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.
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 20
th 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 system
. The 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
http://robbwolf.com/2013/09/19/origin-cancer/
