BOOK RELEASE: Tripping Over the Truth: The Metabolic Theory of Cancer
Hello, this is Travis Christofferson the founder of SCSC. For the last year I have "gone dark" while I wrote a book about the metabolic theory of cancer.
Its finished -- I've reemerged -- and its very nice to be back. It will be for sale on Amazon in about 10 days. The book explores the history, and the human story that has led to the resurgence of Otto Warburg's original metabolic theory first proposed in 1924. It also explores the important therapeutic consequences that travel with the basic science. It includes an in-depth exploration of the promising metabolic therapies highlighted on this site -- the very therapies we are trying to eventually help get into the clinic. Distilled to its essence, the book was an attempt to answer a single question: why in a century of breathtaking technological advancement, and medical progress, has cancer treatment remained so motionless? The death rate today is the same as it was in 1950. Why does this disease continue to mock our efforts to control it? The book is a quest to answer this question. Below I have posted the first chapter. I hope you like it. If you do decided to buy the book, please give it a review on Amazon, the feedback is invaluable.
T R I P P I N G
O V E R
T H E
T R U T H
THE METABOLIC THEORY OF CANCER
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—procuring food, water, and shelter and combating disease. We figure out ways to not be helpless. Just recently we have gotten 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 thirty-one, but between then and now, in about one hundred years, 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 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 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 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. Ethical and moral issues aside, there is nothing mystical about it. It is an engineering project like going to the moon. Stem cells, those wondrous propagators of youth, will be manipulated into forming tissues or 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. They recently 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, 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, and 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 terribly elusive. In a century of breathtaking progress where the word immortality is taken seriously, why 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 that there is not enough funding. Others believe that it is a manifestation of the complexity of the disease itself. Cancer is 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 groupthink, and institutional inertia. Maybe the reason for the stunted progress goes far deeper than we thought. Maybe it is in the scientific bedrock of the disease. Could the reason exist in the guts of the science itself? To utter it is heretical, and to say it out loud invites dismissal or 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 paradigm, and cancer is not a disease of damaged DNA but 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 smart. The idea that cancer was metabolic did not come from Seyfried either, but from a Nobel Prize-winning German scientist named Otto Warburg in 1924. Throughout the century Warburg’s claim was a side note in reviews on the subject of cancer, never really gaining a critical mass of supporters. By the 1960s, 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, be resuscitated. It would have slipped into oblivion if Peter (“Pete”) Pedersen of Johns Hopkins University School of Medicine hadn’t noticed it and nurtured it back to life. In the 1970s and 1980s, he was almost alone in his belief that Warburg was right.
Warburg’s observation was that cancer cells had a perverted method of generating energy. They truncated the conversion of glucose (sugar) into energy. They depended much less on the efficient process of respiratory energy creation, using oxygen, and relied more on the highly inefficient pathway of 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 was damaged, and the cell’s reversion to fermentation gave rise to malignant growth. 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 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 had 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, send a 911 call to the DNA, 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. According to Seyfried, 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 was a bold proclamation, and the majority of cancer researchers disagreed with Seyfried’s assertions, but history was replete with examples of humanity getting big issues wrong for extended periods of time.
Like Dr. Barry Marshall. He was 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. Once Marshall was convinced that he had isolated the elusive bacterium, he grew it until he had a flask brimming with a murky liquid that housed billions of bacterial cells. He then did what he felt was the only option to prove his claim; he drank the liquid. The 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.
The vast majority of cancer biologists still believed that the origin of cancer had been conclusively decided and the chapter was closed. I will show how an experiment in 1976 merged several lines of evidence into a grand unified theory that cancer originated from mutations to DNA. 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 the imagination to envision a different kind of 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, 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 our closest approximation of the truth at a fleeting moment in an 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. Einstein’s theory of relativity replaced it in 1915 and provided a definitive description of the universe. But today, even Einstein’s elegant theory is being chipped away as the cryptic and arcane string theory takes form.
Could Warburg have been right? At this 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. The SMT of cancer was well established, and lifetimes of solid research backed it. Like everybody, I wondered why progress in treating cancer seemed so slow. Breakthroughs were perpetually “around the corner” but never materialized. When I stumbled onto Seyfried’s book, it was enlightening. If true, it explained the profound lack of progress in combating the disease. I was not convinced but was intrigued enough to keep looking. I looked more extensively at the latest incarnation of the government’s war against cancer: a multinational project funded by the National Cancer Institute (NCI) and called The Cancer Genome Atlas (TCGA). It began in 2006.
Most researchers, especially those at NCI, unwaveringly believed that cancer was caused by DNA mutations that were thought to sequentially rewire critical cellular circuitry marching a cell toward an aggressive, uncontrolled, and invasive killer. To understand cancer in totality the entire genome of a cancer cell (all the DNA inside the cell) would have to be sequenced to identify and catalog all the “driver” mutations within the DNA. This was the goal of the TCGA. It was The Manhattan Project of cancer, an outcome-based effort supposed to be the final chapter in the war against cancer. Laboratories throughout the world were churning out the genomic sequence of multiple types of cancer with inconceivable speed and efficiency.
The project compared the sequence of normal DNA to that of different types of cancer to determine the exact mutations responsible for the origin and progression of the malignancies. Researchers would finally know cancer in its entirety—they would be staring the shape-shifting enemy directly in the face. If one could fast forward through one hundred years of research, every intellectual avenue would lead to TCGA as the flagship endeavor for a cure if cancer was 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 three to eight genes that, when mutated, manifested in a specific type of cancer—an identifying signature like a fingerprint. They would work off this mutational signature with cures to follow. What the sequence data revealed was anything but orderly. It exposed an almost random collection of mutations. 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 vastly different from person to person. No single mutation or no combination of mutations could be identified that were 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 were interpreting the data streaming out of TCGA, and their words gave a far different picture: “immense therapeutic implications,” “sobering realization,” and “incredibly complex.” The prominent University of Southern California oncologist Dr. David Agus (he treated Steve Jobs), simmering with frustration, suggested that we stop trying to understand the disease altogether and throw darts at it, hoping to find therapies that worked.
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 gotten something wrong or was missing something. I experienced a collective moment of shock and confusion. Some acknowledged the stunning randomness, capitulating to the complexity of the disease, and 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 moved on. The cancer community was confused and reorganizing.
The success rate of the drugs designed to target the mutations identified by TCGA was abysmal. More than seven hundred were developed, and only one, GLEEVEC, a drug owned by Novartis Pharmaceuticals, made a meaningful difference in the lives of cancer patients. Most “targeted” drugs might give a cancer patient a few more months. Some offered no survival benefit at all and could cost more than $100,000 for a course of treatment. When it came to oncological drugs, a relationship between price and value didn’t exist. The FDA set the bar low for approval, requiring only that a new drug shrink a tumor without considering the ultimate arbiter of success: survival. As a consequence, these drugs got approved. GLEEVEC was hailed as a “proof of principle” that targeting drugs to mutations was the right approach. But some scientists had a much different view of GLEEVEC. They said GLEEVEC was not the exquisitely precise targeted drug it was thought to be, and that in all probability, GLEEVEC exerted its efficacy by altering pathways turned on by damaged metabolism, perhaps by hanging up the 911 call alluded to earlier.
Why had the promised targeted drugs failed to materialize? TCGA failed to identify the mutations that definitively caused any given type of cancer. As a consequence, researchers had not been able to find the right target or targets. Another ominous discovery came from TCGA, one that cast a dark cloud over the hope for breakthroughs. From a genetic perspective, drug design was a brutally difficult game of “catch me if you can.” The mutational targets were not only vastly different from person to person, but they could vary spectacularly from cell to cell within the same tumor, leaving pharmaceutical chemists with an impossibly difficult task. Followed to its conclusion, the SMT of cancer placed the outcome of many cases in the jaws of inevitability.
The therapeutic implications of the metabolic theory were that every type of cancer was treatable, because every type of cancer had the same beautiful, metabolic target painted on its back, regardless of the tissue of origin or type of cancer. Rather than targeting mutations that were here one second gone the next, the metabolic theory put researchers back in the driver seat. It put cancer back in the realm of curable, implying that we were not helpless against cancer. It restored hope.
Although vastly unknown and underappreciated, the therapies derived from the logic that cancer stemmed from damaged metabolism showed remarkable results. Metabolic therapies flowed from a simple framework of logic. Every cancer cell had the same defect and the same exploitable target. We will explore the promising metabolic therapies developed to date and nontoxic approaches that exploite the metabolic intransigence of the cancer cell. A cancer drug discovered by Dr. Young Hee Ko in Pedersen’s lab at Johns Hopkins in 2000 that sneaks into the cancer cell like a Trojan horse, brilliantly exploing the target mapped out by Warburg almost a century ago, but sadly, it was hung up in a heated court battle.
A dietary protocol developed by Seyfried shows promise to slow the growth of cancer and work synergistically with existing therapies while mitigating side effects. Although unquestionably in their infancy, metabolic therapies have demonstrated incredible promise and merit more attention. My hope is that this book will cause that to happen.
Few things ignite passion like questioning an entrenched paradigm, especially one that is emotionally charged and affects so many people. I learned this in 2013 after writing an article, “It Is Biology’s Most Fundamental Question: What Is the Origin of Cancer?” It was posted on the blog of the Paleo Diet advocate, Robb Wolf, and linked to Twitter and Facebook by Wolf’s good friend, Tim Ferriss. Both Wolf and Ferriss were the New York Times bestselling authors, Gen-X Renaissance men, and both had huge followings. After writing the article, I had difficulty finding a home for it. Nobody knew who I was, and nobody was willing to take a chance and publish it. But Wolf and Ferriss are different, they are idea driven, they are motivated by curiosity and the exhilaration that comes from exploring the world from different angles.
This is the e-mail that Wolf sent to Ferriss:
Tim! Hey, hope all is well. This is an article written by a grad student studying the work of one of my favorite researchers...talking about a non-genetic basis for the development of some (possibly many) cancers. So, I REALLY want to run this on my blog...it is fucking gold content. BUT...you have way more bandwidth than I do and this stuff can, will, save lives. It deserves the largest messaging we can muster IMO. I’ve attached an interview I did with Thomas Seyfried (researcher at Boston College) that I did nearly 10 years ago, also one of his papers on ketogenic diet and brain cancer. My business side says “run it yourself!” My hippy-save-the-world side knows you could affect way more change with this, if it’s something you are interested in running. Hope all is well with you, let me know what you think.
Once the article was posted the comments poured in. Challenging dogmatic concepts tends to galvanize people. Some are naturally, almost intrinsically wired to embrace new or different ideas; others are the exact opposite, dismissing them at the first sentence. One thing both sides have in common is an almost instantaneous gut-reaction in one direction or the other, a reaction that usually has little to do with the actual evidence. The article was like a match that ignited a flame. There was so much more to this story. For me this was just the beginning. It was a scientific detective story that had to be told and it became the focus of my life for the next two years. Soon it became apparent, in interview after interview, that the story went far beyond the cold, empirical data, it tapped into base psychology, human limitations, economic incentives, and the deep-rooted, powerful force of groupthink, forces that carry the inertia of the titanic. Scientific progress doesn’t glide from one exalted epiphany to the next, like the story of Isaac Newton getting hit on his head by an apple. It is a torch carried by human beings, it lurches, stumbles, wanders into dead ends, and then finds its way back out. It doesn’t march in a straight line – it trips its way toward the truth. But the beautiful thing about science is that no matter how bumpy the ride, eventually, because of the process itself, the truth is slowly, inevitably, mapped out.
This book is a culmination of that scientific pilgrimage. It is both the scientific and human story of the revival of Warburg’s old theory and the profound therapeutic consequences that travel with it. It is a look into the continuing quest to discover the nature of cancer from a different angle, taking all the puzzle pieces and assembling them in a new way.
This book is about the ongoing quest to discover the true origin of cancer, reduce the problem to its core elements, define it in its simplest terms, and find the critical molecular events that manifest in uncontrolled proliferation. As veteran cancer researcher Bert Vogelstein said, “Make no mistake—we are not there yet.” Agus said we shouldn’t even try to understand the disease, and others said the same thing. We should learn to treat it without understanding it. The question is worth asking: why should we try? Why is it so important? To cure cancer, we first have to know it. If we’ve learned one thing from the battles against disease, it is that progress does not happen without understanding.
This is one of the most important struggles we face. This is one version of the story to uncover the origin of cancer, and it is a story of discovery and hope.