon cancer.  Over 18,000 genes were sequenced, almost 40 times the amount in the initial studies – the most exhaustive sequencing to date.

In the meantime the technology continued to improve.  Sequencing technology became faster, more accurate, and cheaper.  Armed, reinvigorated, and determined, pancreatic cancer was on deck.  This time, in 2008, teams of researchers would again sequence over 20,000 genes, nearly all of the predicted protein coding genes in the human genome from the tumors of 24 individuals suffering from pancreatic cancer.  But it was more of the same.  Again no new mutations of any significance were found, and again the mutations they did find were unable to be assigned as definitely causative.  The somatic mutation theory was in trouble – a modification was needed to make the theory continue to work.

 

The Search for Dark Matter

This is where Bert Vogelstein, the scientist introduced to us in Mukherjee’s book, the one chosen to walk the readers through the results of the Cancer Genome Atlas Project, returns to the story.  Vogelstein knew the Somatic Mutation Theory was in trouble and needed a modification.  Enough data was compiled to conclusively determine that the idea of a nice and tidy series of sequential mutations as the cause of cancer could be scrapped, an idea Vogelstein had championed for decades.  In its place, Vogelstein slightly tweaked the original theory, proclaiming that rather than a defined set of specific mutations being the cause of a given cancer, cancer is caused by mutations that render certain biological systems dysfunctional – systems involved in the qualitative aspects of cancer, like uncontrolled proliferation, inhibition of programmed cell death, and tissue invasion.  In other words; cancer was a cellular systems disease.  A given system might have say 20 or so constituent genes required for it to operate – so the theory goes – if any single one of the constituent genes was rendered dysfunction by a mutation, then the whole system was made non-operational, marching the cell one step closer to malignancy.

Some criticisms by other cancer biologists claim this was simply and ad hoc modification necessary to make a failed theory continue to fit the data.  But I don’t think so.  The modification to a systems disease seemed reasonable to me.  For sure it is a broadening, or a dilution of definition, for sure it would make the data easier to fit.  That is not a reason alone to discard the new modified theory however.   But the data would have to validate it.  Time and more sequencing data would tell.  The authors of the pancreatic cancer study said this about the somatic mutation theory’s new paradigm shift, “From an intellectual viewpoint, the pathway perspective helps bring order and rudimentary understanding to a very complex disease.”

Applying the new modified theory to the pancreatic cancer study determined that pancreatic cancer was caused by the dysfunction of 12 different biological systems.  Now a critical eye must be cast on just how diluted this new, modified theory had become.  In this case it seems it was pretty watered down.  It turns out, the authors had to use some imagination in order to assign some of the mutations to one of the 12 systems implicated in the pathogenesis of pancreatic cancer.  It appeared that some of the mutated genes were friends, of a friend, of a friend, that was definitely part of the implicated system.  By the authors own omission, “Although we cannot be certain that every identified mutation plays a functional role in the pathway or process in which it is implicated.”  Rather than bringing order and rudimentary understanding to a very complex disease – it seemed like the authors were manufacturing order and understanding to a very complex disease.

Despite the confusion, the TCGA soldiered on.  Glioblastom Multiforme was next – brain cancer.  Glioblastom is a mean aggressive-cancer; most will succumb to it within a year even with treatment.  Again, teams of researchers sequenced over 20,000 genes from 22 tumor samples.  This time a novel gene was found to be mutated in 12% of the samples – a big accomplishment.  Its discovery was cited as a validation of the utility of genome-wide genetic analysis of tumors. The authors concluded that GBM was caused by mutations that rendered 3 important biological processes dysfunctional.  However, as with pancreatic cancer, a close look at the data reveled something else.  The disturbing trend continued – none of these studies were able to validate the somatic mutation theory of cancer, not even the new modified version.  None of these studies were able to conclude that mutations were even the cause of the disease at all.  Of the 22 samples only 4 had mutations involving all 3 systems implicated as necessary for GBM to occur.  Nine samples had mutations in 2 of the 3 systems, 5 had mutations in 1 of the 3, and most significant, one sample (sample labeled Br20P) had no mutations in any of the 3 systems yet was a living, growing, aggressive case of GBM.  The profound silence with regard to these inconsistencies in the new and modified somatic theory of cancer speaks volumes.  For the theory to work, the original theory, or the new modified theory, samples like Br20P simply cannot exist.

For the GENETIC theory of cancer to work, the original theory, or the new modified theory, samples like Br20P simply CANNOT exist.

A little over a year ago, the sequence data was released on over 21,000 genes from 100 breast cancer samples, the most comprehensive to date, and for the somatic mutation theory of cancer; the most damning to date.  Like the other studies, the theory itself is not questioned.  Just silence.  The authors do again pay homage to the complexity of the sequence data, declaring, “The panorama of mutated cancer genes and mutational processes in breast cancer is becoming clearer, and a sobering perspective on the complexity and diversity of the disease is emerging.  Driver mutations are operative in many cancer genes.  A few are commonly mutated, but many infrequently mutated genes collectively make a substantial contribution in myriad different combinations.”

That statement does not even approach a realistic description of the complexity found in the mutation-profile of breast cancer, or most types of cancer.  From the 100 samples sequenced, 44 genes were implicated as being involved in the tumorigenesis of breast cancer.  The maximum number of mutated cancer genes in an individual breast cancer was 6, but 28 cases showed only a single driver mutation.  If you were to ask 100 oncologists, or cancer research scientists 10 years ago if breast cancer could be caused by a plethora of different single mutations, all 100 probably would have laughed at you.

Much worse, in yet another glaring omission, the authors failed to even make mention of five samples that had no mutations at all – no driver mutations found, yet these were living, breathing, aggressive killer cancer cells.  Again, for the somatic mutation theory of cancer to work – samples like these can’t exist.

When I asked Dr. Larry Loeb of the University of Washington, one of the key players in the CGAP, to summarize in a few sentences what has been learned so far from the sequence data –he spoke slowly and deliberately, “There are enormous numbers of mutations present in each tumor – and it is very, very difficult to determine which ones are causative.  We do not have an adequate armament of effective drugs to target the spectrum of mutant genes within individual tumors.  The mutational complexity found in cancer is truly daunting.”  In many ways the somatic mutation theory of cancer seems like a grand-scale example of groupthink.  There is no-way mutations can be completely responsible for the origin of cancer – yet so few seem willing to say it – maybe it’s because the discovery of DNA, and its central role as the dictator of life’s processes was such a profound intellectual achievement, that nobody is willing to question its primacy in the etiology of cancer.  Maybe this is just how slow entrenched, dogmatic belief-systems are to change course.  Whatever the case may be, billions are still being spent chasing down and cataloguing the mutations thought to cause cancer.  And billions again are spent developing one failed drug after the next that target these mutations.  Drugs that typically cost up to 100,000 per treatment giving patients maybe a few months at best – many offering no increase in survival time at all.  We must all remember this is no intellectual exercise, this is not theoretical physics or astronomy where one theory slowly discards another, after taking careful consideration, and there is no need for a sense of great urgency.  But in the case of cancer research, there needs to be a sense of great urgency – this is war.  People are still dying.  Time is not a luxury many have.

I emailed Dr. Vogelstein, asking him about the inconsistencies of the data.  Specifically I asked him how he explained samples like Br20P, the brain cancer sample with no mutations in any of the 3 broad systems determined by Vogelstein to be required for the formation of cancer.  He politely referred me to his latest review in the highly esteemed journal Science.

In his review, Vogelstein does attempt to address the problems with the data from the CGAP.  First off, he explains that genomic wide sequencing technology is still far from perfect and has been shown to have a false-negative error rate of up to 37%.  However, even if one takes into account the potential error rate of sequencing the data still doesn’t work – another explanation is needed.  And Vogelstein offers one up in a section titled “dark matter.”

In the 1930’s it was noticed that the orbital velocities of galaxies, including our own Milky Way, didn’t make sense.  Galaxies were rotating much faster than predicted by classic Newtonian mechanics – something else was at work here, something that could not be seen.  The explanation came in the postulated existence of an invisible material termed “dark matter”, an ephemeral, undetected-material that was physically influencing the world around us, and physicists are still hunting for this material today.  In fact, 40 miles from my home is the latest incarnation of this 80 year search for dark matter.  In a now abandoned goldmine in the Black Hills of South Dakota a colossal effort is underway to build the infrastructure necessary to capture just one of these elusive particles, furthering humanities understanding of the universe we live in.

Vogelstein borrowed the term dark matter from astrophysics and applied it to the gaping hole in understanding revealed by the Cancer Genome Atlas Project.  Vogelstein is well aware that some nebulous, presumptive-process is preventing the complete picture of cancer from being realized.  He just has to find the dark matter – it’s just that he might be looking in the wrong place.

 

If cancer is not a genetic disease then what is it?

 If James Watson was filled with optimism in the summer of 2009, then he was equally filled with scathing pessimism in the winter of 2012. It seemed as though cancer had once again dangled a carrot in front of him, only to violently pull it back as he cautiously reached out with hope.  Watson expressed his frustration in a paper published around the world.  The paper appeared the day after the country’s top cancer organizations acknowledged in an annual report that we’re making agonizingly slow progress in reducing the disease’s death rate.  Watson’s frustration this time was not an undertone but instead boiled over – declaring, “the ‘curing’ of many cancers seems now to many seasoned scientists an even more daunting objective than when the ‘War on cancer’ was started by President Nixon in December 1971.” The seemingly random nature of the mutations coming from the TCGA caught everybody by surprise.  But something new came out of Watson’s paper, something he had also addressed in a recent speech at Yale University – the defective metabolism of cancer – even going as far to call it the ‘Achilles Heel’ of the cancer cell.

Let me tell you why this is important — long before cancer was thought to be a genetic disease, resulting from mutations to key oncogenes, it was thought to be a metabolic disease, resulting from defective metabolism.  Metabolism is a general word describing all of the chemical reactions the cell undergoes to generate energy.  However, the metabolic theory was unceremoniously discarded when it was found that the DNA of cancer cells, the profound molecule Watson had just reveled to the world, contained mutations.

Long before cancer was thought to be a GENETIC DISEASE, resulting from mutations to key oncogenes, it was thought to be a METABOLIC DISEASE, resulting from defective metabolism.

The metabolic theory of cancer goes way back to 1924 in Berlin, Germany, — and a curious biochemist named Otto Warburg. While working in his lab Warburg noticed something strange about cancer cells – critically, he noticed they had difficulty using oxygen to generate energy.

Warburg was not your average scientist, not only did he win a Nobel Prize, but he was nominated an unprecedented three times for three separate achievements.  Remarkable in his brilliance and productivity, Warburg single handedly advanced human physiology by leaps and bounds in the early twentieth century.   Since Warburg was Jewish, he was forced by the Nazi regime in Germany to decline a second Nobel Prize Award in 1944. Nevertheless, the government did not imprison Warburg, because it was believed Hitler was terrified of cancer, and Warburg was the world’s foremost expert at the time.

Unlike the mutational profile of a cancer cell’s DNA, the profoundly altered metabolism of cancer cells, Warburg documented, was consistent from one cancer to the next, it was a pervasive feature of the cancer cell.

A healthy cell produces 89% of its energy using oxygen, and 11% through non-oxidative metabolism (non-oxidative metabolism is also known as fermentation.)   While cancer cells continue to produce energy through non-oxidative pathways even in the presence of oxygen – this is called the Warburg effect.   The observation that the Warburg effect was such a consistent and dominate aspect of cancer, spanning the entire spectrum of the disease, led Warburg to propose a hypotheses assigning damaged metabolism as the origin of the disease .  This is how Warburg described the metabolic origin of cancer in 1924, “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 the fermentation of sugar.”

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.  Oxidative energy production takes place in a cellular organelle called the mitochondria.  The mitochondria are commonly referred to as the cellular “power plants” because their primary function is to supply the body with all its energy requirements.  The metabolic theory of cancer contends that the disease begins with damage to the mitochondria thus impairing oxidative energy production — the cell is then forced to produce energy through fermentation in order to survive.  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.

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.

Clifton Leaf’s all-consuming effort to put his finger on the fundamental issues preventing progress in the treatment of cancer for his award-wining 2004 article, ‘Why we’re Losing the War on Cancer’  was no simple task.  He asked dozens of researchers, physicians, and epidemiologists at leading cancer hospitals around the country; pharmacologists, biologists, and geneticists at drug companies and research centers; officials at the FDA, NCI, and NIH; fundraisers, activists, and patients. During three months of interviews in Houston, Boston, New York, San Francisco, Washington, D.C., and other cancer hubs.  Yet virtually all these experts offered testimony that Leaf found, when taken together, describes a dysfunctional “cancer culture”–a groupthink that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs; that fosters isolated (and redundant) problem solving instead of cooperation; and rewards academic achievement and publication over all else.  Leaf’s overall conclusion is that progress has been so slow because:

A. Cancer is a brutally complex problem.

B.  Terrible models – the mouse models researchers use to study cancer do not accuracy represent the real disease.

C. Research grants incentivize researchers to focus on narrow pathways.

D.  A shortage of good, creative ideas, and a groupthink mentality

 

What if the reason progress has been so terribly elusive is not only because of the reasons Leaf has identified above, but also, and more importantly, because researchers have gotten the theory of cancer wrong?  What if this is the deep-fundamental problem — festering below the surface, hidden in plain sight – an invisible straitjacket restraining progress?  It is difficult to explain why the death rates would be the same today as they were in 1950 unless something was profoundly wrong.   How on earth could the tremendous resources dedicated to new therapies – not just at the NCI – but also at almost every major pharmaceutical company around the world not have produced some meaningful results?  Just maybe, as Warburg proposed in 1924; cancer really is a metabolic disease, and researchers throughout the world have been looking in the wrong place.

 

Just One Shade Off

Early on, once it was clear the data from the TCGA did not support the Somatic Mutation Theory of Cancer; Dr. Thomas Seyfried of Boston College didn’t wait around for the data to make sense like so many others.  Instead he and his students dove head-first into an exhaustive review of 100 years of cancer research, attempting to answer the still terribly elusive question:  What is the true nature of cancer?  With over 2.8 million publications dedicated to understanding the obscure molecular mechanics operating within the cancer cell, cancer research lends itself well to a back-room detective approach – with papers scattered all over the floor and tacked to walls, scouring the evidence waiting for patterns and clues to emerge.  His answer – Warburg was right; cancer originates and is driven by defective metabolism.   The culmination of his efforts was a very provocative book titled “Cancer as a Metabolic Disease.”  The comprehensive work was released in 2012 to much acclaim and controversy.  If Dr. Seyfried intended to shock, and rattle-the-cage of the cancer community, then he certainly achieved his goal.  The book pounds home the message chapter after chapter that cancer, as Warburg proposed, originates and progresses by damage to the cell’s mitochondria.  Seyfried calls the mutations observed in the nuclear DNA of cancer “red herrings” that have little to do with the origination of the disease.

Still slightly humming with jet lag, I paced the hallways of Boston College’s Higgins Hall waiting for Dr. Seyfried.  Early for our meeting, but not wanting to break the almost churchlike morning silence by knocking on his office door, I just stood there – transfixed, if not slightly intimidated by the posters decorating the hallway, summarizing decades of cancer research.  I was startled when the office door suddenly flung open.

After the obligatory introductions and small talk Seyfried launched into something more substantive, “My most creative time is in the morning — that’s when I do my best work,” just as the topic switched to cancer, Seyfried abruptly halted, “I’m late for my graduate class on cancer.  Would you like to sit in?” “Of course,” I answered.

“The professors in your other molecular biology and genetics classes will tell you that mutations to genes cause cancer because that is what they were told, and that’s what the professors before them were told, and what their textbook said,”  Seyfried told the graduate students, now talking quite fast as he was unable to contain his own enthusiasm.  “Don’t believe them, look at the evidence and make up your own mind.”  As Seyfried lectured he filled the room with an infectious and palatable excitement. After class we walked down the atrium balcony to his lab.  Students stopped him along the way asking questions.  Once in the lab we sat down with one of his graduate students and for the remainder of the day, the two of them laid out their argument for why the cancer community has mischaracterized the true nature of cancer, and that Otto Warburg had it right — cancer is a disease of metabolism.  As the students came and went you couldn’t help detect the feeling one might feel at an exciting start-up company.  There was energy of innovation, and a sense that here, in Seyfried’s lab, there was a sort-of secret that nobody else yet knew but them – they were positive they had identified the true nature of cancer.

It is not difficult to see how it could happen.   Nature, with her sardonic sense of humor, according to Seyfried, orchestrated the perfect cover up.  When you listen to Seyfried describe it – in exhaustive detail – it seems as though the metabolic theory was covered up by a master criminal — every piece of evidence manipulated to divert attention from the real perpetrator of the crime to an innocent bystander.  The differences between the two competing theories are subtle.  Rather than existing in sharp contrast, they are just one shade off.

The same agents that damage DNA; cigarette smoke, chemicals, and other carcinogens also damage mitochondria.  Once damaged the mitochondria send out signals that activate a series of important oncogenic pathways, altering huge swaths of the genomic landscape, waking-up some genes, putting others to sleep, but when taken together, manifest in uncontrolled proliferation and genomic instability — the most salient features of cancer.  The most important point, the crux of the entire issue, is that the mutations thought to be the decisive event, supersede metabolic dysfunction.  These mutations, although just a side effect of the true origin of the disease, could easily be mistaken as the cause – sending researchers on a multi-billion dollar and multi-decade wild goose chase.

Inherited cancer risk has been historically cited as evidence in support of the genetic theory (inherited cancers only account for 5% to 7% of all cancers, the vast majority arises spontaneously).  When challenged by the assertion that inherited cancer risk provides irrefutable evidence that cancer is of genetic origin, Dr. Seyfried, one by one, explains how inherited cancer causing genes manifest in damage to the mitochondria, thus precipitating cancer through metabolism – again the perfect cover up.  It is like a detective, who after an arduous investigation, finds evidence pointing to 10 different people  whom appear to be responsible for killing members of certain afflicted families – but when the detective digs deeper, he finds out the 10 people were ordering the hits through the same hit-man.

Take for example the BRCA1 mutation which has recently caught the public’s attention as the mutation responsible for Angelina Jolie’s decision to undergo a double mastectomy.  Inheriting a faulty BRCA1 gene jumps the risk of acquiring breast cancer in a women’s lifetime to 60% from 12%. Among other cellular duties, BRCA1 is involved in mitochondrial function, including the biogenesis of new mitochondria.  Therefore an inherited mutation to BRCA1, rendering its protein product defective, would manifest in reduced mitochondrial capacity, the metabolic origin of cancer.

Even Gleevec, the one successful targeted drug, is often cited as proof of principle that targeting drugs to the mutated products of oncogenes is the right strategy. A closer look reveals that although Gleevec binds to a mutated protein, it exerts its efficacy by altering a pathway that is up-regulated by defective metabolism.  Says Seyfried: “Gleevec simply highjacks a mutation that serendipitously down-regulates an oncogenic pathway turned-on by damaged mitochondria.”

“Gleevec simply HIGHJACKS a mutation that serendipitously down-regulates an oncogenic pathway turned-on by damaged mitochondria.”  Dr. Thomas Seyfried

Proponents of the metabolic theory of cancer are quick to point out that the circumstantial evidence in favor of the metabolic theory is everywhere.  For example, the one novel gene discovered so far by CGAP, the one referenced earlier as the most significant finding to come out of the CGAP is isocitrate dehydrogenase, a gene which encodes one of the crucial components of oxidative energy production – linking a mutated oncogene to defective metabolism.

And then there is the curious case of Metformin.  Researchers were scratching their heads when they found out patients with type 2 diabetes, who were taking the drug metformin to lower their blood-sugar, had substantially reduced rates of cancer.  Turns out the blood-sugar lowering drug not only prevents cancer, but can also treat cancer – unequivocally suggesting a connection between metabolism and cancer.

People who practice caloric restriction or periodic fasting have been shown to have lower cancer rates.  Why?  When calories are reduced to a certain threshold the body initiates a process called autophagy (self-digestion).  Autophagy is a cellular process that consumes damaged cellular components, including damaged mitochondria, and will use the digested components to meet energy requirements, a cleaning house process if you will — cleaning out the damaged mitochondria that are the incipient seeds of malignancy.

Metastasis is unquestionably the most important feature of cancer resulting in 90% of cancer deaths.  Metastasis involves aggressive and versatile cancer cells with the ability to degrade membranes, enter into the circulatory system, invade into new sites, change shape, and secrete growth factors and cytokines.  The genetic theory of cancer, of course, proposes critical sequential-mutations will result in a less aggressive cancer acquiring all these metastatic features – random mutations that result in a tremendously complex gain of function.  Not surprisingly, a TCGA follow up study, attempting to identify metastatic specific mutations found none.

Proponents of the metabolic theory of cancer are quick to point out that the CIRCUMSTANTIAL EVIDENCE IN FAVOR of the metabolic theory is everywhere.

It turns out tumors are already full of cells called tumor-associated macrophages (TAMs) that have all of the metastatic qualities mentioned above.  TAM’s are tough, gritty immune cells that are already capable of infiltrating tissues, hitch-hiking rides in the circulatory system, and setting-up camp in different organs.  It is well documented that cancer cells fuse with TAM’s in the context of the chaotic tumor microenvironment.  In doing so, TAMs acquire all the genetic and cytoplasmic material present in cancer cells, including damaged mitochondria, marching these cells one step closer to malignancy.  The chronic and highly-inflammatory microenvironment will continue to damage TAM’s mitochondria unleashing cells capable of full blown metastasis.  The metabolic theory provides a simple and elegant explanation for metastasis that is in complete harmony with empirical evidence — in complete contrast to the genetic theory.  As Einstein said, “The simplest explanation is usually the correct one.”

 

Fertilizer to a Gardener

What about treatment?  Rather than targeting elusive, shape-shifting, here-in-one-case, gone-in-the- next, mutations – the metabolic theory of cancer provides researchers with one big-beautiful-target – cancer cells of all types, regardless of the tissue of origin, have to ferment glucose for energy because of their damaged mitochondria, normal cells have other options.  In the end, any theory used to explain cancer is only as good as the therapies that flow from it -this is where the metabolic theory leaves the theoretical and enters the real world.

If cancer is caused by defective metabolism then the first and most obvious place to implement treatment is through diet – after all, diet is the quickest and surest way to alter metabolism.   It turns out there is a way to manipulate the diet that dramatically reduces the blood glucose that cancer cells so heavily rely on, forcing the body to generate new fuels from fat called ketone bodies — a fuel source that cancer cells are unable to utilize because they can only be burned through oxidative pathways, in healthy fully-functional mitochondria – cancers ‘Achilles Heel’ as Watson put it.

What about treatment?  Rather than targeting ELUSIVE, shape-shifting, here-in-one-case, gone-in-the- next, mutations – the metabolic theory of cancer provides researchers with one BIG-beautiful-target.

Relegated as an obscure side note in medical journals, the ketogenic diet was observed to be an effective, if not strange therapy for pediatric epilepsy in the 1920’s, around the same time Warburg was noticing the striking metabolic deficiencies of the cancer cells in his petri dishes.  However, once anticonvulsive drugs were developed in the 40’s, it was largely forgotten.

The current resurrection of the ketogenic diet, this time to treat cancer, dubbed the restricted-ketogenic diet, was born from the work in Dr. Seyfried’s lab.  Using very aggressive mouse models of brain cancer, they have achieved staggering results — and they were achieving them simply through diet.

The restricted ketogenic diet restricts overall calories and virtual eliminates carbohydrates – driving down blood glucose from about 100 mg-dl to around 55 or 65 mg-dl, forcing the liver to begin manufacturing small molecules called ketone bodies from fat, taking over the role of glucose as a circulating fuel.  “Once a patient is in this state of ketosis their cancer cells are put under tremendous pressure because they are being starved for energy while healthy cells simply switch-over to burning ketone bodies in their intact and functional mitochondria,” says Seyfried.

“The parallel history of the Ketogenic diet as a cancer treatment, and the ketogenic diet as a treatment for epilepsy, are hauntingly similar,” says Hollywood movie director, writer, and founder of the world-renowned Charlie Foundation, Jim Abrahams.

Nobody knows the history of the ketogenic diet better than Jim.  In the mid-1990s, before he had ever heard of the ketogenic diet, Jim was at the end-of-his-rope.  His son Charlie’s severe epilepsy wasn’t responding to drugs, and 5 different neurologists offered little in the way of hope.  “Once I heard about the ketogenic diet we immediately tried it – within days Charlie was seizure free.  I was baffled and angry at the time.  How could the public not know about this?” Jim’s efforts to inform the public included an appearance on NBC’s Dateline program and ‘First Do No Harm’, a made-for-television film starring Meryl Streep, and ultimately the formation of the Charlie Foundation. “When I started the Charlie Foundation, I thought it would be a straight line – we would inform the public of this incredibly effective dietary treatment for epilepsy and that would be it – unfortunately it just wasn’t that simple.  Today, all the myths that had been used to detract from the diet have been disproven.  Efficacy has been scientifically established, long term side effects have been dispelled, palatability has been dramatically enhanced, and difficultly of administration has been equally dramatically reduced.  The biggest problem today is trying to figure out how hospitals can reimburse trained ketogenic diet dietitians for their time.”

“The efficacy of this diet is really remarkable,”   says Dr. Seyfried, “If one was able to patent and package the ketogenic diet as a pill for cancer it would be a blockbuster.  It would be all over the media.  The irony is because it is free, nobody is interested.”   Dr. Seyfried and his colleagues, like Dr. Dominic D’Agostino of the University of South Florida have seen the tremendous power of the ketogenic diet first-hand.  Says D’Agostino: “We have seen complete remissions – despite tremendous odds.”

“The efficacy of this diet is really remarkable. If one was able to patent and package the ketogenic diet as a pill for cancer it would be a blockbuster.” Dr. Thomas Seyfried

It’s not hard to find those who will testify on behalf of the diets cancer fighting prowess.  Like Miriam Kalamian, a highly-energetic parent and advocate of the ketogenic diet, who says it saved her son’s life, “In December of 2004, our 4 year old son Raffi was diagnosed with a brain tumor.  After three surgeries and several failed drug protocols, it was clear that the tumor was winning. Our little fighter had done everything we asked of him, but he was no match for his opponent. In March of 2007, we discovered research from Boston College that had demonstrated that a calorically restricted ketogenic diet could slow progression of brain tumors….We had nothing to lose, so with the support of his pediatrician and oncologist, Raffi began a restricted ketogenic diet concurrent with a low-dose chemotherapy drug (the same drug that failed to work previously). Amazingly, the tumor shrank by 15% in the first 3 months!  Chemo was discontinued in December of 2007 and Raffi continued with the ketogenic diet as his sole therapy for 3 more years.”*

And Dr. Fred Hatfield, who was sent home to die.  “The bones in my entire pelvic girdle were riddled with metastatic prostate cancer.  I was confined to a wheelchair – the bones had cracks in places.  Three separate doctors had given me three months to live.  I heard about Dr. D’Angostino and the ketogenic diet and decided why not give it a try?  The next scan I had was completely clear.”  I called Dr. Hatfield to see how he was doing recently; he had to call me back because he was in the middle of putting up wall-paper. “All clear, I make sure I go into ketosis at least once a month.  Metabolic therapy saved my life.”

Miriam Kalamian and Dr. Hatfield are far from alone.  Many desperate cancer patients have found out about the ketogenic diet and are treating themselves, some with remarkable success.  You will find them on internet-forums, through emails, they are a silent but growing community, and many are confused why doctors know so little about this.

“Metabolic therapy is defiantly gaining traction, the number of emails I receive from people interested in treatment, or that are already implementing treatment, has increased exponentially,” says Dr. Seyfried.  And this is not an isolated observation – everybody involved with the ketogenic diet says the same thing.

“We are changing our name,” says Jim Abrahams of the Charlie Foundation, “from the Charlie Foundation to Help Cure Pediatric Epilepsy, to the Charlie Foundation for Ketogenic Therapies.  It used to be the only people that contacted us where those interested in the diet for epilepsy, now about half the people that contact us are interested in the ketogenic diet for other afflictions, including cancer.”

“Once you frame cancer in the light of a metabolic disease the treatment options get exciting.  The ketogenic diet is just the first piece of low-hanging fruit – the drugs that target cancer’s defective metabolism are just getting started – and when you combine the two — that’s when things get really interesting,” says Dr. Seyfried.  The important point emphasized by scientists who study the combination of the ketogenic diet combined with drugs that target metabolism – is that the ketogenic diet differentiates in a way that no chemotherapeutic drug on the market is able to – the ketogenic diet makes healthy cells healthier and sick cells sicker – allowing a synergistic effect when adjunctive agents are utilized.  It prepares the therapeutic landscape to be more receptive to additional treatments that target metabolism – When taken together as a comprehensive therapeutic strategy; the ketogenic diet could be thought of as primer to a painter, or fertilizer to a gardener.

When taken together as a comprehensive therapeutic strategy; the ketogenic diet could be thought of as PRIMER to a painter, or FERTILIZER to a gardener.

 

Sitting on the Bench

If there is a modern-day incarnation of the spirit, brilliance, and tenacity of Otto Warburg, then he is in the form of Dr. Peter Pedersen of John Hopkins School of Medicine in Baltimore.  If the Warburg theory of cancer was a raging fire in the early 20th century, then it dimmed to a single ember by the middle of the century – an ember that Dr. Petersen alone nurtured and kept alive. “I’ve watched interest in the metabolism of cancer go down to zero in the 70’s, but now interest is returning.  There were times in my early career when I felt almost alone in considering energy metabolism as important to the cancer problem. I even remember one of my colleagues, an expert in DNA technology, dumping Lehninger’s “Warburg Flasks” in the trash as relics of a bygone era in cancer research.”

Nevertheless, Pedersen undeterred, kept on with the heavy-lifting — mapping the critical molecular architecture in the inner-city of cancer’s defective metabolism.  Once his lab had elucidated the pathologically altered infrastructure embedded within the cancer cell’s mitochondrial outer-membrane, they began to screen for drugs that would target and exploit the structural differences Pedersen had identified between normal and cancerous cells.  “After screening only nine compounds we found one, called 3BP, that was incredibly powerful.  Pharmaceutical companies typically screen thousands and thousands of compounds before finding one that might be effective – we only went through nine.”  When his lab began to test 3BP in rats however, they encountered a new problem.  “One problem we have in the lab is what to do with all the rats we test 3BP on because we cure them all – we had to figure out how to take care of them all,” says Pedersen.

In the winter of 2009 it was time for 3BP to leave the parental confines of Pedersen’s laboratory and enter the real-world testing ground – from lab side to bedside — 3BP was about to enter its first human  cancer patient.  The patient was a 16 year old with hepatocellular carcinoma (HCC), i.e., liver cancer.   3BP was administered more than half a dozen times about 2 weeks to a month apart.  Again, the problem they encountered was the staggering efficiency with which 3BP killed cancer cells.

Initially, the patient presented with a large tumor burden in his liver as 3BP swiftly destroyed massive numbers of cancer cells with staggering speed the patient suffered from a transient case of tumor lysis syndrome – a toxic collateral burden imposed on the body from the simultaneous death and release of malignant shrapnel into the bloodstream.  Luckily, the tumor lysis syndrome proved to be transient, and soon regeneration was initiated in the young patient’s liver. The patient started to retrain his body to perform normal activities, i.e., normal eating, sleeping, walking, etc. While the fresh liver regeneration was in process, the patient had to take some antibiotics due to an unexpected pneumonia infection. Unfortunately, his regenerating liver could not detoxify the administered antibiotics and he passed away. If such infection could have been prevented, the outcome may have forced the research community to pay closer attention.

“3BP doesn’t just slow growth like the vast majority of chemotherapeutic agents – it explodes cancer cells.  In the future we have to be very careful as we move it through the clinic because of its incredibly powerful and explosive nature,” Says Dr. George Yu of George Washington University, who is as eager to see 3BP enter clinical trials as anybody.  “I would love to see 3BP in conjunction with a restricted ketogenic diet, because the diet is pro-apoptotic, and will alter the way the cancer cells die – they will die more orderly, with less inflammation and toxic release.”

“3BP doesn’t just slow growth like the vast majority of chemotherapeutic agents – it explodes cancer cells.  In the FUTURE we have to be very careful as we move it through the clinic because of its incredibly powerful and explosive nature,” Dr. George Yu

3BP was born from theoretical elegance – a product of human ingenuity – a child of logic and reason.  But as a passive observer — with no dog in the fight — I can’t help but compare 3BP to an all-star slugger that came to a struggling team out of nowhere, a player that looks capable of hitting a home run virtually every time at bat – yet for some unknown reason, he is still just sitting on the bench.

3BP is not the only promising player sitting on the bench.  Other journal documented case studies exist of cancer patients ordering the handful of compounds known to target tumor metabolism from chemical supply houses and administer it to themselves – achieving complete and enduring remissions.  One such study is of dichloroacetate (DCA), a metabolism targeting drug that received a spike of media attention after New Scientist magazine published an article titled “Cheap, ‘safe’ drug kills most cancers,” only to again fall to obscurity after funding proved nonexistent for the cheap drug.   One such study reports on a man fighting for his life against non-Hodgkin’s lymphoma.  After the state of the art chemotherapy failed, and the cancer returned aggressively months later, he decided to treat himself with DCA – not wanting to go through the nausea and fatigue caused by the chemotherapy again.  After doing his own research, the patient began to mix 1000 mg of DCA into a bottle of Mt. Dew every morning – “Within 2 weeks of starting this regimen, the patient reported significant reduction in night sweats, low grade fever, anorexia and fatigue.  One month after initiation of the DCA protocol, the neck nodes were noticeably smaller, and at 2 months no nodes were palpable. At 71 days into the DCA protocol, complete resolution of all systemic symptoms had occurred.  The patient reported a good energy level and appetite, the ability to sleep well and no side effects.”

“If you were to plot a graph of time and money spent versus the realized results for all the treatments born from the Somatic Mutation Theory of Cancer it would tell you unequivocally you’re insane to keep throwing good money at this flawed scientific paradigm,” says Dr. Seyfried, “If you were to plot the same graph – time and money spent versus results seen so far for metabolic treatments — the promise and potential would be obvious to a child.”

“It is very difficult not to be cynical about this stuff – but it usually comes down to money,” says Jim Abrahams,  “the hard reality is diet is free, so there is little interest from anybody – the usual channels of funding (pharmaceutical companies) just don’t give a rat’s ass.”  The drugs that target the metabolism of cancer face the same challenges as the ketogenic diet – most are non-patentable, so there is little interest – the 100 million plus bill to take a drug from the lab through the clinic is usually picked up by pharmaceutical companies — a bill that is typically paid back in massive multiples of the original cost once a patent is received.

“If you were to plot a graph of time and money spent versus the realized results for all the treatments born form the Somatic Mutation Theory of Cancer it would tell you unequivocally you’re insane to keep throwing good money at this FLAWED scientific paradigm. If you were to plot the same graph – time and money spent, versus results seen so far for metabolic treatments — the promise and potential would be obvious to a child.” Dr. Thomas Seyfried

As a consequence the clinic for these therapies has morphed into the public at large.  Advocates that have heard the claims from others, and then in-turn demand it from their doctors.

Sometimes in medicine a few adventurous individuals end up teaching the entire medical complex – the tail wags the dog.  Like Barry Marshall, labeled a quack by the medical community for his claim that a yet unknown species of bacteria, an organism that according to convention, could not exist in the acidic environment of the stomach, was the true cause of ulcers rather than stress — the accepted, but ambiguous perpetrator.   Once Marshall was convinced he had isolated the elusive bacteria, he grew it in a flask and drank it.  The highly publicized ulcer he gave himself was documented in a medical journal – unequivocally proving to the establishment that bacteria (now identified as helicobacter pylori) can cause ulcers – Marshall was later awarded a Nobel Prize.

 

Dark matter discovered?

When Bert Vogelstein postulated the existence of cancer biology’s ‘dark matter’ the most obvious possibility he suggests, are epigenetic drivers.  Epigenetics is a term used to describe all of the ‘other’ influences that operated on DNA beyond the fixed genetic code.  Unlike genetic code, epigenetic drivers are plastic, fluid, and transient forces that influence the expression of genes.   The crucial link, the one process that Warburg was unable to identify that would have tied his theory of cancer into a single and beautiful unified-explanation of cancer, from the beginning to the end, is epigenetic signaling.  Dr. Seyfried and others propose that chronic and persistent damage to cellular mitochondria ultimately triggers an epigenetic signal from the mitochondria to the nuclear DNA, altering the expression of a plethora of key cancer causing genes – a classic epigenetic systemThe question then begs to be asked; could the metabolic theory be Vogelstein’s elusive dark matter?

Could it really be possible that so many brilliant minds have gotten this wrong?  History provides the perspective to approach this question with – every generation thinks they are on the cutting-edge of modern technology – when in truth; our reference frame is just a blink-of-an-eye in the continuum of time.  Without question, some medical student, hundreds of years from now, will read about the way we treated cancer patients, and feel a sharp-pang of empathy for our unenlightened and barbaric methods that so many suffered through and died from.  The cancer-research medical complex, with its massive infrastructure, all the investment, and livings derived from it – from the businessmen and salesmen, to the doctors and nurses, is as encompassing as a black-hole, and struggles to move with the inertia of an arctic glacier. Somewhere in the middle of the colossal-beast are the research scientists, the secular high-priests of the entire system.  With the faith of a devout congregation, we fill the tithe-tray with our tax-dollars and charitable donations, providing them with the resources they need to continue their arcane craft – and then we wait and hope, with faith and trust that they will find a cure.  Their work so foreign, their degrees so prestigious –we deem them as infallible.  Institutions like this are in many ways, the most likely to get a big-picture problem wrong.  History is replete with examples of humanity getting huge scientific issues dead-wrong for protracted periods of time – often with large institutions behind it –persecuting the intrepid few who first question the status quo.  Remember, the earth was once flat and the sun orbited around it, blood-letting was thought to cure hemophilia, we cut holes into heads to release demons and we burned witches.  Human progress is full of stops and starts, dead-ends and epiphanies, why would now be any different?

After traveling to Boston to interview Dr. Seyfried, he returned the favor, and generously accepted my invitation to come to my hometown, Rapid City, South Dakota, and speak to the M.D.’s at our regional hospital about the metabolic theory of cancer and the treatments derived from it.  The morning before his lecture, we drove the 30 miles to Mt. Rushmore where we walked the scenic half-mile wooded path that meanders through the colossal chunks of granite and pine trees directly under the National Monument.  It was a perfect June morning, mid 70’s, with only an occasional cloud breaking the brilliant blue sky.  The wandering, unhurried-path through the beautiful scenery inspired uninhibited conversation.  “What do you think would happen if all the resources dedicated to the genetics of cancer were redirected to the metabolism of cancer?”  I asked him.  Dr. Seyfried paused, reflecting, “Ten years, I bet we could have real cures in 10 years if that were to happen.”

 

Travis M Christofferson  M.S.

Founder,

SingleCauseSingleCure.Org

*Raffi passed away in April of 2013 – Mirrian is convinced Raffi may still be with us if he would have started the ketogenic diet from the time of diagnosis.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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  1. Meredith
    September 19, 2013 at 8:52 am

    Thank you for this… this is so hopeful…

  2. Bjjcaveman
    September 19, 2013 at 9:19 am

    Holy cow. What an amazing article. I couldn’t stop reading this.

    Really…. Bravo.

  3. Chris Wark
    September 19, 2013 at 10:32 am

    Quite the lengthy and well researched article, for which I applaud you.
    One problem though.
    Where are the ketogenic diet success stories?

    This is the elephant in the room.

    What many do not know is that Dr. Robert Atkins tried the Ketogenic diet with many cancer patients for years and it did not work.

    As someone who used nutrition and natural therapies (juicing, raw vegan diet for 90 days and then adding back some clean meat and cooked food) instead of chemo nearly ten years ago,
    I am obsessed with nutritional anti-cancer protocols and was once infatuated with the ketogenic diet for cancer. It started when I met a very nice woman who claimed to have healed herself with it and even wrote a book about it, but the cancer returned about a year later. Uh oh.

    Cancer can be healed naturally, but different diets work for different patients, depending on the type of cancer and metabolic needs. So far the Keto diet has had little to no success.

    I recommend you read this series by Dr. Nicholas Gonzalez M.D., a practicing physician and expert on the history use of the ketogenic diet in treating cancer.

    http://www.naturalhealth365.com/ketogenic_diet/cancer_part_1.html

    And while your at it check out my site too!
    There are lots of natural survivor stories

    http://www.chrisbeatcancer.com

    • Dominic D'Agostino
      September 19, 2013 at 6:09 pm

      Regarding Dr. Nicholas Gonzalez: “A test of his protocol, published in 2009, found that Gonzalez’s patients died faster than those treated with conventional chemotherapy, and had significantly worse quality of life.[8]
      http://www.ncbi.nlm.nih.gov/pubmed/19687327

      http://en.wikipedia.org/wiki/Nicholas_Gonzalez_%28physician%29

    • SteveK
      September 26, 2013 at 12:21 pm

      You may find this interesting: http://articles.mercola.com/sites/articles/archive/2013/03/10/ketogenic-diet.aspx

    • Rita
      April 6, 2014 at 8:35 am

      There is this new study by Mina Bissell & Onodera “Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways”. It says that “glucose uptake level is a critical determinant of whether breast cancer cells form colonies with malignant or nonmalignant phenotypes”.

      As far as I understand from the study, as a layperson, is that a ketogenic diet would put cancer cells to dormancy, make them behave like normal cells, but would not kill them. So, the cancer patient would need to keep a lifelong anti-cancer diet, because he would always have these quiescent cancer embryonic stem cells lying dormant somewhere ready to grow uncontrollably as soon as he begins to indulge in the wrong foods. This is also the experience of some practitioners of alternative therapies: soon after the patient returns to the wrong diet, the cancer returns.
      My question is: is it better to have long fasts, followed by long feasts; or short frequent fasts + short frequent feasts, or a calorie restricted diet with no fasting and no feasting periods? From my experience the high fat diet is very hard on the liver, which is needed to fight cancer; the long fasts weaken the immunity, which again is needed to fight cancer; therefore a hybrid between the Gerson Therapy & Nicholas Gonzales therapy & ketogenic diet is needed: raw root & leaf vegetables+ nuts+ organ meats, in a calorie restricted diet.

      Perhaps, the Gerson Therapy and the Nicholas Gonzales protocol are being successful despite the high amount of carbs they have, because the anticancer compounds, the carrots, beets, leafs etc. have, counteract the cancer promoting effect of carbs.
      Many testimonies of people cured with alternative therapies involve long periods of fasting or calorie restriction(they say “I lost x pounds”). Lorraine Day, Aajonus Vonderplanitz and others were healed after unwillingly water fasting.

  4. zack
    September 19, 2013 at 11:33 am

    My question is probably the question most people have… if you or someone you know has cancer, who should they contact?

  5. David Ferguson
    September 19, 2013 at 12:22 pm

    An interesting article. You might also know of Dr Eugene Fine’s small study in the same area:-” http://bit.ly/RmULUy “. He also points out that 1) while many cancers exhibit the changes described by Warburg, some do not ( Red blood cells, prostate cancers), and 2) cancers are so good at evolving within different environments, he thinks the major benefits of ketogenic diets might be in prevention. I would welcome your thoughts.

    DF

    • Travis
      September 19, 2013 at 7:01 pm

      95% of all cancer are know to be PET positive — meaning they overwhelmingly ferment glucose, and ‘light-up’ a PET scan. The aggressiveness of the cancer also correlates to the degree of glucose consumption. Without question the ketogenic diet, or even periodic fasting, for the sake of prevention may be the most efficacious use of the diet overall.

    • Dominic D'Agostino
      October 1, 2013 at 7:34 pm

      Prostate cancer is not PET positive, but still seems responsive to the ketogenic diet. Dr. Fred Hatfield’s primary cancer was prostate

  6. Paleo Dinner Recipes
    September 19, 2013 at 12:46 pm

    Great analysis!
    You should write more entries like this one!

  7. Mark
    September 19, 2013 at 1:11 pm

    This is one of the best articles I have ever read. My mother has had skin cancer removed 3 times so far. I am going to “force” her to read this article. :)

    Thanks very much for posting it.

  8. Ted Hutchinson
    September 19, 2013 at 1:32 pm

    I find this research a bit disturbing
    Ketone body utilization drives tumor growth and metastasis

    • Robb Wolf
      September 19, 2013 at 3:47 pm

      Pretty interesting.

      • Gemma
        September 20, 2013 at 9:19 am

        Well, read what Peter the Hyperlipid has to say to this: http://high-fat-nutrition.blogspot.cz/2013/08/starvation-and-cancer-growth-sauer-vs.html

        • Joshua
          September 20, 2013 at 2:00 pm

          My favorite part of Peter’s post is “When people come to look in earnest at ketogenic diets for cancer management the omega 6 content of adipocytes is going to be one hell of a confounder. You will almost need to eliminate weight loss in order to eliminate or at best reduce the release of omega 6 PUFA if the patient has been living on soy oil or Flora for a lifetime…”

          i.e. if you’ve been eating an excess of n-6 your whole life, that’s going to be the fuel you burn if you’re in a calorie deficit, and cancer seems to love n-6 for some reason.

  9. Tokirbymd
    September 19, 2013 at 5:04 pm

    As an oncologist, this is fascinating work. Imagine- genetic mutations aren’t the CAUSE of cancer, merely a BYPRODUCT (albeit quite harmful) of underlying metabolic mitochondrial abnormalities. Some mitochondrial abnormalities are inherited from your mother which may partially explain some genetic predisposition yet also leaves room for environmental insults to our mitochondrial process that cause subsequent damage and resulting somatic DNA mutations. So the first part makes some sense. I have seen targeted agents continue to have only partial response due to the tremendous number of somatic mutations in a tumor mass. however I think the second part, that ketosis diets will CURE cancer is less likely. Certainly some cancers have not generated enough subsequent mutations so that ketosis and fixing an underlying metabolic defect will allow the body to repair what is left. However, some cancers are far enough developed with enough genetic mutations that even repairing the underlying problem doesn’t cure the cancer- think killing termites. If you catch them early you can save your house, but if too late, even if you eradicate them all, the damage isalready done. Definitely an intriguing line of research. If we can either prevent the mitochondrial damage to begin with, or catch the cancer before the multiple mutations have occurred then we may have found a true cure.

    • Robb Wolf
      September 19, 2013 at 7:38 pm

      Another interesting feature of ketosis is it appears to spare much of the damage caused to normal tissue via radiation and chemo. Because we are fully invested in this genetic basis of cancer, the primary targets have been attacking DNA in rapidly dividing cells…what if ketosis could help mitigate these deleterious effects? Prof. Seyfried’s work seems to make this plausible.

  10. Stephen
    September 19, 2013 at 5:29 pm

    Question for Robb or anyone who might know: Years ago I read a book by G. Edward Griffin, “World Without Cancer: The Story of Vitamin B17″ in which it was stated that Laitril/Amygdalin (sp?), substances similar to the stuff in apricot seeds would kill cancer. Anybody heard of this? What do you guys think? A friend of mine is in the hospital fighting lung cancer with chemo/radiation and I’d sure like to help him. Thank you so much for your responses.

    • Robb Wolf
      September 19, 2013 at 7:36 pm

      What that is describing is a cyanide derivative if I recall correctly. Due to it’s potent polarity, it has a tendency of binding to DNA and causing problems for rapidly dividing cells…unfortunately, i do not think any of these approaches (even ketosis) will be a one-stop-shop for all cancer types. But, ketosis is likely to e of benefit in endoderm derived cancers like breast, colon, prostate,astrocytomas and glioblastomas.

  11. Dominic
    September 19, 2013 at 5:29 pm

    We addressed in a recent paper…”In these studies, the authors created immortalized fibroblasts which were altered to overexpress rate-limiting enzymes in ketone body production, and co-cultured these cells with human breast cancer cells altered to overexpress enzymes involved in ketone body utilization. While this phenomenon may occur in the genetically altered culture system used by the authors, there is no evidence that this occurs naturally in cancer cells in vitro or in tumors in vivo. On the contrary, the literature as a whole strongly suggests that cancer cells cannot effectively use ketones for fuel. As described, most cancers do not express the SCOT enzyme which is necessary for ketone body utilization [65,66]. Several studies have reported a deficiency of cancer cells to metabolize ketone bodies in vitro [24,25]. Furthermore, it is widely accepted that ketone bodies are produced nearly exclusively from fatty acid b-oxidation in the liver. There is no known metabolic pathway by which fibroblasts can produce ketone bodies from glucose. Without additional compelling evidence to support these claims, we remain propo- nents of the notion that cancer cells cannot utilize ketone bodies as efficient energy substrates” http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0065522

    • Robb Wolf
      September 19, 2013 at 7:33 pm

      I was wondering about the fibroblast/ketone production story. Liver, and to a very limited degree, astrocytes, can produce ketones. Would not be surprised if a few other tissues can as well, but we are not finding many.

  12. Dominic D'Agostino
    September 19, 2013 at 6:07 pm

    Much of the evidence to support the Science is found here:
    http://www.amazon.com/Cancer-Metabolic-Disease-Management-Prevention/dp/0470584920

  13. Jesse Davis
    September 19, 2013 at 6:28 pm

    Regarding the ketone study above, it would seem conflicting if the take-away from the article was ‘ketones kill cancer,’ which is not the point of the article.
    Rather, the argument appears to be that cancer cells can only rudimentarily metabolize glucose, leaving ketones as the substitute. I don’t think anyone’s suggesting we start supplementing with ketone bodies, which is what that study would seem to be replicating in vitro.

    Thanks for sharing Robb, I look forward to looking at this in more depth.

    • Robb Wolf
      September 19, 2013 at 7:31 pm

      Jesse-
      Actually, what IS being proposed is a ketogenic/CRAN diet for certain (unfortunately not all) cancers. Another commenter posted a comment from Prof. Seyfried on this paper…there do appear to be osme holes with the findings.

      • Jesse Davis
        September 19, 2013 at 8:15 pm

        Yes, that last part of my comment was poorly worded, not adding ketones, but rather engineering the ability to burn them. And I agree with the statement about molecular geneticists below, I was definitely guilty.

  14. Travis
    September 19, 2013 at 6:43 pm

    I recently asked Dr. Seyfried about that same paper. It seems the group proposing it has some very profound holes in there research.

    From Dr. Seyfried: “Dr. Lisanti and his group have published several papers, all in his journal “Cell Cycle”, claiming that lactate and ketones drive tumor growth and that respiration is normal in cancer cells. Unfortunately, there is no scientific support for their central hypothesis. We address this issue in the discussion of our attached paper (Poff et al., page 6).

    The Lisanti argument is not only at odds with our empirical findings in tumor tissue, but is also at odds with findings from the vast majority of scientists working in the cancer field. He claims that the abnormal energy metabolism in cancerous tissue is not due to the neoplastic cells, but rather to the cells in the supporting stroma. He suggests that tumor fibroblasts feed ketones and lactate to drive growth in the respiratory competent neoplastic cells. Moreover, the ketone bodies are thought to be synthesized from carbohydrates rather than from fat. There is no known biochemical pathway by which ketone bodies (a byproduct of fat metabolism) can be synthesized from carbohydrates.

    It is unfortunate that many of the great biochemists have passed on leaving the field to molecular biologists, who often lack knowledge of foundation biochemical principles of cellular energy metabolism.”

  15. Jamie
    September 19, 2013 at 7:50 pm

    My Dad was an ardent keto dieter but he still died from cancer. While I do think keto diets can help improve quality of life, in the case of my poor dad, it didn’t save him.

  16. Francois Quirion
    September 20, 2013 at 12:38 am

    i am studying a lot about cancer recently as it seems pretty much everything to do with health ends up relating to chemistry-biochemistry and cells. What are we feeding our trillions of cells?
    I just read the book called “The doctor who cures cancer” by William Kelly Eidem.
    this book tells the story of an incredible scientist Dr. Emmanuel Revici (medical doctor and PHD in chemistry) who died at 101 years of age after spending all is life researching cancer and having tremendous success curing terminal cancer patients. Again he was attacked non-stop by the vested interests of the cancer industry. He write a 700 page book published in 1961 title RESEARCH
    IN PHYSIOPATHOLOGY,/
    \ —’/
    AS BASIS OF
    GUIDED CHEMOTHERAPY
    With SpeciaAl ppliration to Carrcer
    EMANUEL EEVICI, M.D.
    ScientificD irector, Instituteo l A pplied Biology,
    New York, N. f.
    Chict ol Dept, ol Oncology, Tralalgar Hospital,
    Ncw York, N. Y.
    Published lor the Amcrican Foundation lor Cancer Research, Inc., by
    D. VAN NOSTRAND COMPANY, I N C .
    PRINCETON, NEW JERSEY
    TORONTO
    NEW YORK
    LONDON

    i have downloaded it for free in PDF from Google and it is incredible reading.

    I have also read “The hidden story of cancer” by Brian Peskin and totally recommend it. It it mainly based on Dr.Otto Warburg mentioned in your article.

    It is my opinion that the answers to health including cancer are all there but are being suppressed by certain groups.

    Life is in each cell, in each bacteria.

    we need amino acids, essential fatty acids, vitamins and perhaps even more importantly minerals.
    we dont need sugar.

    Francois
    Quebec canada

  17. Celest
    September 20, 2013 at 1:00 am

    As a diabetic how would you recommend doing any of the fasting / keytone plan? This question is for Dr. Seyfried, so if you could pass along I would be grateful.

    BTW, I am a pump wearing diabetic.

    thanks

  18. Glenn Nicholas
    September 20, 2013 at 2:43 am

    This is a tremendously exciting concept Travis .. that potentially reducing sugar intake could starve cancer cells.

    There is useful and detailed information about ketosis / ketogenic diets on Peter Attia’s Eating Academy site. He also has very specific information about the risks of ketogenic diets for diabetics.

    Is Ketosis Dangerous:
    http://eatingacademy.com/nutrition/is-ketosis-dangerous

    Understanding Ketosis:
    http://eatingacademy.com/nutrition/ketosis-advantaged-or-misunderstood-state-part-i
    http://eatingacademy.com/nutrition/ketosis-advantaged-or-misunderstood-state-part-ii

  19. Flemming Rasmussen
    September 20, 2013 at 3:38 am

    The march through the research to date in this article resonates well. This overview highlights some fairly significant milestones. Looking at this from the aspect of a marathon or a relay race, the race isn’t over. Dr Watson’s leg of the race was helpful, but remaining affixed to the genes as the cause is a bewildering path for research to remain on. Dr Colin Campbell’s (aka China Study) has a new book out titled “Whole”. Comments like ‘height of hubris’ in relation to the pitch by geneticists to ‘repair or replace’ genes provides a new perspective. Love Dr Seyfried’s work and his recent book. Thinking we have a novel thought on cancer too which you are invited to browse in my linked website – suggest Cancer Root’s tab and the Welcome as most relevant to this article

  20. Adam Ball
    September 20, 2013 at 7:05 am

    Hey Guys,

    Great article, I’ve missed the heavy sceientific articles on this site!

    I attended a presentation by a Doctor from the Children’s Hospital of Eastern Ontario who was quite excited about a new angle in treating cancers. One of the features of a cancer cell is apparently a down-regulated call to action to the immune system, as the cancer cells do not want to be found. The presenter had suggested that this leaves an opening for us to “attack” the cancer cells with certain viruses or bacteria, as they would be easily infected, and would lack the ability to call for help to the bodies immune system. They’ve been working on guinea pigs I believe and achieving great results.

    It’s interesting, as then healthy cells can recover from the infection while the cancer cells can’t.

    It sounds more allopathic than I’d like, and strangely like I Am Legend, but refreshing that they’re taking a new angle!

    • Adam Ball
      September 20, 2013 at 11:40 am

      Here is a link to the researcher I’m speaking about, and links to a bunch of his past and current research.

      http://www.cheori.org/en/researchers?id=92

    • james peters
      March 13, 2014 at 1:50 am

      What is Nagalase?

      Nagalase is a protein made by all cancer cells and viruses (HIV, hepatitis B, hepatitis C, influenza, herpes, Epstein-Barr virus, and others). Its formal, official chemical name is alpha-N-acetylgalactosaminidase, but this is such a tongue-twisting mouthful of a moniker that we usually just call it “Nagalase.” (Sometimes, when I want to impress friends with my brilliance, I’ll say the entire word real fast: “alpha-N-acetylgalactosaminidase.” I have found that it’s important to practice beforehand if one doesn’t want to embarrass oneself.)

      Why is Nagalase important?
      Nagalase causes immunodeficiency. Nagalase blocks production of GcMAF, thus preventing the immune system from doing its job. Without an active immune system, cancer and viral infections can grow unchecked.
      As an extremely sensitive marker for all cancers, Nagalase provides a powerful system for early detection.
      Serial Nagalase testing provides a reliable and accurate method for tracking the results of any therapeutic regimen for cancer, AIDS, or other chronic viral infection.

      Nagalase proves that cancer cells break all the rules

      Normal healthy cells cooperate with one another in a concerted effort to further the good of all. Cancer cells refuse to play ball. Their disdainful attitude toward the rest of our cellular community is appalling. For example, these cellular scofflaws ignore clear messages to stop growing and spreading and encroaching on their neighbor’s space. How would you like it if your neighbor moved his fence over into your backyard?

      Of all the rules cancer cells break, none is more alarming than the production of Nagalase, the evil enzyme that completely hog-ties the immune system army’s ability to stop cancer cells.

      Virus particles also make Nagalase. Their goal is the same as that of the cancer cells: survival by incapacitating their number one enemy: the immune system.

      Nagalase precision

      Like a stealth bomber, the Nagalase enzyme synthesized in and released from a cancer cell or a virus particle pinpoints the GcMAF production facilities on the surface of your T and B lymphocytes and then wipes them out with an incredibly precise bomb. How precise? Let me put it this way: Nagalase locates and attacks one specific two-electron bond located at, and only at, the 420th amino acid position on a huge protein molecule (DBP), one of tens of thousands of proteins, each containing millions of electrons. This is like selectively taking out a park bench in a major city from six thousand miles away. More astonishing, if that is possible, Nagalase never misses its target. There is no collateral damage.

      As you already know, GcMAF is a cell-signaling glycoprotein that talks to macrophages, enabling them to rapidly find, attack, and kill viruses and cancer cells. By activating macrophages, GcMAF triggers a cascade that activates the entire immune system. Blockage of GcMAF production by Nagalase brings all this wonderful anti-cancer and anti-viral immune activity to a screeching halt, allowing cancer and infections to spread.

      What does Nagalase actually do? How does it destroy immune functioning and deactivate macrophages?

      Once synthesized and released into nearby tissue or into the bloodstream, Nagalase, like that drill sergeant at boot camp, shouts harsh commands at the vitamin D binding protein (DBP) that is about to be turned into GcMAF. Nagalase demands that DBP not, under any circumstances, attach itself to a specific sugar molecule (galactosamine). If DBP has already grabbed (i.e., connected to, using a two-electron, “covalent” bond) a galactosamine sugar molecule, it is commanded to immediately let go. “Leave galactosamine alone, or you’ll be in big trouble!!!” is the Nagalase sergeant’s command. We’ll probably never know whether or not, on some deeper level, DBP knows that Nagalase’s motives are dastardly—but it doesn’t really matter: DBP will definitely always obey. Like the army private, the DBP literally has no choice. Because of the way hierarchies work in cellular biology, proteins must do the bidding of their enzymes. The enzymes, like Nagalase, are the drill sergeant and the proteins, like DBP, are the privates. That’s just the way it is. Obeying the drill sergeant’s command means DBP can’t do its assigned task, that of becoming GcMAF. It is rendered useless. For DBP, on a molecular level, life no longer has meaning.

      Unfortunately for cancer and viral patients, DBP had been on its way to becoming GcMAF until the Nagalase drill sergeant so rudely interrupted. Now GcMAF—the one protein our bodies need in order to activate our immune systems—can’t be made. Immune activity screeches to a halt. The defense system protecting us from cancers and viruses has been snuffed out.

      Nagalase, using this astonishingly simple yet cunningly subversive technique, emasculates the GcMAF precursor protein (DBP) by knocking off its three sugar molecules. One quick whack by Nagalase and the DBP protein that would have become a GcMAF molecule now limps off into the sunset, permanently disfigured and disabled. With one simple, swift maneuver, Nagalase has brought the entire immune system to its knees.

      Here’s how Dr. Yamamoto put it (for clarity, I’ve replaced some of the technical words):

      “Serum vitamin D3-binding protein (DBP) is the precursor for the principal macrophage activating factor (GcMAF). The precursor activity of serum DBP was reduced… These patient sera contained alpha-N-acetylgalactosaminidase (Nagalase) that deglycosylates (removes the sugars from) DBP. Deglycosylated DBP cannot be converted to GcMAF, thus it loses the GcMAF precursor activity, leading to immunosuppression.” (Microbes Infect. 2005 Apr;7(4):674-81. Epub 2005 Mar 22. Pathogenic significance of alpha-N-acetylgalactosaminidase activity found in the hemagglutinin of influenza virus. Yamamoto N, Urade M.)

      Nagalase testing: former mass murderer now works for the good guys

      It’s easy to be a little schizy about Nagalase. On the one hand, this nasty protein’s behavior toward us has been reprehensible and disastrous. Working in cahoots with cancer and HIV—not shy about getting into bed with our mortal enemies—Nagalase can rightfully claim direct responsibility for billions of human deaths. And it would just as soon add you to the list, so we don’t have to be shy about placing Nagalase in the “genocidal murderer” column.

      With the advent of Nagalase testing, however, this bad actor now will be harnessed to a useful purpose. By providing us with precise and reliable advance information about enemy operations, Nagalase blood level testing becomes a “Deep Throat” double agent for cancer. He helps us by giving us an early warning sign.

      Early detection (using AMAS or Nagalase) saves lives

      You don’t want a cancer to have gotten out of control by the time you find and start treating it. When cancers are still young and small, gentle natural therapies are the most effective. Alternative treatments work best on early small cancers by enhancing immune functioning and removing the source of the inflammation that is causing the cancer in the first place. Cancers that have become large enough to see on imaging pose a much more significant threat, and the big guns now become necessary.

      The current method for diagnosing most cancers requires us to wait until a mass shows up on imaging (e.g., a mammogram, chest X-ray, or colonoscopy). This approach wastes valuable time and causes needless deaths. But long before imaging can find it, a positive Nagalase (or AMAS test) can tell us that early stage cancer exists somewhere in the body. By enabling earlier and therefore less invasive treatment options, this information provides a huge head-start.

      Normally present at only trace levels, Nagalase shows up in the blood when a cancer or virus appears

      The malignant and viral entities that make Nagalase are not normally present, so its appearance is a big deal from a diagnostic perspective. When Nagalase shows up, even in very small amounts, we have the earliest glimpse of a new cancer or viral infection. The old adage, “Where there’s smoke, there’s fire” applies here. A positive Nagalase test notifies us that a cancer (or a nasty virus) lurks within.

      Nagalase appears in the blood stream when a nascent cancer is just a minute cluster of abnormal cells, long before conventional diagnostic methods can detect it. Through blood testing, we can find this red flag, even when present at exceedingly low levels. Providing us with this early warning sign might not quite qualify Nagalase for the “Good Samaritan” award, but I could go with “extremely useful.” Like a rehabilitated criminal on parole, the potential for harm is still there. For now, however, he’s staying out of trouble and doing community service. Turn your back and he’s a mass murderer again.

      Using Nagalase testing to track cancer treatment

      Rising Nagalase levels indicate a cancer or virus is growing and spreading. Conversely, Nagalase levels will decrease if the cancer or infection is being effectively destroyed.

      Any treatment that lowers cancer cell (or viral numbers) will lower Nagalase levels. Nagalase will, for example, always drop after surgery (whether or not the entire tumor was removed). Chemotherapy and radiation also reduce Nagalase levels. So does GcMAF. If, after these treatments, the depressed level begins to rise again, this is the warning sign that the cancer was not completely removed, and/or that metastatic disease is hiding out somewhere. With viral infections, increasing Nagalase levels indicate return of the infection.

      Consecutive rising Nagalase levels are therefore a red flag, warning us it may be time to entertain new treatment options. Conversely, if levels are going down, stay the course: the cancer or virus is going away.

      Flat-earth medicine

      Many medical professionals don’t feel comfortable with “nonspecific” tests like Nagalase. It drives them nuts to discover that a cancer is lurking somewhere inside without knowing exactly where it is located. “How,” they ask, “do you expect me to treat a cancer I can’t see? Why, I’m not going to tilt at windmills!” This may be a signal that you need to find a different doctor, perhaps one who works in an alternative cancer clinic. Here you will find highly-trained professionals who understand the concept that cancer is a molecular biological change long before it presents visually (by this I mean becomes viewable on imaging).

      When GcMAF becomes available, the answer will be easier: a six month course of weekly 100 ng GcMAF intramuscular injections with monthly Nagalase level tests to follow the Nagalase level as it goes back down to baseline. The cancer can be declared cured, even though it never reached life-threatening proportions. (We have a long way to go before this kind of medical behavior will be commonplace and acceptable. The sooner the better, however.)

      Nagalase role “under-appreciated”

      Nagalase, arguably our most immunosuppressive protein molecule, poses an enormous threat in terms of cancer perpetuation and viruses’ ability to continually defeat us. Yet cancer researchers have not shown any interest in it. (Maybe I’m being a little too generous here; perhaps “clueless” would be more a more accurate depiction.) Why don’t they get it that blasting cancer cells into oblivion with chemo and radiation is usually not sufficient to stop advanced disease and does nothing to address the cause: immunosuppression. Even if we ignore for the moment the excessive collateral damage caused by chemo drugs and radiation, the patient also needs—requires—a healthy immune system to finish the job. If we don’t revive immune function by disabling Nagalase, the cancers and viruses will just keep roaring back. Restoring immunocompetence by negating the stultifying effect of Nagalase should therefore become a primary research goal.

      http://gcmaf.timsmithmd.com/book/book/4/

      • Robb Wolf
        March 13, 2014 at 10:42 am

        James-
        this should really be a blog post, not a comment!! Contact Squatchy via the contact form, let’s get this in front of folks.

  21. Dr. Cindy Gale
    September 20, 2013 at 8:04 am

    It has been suggested by many over the years that sugar feeds cancer, and after reading this article, I feel that this must be true. What astounds me is that no doctor who treats Cancer patients, of which I am aware, even bothers to mention changing their patient’s diet to avoid carbohydrates. I believe that THEY believe the patient is going to die anyway, so why not let them enjoy whatever they want to eat while they still can. Not only that, the doctors take away their patient’s hope by limiting the length of time they have left to live and take no measures to support their patients in take responsibility for their own health. Instead, the patients and their families falsely think that the Chemo and Radiation will cure them, when everyone knows that is not the case. When you address the symptoms instead of the cause, the most you can get is a temporary fix. It is appalling to me that most medical doctors do not take diet into consideration when treating their patients! As a Chiropractor, I have always made the effort to get to know my patients and educate them as to how to avoid becoming sick, as well as “alternative” methods other than allopathic treatments to heal themselves. The body is amazing and miraculous, and instead of giving our power away to the doctors who prescribe drugs and surgery, we need to be advocates for ourselves. This article allows that opportunity, and I am going to share this information with everyone I know. Thank you for giving hope back to the people.
    Yours in good health,
    Dr. Cindy Gale

    • Robb Wolf
      September 20, 2013 at 9:23 am

      Doc-
      I also hear from practitioners that a ketogenic diet will be “too hard.” Also, there is very misguided concern of weight loss. Sigh. This will all change, it’s just going to take some time.

      • Amy B.
        September 20, 2013 at 10:50 am

        Not sure what’s happened in the (limited) human studies, but you would think cancer cachexia would be *improved* with a ketogenic diet, since healthy tissue would have access to a fuel they can use — specifically, one the cancer cells won’t “steal” from them like, like they do with glucose. Almost like a weight normalizing plan — those who need to lose weight do, and those who need to gain do, too.

        And yes, ketogenic diets are hard. But so is dying from cancer. Given even the possibility (and maybe even a strong probability) that the former could give someone a fighting chance against the latter, or just make it more bearable, patients should at least have access to the information so they can make their own choice and decide just how “hard” they think it would be.

        A friend’s mother died from breast cancer and while she was in the hospital, they loaded her up on Ensure shakes just to get some calories in. Oy…

        NEVER STOP putting this information out there, Robb! (And Travis.)

  22. matt
    September 20, 2013 at 10:44 am

    First let me say that I don’t think the current health care/pharma system has any interest in a cure. And if someone does come up with a cure that is not profitable or can’t be patented, they will be discredited quickly.

    With that being said I do not think that a ketogenic diet will cure cancer. I think that stabilizing blood sugar levels would be important in potentially slowing down the growth of the cancer.

    I do think that animal fat versus vegetable oils/trans fats/margarine probably plays a much bigger role in cancer then people think. If vegetable oils are used during organ transplants to lower the immune system what happens when saturated fat is replaced with vegetable oils in most diets?

    • Joshua
      September 20, 2013 at 2:40 pm

      matt- I don’t think I’d agree that there is such active malice towards a cure in the current health/pharma system, but I think you’re right that they have little interest in a non-profitable cure.

      I actually think that’s fine. The problem I have is with the way they have captured the FDA system to keep out drugs and companies that can not afford the hurdles that keep smaller operators out of the market. If the FDA was truly functioning for the good of Americans, it would spend more time letting novel solutions in than keeping them out. Treatments with few customers or low profit potential just can’t afford the journey to get past the regulations currently in place. I’m sure they THINK they’re serving the good, but they’re not.

      • Robb Wolf
        September 20, 2013 at 5:10 pm

        Josh, straight from the book “Healthy Competition.” good stuff.

  23. Joshua
    September 20, 2013 at 2:12 pm

    One thing I haven’t seen discussed is physiological insulin resistance. It seems that most of the folks who use a ketogenic diet actually see their fasting blood sugar rise in the long term. They will never see the spikes that sugar burners do, but they will have more sugar available at any other given moment. This seems perfectly healthy in an otherwise healthy individual, but for a somebody who has a sugar loving cancer, it seems like a bad idea.

    It seems like any treatment of cancer with diet will have to take this into effect. Maybe with metformin? Or is the avoidance of sugar spikes enough?

    • Robb Wolf
      September 20, 2013 at 5:13 pm

      It’s a good question. We usually see long term ketosis settle in the 80-90′s range…if folks are becoming insulin resistant we often see higher levels than this AND carb bolus from food…I still think we come out ahead with that. Plus the IR may have some nutrient partitioning effects. Good question though.

      • Bill
        June 6, 2014 at 12:47 pm

        Robb,
        In Cancer as a metabolic disease, Thomas Seyfried mentions the possibility of IR. My understanding is that is why he recommends calorie restricted, ketogenic diet.

    • Tim Lundeen
      August 11, 2014 at 12:08 pm

      You can manage blood glucose levels in ketosis by changing the ratio of long-chain to short-chain saturated fatty acids. If your fasting blood levels increase, add more coconut oil. Long-chain sat fat stabilizes blood sugar, short-chain lowers it.

      This is why the Kitavans had such low fasting blood glucose despite eating saturated fat — almost all the fat they ate was short-chain.

      Peter at hyperlipid has a lot more about the biochemistry of all this (of course).

  24. Travis
    September 20, 2013 at 5:57 pm

    Josh, Clifton Leafs new book “the truth in small doses” does a great job addressing those issues. In the end, he concludes, there really are no villains. It easy to be a little more cynical however, for example, it is not uncommon for the FDA to approve a new “blockbuster” drug that gives a month survival at best. Some offer no increase in survival, but because they exhibit an initial tumor response, they win approval — costing up to 100,000 per treatment. It is hard not to label this ‘taking advantage of people at their most vulnerable.” I feel for the oncologists, because the tool belt pharma provides them with is mostly weak and ineffectual. Think: radiation has been around for over 100 years. Cisplatin, the ‘penicillin’ of cancer was discovered in the 70′s. Hard to think of a more stagnant technology.

  25. Kevin Foureman
    September 20, 2013 at 7:59 pm

    Travis, I really liked your article and much of what you are saying in it matches up to a lot of other research I have done over the years concerning this subject. Though I am far from being well studied in this subject at least from a prefessional point of view. This is a fascinating subject to me.

    A friend of mine who read the repost I opsted on FB who is going to school for science and studying into this area himself was wondering about your background or credentials or if you yourself have written any published scientific papers. He had not been able to find any and didn’t notice any references at the end of your article. He is not on this forum so I said I would enquire. He is all about wanting to see the references as to your qualifications to write on the subject.

    • Robb Wolf
      September 22, 2013 at 2:53 pm

      Travis is a grad student in Prf. Seyfrieds lab. That should be remarkably easy to find…if your friend could not track that down I’m dubious as to what any credentials or publications will mean.

      • Ted
        September 23, 2013 at 12:40 pm

        No Robb, this person does not have any published scientific articles. Being a postdoc and being a published scientist are two different things. Postdoc or not, Mr. Christofferson is a medical writer. A PubMed search shows nothing.

        http://www.ncbi.nlm.nih.gov/pubmed/?term=Christofferson+TM

        • Robb Wolf
          September 23, 2013 at 3:09 pm

          I never said they were NOT different things, we had the classic dismissal brewing of the credential shell game. Let’s look at the theories and their merits first, k?

          • Ted
            September 24, 2013 at 5:57 am

            No, it was implied when the commenter asked for credentials, you said he was a postdoc whose papers should be easy to find. There are none. How about instead of defending the guy, you just post his credentials in addition to his hypotheses so that people can judge the whole package?

  26. John Atkins
    September 21, 2013 at 9:03 am

    I have a bowel tumour and until fairly recently I had metastatic bowel cancer in my liver. After 7 courses of Oxalyplatin chemo and 6 months of low carb diet my liver is now cancer free. Although I have not had any chemo for nearly 5 months my bowel tumour is still ‘subdued’ and not presenting blood and other extreme symptoms as it did 9 months ago. In a week or two I hope to have the remains of the tumour removed surgically. Throughout, I have struggled to keep in ketosis mostly due to my sweet-tooth but also due to intermittent worries about nutrient and fibre intake etc, but at the very least have been consistent in keeping my diet low carb except for about a week in July when I was persuaded to do ‘carbo-loading to strengthen myself’. After my week of carbo loading I had a return of bleeding, presumably from my bowel tumour, which stopped again once I got back into ketosis, and hasn’t returned to date. I am not a doctor but would not hesitate to recommend the keto diet to anyone finding they have a bowel tumour or similar. One of the earlier commenters remarked that there was a lack of evidence that keto diet was effective in fighting cancer but imo the lack of evidence is mainly due to a complete lack of interest in diet amongst the medical community( certainly in the UK where I live). It would be quite difficult for Joepublic to present hard evidence without professional medical support. Despite the amazing results I got on my liver recently I saw no attempt by medics to understand why the better than expected outcome had occurred.

    • Sue
      September 22, 2013 at 11:32 pm

      John, you should join our forum for colon cancer members at http://www.colonchat.net and fill us in on your treatment / low carb ideas. We love having people like you who are open to new ideas. We strive to all help each other by sharing ideas. I hope you come on over. Good luck to you!!!

    • Hamish Oudney
      October 23, 2013 at 10:30 pm

      John

      I’m fascinated by what you’ve accomplished with your disease. I wonder if you’d be able to share a little more with me. My wife is 31 and has metastatic bowel cancer in her liver just like you. None of the team at our oncology ward have any interest in discussions on the topic of a dietary approach. If you could drop me an email – Hamish.oudney@gmail.com – so I can bombard you with questions, I’d be very grateful.

      Hamish

  27. Dr Elizabeth Ruggiero
    September 21, 2013 at 9:06 am

    I am finding the mental health ramifications of high carbs within my daily work. I would love to see more work and stats on the fantastic results in Ketogenic diets on ADD, ADHD, behavioral issues and overall mental health issues. I have long said we are overmedicating children as we send them to school on cocoa puffs and then expect them to sit still, not bully and not get diabetes….
    If any medical doctor would like to do some mental health collaboration, Im in!!!
    Elizabeth Ruggiero, LMFT, LPC, NHA
    Systemic Therapist

  28. Bryan
    September 21, 2013 at 11:45 am

    Robb, could you try and get Dr Seyfried to do the podcast?

    • Robb Wolf
      September 22, 2013 at 2:50 pm

      absolutely.

      • Bryan
        September 24, 2013 at 7:33 pm

        I’ve been reading all the papers possible and it looks like two researchers, Peter Pederson and someone named Young Hee Ko from John Hopkins have basically found the cure for cancer in 3-bromopyruvate. It would be great to give Dr Young Ko some more attention on the web somehow, since her results are remarkable but don’t garner enough attention yet due to the drug being based on the metabolic/mitochondrial theory of cancer.

  29. Lee J
    September 21, 2013 at 9:16 pm

    Robb, I think you get too caught up in what’s exciting and don’t really understand it well enough.

    First, let me address the point of the article: You debunk the genetic theory of cancer in its entirety but are missing some key points

    *Cancers are clonal proliferations. Thus they are genetic in nature by definition.

    *We don’t understand all the genes, but certain mutations make the risk of cancer very well known. BRCA+ patients for example have a TREMENDOUS risk of aggressive cancer.

    *Yes, 5% of known cancers come from people with a known family history of said cancer. However, when you look at it more appropriately a family history independently increases anyone’s risk for cancer. A woman who had any relative with breast cancer has a 2x above the average population risk for developing cancer and nearly 4x risk if 2 first degree relatives had breast cancer. Given that your average woman has a 1 in 8 chance of developing breast cancer this moves someone’s risk to nearly 50%. This is the effect of family history and genetics and it is quite clear and can’t just be blamed on diet and metabolism.

    *If you have one cell with metabolic abnormalities and it proliferates, if it were not genetic the metabolic abnormalities would not proliferate. But they do. Because cancer is clonal. Which is genetic. You can do hand waving, but you can’t ignore the fact that the property is passed along to other cells.

    *The genome project offers us more information that we can reasonably analyze right now. Saying that we know a putative function for every gene isn’t even true. And most genes and their proteins have multiple functions. Which may vary among cell types and isotypes. And new functions are identified for many proteins that we hadn’t realized before. So telling me that people doing massive genome wide screening of mutations and can’t accurately assess the functions for all of these genes doesn’t surprise me. It’s what I’d expect to find after the results.

    *Cancer cells having metabolic abnormalities does not rule out genetic abnormalities. It is an exciting area of research for sure, but harping on a early preliminary area of research and acting as if it disproves everything we know is a little ridiculous.

    * I THINK MOST IMPORTANTLY AND FUNDAMENTALLY. Cancer is not one disease. It is many different diseases. Even something like “breast cancer” is MANY DIFFERENT DISEASES. People like John Watson and pop scientists try to over simplify things for sound bites but CANCER IS NOT ONE DISEASE. That’s the reason we haven’t CURED CANCER because CANCER IS MANY DIFFERENT DISEASES that have certain properties in common. If you think of them all like one disease you’re not going to think of them correctly. There’s not one magical cure for “cancer” just like there’s not one magical cure for “infection” (which is also a wide subset of disease that includes a variety of different bacteria, viruses, fungi, and (depending on how you define it) prions). Yes I know you’re speaking to the layperson, but you use various different cancers interchangably in your arguments without even realizing that you’re using apples as evidence that oranges are the same as grapes.

    I really applaud your effort, and realize that the point of this article is to sell new information, which may be exciting and promising, but it’s counterproductive and intellectually flawed to think that this debunks what is known.

    • Robb Wolf
      September 22, 2013 at 2:49 pm

      Lee-
      Good to know you are drawing this from your lab which has done primary research on the topic for more than 20 years…

      • Robb Wolf
        September 23, 2013 at 3:25 pm

        Also Lee, this concept is new to you, not me. I interviewed Prof. Seyfried almost 10 years ago on this topic:
        http://www.crossfit.com/cf-journal/seyfriedInterview.pdf

        You are telling me I “do not understand it well enough” yet have no idea what I actually do or do not know on the topic. I also get the sense you were unaware this was another person writing on this topic until late in the game.

    • Ted
      September 23, 2013 at 12:44 pm

      I agree with Lee’s post and can’t really understand why Robb would be sarcastic about it. Lee is exactly right: Cancer is not one single disease. Anyone who thinks otherwise is completely missing the point. We aren’t “winning” the war on cancer because the name itself implies one thing. We *are* winning the war on individual therapies for individual diseases. The comment made by Mr Christofersson that cancer death rates haven’t changed since 1950 is completely incorrect. Mortality rates for gastric cancer have plummeted. Mortality for lung cancer has increased *and* decreased in that amount of time. Taking two arbitrary points in time for a collection of diseases and saying “nothing has changed” is ridiculous. I honestly don’t see much value in what was written other than to promote a website and Dr. Yu’s work.

      • Travis
        September 23, 2013 at 4:27 pm

        Ted, You are absolutely correct, researchers have made great strides on some types of cancer, especially CML – with Gleevec. However, the raw death rate does not lie. I urge you to go and just read the first part, titled the “Burden,” of Clifton Leaf’s new book “the truth in small doeses.” Most progress is measured in months — but the end result is still death.

        • Ted
          September 23, 2013 at 11:31 pm

          Yes Travis, the end result will always be death. Extending survival by months is an improvement. Steve Job’s cancer is among the most fatal (~95%). You don’t seem to be addressing any of the reductions in fatality from the more common cancers and choose instead to nitpick among the many others. As I had said in my first point, you appear to be promoting a single author, a single website, and now, a book.

          • Travis
            September 24, 2013 at 6:01 pm

            Ted,

            You said: ” The comment made by Mr Christofersson that cancer death rates haven’t changed since 1950 is completely incorrect.”

            The point from the link I was referring to: “After all, despite a half-century of research by some of the best medical minds in the world, the death rate from cancer hasn’t changed much since the 1950s”

            It makes me a little sad that all you got out of the article is that I’m trying to promote an author, a website, and a book. If you mean I’m trying to promote the foundation website, I am. I hope the foundation can fund trials that lead to cheap, effective treatments — no one else is funding them. I get nothing from the foundation. When you work this hard on something, to have someone drench it in skepticism, questioning motives, not sure what good that does, or where it comes from. If you have issues with specific points, or the science in the article, ask. It is all backed by references. I completely understand this is a controversial subject — but everyone I’ve interviewed or emailed for this article, including all those who don’t agree with the metabolic theory — have been open, willing to share, and perfectly pleasant. In fact, some have gone out of their way to help — giving much more of their time than was asked. As Clifton Leaf said, “in the war on cancer, there are no villains.” Dr. D’Agnostino, Dr. Seyfried, Dr. Petersen, Dr. Yu are some of the finest quality people I’ve ever encountered in my life. Their generosity and the purity of their motives is unmatched. EVERYONE I’ve encountered writing this article has the right motives, but the science is at a very seminal, and controversial moment. It is OK to ardently defend a position, and walk away friends. Maybe take a little time to think before questioning someone’s motives…that’s all.

      • Travis
        September 23, 2013 at 4:35 pm

        Here is a link to a fortune magazine article of Steve Jobs Oncologist quoting the exact statistic that you said was “ridiculous”

        http://management.fortune.cnn.com/2012/02/17/david-agus-end-illness/

        • Robb Wolf
          September 23, 2013 at 6:58 pm

          Wait…this was not an opinion piece!? It ahs fact behind it! MIND-BLOWN.

          • Ted
            September 23, 2013 at 11:37 pm

            Robb,

            For someone who earned himself a PhD in a hard science, you sure do drink the cool-aid pretty quickly when a single scientist has a viewpoint that you like. Amazing, though, that you aren’t much of a fan of consensus.

            Travis,
            If metabolic imbalance is the root of all evil, why did you send a link which describes genetics as the root of all evil? Also, again, who exactly cares what the physician of a famous (now deceased) man thinks? The last thing I trust physicians to do well is research.

          • Robb Wolf
            September 24, 2013 at 9:23 am

            Connecting the dots is drinking cool-aide? good to know, thanks.

    • Joshua
      September 23, 2013 at 1:55 pm

      Lee,
      You seem to have missed the point entirely. I did not understand Travis to be arguing that there was no genetic influence on cancer, but that it was not the root cause.

      Most of your points are addressed by this one sentence: “Dr. Seyfried and others propose that chronic and persistent damage to cellular mitochondria ultimately triggers an epigenetic signal from the mitochondria to the nuclear DNA, altering the expression of a plethora of key cancer causing genes – a classic epigenetic system.”

      I’m not entirely convinced of the theory, but it certainly sounds plausible to me. I’m eager to learn more about the mechanism whereby the mitochondria mess with the nuclear DNA.

    • Travis
      September 23, 2013 at 4:18 pm

      Hi Lee, great response.
      First bullet: *Cancers are clonal proliferations. Thus they are genetic in nature by definition.
      How do we know this in all cases?
      Inter-tumoral heterogeneity is well established, and can’t account for origination in many cases (and that’s not me talking that is from reviews of the sequence-guys themselves.) Before the recent advent of “deep-sequencing” technology, researchers have not been able to go very “deep” into intra-tumoral heterogeneity to always establish a clonal origin. These studies are just getting started. Here is a recent one that employs deep-sequencing that did not find a consistent clonal origin of metastasis. http://www.ncbi.nlm.nih.gov/pubmed/?term=glioblastoma+patient+with+a+double+nickle
      This link graphically explain the next-generation, deep-sequencing: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375045/figure/F5/

      Without establishing a clonal origin the entire somatic theory is blown apart. I called one of the authors of that study and asked her, “Without a consistent mutation that permeates all met’s, how do you account for a clonal origin at all? Answer: “Well that’s just how heterogeneous cancer is.”

      I also had a conversation with Charles Swanton, in the UK branch of TCGA. He said they recently found intra-tumoral samples without a clonal mutation, only copy-number clones. He was amendable to a metabolic origin of the disease. In time, I bet deep-sequencing will find met’s or intra-tumoral samples without clonal mutations. Time will tell.

      When you really look into the history cancer biology, there have always been competing theories to account for origin. From Pott’s first documentation of an external carcinogen in 1775. To Rous’s sarcoma virus in 1909 — starting the viral theory of origin. To von Hanselmann noticing the chromosomes of cancer were bent, broken, in chaos in the late 1800’s. All the time Warburg, in the background, insisting cancer is of metabolic origin until his death in 1970. It wasn’t until 1976, when biologists discovered that one of the genes of Rous’s virus, was a mutated version of a gene that we all carried in our genomes — this one event crystalized all the competing theories, and firmly established the somatic theory. No one ever looked back. (In the nutrition world it is the equivalent of carbs=good, fat=bad. That dogma has been so hard to reverse even though we now know certain fats (most) ,are good and too many carbs are terrible) But dogma, one established, is THERE. No one argues that there is a GERM-LINE genetic origin — it’s just that it may very well manifest through damage to OXPHOS. BRCA1- which you brought up — is intimately tied to mitochondrial function. So is p53, and RB, and xeroderma….

      There are so many inconsistencies to the somatic theory. Some of the most damning (I was not able to get into the article) are from nuclear transfer studies. Taking an entire nucleus of a cancer cell, with all of it’s genetic material, and putting it into the cytoplasm of a healthy cell, with functional mitochondria. What do you get? — healthy cells, even though the new cells contain all of the purported “driver” mutations of the cancer cell. What do you get when you take the nucleus of a normal cell and put it into the cytoplasm of a cancer cell (with damaged mitochondria) — cancer cells. Not all experiment are created equal and the elegant simplicity of these transfer studies are hard to poke holes in. When it comes to cancer – the mitochondria are in the driver’s seat.

      How is damaged mitochondria “clonal” ? How does it propagate? — I don’t know, but it does. It can easily be measured.
      Here are the ref’s to the nuclear transfer studies:
      Israel BA, Schaeffer WI. Cytoplasmic suppression of malignancy. In Vitro Cell Dev Biol. 1987;23: 627– 32.
      Israel BA, Schaeffer WI. Cytoplasmic mediation of malignancy. In Vitro Cell Dev Biol. 1988;24: 487– 90.

      Sorry to do this Robb, but some have requested ref’s so here are some.
      The ref’s to TCGA data comes right off the NCI web site. It is a wonderful resource.

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      32. Zuccoli, G., et al., Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. Nutr Metab (Lond), 2010. 7: p. 33.
      46. Simonnet H, Alazard N, Pfeiffer K, Gallou C, Beroud C, Demont J, et al. Low mitochondrial respiratory chain content correlates.

      • Robb Wolf
        September 23, 2013 at 7:00 pm

        Bandwidth is cheap, refrence away. That people will actually take the time to read them…that’s another thing entirely.

      • Todd N
        September 23, 2013 at 8:04 pm

        Well played sir!

      • Dominic D'Agostino
        October 1, 2013 at 7:47 pm

        Thanks Travis. Great stuff. I’m covering this issue in my class tomorrow

    • SteveK
      September 26, 2013 at 2:50 pm

      So you’re saying its the mitochondrial DNA that’s mutated?

  30. Lipslife
    September 22, 2013 at 6:28 am

    WOW!!!!!! Thank you!!!!!!!!!!!!

  31. Tony
    September 22, 2013 at 2:55 pm

    Josh, it is the spikes that do the harm, but one thing that hasn’t been discussed is CRKD or just KD, or can you go just CR? I have done CRKD for 3 months and felt great. (first month was tough)

    I also discussed Lissanti’s theory with Dr Seyfreid however Lissanti and his wife ignored my questions and emails, of course that is their prerogative.

    More research is needed for sure and it may not be a ‘cure all’ but who will fund it? seems KD + DCA/Metformin/2DG might just be a game changer for some folk.

    • Joshua
      September 23, 2013 at 2:14 pm

      Tony – given Peter Dobromylskyj’s post (linked above) about Lisanti’s research, I have to think that calorie restriction is only as good as your adipose tissue. If you’ve stored away lots of omega 6 fats (as I have), then restriction will cause you to burn those and that will, as I understand it, feed some cancers. If you are storing/burning mostly saturated and mono-unsaturated fats, it seems cancer doesn’t like that as much.

      If you’re born & raised on the SAD, it seems like a eucaloric ketogenic diet would be safer than calorie restriction.

  32. Charlie
    September 22, 2013 at 8:47 pm

    I know this is nitpicking, but a bit of editing would be nice. Specifically, the word “defiantly” is used repeatedly where the meaning clearly is “definitely”. Also at one point “begging” is used instead of “beginning”, and arctic comes out as “artic”.

    I know plenty of geniuses with far worse spelling skills, so this shouldn’t reflect at all on the article’s technical merits. But many others would spot those minor mistakes and immediately assume the writer must be uneducated. Sad but true.

    • Robb Wolf
      September 23, 2013 at 9:39 am

      charlie-
      We had two folks proof this…shit slips through. If you want to ping squatchy the fixes, I’d be eternally grateful (chris at robb wolf dot com)

  33. Jason David
    September 23, 2013 at 11:51 am

    I just got done reading The Biology of Belief by Bruce H. Lipton Ph.D. I mean – I just finished it the other night…

    As I was reading this article I kept thinking to myself – wow! This is exactly the same thing this guy is saying (about the cells/environmnet etc) in regards to epigenetics!

    Crazy!

  34. david fishkin
    September 24, 2013 at 6:46 am

    I am responding to the many comments from the perspective as a healthcare provider who has had the occasion to diagnose and tell a patient the devastating news of a cancer diagnosis and as the caregiver of a close family member who has been battling chronic cancer for many years. I have read the original paper by Warburg, have read many research papers by Dr. Peterson, and Dr. Ko and Dr. Seyfried’s textbook. They all point to a plausible and equally likely cause for cancer. The genomic and metabolic theories do not have to be mutually exclusive and probably aren’t. And to argue that one drives the other in only one direction may also not be true as is argued by genomics, that the metabolic dysfunction is a result of some genetic error. As someone who has sat in front of an oncologist with a patient to hear the far off promise of genetic analysis with a targeting drug is not very hopeful at all. However, the basic science and the scientists who have worked on the metabolic mechanism across time from 1926 to the present leave little doubt as to the weight it brings to bear on the issue. That, combined with what we know about calorie restriction and in my opinion, carbohydrate restriction to induce and maintain ketosis for periods of time to weaken and perhaps break the Achilles heel of cancer cells. Combining that with anti-glycolytic, and anti-glutamine pathway compounds and perhaps other supportive measures such as IV vitamin C, Alphalipoic acid and hyperbaric oxygen therapy give a patient a measure of hope and control over their own destiny that the current paradigm does not really provide in many cases. I would not want to live in a world without allopathic medicine and all that it offers, but I also do not want to live in a world where it is the only thing that is offered.

    • Francois Quirion
      September 29, 2013 at 4:28 pm

      hi David i think your comment is great and really tells it like it is with the perfect mixture of personal and emotional content as well as knowledgeable scientific understanding….i wish everyone involved with cancer would approach that honestly and without ego

      • david fishkin
        September 30, 2013 at 12:47 pm

        Thanks Francois, lets hope that those who have the means to shift the tide hear it and take action.

  35. Erik
    September 24, 2013 at 7:31 pm

    Wow what a great article! This is for sure a must read!

  36. Francois Quirion
    September 25, 2013 at 3:17 pm

    as a lay person i think this is all wrong.
    Robb practices Brazilian Jujitsu and i practice reality based “selfdefense” and i am sure he would agree with me that it is all about “WHAT YOU DO TO THE OTHER GUY”. In my mind that is senior to techniques (science)
    In this case CANCER is the “other guy” and we want to see it dead or knock-out.
    But it seems the word cure as become illegal.
    Where are the RESULTS.

    The people who have had results such as DR. Seyfried. DR. Warburg (both medical doctor and chemistry PHD and Nobel price winner) Dt Emmanuel Revici(also PHD and Doctor) Dr Stanislas Burzynski(also PHD and Doctor) and even any one in the non-medical non-scientific field who managed to survive or extend his/her life by any method such as Elaine Cantin (who wrote a book on ketogenic diet)would appear to be the least talked about in cancer discussions.

    It is my personal belief that ALL life in every moment attempts to SURVIVE and it makes total sense to me that cells revert to another method of survival when somehow threatened according to Dr.Warburg by an alteration of the respiration process…

    In BJJ we say when you choke the guy out either he taps or he passes out!

  37. PJ
    October 7, 2013 at 12:01 pm

    If only a Ketogenic could kill off all the trolls on the internet… Then we’d be on to something!

    Great post and very interesting stuff.

    Travis, thanks for what you do!

  38. Lala
    October 21, 2013 at 5:07 pm

    Dear Travis and Robb,
    Great article! I’m fascinated by this research and, as a cancer patient myself, I’m trying to implement it to the best of my abilities.

    I have a question for you though. In “Cancer as a metabolic disease” dr. Seyfried mention at some point that the calorie restriction is more important that the type of diet.
    Of course, this maybe because whatever you eat, if you eat only 600calories a day you may enter ketosis, but I don’t really know if this is correct.

    Could you please clarify if a ketogenic calorie restricted diet would work as well as a non-ketogenic calorie restricted diet?

    I’m not opposed to the ketogenic diet at all, just wondering because of the rest of the nutrients (enzimes and vitamins) than the body need (particularly if undergoing chemo) maybe better provided with a different type of diet.

    Many thanks!

    • Robb Wolf
      October 22, 2013 at 9:43 am

      My understanding is cal restricted+ keto is optimal. We are limiting both carbs AND potential gluconeogenic protein.

  39. Lala
    October 23, 2013 at 8:25 am

    Thanks!

  40. Vadim Shapoval
    October 29, 2013 at 12:33 am

    Cancer is a disease of DNA? Cancer researchers ignore Ferromagnetic Cancer Theory (Theory from The OLD TESTAMENT; Iron Conception). Any cancer is initiated by accumulation of superparamagnetic, ferrimagnetic and ferromagnetic nanoparticles within pre-tumor cells. Intracellular molecules FeO;Fe2O3;Fe3O4 are the main creators of these nanoparticles (any cancer is a subtle iron disease). These nanoparticles chaotically distort DNA and shift chromosomes by local magnetic fields. Any cancer is intracellular superpara-ferri-ferromagnetic infection. Accurate anti-iron methods of The Old Testament can successfully beat any cancer. Anti-iron intratumoral injections [sulfur (2%) + olive oil (98%); 36.6C - 39.0C] (by ceramic needles) can suppress any tumors and large metastases; can give harmless infiltrations (harmless necroses; deposits of cells that die; benign capsules). Anti-iron slow blood loss (even 75%) [hemoglobin control], anti-iron goat milk diet and anti-iron drinking water containing hydrogen sulfide can neutralize any micrometastases. http://robbwolf.com/2013/09/19/origin-cancer/ ; http://www.medicalnewstoday.com/opinions/103745/ ; http://www.medicalnewstoday.com/opinions/122203/ ; http://healthland.time.com/2011/07/13/almost-every-type-of-cancer-kills-more-men-than-women-study-shows/ ; Robb Wolf & Medical News Today & TIME & Vadim Shapoval

  41. Skeptical Richard
    October 31, 2013 at 8:30 am

    Detailed post, lots of great info there and in all the comments as well. To me the take-home that I think everyone can agree on (even if they aren’t convinced the KD is helpful) is the importance of epigenetics. Knowing that genetics isn’t destiny urges us to seach for the factors we can control that determine disease expession.

  42. Savita Seru
    December 23, 2013 at 3:54 pm

    It is a very informative article . “MUST READ” for everyone & share with their friends & families

  43. Al Pong
    January 31, 2014 at 4:23 am

    My recent blood test indicated that my PSA was elevated and my Urologist
    wanted me to have a biopsy. I didn’t like that idea and decided to do some
    research on my own. I came across the article, What is The Origin of Cancer?.
    There are some questions –

    1. Dr Warburg discovered that cancer cells are anaerobic (do not breathe oxygen) and cannot survive in the presence of high levels of oxygen. My question is why oxygen was not mentioned in the article?

    2. Citrus Shows Promise For Certain Childhood Cancer, file:///C:/Documents%20and%20Settings/User/My%20Documents/Citrus%20Shows%20Promise%20For%20Certain%20Childhood%20Cancer.html. This study was done in 2004 and it stated, ” This part of the research revealed that with only 5 micromoles of a limonoid known as LG, the cancer cells were dying in as little as 12 hours.”…”Harris explained that flavonoids and limonoids – nutrient-packed pigments that give color and taste to fruit – may work against cancer in any of three ways: prevent it from forming, slow the growth of existing cancer, or kill cancer cells.”…”The limonoids, which differ structurally from flavonoids, seem to do all three,” This is a very powerful study because 5 micromoles are very very very small and I have, yet, see any follow-up study on it. BTW, Harris said. “It’s intriguing that this amount appeared to have no effect on normal cells and only certain types of cancer cells are vulnerable. Fortunately, breast cancer cells are on the list of vulnerable cells…” My question is why no follow-up studies?

    I would like to have a discussion on the answer(s) probably with more questions.

    • Boundless
      February 7, 2014 at 10:27 am

      > My recent blood test indicated that my PSA …

      The PSA is close to a worthless test, right up there with Total Cholesterol and TSH. False negatives and false positives abound. It appears that an actually useful test (kallikrein) is now coming to market. I don’t know if that’s widely available yet.

      > … was elevated and my Urologist wanted me to have a biopsy.

      Other than to your wallet, there’s little risk in the biopsy. In the case of a family member with an elevated PSA, the biop confirmed that it was a false positive. Patient switched to an LCHF diet (probably at least part-time keto) and has ceased worrying about it (BPH symptoms have receded markedly too).

      > My question is why oxygen was not mentioned in the article?

      Dominic D’Agostino, active on this thread, is researching exactly that (hyperbaric therapy).

      > My question is why no follow-up studies?

      Violates dogma? Funding source didn’t like where it was headed? Many possible explanations. One might as well ask why the majority of the medical profession still parrots the Lipid Hypothesis, when data debunking it has existed for decades, and the chronic disease trends are all precisely inversely correlated with the diet shift that the LH generated.

    • Tim Lundeen
      August 11, 2014 at 12:23 pm

      Re prostate cancer, there is a new test called PHI (Prostate Health Index) that is supposed to be much more accurate/specific compared to PSA.

      I’m not wild about needle biopsies because of the risk of metastasis.

  44. Ricardo
    February 15, 2014 at 12:58 pm

    Thank you for the fascinating article. I have only recently come across the works of Drs. Seyfried and D’Agostino and am curious to learn more.

    As Kiefer might say, not to turn this into a pretzel, but apart from its effects on cancer, ketogenic diets can reduce the risk of CVD, treat and prevent neurodegenerative diseases, not to mention its beneficial effects on epilepsy and weight loss. At the same time, I have a hard time accepting that being in a constant state of ketosis is the de facto ideal metabolic state for humans since we are clearly adapted to use glucose.

    If a person is currently without disease, is the “ideal” regimen a cyclic ketogenic diet? Is there even such a thing as an “ideal” regimen for all?

  45. Donna Minighini
    February 20, 2014 at 5:13 pm

    What a great article sharing what is going on, and data available, other than chemotherapy and radiation, for cancer treatment!
    I am especially enthused about the resurfacing of the metabolic theory of cancer, and how a restricted Ketogenic diet and fasting (state of ketosis) has brought remission results in epilepsy and cancer! I am a breast cancer patient and chose hollistic treatment of cruciferous vegetables and specific diet, supplementation (to detox, build immunity, inhibit cancer cells, angiogensis, and growth, and strengthen overall health), exercise – and I will be changing to the Ketogenic diet for cancer management. The stories and facts in your article were outstanding and brings alive that there ARE healthy treatments we all can do, instead of being forced to take harmful drugs that have more harmful side effects and can cause secondary cancers in the future. There is not enough people who are informed in this way. There are options and good ones.

  46. Rita
    April 6, 2014 at 8:38 am

    There is this new study by Mina Bissell & Onodera “Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways”. It says that “glucose uptake level is a critical determinant of whether breast cancer cells form colonies with malignant or nonmalignant phenotypes”.

    As far as I understand from the study, as a layperson, is that a ketogenic diet would put cancer cells to dormancy, make them behave like normal cells, but would not kill them. So, the cancer patient would need to keep a lifelong anti-cancer diet, because he would always have these quiescent cancer embryonic stem cells lying dormant somewhere ready to grow uncontrollably as soon as he begins to indulge in the wrong foods. This is also the experience of some practitioners of alternative therapies: soon after the patient returns to the wrong diet, the cancer returns.
    My question is: is it better to have long fasts, followed by long feasts; or short frequent fasts + short frequent feasts, or a calorie restricted diet with no fasting and no feasting periods? From my experience the high fat diet is very hard on the liver, which is needed to fight cancer; the long fasts weaken the immunity, which again is needed to fight cancer; therefore a hybrid between the Gerson Therapy & Nicholas Gonzales therapy & ketogenic diet is needed: raw root & leaf vegetables+ nuts+ organ meats, in a calorie restricted diet.

    Perhaps, the Gerson Therapy and the Nicholas Gonzales protocol are being successful despite the high amount of carbs they have, because the anticancer compounds, the carrots, beets, leafs etc. have, counteract the cancer promoting effect of carbs.

    Many testimonies of miraculous healing from cancer talk about involuntary water fasting, or calorie restriction.\

  47. Nadine Napolitano
    June 11, 2014 at 1:26 pm

    This was a tremendously written article and specifically pointed out the very things those not involved with mainstream medicine have believed. Most scientists do not want to be proven wrong therefore they will manipulate data in order to create a reasoning of probabilities to continue their support of the theory they so adamantly adhere to. When it is cancer and the lives of millions are at stake the thought of trying to remain right when wrong costs lives; this is not a good image.

    At our organization we advocate balance and harmony; believing that a person that is in harmony and balance will have a natural inherent ability to maintain health where by the only real defense, the immune system, our bodies have will be the strongest. This does not mean a balanced and harmonious person will not have cancer or that if they have cancer will rid themselves of it; our experience have shown they have the best possible defense but the true cause still lurks.

    Our experience is showing most cancer patients that take the time to do a regression of sorts will find exposures to toxins and chemicals, often over time, being the beginning of their health problems resulting in cancer. Balance and harmony with detoxing on a regular basis, with do no harm treatments to treat the symptoms the condition is best to bring about a resolution. Cancer occurs as we see when the body is toxic, the body weakened by imbalance and disharmony. Our environment including what we eat, touch and breathe containing chemicals and toxins create a toxic dump within, perfect for breeding pathogens, allowing imbalances to weaken the body giving cells a chance to mutate, change and proliferate. It is that western medicine fails to seek the cause but to justify their proliferation of drugs doing nothing to stop the disease or prevent it wisely.

  48. Vadim Shapoval
    July 8, 2014 at 8:15 am

    The Origin of Cancer. Most researchers continue to view cancer as a form of genetic lottery. Some cancers run in families because cancer-causing habits in families. Researchers say that for most people who develop cancer, the cancer-causing gene mutations happen over the course of a lifetime; cancer is the result of an accumulation of a large number of individual genetic mutations. Some people are born with abnormal iron metabolism that they inherited from their mother or father. Iron overload is a condition where excessive iron accumulates in the organs and tissues from a wide variety of causes. It can be inherited from parents or it can be acquired during life. Cancer is a form of iron lottery. Lung cancer affects persons who have excessive iron deposits within the tissues of the lungs. Pancreatic cancer affects persons who have excessive iron deposits within the tissues of the pancreas. Brain cancer affects persons who have excessive iron deposits within the tissues of the brain. Lymphoma affects persons who have iron-overloaded lymphocytes. Normal cells become cancer cells because cellular iron overload affects organelles, DNA and chromosomes (chromothripsis). Cancer cells are iron-rich (iron-saturated, iron-overloaded) cells. Cancer is always caused by iron-related genes (genes involved in iron metabolism) and iron-related events (when excessive iron accumulates within the cells, tissues, and organs due to various carcinogenic events). The number of cancer cases and deaths worldwide will nearly double by 2030 because researchers invent useless anticancer drugs. Cure worse than the disease. Where does this term come from? Trepanning was used to release evil spirits from the skull. Bloodletting was used to treat anemia. Mercury was used to treat syphilis. Antibiotics have been used for decades on patients with viral infections. http://www.medicalnewstoday.com/opinions/177506 ; http://www.medicalnewstoday.com/opinions/177299 ; http://www.medicalnewstoday.com/opinions/177370 ; http://www.medicalnewstoday.com/opinions/177452 ; http://www.medicalnewstoday.com/opinions/171557 ; https://plus.google.com/107119198688120551734/posts ; http://galacticconnection.com/father-oncology-vadim-shapoval-says-cell-needs-iron-overload-becomes-cancerous/ ; http://healthland.time.com/2013/04/01/the-conspiracy-to-end-cancer/ ; http://www.ovarian-cancer-facts.com/cancer-facts.html ; http://www.ovarian-cancer-facts.com/what-is-cancer.html ; https://www.youtube.com/watch?v=k2ETte7FQlM ; http://www.youtube.com/watch?v=cCUGua_1dpg ; http://robbwolf.com/2013/09/19/origin-cancer/ ; Together We (Robb Wolf, Medical News Today, Galactic Connection, Ovarian Cancer Facts, News-Medical.Net, TIME, Google, YouTube, YAHOO!, Facebook and Vadim Shapoval) Will Beat Cancer

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