Marios Dimopoulos Clinical Nutritionist, Author, Fellow of the American Council of the Applied Clinical Nutrition

Πέμπτη, 2 Οκτωβρίου 2014

What Is The Origin of Cancer?

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.

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