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The work in the 1930s of Nobel laureate Otto Warburg describing the initial metabolic disturbances in tumors as the trigger of cancer growth was no longer taken seriously enough to direct research efforts. Following his extensive research on tumor metabolism, Otto Warburg stated, “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.” However, despite the evidence for the metabolic origin of cancer, the NCI website ignores this and states that “cancer is a genetic disease,” even though it has been documented that inherited genetic mutations play a major role in only 5 to 7 percent of all cancers.
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It’s safe to say that the evidence strongly supports the implementation of metabolic-based therapies in situations of managing advanced brain cancer and metastatic cancer, especially if the tumor expresses a prominent Warburg effect and thus expresses intense visualization with a PET scan, a sign of excess sugar consumption and cellular proliferation.
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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.
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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.”
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Seyfried noted that, across the board, cancer cells have damaged cellular organelles called mitochondria (singular, mitochondrion).
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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. The damaged mitochondria (later pages will show how the damage occurs in the first place), 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 a primordial survival mechanism designed to nurture cells through the transient moments when little oxygen was available that undoubtedly occurred as the planet’s first cells evolved toward increasing complexity. 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 really only a side effect and have sent 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.
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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 exploit these mutational signatures then to design cures. But what the sequence data revealed was anything but orderly. It exposed an almost random collection of mutations—no single one, or any combination for that matter, being absolutely responsible for initiating disease. For the SMT to work, mutational patterns that explained the origin of a given type of cancer had to be found. 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 combination of mutations that was absolutely required for the disease to start could be identified. Other than a few commonly mutated oncogenes, the mutational pattern appeared largely random.
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But in all probability, imatinib exerts its efficacy by altering pathways turned on by damaged metabolism—perhaps by hanging up the 911 call alluded to earlier.
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The therapeutic implications of the metabolic theory are that every type of cancer is treatable, because every type of cancer has the same beautiful, metabolic target painted on its back, regardless of the tissue of origin or type of cancer. Rather than targeting mutations that are here one second gone the next, the metabolic theory puts researchers back in the driver’s seat. It puts cancer back in the realm of curable, implying that we are not helpless against the disease. It restores hope.
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During a career devoted entirely to research and extending over 60 years, he made an exceptionally large number of highly original and far-reaching contributions to cell biology and biochemistry. Lewis and Randall, [in] the preface to ‘Thermodynamics and the free energy of chemical substances’, liken the edifice of science to a cathedral built by the efforts of a few architects and many workers. In this sense Warburg was one of the small band of real architects of his generation. —Hans Krebs, author of Otto Warburg
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The components the dye did stain were threadlike objects that elegantly lined up in the center of the cell right before cellular division took place, like schoolchildren told to form a line. Fleming had no idea what these objects were, so he coined the term chromosomes (colored bodies). Hansemann heard about Fleming’s work with the dye and wanted to try it on cancer cells. He noticed something striking. Rather than the symmetry and order that Fleming observed, the chromosomes of cancer cells were in complete chaos. They were bent, broken, and duplicated. Rather than recalling children lining up neatly, they looked like kids at play.
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pathogenesis of cancer to asymmetric mitoses. As he described it, “the conversion of normal cells to cancerous ones involves the acquisition of intracellular-arising abnormalities to their hereditary material.”
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anaplasia and dedifferentiation. Both describe the qualitative path that a tumor cell travels from a state of differentiation to a state of less differentiation, as if the cell was traveling in reverse. Differentiation describes the final tissue type of a cell. For example, during the developmental process, an undifferentiated stem cell differentiates into a liver cell, thus allowing for the tissue level of specialization. The fact that Hansemann was able to establish this as a dominant feature of cancer in 1890 was remarkable. Even today, the loss of differentiation (anaplasia) is considered one of the most important aspects of cancer. Cancer cells can undulate wildly from a state of dedifferentiation and back, which explains why some tumors contain multiple tissue types. Even teeth and hair follicles had been found inside tumors.
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The discovery that viruses could cause cancer would prevent the formation of a single, comprehensive theory on the origin of cancer for most of the twentieth century.
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At the time, it was known that human cells used oxygen to create energy. The French scientist Louis Pasteur, whom Warburg admired, termed this type of energy creation aerobic respiration. The other type was without oxygen and with the formation of lactic acid, and Pasteur termed this anaerobic respiration. One form of anaerobic energy creation was a primordial pathway that extracted a fraction of the intrinsic energy within a molecule of glucose. Because life flickered into existence in an atmosphere with no oxygen, fermentation was the first pathway to evolve. It is conserved across a broad span of living things, from humans to monkeys, birds, yeast, spinach, bacteria, and everything between. But the pathway is extremely inefficient. It takes eighteen times more glucose to extract the same amount of energy from fermentation than from aerobic respiration. If the two pathways, aerobic and anaerobic, were represented by cars—the only difference being the motor—the aerobic model would get 38 miles per gallon, and the anaerobic model would get 2 miles per gallon.
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Warburg’s surprise, he found that cancer cells generated abnormal amounts of lactic acid. They were generating energy through the antiquated fermentation pathway. Even more surprising, they did it in the presence of oxygen. True to his meticulous nature, he set out to ensure that the observation was unique to cancer cells. He tested different tissues to see if any could ferment in the presence of oxygen, but none of them did. This led to Warburg’s famous distinction: Unlike normal cells, cancer cells ferment glucose in the presence of oxygen, a characteristic now known simply as “the Warburg effect.”
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Warburg made another critical observation that hinted at why cancer cells were fermenting in the first place. He showed that when normal, healthy cells were deprived of oxygen for brief periods of time (hours), they turned cancerous. No other carcinogens, viruses, or radiation were needed, just a lack of oxygen. This led him to conclude that cancer must be caused by “injury” to the cell’s ability to respire. He contended that once damaged by lack of oxygen, the cell’s respiratory machinery (later found to be mitochondria) became permanently broken and could not be rescued by returning the cells to an oxygen-rich environment. He reasoned that cancer must be caused by a permanent alteration to the respiratory machinery of the cell. It was a simple and elegant hypothesis. Warburg would contend until his death that this was the prime cause of cancer.
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This allows each cell type to express a defined set of genes—a phenomenon known as cell specialization. Directed by a continuous dance between DNA and the environment, proteins dictate the three-dimensional architecture of DNA, allowing for specialization and adaptation. In a hair follicle, for example, the gene encoding for the hair protein is exposed, but in a liver cell, it is wrapped up.
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Hopkins. Back in his lab Pedersen began investigating the biochemistry of the rats’ tumors, and he discovered a powerful correlation. Critically, the faster a tumor grew and the more aggressive it was—the lower the overall number of mitochondria and the more it fermented glucose. He
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mitochondria from the fastest-growing cancer cells were rife with a spectrum of structural abnormalities. They were smaller, less robust, cup shaped, dumbbell shaped, missing important internal membranes, and had numerous abnormalities in their protein and lipid content.
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ATP is generated by the cell in two pathways: fermentation (glycolysis) or aerobic respiration (mitochondrial energy generation utilizing oxygen). Glycolysis starts with one molecule of glucose and, through a series of ten steps, transforms it into two molecules of pyruvate. Once pyruvate is generated, the cell has a decision to make: It can take pyruvate and shuttle it into the mitochondria, where it will begin the respiratory energy cycle—the highly efficient process that employs oxygen to generate a staggering twenty-three molecules of ATP. Alternately, the cell can ferment pyruvate, an inefficient method of energy production that produces only two molecules of ATP and generates lactic acid, a waste product.
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The protein that catalyzes the first step of glycolysis (converting glucose into glucose-6-phosphate by tagging it with a phosphate group) is called hexokinase, and it alone determined the how of the Warburg effect. The how is the result of molecular square dance. The behavior of the cancer cell is drastically altered as one form of hexokinase “do-si-does” into a slightly different form of hexokinase, dramatically altering the way the cell behaves. The “cancerous” version of hexokinase is a vestige of the past, a result of the evolutionary process as it moved through time. To understand where it came from or how it came into existence, we have to briefly explore the dynamics of DNA as it journeyed through time and space.
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peered inside the cancer cell, they noticed a drastic alteration in the way hexokinase was normally expressed. First, the cancer cell switched from its normal hexokinase isozyme to a rare form called hexokinase II. Second, the cells were producing vastly more of it. This singular molecular detail, Pedersen reasoned, could be the how behind the Warburg effect. Normal hexokinase is self-regulating (in the same way a full stomach sends an “I’m full” signal to the brain). As the product of the hexokinase reaction (glucose-6-phosphate) builds up, it signals hexokinase to slow down; this is called product inhibition. The irreverent form of hexokinase, hexokinase II, however, ignores the signal to slow down and keeps the valve wide open, shoving as much glucose as it can down the fermentation pathway. In addition to the embezzlement of the body’s energetic reserves, Pedersen envisions another consequence of hexokinase II’s proclivity to force glucose down the cell’s throat: “Lactic acid may build up, damaging surrounding normal tissue, helping pave the way for invasion and metastasis.”
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Once hexokinase II “tagged” glucose with a phosphate molecule, it is trapped inside the cancer cell. The hyperactivity and overexpression of hexokinase II results in cancer cells that are bloated with glucose. Here was the contrast between normal and diseased tissue that had been needed for the diagnostic application of a PET scan. All that was then needed was a form of labeled glucose that the detectors could pick up, and it came shortly in the form of fluorodeoxyglucose (FDG), a molecule that looks like glucose but has a single oxygen atom replaced by an isotope of fluorine. This was the atom that would provide the signal.
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months.” A decade later, a follow-up study revealed that adding trastuzumab to standard chemotherapy was able to increase absolute differences in overall survival by 2.9 percent at four years, 5.5 percent at six years, 7.8 percent at eight years, and 8.8 percent at ten years. This was significant to the fraction of patients who fell into the percentage saved but maybe not worthy of the hyperbole showered on the drug. Mark Twain said, “Facts are stubborn, but statistics are more pliable.” Beyond the statistical sledgehammer—that the most-anticipated drug provided a marginal benefit in overall survival in maybe 15 to 20 percent of breast cancer cases—was an unspoken observation.
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Together they showed that hexokinase II didn’t exist in isolation; it bound to another mitochondrial membrane protein called the voltage-dependent anion channel (VDAC). VDAC acts as a gateway for molecules (like ATP) to enter and leave mitochondria. Additionally, VDAC serves a role in the process known as apoptosis, “programmed cell death,” by allowing the release of trigger molecule cytochrome c into the cytosol, which then initiates a cascade of events that culminate in the death of the cell.
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Pedersen and Colombini discovered that hexokinase II interacted with VDAC. When bound to hexokinase II, VDAC locked the gate, preventing the release of cytochrome c, thereby preventing apoptosis and effectively immortalizing the cell—one of the most salient and awe-inspiring qualities of the cancer cell.
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hexokinase II occurred in virtually every cancer cell.
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hexokinase II positioned itself perpendicularly to a protein called ATP synthasome, a rotating, machinelike protein that belched out the cellular energy currency, ATP. Hexokinase II’s positioning allowed it to steal ATP before it had the chance to escape, putting the cancer cell’s insatiable appetite for glucose before other cellular needs. Like a plundering pirate, hexokinase II steered its ship next to and then tethered itself to the side of a merchant ship loaded with treasure, unabashedly stealing its bounty.
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Ko entered his lab with glowing recommendations. Four of her former professors wrote to Pedersen on her behalf, and her doctoral thesis advisor, Bruce McFadden, wrote that one of her research proposals was “the best and most original . . . [he] could remember in twenty-five years at Washington State.
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Yet even with a master’s degree, Ko felt unsatisfied. She had grown to feel that nutrition only skimmed the surface, and craved a “deeper understanding of the way life operated” at the most fundamental level, so she enrolled in the PhD program of biochemistry at Washington State University and completed it in 1990.
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carbon monoxide poisoning from an idling car in a shut garage. Being the survivalists they were, cancer cells therefore overproduced a membrane-embedded protein called a monocarboxylate transporter (MCT). The porous protein acted as a door, selectively allowing lactic acid and pyruvate (pyruvate is similar to lactic acid) to enter and leave the cell. Ko realized that cancer cells produced many more “doors” than normal cells. Essentially, the door for a molecule that “looked like” lactic acid or pyruvate, typically shut on normal cells, was left wide open in cancer cells. This difference was just the disparity she needed and the opening she would exploit.
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That statement is worth repeating: twenty-eight cases showed only a single driver mutation. The data flew in the face of everything predicted by the SMT of cancer. Vogelstein’s model, proclaiming that the hallmark features of cancer were acquired by a progressive series of mutations, did not account for the existence of a mature cancer with a single driving mutation, yet there it was. Much worse, in another glaring omission, the authors failed to mention five samples that had no mutations at all. No driver mutations were found, yet like sample Br20P, these were living, aggressive killer cancer cells, histologically identical to the other samples. Again, for the SMT of cancer to work, samples like these couldn’t exist. Embedded within the findings was the implication that something other than mutations was initiating and driving the disease.
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The cell has a rich armament consisting of legions of repair proteins, many with overlapping duties, whose sole purpose is to scan the landscape of the genome and ensure its fidelity, tirelessly, over and over again. According to Loeb’s calculations, few mutations slip through the cell’s repair systems. This presents a conundrum for the SMT of cancer. Puzzled by the low mutation rate yet high rate of human cancer, Loeb asked a vital question: “Thus if cancer requires as many as twelve different mutations to arise . . . and the mutations rate is as low as calculated . . . how can cancer possibly occur within the human lifetime?”
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In his 2013 review he addressed the problems with the TCGA data. He explained that genomic-wide sequencing technology was far from perfect and had been shown to have a false-negative rate of 15 to 37 percent. However, even taking into account the potential error rate, the data still didn’t draw a discernible line between cause and effect. Another explanation was needed, and Vogelstein offered one in a section titled “dark matter.”
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As the sequencing machines began their trek into the mutational landscape of single tumors, it became apparent that tumors were not just vastly different from person to person (intertumoral heterogeneity) but also within the same tumor (intratumoral heterogeneity).
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The last member of the heterogeneity family is intermetastatic heterogeneity: the mutational heterogeneity observed between the cells in the primary tumor and the cells at distant sites where the tumor has metastasized. Where intratumoral heterogeneity exists across the geography of a single tumor, intermetastatic heterogeneity describes the increasing mutational complexity that is displayed across expanses of the body, from one site of metastasis to the next. A typical metastatic lesion can have up to twenty mutations not shared by other metastatic sites within the same patient.
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“I would advise you to get away from these linear models of tumor evolution because by and large they are an oversimplification of what’s happening.” As Swanton followed the mutation back to the origin of the tumors, he encountered some “bewildering” data. The data were not yet published, but he said that the results were “blowing our minds” and once published would “turn some heads.” With respect to the exact mutational events that precipitated cancer, Swanton said, “I’m not sure we understand it—it’s phenomenally complex.” In general, they found that the number of drivers that seemed to kick off the disease was much smaller than once thought. Some cases had a single driver as the “founding” or “trunk” mutation, a fact that threw an exclusively mutational origin of cancer into question and led Vogelstein to postulate dark matter. Although it was not direct evidence for the metabolic theory of cancer, it is what one would expect if the origin was metabolic and not genetic. To be sure, even by itself the nature of intratumoral heterogeneity was an ominous discovery to add to the pile of inconsistencies that plagued the SMT.
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TCGA showed the face of cancer to be a distorted, blurry image with no borders. The mutations integral to the SMT of cancer had yet to fall into a predictable pattern, even within the loosened boundaries of the systems theory. The bewildering degree of intertumoral heterogeneity did not allow the origin of any type of cancer to be conclusively assigned to a specific set of mutations. It painted cancer as a disease that changed the rules on a whim, a capricious monster that played outside the realm of cause and effect. Intratumoral heterogeneity did little to clarify the image. It only grew more hazy as investigators followed a tumor’s “family tree” of mutations toward the original trunk. The answer lay within the nebulous realm of Vogelstein’s dark matter. It alone held the answer to the origin of cancer, but what would researchers find as they began to illuminate it?
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one of the most meaningful discoveries to come out of TCGA was Vogelstein’s 2008 discovery of the oncogene isocitrate dehydrogenase that had been found in 12 percent of glioblastoma cases. It is the function of this particular oncogene that is interesting. Isocitrate dehydrogenase is an enzyme that is normally one of the crucial components of oxidative energy production. The finding of its mutated gene linked an oncogene directly to defective energy production. Then there was the curious case of the drug metformin. Researchers around the world were shocked in 2006 when a retrospective study found that patients with type 2 diabetes who were taking metformin to lower their blood sugar had substantially reduced rates of cancer. Although the exact details of how metformin prevented cancer from developing were unknown, it was almost certainly operating through metabolism. In addition, beyond the obvious preventative measures like not smoking and avoiding other carcinogens, the only established way to reduce overall cancer rates was through caloric restriction or periodic fasting, a practice known to restore mitochondria, again linking cause to metabolism. The science was funneling researchers toward metabolism whether they liked it or not. “The reason the metabolism of cancer has had a recent rebirth is because of the discovery of genes like isocitrate dehydrogenase. P53 and KRAS [another famous oncogene] have both been linked to metabolism, and so now there are a lot of people paying attention,” Vogelstein said.
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Weinberg’s hallmarks read as follows: Cancer cells (1) stimulate their own growth, (2) evade growth-suppressing signals, (3) resist cell death (apoptosis), (4) enable replicative immortality, (5) induce the ability to grow new blood vessels enabling tumor growth (angiogenesis), and (6) spread to distant sites (metastasis).
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A recent TCGA follow-up study attempting to identify the mutations driving Weinberg’s sixth hallmark of metastasis found none. “Comprehensive sequencing was unable to find a single mutation responsible for the most important quality of cancer, the single feature of cancer responsible for 90 percent of all cancer deaths.
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Science writer Ralph Moss noticed the odd criteria that the FDA used to approve drugs that allowed scores of ineffectual drugs to gain approval: If you can shrink the tumor 50 percent or more for 28 days you have got the FDA’s definition of an active drug. That is called a response rate, so you have a response . . . [but] when you look to see if there is any life prolongation from taking this treatment what you find is all kinds of hocus pocus and song and dance about the disease free survival, and this and that. In the end there is no proof that chemotherapy in the vast majority of cases actually extends life, and this is the GREAT LIE about chemotherapy, that somehow there is a correlation between shrinking a tumor and extending the life of the patient.
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Mitochondria are so important to the fidelity of an organism that a predominant theory is called “the mitochondrial theory of aging.” It contends that the condition of the mitochondria dictate the capacity of the cell to function over time. As mitochondria decline, cellular operations decline with them (just as if electricity and oil were cut off, the economy would grind to a halt). As the mitochondria lose the ability to function efficiently, the body begins the process of functional decline known as aging. Oxygen is a double-edged sword. While necessary for sustaining life, it is also responsible for the slow erosion of mitochondria. As energy is generated within the mitochondria by whipping electrons through the electron transport chain—an inherently reactive process that requires oxygen—free radicals are generated. To combat free radicals, mitochondria developed an important antioxidant network consisting of glutathione, vitamin C, vitamin E, lipoic acid, uric acid, and antioxidant enzymes. They work synergistically. A deficiency in one can be compensated for by the others. But as we age, this network degrades, leaving the mitochondria vulnerable to free radical assault. Researchers at the Linus Pauling Institute in Oregon have shown how banged up old mitochondria get. On average they lose up to half of their important structural lipids, energy-shuttling compounds, and antioxidants with advanced age. Much of the body’s decline with age is due to this “rusting” of mitochondria. As the mitochondria go, so does the rest of what we call ourselves.
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He began testing other drugs, and it turned out that many of them did, including ImClone’s cetuximab (Erbitux, the drug known from the Martha Stewart insider trading scandal). “Many of these drugs were doing nothing but making the mice lose their appetites. It was the reduced calories that had the antitumor effect.” But why would reducing calories in general affect tumor growth? That question spun him away from ganglioside research and into the metabolism of cancer.
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While looking for the link between damaged respiration and uncontrolled growth, Seyfried proposed that chronic and persistent damage to the cell’s ability to respire aerobically triggered an epigenetic signal from the mitochondria to nuclear DNA. The signal then altered the expression of a plethora of key cancer-causing oncogenes—a classic epigenetic system. Vogelstein readily admitted that epigenetics may play a much larger role in cancer than expected. One problem, he said, was that “epigenetics just don’t lend themselves well to experiments.” Nevertheless, Seyfried illuminated the basic research showing the important epigenetic signaling that travels from the damaged mitochondria to the nucleus, the missing link to a complete metabolic theory of cancer.
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Pedersen had shown that the single transformation of hexokinase to hexokinase II drastically alters the metabolic landscape of the cell. By binding to the mitochondrial outer membrane, it turns the cells into immortal, crazed fermenters. In 2012, when Seyfried released his book, there was substantial experimental evidence showing how damaged mitochondria send a distress signal, called “the retrograde response,” to the nucleus. The signal tells the nucleus to transcribe a host of genes responsible for preparing the cell to ferment glucose in order to compensate for declining oxidative energy production. The genes that respond to the mitochondrial distress call have foreign-sounding names: MYC, TOR, RAS, NFKB, and CHOP. Collectively they have profound consequences when turned on. MYC, a protein with global operations, acts as a transcription factor. It alone controls 15 percent of the entire genome. It affects vast swaths of the genomic landscape, turning some genes on and putting others to sleep, but most significantly it begins the process of tumorigenesis. Most of the genes turned on by damaged mitochondria sit at signaling hubs and therefore dictate multiple operations such as cell division and angiogenesis (the growth of new blood vessels to supply the tumor). Seyfried contends that if the retrograde response signal is chronically “on”—as is the case when mitochondria are damaged beyond repair—trouble ensues. In addition to ramping up the proteins necessary for a massive increase in energy creation through fermentation, a persistent retrograde response would cause side effects such as uncontrolled proliferation. A sustained retrograde response has even more dire consequences. As the response becomes chronic and genomic signals transition the cell into a different cellular architecture, the legions of proteins designated to protect and repair DNA begin to stand down—drying out the moat and leaving the castle unguarded.
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The timing is critical: The retrograde response comes first, then genomic instability. This single detail, the timing, is crucial, implying that the mutations thought to initiate the disease are merely a side effect.
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The fact that both groups had demonstrated that the cytoplasm of a normal cell, with normal mitochondria, could suppress cancer was one thing, and ardent devotees to the SMT may have been able to turn the other cheek on an isolated series of experiments. But when Schaeffer’s group proved irrefutably that the cytoplasm of a tumor cell on its own could initiate and drive cancer, it was impossible to ignore the results. Schaeffer claimed, “Here we present the data which, for the first time, provide unambiguous evidence indicating a role for cytoplasm in the expression of the malignant phenotype.”
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design, it seemed on the surface to validate the SMT of cancer. It appears that CML originates and progresses due to a single, pervasive genetic alteration. Digging deeper, however, researchers found that the Philadelphia chromosome exists in perfectly healthy people who will never develop CML—this was a small but critical detail. That simply cannot be. If the Philadelphia chromosome alone causes CML, these blissfully ignorant individuals should harbor the malignancy, but this is not the case. The out-of-control kinase produced by the BCR-ABL gene is not enough by itself to cause CML. Further, more advanced cases of CML do not always respond to imatinib. Twenty percent of advanced cases succumb to CML even with imatinib therapy and even with a single supposed “founding” mutation that permeates the entire genetic landscape of the cancer—a single mutation that a targeted therapy could grab hold of in every cancer cell, not just a fraction. These two facts provide clear proof that something else beyond BCR-ABL is driving the disease.
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The wildly hyperactive kinase BCR-ABL leads to the permanent activation of a network called the PI3K/AKT signaling pathway. The pathway is also activated by damaged mitochondria followed by the retrograde response. Whether the pathway is activated by the retrograde response or by BCR-ABL, a set of specific genes are aroused from their slumber and cajoled to order the manufacture of a network of proteins that then manipulate the biochemical personality of the cell toward the Warburg effect with all its manifestations. The PI3K/AKT pathway dramatically increases glucose uptake and use. When CML patients swallow an orange imatinib pill, their cancer cells lose their insatiable appetite for glucose, and oxidative energy creation is restored—a reversal of the Warburg effect.
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It is worth noting that GLEEVEC kills RPM18226 cancer cells by depleting cellular ATP. Therefore, it is speculated that GLEEVEC acts as a metabolic inhibitor by binding nonspecifically to several tyrosine kinases and ATP binding/hydrolyzing proteins including ATP synthomes. Significantly, our results are consistent with the view of Dr. Thomas Seyfried that cancer is a disease of energy metabolism.
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P53 is biblical in nature, and like the Bible, its importance depends on the interpreter. Proponents of the SMT see p53 as the “guardian of the genome”—its mission is to protect the kingdom. When the nuclear walls are breached, p53 orchestrates legions of workers to repair any damage. If the damage is too extensive to be repaired, p53 sounds the trumpets, ordering the cell to commit suicide before it can be corrupted. Proponents of the metabolic theory see p53’s mission as crucial to maintaining oxidative energy generation. P53 is responsible for the transcription of a critical component of the electron transport chain without which the mitochondria can’t do their job. Persons born with a germline mutation to the p53 gene have an almost certain chance of developing cancer in their lifetime, and 50 percent of people with the rare disorder develop tumors in early adulthood. (The condition is called Li-Fraumeni syndrome.) The question is how the inherited p53 mutation is causing the increased predisposition to cancer. Most cancer biologists say that it is because the genome is left vulnerable, increasing the chances that a mutation will strike other critical proto-oncogenes. Proponents of the metabolic theory say that mutated p53 slowly erodes the cell’s ability to generate energy oxidatively. This results in a conversion to the Warburg effect followed by the retrograde response and uncontrolled growth.
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Like p53, the BRCA1 protein has multiple cellular functions, and also like p53, the BRCA1 protein is one of the many proteins responsible for the repair of DNA damage. BRCA1 does not cause cancer directly, rather, proponents of the SMT contend that it allows it to happen. It sets the stage. It increases the likelihood of mutations that unhinge proliferation. BRCA1 also is implicated in mitochondrial function. It has been shown to be intimately involved in the biogenesis of mitochondria. The faulty version could limit the mitochondria’s ability to reproduce, leading to the tremendously reduced numbers within the cytoplasm of cancer cells that Pedersen and others have seen.
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Caloric restriction drives down blood glucose, forcing cancer cells to ferociously compete with healthy cells for the fuel they so desperately crave. But he reasoned he might be able to do better. He modified the diet slightly, keeping overall calories restricted but eliminating carbohydrates in favor of fats, a modification that might put even more metabolic pressure on the cancer cells. With no carbohydrates, the body is jerked out of its preferred state of metabolic energy generation. It is forced to manufacture molecules called ketone bodies to take the place of glucose as a source of circulating fuel. Once cancer is framed as a metabolic disease, ketone bodies develop an interesting therapeutic potential. Unlike glucose, ketone bodies burn oxidatively. They have to be metabolized in healthy, functioning mitochondria, which Seyfried knew, cancer cells don’t have many of. Metabolically, normal cells have other options, but cancer cells do not. If cancer was truly a disease of dysfunctional mitochondria, a dietary regimen that he coined the “restricted ketogenic diet” (R-KD), one that transitions away from utilizing glucose as an energy source to the use of ketone bodies, might have more impact than simple caloric restriction.
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of approximately one gram of protein per kilogram of body weight per day, with almost no carbohydrates and the rest of the calories consumed from fat. The results for those with epilepsy were profound. The ketogenic diet significantly reduced the number of seizures or eliminated them altogether. However, when anticonvulsive medications were developed in the 1940s, Wilder’s ketogenic diet was relegated to a sidenote in medical textbooks.
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Veech, among others, was aware of the almost magical properties of ketone bodies. He was intrigued by a report from the 1940s showing that ketone bodies were unique among sixteen other carbohydrates, fatty acids, and intermediate metabolites in their ability to increase the mobility of sperm while decreasing the amount of oxygen consumed. Ketone bodies turned sperm into faster, more efficient swimmers. Determined to see if the report of decreased oxygen consumption was true, Veech added ketone bodies to a glucose solution containing rat heart muscle. The ketone bodies increased the amount of work performed by the heart muscle while significantly decreasing oxygen consumption. Veech then noticed something else. Not only did the ketone bodies result in greater efficiency, but they showed a strange ability to drastically increase the amount of ATP produced inside the cell. He discovered that by widening a critical energetic gap in the electron transport chain, ketone bodies changed the intracellular landscape, effectively supercharging the cell. The metabolic transformation inspired him to dub the molecules “superfuel.” He then took a bird’s-eye view of the obscure fuel and attempted to figure out how ketone bodies came to exist in the first place. He concluded that the molecules probably helped our ancestors develop a larger, more complex brain. In terms of survival advantage, a larger brain gave us a leg up on every other species, but in strictly metabolic terms, it was an enormous burden—it had an insatiable appetite. The brain consumes 20 percent of the energy we consume at any given time. Worse, while other tissues in the body can transition to burning fatty acids, the brain is hamstrung by the fact it can burn only glucose, leaving it uniquely vulnerable. When food is a scarce resource—as no doubt had frequently occurred in our past—our best friend turns into our worst enemy. But evolution found a solution: a metabolic conversion during times of deprivation into a state of hyperefficiency, or ketosis. Because the brain could transition from burning glucose to ketone bodies, the molecules could rescue the brain from its metabolic plight, providing a backup fuel to feed its monstrous appetite. More than any other mammal, humans can produce “superfuel” in lean times, making us gritty, efficient survival machines. As Veech noted, “The survival benefit is obvious; ketone bodies allow a normal-weight human to go from two to three weeks without food to about two months. An obese man can live close to a year without food.” From an evolutionary standpoint, it may be impossible to separate the two: Ketosis may have facilitated or allowed our huge brains to evolve in the first place.
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But time after time the molecules showed a broad neuroprotective effect. The benefits from ketosis can be traced back to the mitochondria. Because ketone bodies are used so efficiently, they reduce the oxidative burden imposed on mitochondria from energy creation. Like a cleaner-burning fuel, ketone bodies appear to preserve, or even restore, damaged mitochondria. But viewed from another angle, the almost miraculous effects of ketone bodies may not be so miraculous after all. Maybe humans are supposed to exist in the state of ketosis from time to time. As Veech said in an article in the New York Times, “Ketosis is a normal physiological state. I would argue it is the normal state of man. It’s not normal to have a McDonald’s and a delicatessen around every corner. It’s normal to starve.” Maybe many modern diseases are an artifact of civilization, and maybe, as Veech suggested, a little deprivation would do us a ton of good.
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As encouraging as the results appeared clinically, PET scans would show if the diet was choking off the sweet tooth of the tumors. When Nebeling received the results, they revealed a 22 percent reduction in uptake, reflecting a sharp decrease in glucose consumption. Over the nine-month course of the protocol, Nebeling meticulously monitored the girls, adjusting their diet when they were sick and performing blood tests to ensure that they were properly nourished.
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The short Würzburg trial confirmed what Nebeling’s study alluded to: The diet seemed to be affecting the growth of cancer cells. Of the five patients who completed the three-month trial, all remained alive, with their tumors’ growth either slowing, stopping, or in some cases, shrinking.
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He found the R-KD to be antiangiogenic—it choked off the production of new blood vessels supplying the tumor, as Rous had discovered almost one hundred years earlier. The diet was also proapoptotic, in that it facilitated orderly cell death. This was in sharp contrast to the chaotic cell death caused by chemotherapy and radiation, a disorderly process known to increase inflammation and fan the flames of malignancy. As practitioners of periodic fasting or caloric restriction had documented for years, the diet proved to be anti-inflammatory, a loosely defined process associated with initiating and driving cancer.
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Very aggressive mouse models of metastatic cancer spread to fewer sites while the mice were on the diet. The diet influenced hormones like IGF-1, implicated as fuel for tumor cells, attenuating its malevolent influence. It turned down the PI3K/AKT pathway, the same pathway that imatinib was found to influence. Everywhere he looked, in every biochemical process subverted by cancer, the diet pushed back, pressuring the cells to a state of normality. “All oncologists should know that dietary restriction is the nemesis of many cancers,” he wrote in his book.
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The ketogenic diet, as he showed, supercharges normal cells, lifting them to a vigorous state of health. In addition to bathing the cells in a superefficient fuel, ketone bodies do something else: They prepare normal cells to deal with free radicals—the hyperactive wrecking balls blamed for every malady from cancer and neurodegeneration to the mother of all disease, aging itself.
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Veech noticed, ketone bodies dramatically tilt the ratio of armed glutathione (the antioxidant form) to unarmed glutathione, beefing up the cellular defense of healthy cells as they transition to ketone body metabolism. As healthy as the conversion to ketosis is for normal cells, it is equally and inversely detrimental to cancer cells, widening the therapeutic gap alluded to earlier. Unable to make the transition, cancer cells must to rely on an alternate pathway to arm glutathione—a pathway dependent on glucose. As the transition to ketosis drives down blood glucose levels, a cancer cell had both its energy source and its capacity to prepare glutathione for battle against free radical assault taken away. When administered to a cancer patient, R-KD makes healthy cells healthier and cancer cells sicker. This potentiates other therapies, making them more effective and less toxic.
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This relationship is important for two reasons. First, the most important pathway to killing cancer cells is through apoptosis, and it appears that apoptosis in many cases is triggered by quick bursts of free radicals. Second, many current cancer therapies operate by inducing bursts of free radicals, thus triggering apoptosis. Free radicals are also called reactive oxygen species (ROS), and research has shown that cancer cells have unusually high amounts of ROS. Most ROS is generated as a by-product of mitochondrial metabolism, so the damaged mitochondria in cancer cells are likely to “leak” much more ROS, leaving cancer cells in a precarious state of oxidative chaos. Watson believes that many more cancer therapies than previously thought probably work by nudging cancer cells over the oxidative edge by overloading them with ROS. He contends that entire classes of chemotherapeutic drugs in all probability operate by generating an intolerable amount of ROS, killing the cancer cell in the process. The “first in class” mitochondrial drug elesclomol, developed by Synta Pharmaceuticals, kills by promoting ROS generation. Proof of this mechanism is easy to come by. Simply coaxing the cell to manufacture more of the antioxidant glutathione halts the drug’s “preferential killing of cancer cells,” Watson wrote.
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Rather than antioxidants diffusing into cancer cells through the bloodstream and thwarting the ROS needed to induce apoptosis, R-KD does the opposite. It cuts off the cancer cell’s ability to manufacture its most important antioxidant—glutathione—rendering it defenseless against most cancer treatments. As an added bonus, because R-KD affects cancer cells and normal cells differently, the diet forces healthy cells to manufacture more glutathione, thus preparing them for the corrosive effects that ROS-generating therapies collaterally imposes on healthy tissue. R-KD appears as a dream scenario: It sensitizes cancer cells to ROS, leaving them perched on the edge of a cliff, while it prepared the rest of the body to handle any additional ROS-generating therapies, thus minimizing treatment side effects.
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First, by prepping normal cells to handle ROS, did R-KD attenuate the side effects, promoting tolerability of ROS-generating therapies? And second, did R-KD enhance ROS-generating therapies like radiation? Experimental evidence strongly suggests that the answer to both questions is yes.
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Across the board, the fasting patients reported less severe side effects in fourteen different categories. Subjective side effects like fatigue, nausea, headaches, weakness, memory loss, numbness, decreased sensation, and tingling were all reported as less severe as were measurable effects like vomiting, hair loss, diarrhea, and mouth sores. The trial provided empirical evidence that fasting prepared normal cells to withstand a chemotherapeutic assault.
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Seyfried showed the synergy between the diet and a drug called 2-deoxyglucose (2DG), a molecule that looks like glucose but can not be further metabolized, effectively bringing fermentation to a halt. The diet or the drug alone each showed the ability to slow tumors, but when they were combined Seyfried found that the result was profoundly synergistic.
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It seemed that in every scenario, entering ketosis enhanced other therapies while keeping toxic shrapnel from damaging healthy tissues. The diet appeared to slow cancer growth, but that alone did not appear to be R-KD’s strong suit. The way it prepares the therapeutic landscape makes it unique. It was like primer to a painter or fertilizer to a gardener. It conditions the environment in which the cancer exists, enhancing other therapies while attenuating side effects.
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The theory behind these new drugs was gorgeous in concept. They operate by harnessing the latent power of the immune system. Rather than stimulating the immune system, ipilimumab works by uninhibiting a class of cancer-killing immune cells called cytotoxic T lymphocytes (T cells), unleashing the aggressive mercenary cells and allowing them to patrol the body without caution.
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D’Agostino was observing the ROS-generating ability of hyperbaric oxygen chambers to explode cancer cells. In addition to saturating pockets of tissue that may be hypoxic, hyperbaric oxygen generates ROS, the crucial element of most cancer therapies (according to Watson). A phone call was all it took. Seyfried and D’Agostino recognized the potential and worked out a collaboration.
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R-KD and hyperbaric oxygen slowed tumor growth, but together, they eviscerated it. The diet alone increased mean survival by 56.7 percent compared to the control mice, and when it was combined with hyperbaric oxygen, the mean survival jumped to 77.9 percent.
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“synergistic combination of nutritional ketosis, cancer metabolic drugs (like 3BP, DCA, and 2DG) and hyperbaric oxygen therapy (HBOT).”
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They say that R-KD combined with HBOT “could potentially kill tumor cells as effectively as radiation without causing toxic collateral damage to normal cells.”
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Like R-KD with HBOT, 3BP appears to be a largely nontoxic therapy that could potentially treat any cancer that is PET positive, which equates to 95 percent of cancers. Rather than treat cancer as two hundred different diseases, 3BP and R-KD with HBOT treat cancer as one disease. The amount of 3BP that eradicated Yvar’s cancer cost less than $100. R-KD was essentially free, although a cancer center would have to retrain staff nutritionists, and HBOT was comparatively cheap.
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