Tripping over the Truth The Metabolic Theory of Cancer

223 Pages·2014·1.1 MB·English

by  Travis Christofferson

Tripping
Over the
Truth

The Return of the Metabolic
Theory of Cancer Illuminates a
New and Hopeful Path to a Cure

Travis Christofferson

Copyright © 2014 Travis Christofferson
All rights reserved.

ISBN: 1500600318
ISBN 13: 9781500600310
Library of Congress Control Number: 2014913140
CreateSpace Independent Publishing Platform
North Charleston, South Carolina

Contents

In the Beginning
Part 1: How Cancer Became Known as a Genetic Disease

Chimney Boys
Chaotic Chromosomes
Is Cancer Infectious?
Warburg’s War
The Secret of Life
A Question That Had Passed Him By
Everything Was in a Fog

Part 2: Chemotherapy and the Gates of Hell

Ying and Yang
MOPP
Total Therapy
“That Son of a Bitch”

Part 3: Breakthroughs and Disappointments

Into the Dustbin of History
A Flickering Ember
PET Scan
A New Era
An Old Target Is New Again
The Good, the Bad, and the Ugly
“If I Hadn’t Seen It with My Own Eyes, I Wouldn’t Have Believed It”

Part 4: Dark Matter

“Is It Possible to Make Sense Out of This Complexity?”
A Paradigm Shift
The Tortoise and the Hare

Part 5: Watson Reconsiders

Part 6: Mitochondria: An Old Theory Is New Again

Things May Not Be as They Seem
Superfuel
Nemesis
The Most Important Game in Town
Gorgeous in Concept (More of the Same)
Press-Pulse

Part 7: Where Do We Go from Here?

Appendix A

Putting Metabolic Therapies to Work
Implementing the Restricted Ketogenic Diet
Ketogenic Diet Therapy
Miriam Kalamian’s Story
The “Pulse”, the power of synergy

Appendix B
Notes

Acknowledgments

Tom Seyfried, Pete Pedersen, Young Ko, and Dominic D’Agostino – thank you
for your extraordinarily generous spirits – and for your grit, creative-vision,
passion and tenacity. My wife, when I asked her to read the book, she said, “I
don’t have to, I lived the book.” Thank you for “living” the book with me
darling. My shining-star kids, for just being the people you are. That an intrinsic
biological program caused atoms from disparate parts of the planet to come
together, and sculpt little people capable of wonder, reason, and delightful
humor – through such little effort on my part – still befuddles me. My editor,
Betty Kelly Sargent, for so adroitly and gently sanding away the rough edges. To
my beautiful nieces, my sister-in-law, and Henry, my hilarious nephew. My
Parents, I love you. My buddy Joe Pfeiffer for always meeting me at the
Independent Ale House after a long day of writing and patiently listening to me
babble over a pint.

Both science and non-fiction story telling intrinsically rely on the work of

others. It’s a building that is continually under construction with scientists
knocking out walls, adding rooms, pouring new foundations; while science
writers go in and redecorate from time to time. To the builders: Tom Seyfried’s
Cancer as a Metabolic Disease, Pete Pedersen’s lifetime of research, Young
Ko’s tireless efforts, Bert Vogelstein and Charles Swanton’s outstanding work,
writing, and generosity of time. And to the decorators: Siddhartha Mukherjee for
his “masterpiece” The Emperor of All Maladies. More than any other you have
established the words that capture the disease of cancer. Robert Bazell for his
wonderful book HER-2. And Clifton Leaf for both his incredibly insightful book
The Truth in Small Doses, and for the advice and kind encouragement. You are
nothing but class. All of their works I borrowed from heavily. It felt silly re-
telling the stories they had already told, especially so considering they were told
better than I could ever tell them, but I had to for the natural progression of the
book. Thanks to Ilona McClintick for your indispensable advice, and George Yu
for “believing in me”. Thank you Harrie Verhoeven for allowing me to tell the
story of Yvar’s courageous fight with cancer. I hope, in the end, it helps to save
the lives of others. Everybody at Green’s, I love you guys. Thanks to Ed and

Lisa Engler, Gay Whalin, and Alisha Butterfield for proofing sections.

Special thanks to Robb Wolf for kicking this whole thing off.
And last, to Brady Christofferson, for being a business partner, an editor, a

psychologist, a friend, and a brother.

Dedicated to Blu

The truth of a theory can never be proven; for one never knows if
future experience will contradict its conclusions.

-Albert Einstein, 1919

In the Beginning

Few words are as emotionally charged as the word cancer. For cancer biologists
it is a riddle yet to be solved; a cruel killer and a masterful escape artist. To those
it has yet to affect, it is an abstraction, something terrifying but distant. Many
have intimate stories attached to the word. Some are stories of triumph, but
many are of a struggle with a foe that proves too relentless, too savvy, and too
hard to pin down. Still today, perhaps the most terrifying quality of cancer is
profound helplessness. We all know that if cancer wants to win, it most likely
will.

Human history is a story of conquest over the natural world—our triumph

over the procuring of food, water, and shelter and combating disease. We figure
out ways to not be helpless. Just recently we have gotten very good at it. When
we lived in caves and throughout the Bronze and Iron Ages, humans could
expect to live into their twenties. The Romans were only able to boost life
expectancy to the late twenties. By the early twentieth century, the average life
span was up to thirty-one, but between then and now, in only about one hundred
years, the average global life expectancy has more than doubled. Today an adult
male, born in the West, can expect to live to be about seventy-six and a female to
eighty-one. The global average is sixty-seven.

Infectious disease alone conspired to keep life-expectancy abysmally low

throughout the majority of our past. When Louis Pasteur showed the world that
there were invisible, alien-like microbial life forms lurking all around us and
thriving in the inner city filth created by the industrial revolution, it was largely a
matter of simply cleaning up. After that came vaccines, and on the heels of
vaccines came the miracle of antibiotics, “substances that do deeds transcending
all medical preconceptions,” as Nobel laureate Peyton Rous so elegantly put it.
One by one, we were beating back the forces that prevented us from living out
our natural life span.

Our drive to live unencumbered by the shackles of nature is so relentless

that even our natural life span is now on the table. Scientist Leonard Hayflick
described aging as “an artifact of civilization,” opening the door to the
possibility that aging is not the inevitable process it was always thought to be. It

might be malleable, delayed, or switched off entirely. This enticing possibility
has put aging in the cross hairs of an imaginative new sect of molecular
biologists who see no limit to what can be achieved. Mankind’s unique desire to
live forever, to discover a fountain of youth, is now said to be within reach. It is
only a matter of time. Ethical and moral issues aside, there is nothing mystical
about this. It is just an engineering project like going to the moon. It really is just
a matter of time. Stem cells, those wondrous propagators of youth, will be
manipulated into forming tissues or even entire organs, replacing our parts as
they wear out. Genes will be tweaked, turned on, and turned off, unfolding an
intrinsic program of eternal youth. Even Google is in on the dream. Recently
they announced a venture called California Life Company (CALICO), and its
stated goal is to employ the power of supercomputing to “fight aging and solve
death.”

The uncomfortable truth of cancer threatens our exalted march toward

immortality. Cancer stands alone as our most ardent, confusing, shapeshifting,
and devastating enemy. The numbers don’t lie. This year, almost six hundred
thousand Americans will die from cancer. One in two men and one in three
women will be diagnosed in their lifetimes. Despite embellished announcements
from government actuaries, the real death rates from cancer are the same today
as they were in the 1950s. We can’t seem to penetrate its elusive armor, and it’s
not for lack of trying. Cancer receives more funding from the National Institutes
of Health (NIH) than any other disease. Not to mention that it is under
investigation at every major pharmaceutical company around the world.

This book is the result of my journey to discover why cures for cancer have

remained so elusive. Why in a century of breathtaking progress where the word
immortality is actually taken seriously, has progress in treating cancer remained
so static? Radiation, still one of the main methods of treatment, was invented
well over one hundred years ago when horses and buggies occupied the streets.

There is no shortage of ideas for the stagnant progress. Some suggest that

because of the collective failure of academia, government, and industry, a
culture has developed that discourages risk taking and encourages narrow
thinking. Some say it is simply due to not enough funding. Others believe that it
is a manifestation of the complexity of the disease itself. Cancer is just that
difficult.

I’ve tried to look for the answer to this question in a place others haven’t—

one protected by an invisible dome of dogma, large-scale group think, and
institutional inertia. Maybe the reason for the stunted progress goes far deeper
than we thought. Maybe it is fundamental, going all the way to the scientific
bedrock at the true heart of the disease. Could it be a reason that exists in the

guts of the science itself? To utter it is heretical, to say it out loud invites scoffs,
dismissal, even outright anger, but here it is. Maybe we’ve mischaracterized the
origin of cancer. Maybe cancer is not a genetic disease after all. Maybe we are
losing the war against cancer because scientists are chasing a flawed scientific
paradigm, and cancer is not a disease of damaged DNA but rather one of
defective metabolism.

This idea didn’t start with me. I stumbled onto it a few years ago when I

was introduced to the idea in a book called Cancer as a Metabolic Disease. Its
author, Thomas Seyfried, PhD, of Boston College, is bold, confident, outspoken,
and very smart. The idea that cancer was metabolic did not come from Seyfried
either. The original claim came from a remarkable German scientist named Otto
Warburg in 1924. Throughout the century Warburg’s claim was a side note in
reviews on the subject of cancer. It never really gained a critical mass of
supporters. It remained just a curious observation. By the 1960’s, his theory had
all but faded into oblivion. When he died in 1970, his antiquated hypothesis
could have died with him, but ideas can live on and, as in Warburg’s case, can
even be resuscitated. It would have slipped into oblivion if Peter (“Pete”)
Pedersen of Johns Hopkins University School of Medicine hadn’t noticed it and
methodically nurtured it back to life. In the 1970s and 1980s, he was alone in his
belief that Warburg was right.

Warburg’s observation was this: cancer cells have a perverted method of

generating energy. They truncate the conversion of glucose (sugar) into energy.
They depend much less on the efficient process of respiratory energy creation,
using oxygen—instead relying much more on the ancient and highly inefficient
pathway known as fermentation. Later in his career, Warburg contended that this
was the true origin of cancer. The cell’s ability to generate energy through the
oxidative pathway is damaged, and the cell reverts to fermentation. He said,
“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 a fermentation of sugar.”

In the summer of 2012, Seyfried released his book, and his ideas to the

world. Expanding upon Warburg’s hypothesis (and Pedersen’s work, following
Warburg’s death), Seyfried noted that across the board, cancer cells have
damage to a cellular organelle called a mitochondrion or, if more than one,
mitochondria. Typically each animal cell, including those of humans, has one
thousand to two thousand mitochondria. Mitochondria are thought of as the
cellular power plants. They generate energy through oxidative respiration,
supplying the body with the energy it needs to function (later pages will show

how mitochondria are damaged in the first place). The damaged mitochondria,
unable to generate enough energy for cellular survival, then send out emergency
signals to the nucleus, a 911 call pleading for it to switch on emergency
generators. Once this call is made and DNA responds, the entire complexion of
the cell changes. It begins to exhibit the hallmark features of cancer:
uncontrolled proliferation, genomic instability (the increased probability that
DNA mutation will occur), evasion of cell death, and so forth. The process is
probably an ancient mechanism designed to nurture cells through transient
moments when little oxygen was available that undoubtedly occurred as the
planet’s first cells evolved toward increasing complexity—a primordial survival
mechanism, a vestige of our evolutionary past. The bottom line is this: damage
to mitochondria happens first, then genomic instability, and then mutations to
DNA. The upshot, according to Seyfried, is that the mutations to DNA, thought
to precipitate and drive the disease, are only a side effect, sending researchers on
a multidecade, multibillion-dollar wild goose chase. It is a bold proclamation,
and the majority of cancer researchers disagree with Seyfried’s assertions, but
history is replete with examples of humanity getting big issues wrong for
extended periods of time.

Like Dr. Barry Marshall, labeled a quack by the medical community for his

claim that an unknown species of bacteria caused ulcers rather than stress, the
accepted but ambiguous perpetrator. According to medical convention, bacteria
couldn’t exist in the acidic environment of the stomach. Undeterred, once
Marshall was convinced that he had isolated the elusive bacterium, he then grew
it until he had a flask brimming with murky liquid that housed billions of
bacterial cells. Then, in an act of desperation, he did what he felt was the only
option to prove his claim: he drank the liquid. The highly publicized ulcer that
erupted in his stomach was documented in a medical journal, unequivocally
proving to the establishment that the bacterium (identified as helicobacter
pylori) could, by itself, cause ulcers. Once ridiculed for his outlandish
proclamation, Marshall was awarded a Nobel Prize.

Of course the vast majority of cancer biologists still believe that the origin

of cancer has been conclusively decided and the chapter is closed. I intend to
show how a single experiment in 1976 merged several lines of evidence into a
grand unified theory that cancer originated from mutations to DNA. The theory,
called the somatic mutation theory (SMT) of cancer, was accepted conclusively.
There was a worldwide eureka moment. There were cheers and backslapping.
Nobel Prizes were given. The war was waged with a new sense of resolve. It was
not a bold leap of imagination to envision a smart war from there, one that used
drugs “targeted” to the products of oncogenes (cancer-causing genes), honing in

on cancer cells and sparing normal cells. The days of toxic chemotherapy and
radiation would soon be relics of an era of medieval medicine akin to
bloodletting and leeches.

Any scientist will tell you that theories are anything but permanent. It is a

mistake to be seduced into believing that textbooks alone provide validation of a
scientific theory. Theories are ephemeral things. They are only our closest
approximation of the truth at a fleeting moment in an otherwise infinite
continuum of discovery. Look at the cycle of succession that physics has
experienced in its quest to describe the universe over the last three hundred
years. Newton’s classic mechanics established the laws of the universe in 1687.
That is until Einstein’s theory of relativity replaced it in 1915, once and for all
providing us with a definitive description of the universe. But even Einstein’s
elegant and once undisputed theory is now being chipped away as the cryptic
and arcane string theory takes form.

Could Warburg have been right? At this strange junction only one thing is

certain. Our understanding of cancer is still in its infancy.

When I completed my undergraduate degree at Montana State University, I

believed what the textbooks said—after all, the SMT of cancer was well
established, lifetimes of careful thinking and solid research backed it, or so I had
been told. Like everybody, I wondered why progress in treating cancer seemed
so slow. It seemed like breakthroughs were perpetually “around the corner” but
never materialized. When I stumbled onto Seyfried’s book during my last year
of graduate school, it was certainly enlightening. If true, it explained the
profound lack of progress in combating the disease. I was not entirely convinced
but intrigued enough to keep looking. That’s when I looked more extensively at
the latest incarnation of the government’s war against cancer: a massive,
multinational project funded by the National Cancer Institute (NCI) called The
Cancer Genome Atlas (TCGA) that began in 2006.

Most researchers, especially those at the head of the NCI, unwaveringly

believe that cancer is caused by DNA mutations that are thought to sequentially
rewire critical cellular circuitry – marching a cell, step by step, toward becoming
a chaotic, aggressive, uncontrolled, and invasive killer. So in order to understand
cancer in its entirety, the entire genome of a cancer cell (all the DNA inside the
cell) would have to be sequenced identifying and cataloging all the “driver”
mutations within the DNA. This is the goal of the TCGA. It is The Manhattan
Project of cancer, an outcome-based effort supposed to be the final chapter in the
war against cancer. Laboratories throughout the world are churning out the
genomic sequence of multiple types of cancer with inconceivable speed and
efficiency.

The project compares the sequence of normal DNA to that of different

cancer types to determine the exact mutations responsible for the origin and
progression of the malignancies. Researchers will finally know cancer in its
entirety—they will be staring the shapeshifting enemy directly in the face. Make
no mistake, everything has led to this—If one could fast forward through one
hundred years of research, every intellectual avenue would lead to TCGA as the
flagship endeavor required for a cure. That is if cancer is really precipitated and
driven by mutations to DNA.

When I dug into the data coming out of TCGA, what I found was stunning.

Nothing made sense. Prior to the project, researchers largely believed the
sequencing data would reveal an orderly sequence of maybe three to eight genes
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. But what the sequence data revealed was anything but
orderly. It exposed an almost random collection of mutations—not a single one,
or any combination for that matter, being absolutely responsible for initiating the
disease. For the SMT to work, mutational patterns had to be found that explained
the origin of a given type of cancer. The cause had to precede and explain the
effect. Critically, the mutations determined to start and drive the disease were
different from person to person, vastly different. No single mutation or no
combination of mutations could be identified that were absolutely required for
the disease to start. Other than a few commonly mutated oncogenes, the
mutational pattern appeared largely random.

Beyond the hype of the media and pharmaceutical companies, hidden deep

in the scientific journals, the scientists are interpreting the data streaming out of
TCGA, and their words give us a far different picture: “immense therapeutic
implications,” “sobering realization,” and “incredibly complex.” The prominent
University of Southern California oncologist Dr. David Agus (who treated Steve
Jobs), simmering with frustration in a recent speech, even suggested that we stop
trying to understand the disease altogether and just throw darts at it, hoping to
find therapies that work.

This is when the story became really interesting. In the fall of 2012, I

began to call and e-mail the scientists involved in the project. I wanted to know
if they saw what I saw or if I had misinterpreted the data or was missing
something. What I found was a collective moment of shock and confusion. Some
acknowledged the stunning randomness, capitulating to the complexity of the
disease, declared their resignation—“Maybe it is just too hard to figure out.”
Others had begun to modify the SMT in order for it to continue to make sense.
Some, like Pedersen and Seyfried, had already moved on. To be sure, on the