A Review of Thomas Seyfried's Cancer As a Metabolic Disease
Once in a long while, a book comes along that revolutionizes our understanding of the cancer problem. Such a book is Cancer as a Metabolic Disease (Wiley 2012) by Thomas N. Seyfried, PhD. Formerly a cancer researcher at Yale University, Seyfried is a professor of biology at Boston College and the author of more than 150 PubMed- indexed scientific articles.
With its 400-plus pages, and over 1000 scientific references, Cancer as a Metabolic Disease covers very broad territory. It attempts to explain the essential nature of primary tumors and of metastases, at the same time providing practical advice on the management and prevention of cancer.
The book's central message stands in stark contrast to the prevailing dogma in cancer research. But Seyfried's approach is rational, methodical, and scientific. It is grounded in the fundamental biochemistry of cancer and is up to date. This book should be required reading for all scientifically literate people involved in the cancer problem. You need to buy, read, and assimilate this book in its entirety if you expect to thoroughly understand the debate over cancer.
As a result, we now have a thorough picture of how defects in metabolism drive the various changes seen in cancer, including its famous "genome instability." It is an amazing intellectual achievement. Stephen Strum, MD, FACP, agrees. He has written as follows:
I am a board-certified medical oncologist with 30 years experience in caring for cancer patients and another 20 years of research in cancer medicine dating back to 1963. Seyfried's Cancer as a Metabolic Disease is the most significant book I have read in my 50 years in this field. It should be required reading of all cancer specialists, physicians in general, scientific researchers in the field of cancer and for medical students. I cannot overstate what a valuable contribution Thomas Seyfried has made in writing this masterpiece.
I would prefer if every reader went out and bought a copy of this book immediately. (It is available on Amazon.) But Townsend Letter readers might appreciate a summary, so that they can at least become familiar with its major points.
The Somatic Mutation Theory
The conventional theory of cancer, subscribed to by the vast majority of scientists, is the somatic mutation theory (SMT; Fardon 1953; references below).
The basic premise of the SMT is that cancer is a genetic disease. While some forms of cancer are linked to inherited (or germ line) mutations, the primary thrust of the theory is that cancer typically originates in the course of a person's lifetime as a result of a cascade of genetic injuries. These "somatic mutations" lead, step by step, from a quiescent normal cell to a lethally proliferating one.
Seyfried's differences with the majority of his colleagues begin at this point, for he regards a normal cell as fundamentally proliferative, like primitive bacteria, and not naturally quiescent, as most biologists believe. Cancer, he says, involves a fundamental loss of control rather than the acquisition of numerous mutations that ultimately convey some hitherto-unsuspected ability to replicate wildly. There is not enough room in this article to explain his argument in detail, but I found it compelling.
"The SMT has not been rigorously tested, and several lines of evidence raise questions that are not addressed by this theory," according to two professors at Tufts University School of Medicine, Boston (Soto 2011). Seyfried agrees. But the SMT has received a huge boost in the past 10 or so years due to scientists' ability to sequence a cell's genome (i.e., its complete collection of genes) and to do that economically. To sequence the first human genome cost around $3 billion. But news stories in 2012 announced that a person's genome could now be sequenced in one day for a mere $1000 (Hayden 2012).
This increasingly easy access to a complete genomic analysis of both normal and malignant cells has led to the discovery of an incredible genetic diversity within cancer cells. Consider for instance this paragraph from Science magazine's review of cancer research for the 40th anniversary of the War on Cancer:
We now know that there are usually between 1,000 and 10,000 somatic substitutions in the genomes of most adult cancers, including breast, ovary, colorectal, pancreas, and glioma….There are cancer types that generally carry relatively few mutations – for example, medulloblastomas, testicular germ cell tumors, acute leukemias, and carcinoids, whereas others, such as lung cancers and melanomas, have many more mutations (occasionally more than 100,000) Even within a particular cancer type, individual tumors often display wide variation in the prevalence of base substitutions" (Stratton 2011).
Imagine, then, trying to devise a treatment regimen that must target 1000, 10,000, or even 100,000 separate mutations! With new analyses of various cancer genomes emerging almost weekly, the variations among tumor cells have grown to gargantuan proportions.
Deciphering the human genome was a dazzling technical accomplishment. But it is not necessarily relevant to solving the cancer problem. Any theory of cancer as a single disease with many manifestations is now firmly rejected in favor of cancer as a "disease complex," not just of 100-plus anatomically defined tumor types, but with 1000, 10,000, or 100,000 individual peculiarities. These highly individualized presentations of cancer supposedly require a correspondingly complex set of treatments in order to fully "personalize" drug therapy.
Theory of Metastases
Seyfried also proposes an uncommon theory of metastasis, in which wandering cells do not just break away from the primary tumor but are themselves either transformed macrophages or at least fusion cells made up of cancer cells and macrophages. I was surprised to learn that Prof. Otto Aichel of Germany proposed this theory in 1911. John Pawelek, PhD, of the Yale School of Medicine and the author of nearly 200 peer-reviewed papers, has revived this theory in our era (Lazova 2011).
In their famous "Hallmarks of Cancer" articles (2000 and 2011), Weinberg and Hanahan claim that genome instability is the essential "enabling characteristic" of all cancers, including metastases. But Seyfried proposes an alternative view; that is, that the key lethal flaw in cancer does not originate in the nucleus at all but in the mitochondria. Mitochondria are the power plants of the cell, where a person's energy is created.
Through the tricarboxylic acid (TCA) cycle, mitochondria can turn one glucose molecule into ~30 packets of energy (i.e., adenosine triphosphate, or ATP. The theoretical yield in a normal cell is 38 ATP molecules from each oxidized glucose molecule. In practice the yield is usually between 29 and 30.) This process is called oxidative phosphorylation – or OxPhos, for short (Rich 2003).
Seyfried affirms the commonly held view that cancer originates in the impact of carcinogens (radiation, tobacco smoke, asbestos, etc.) but that this damage crucially affects the mitochondria, not only the nucleus. This damage causes chronic inflammation and respiratory insufficiency. Some cells, deprived of sufficient oxygen to function, simply die. But others, in order to survive, find a way to generate energy without the use of OxPhos. Like yeast growing in beer or bread, they inefficiently transform glucose into a very limited amount of energy, and produce as waste products carbon dioxide and lactic acid. This is fermentation among mammalian cells, and cells adopt it as a way of compensating for the breakdown of the TCA cycle. That is why it is called compensatory fermentation. This provides energy for a cancer cell's survival and replication, provided that the patient in question provides an abundant supply of glucose or its carbohydrate precursors. That is why cancer is an avid "sugar junkie" and why FDG-PET scans (which detect a radioactive form of glucose) are now used all over the world to detect cancer.
Enter Otto Warburg
In its basic outlines, this theory of cancer is hardly new. In fact, it was propounded by Otto H. Warburg, MD, PhD, from 1923 until his death in 1970. Warburg won the Nobel Prize for this work in 1931. Warburg was indisputably one of the greatest scientists of biochemistry's golden age. Then came World War II, with all its tragic consequences. After the war, Warburg's claims that cancer ferments instead of engaging in healthy OxPhos came under withering attack from critics, primarily Prof. Sidney Weinhouse of Philadelphia (1909–2001), editor of Advances in Cancer Research.
Warburg's point of view, says Seyfried, was fundamentally right. But, with the perspective of time, his theory had some weaknesses as well. For instance, it did not account for: (1) the role of tumor-associated mutations, which were increasingly coming to the fore in cancer research; (2) the entire phenomenon of metastasis; and (3) the molecular mechanisms of uncontrolled cell growth and how they related to impaired respiration. Even his student, the Nobel laureate Hans Krebs, finally agreed that the fermentation of glucose in the presence of oxygen (aerobic glycolysis) was merely a symptom of cancer, not (as Warburg maintained until his death) the cause. In the US, his chief American disciple, Dean Burk, PhD, cofounder of the National Cancer Institute (NCI), remained true to his fundamental vision.
The strongest evidence against Warburg was Weinhouse's demonstration that many tumors continued to utilize oxygen while also engaging in fermentation. This seemed to show that OxPhos continued, while the cancer cell fermented as a side activity. If this were truly the case, then Warburg's theory was fundamentally contradicted. Burk and a few others tried to salvage Warburg's theory, but the data went against them. In fact, it was only fairly recently that Seyfried and others showed that this utilization of oxygen by tumors is without any energy-generating capacity. It is oxidation "uncoupled" from any normal or productive usage.
Due to the work of Prof. Peter Pedersen of Johns Hopkins University, Seyfried, and others, Warburg's theory is now experiencing an unexpected revival. In 2011, Weinberg and Hanahan revised their 2000 Cell paper, to include "reprogramming of energy metabolism" as another (seemingly forgotten) hallmark of cancer (Pedersen 2007; Hanahan 2011).
The Nobel laureate Thomas D. Watson, PhD, codiscoverer of DNA's molecular structure, has called into question the search for treatments based on genetic abnormalities and has urged his fellow scientists to turn toward a study of metabolism. In December 2010, Science magazine published a review of metabolic energetics in cancer. In it, Prof. Arnold J. Levine (codiscoverer of the p53 tumor suppressor protein) of the Institute for Advanced Study, Princeton, and a colleague restated the classic Warburg hypothesis. Studying altered metabolic pathways, they said, "could lead to a new approach in cancer treatments."
So, the situation today is that almost nobody doubts that cancer cells exhibit both genetic and metabolic abnormalities. The conundrum is which abnormality is cause and which is effect. Even among those who stress the importance of metabolic targets, there is a belief that genes must be driving abnormal metabolism and not the other way around. Molecular biology is locked in a kind of genetic determinism.
Only Seyfried, Pedersen, and a few others have taken a truly Warburgian approach, unequivocally stating that cancer is a disease of injured mitochondria and its resulting compensatory fermentation and that this causes the genome to degrade in unpredictable ways.
In this comprehensive book, Seyfried shows that oxidative insufficiency and its resulting compensatory fermentation cause genome instability. "All hallmarks of cancer including the Warburg effect can be linked to impaired respiration and energy metabolism," he writes (p. 26). These are "downstream effects of damaged mitochondrial function."
He cites research showing that if you transplant a nucleus containing mutations from a cancer cell into a normal cell (from which the nucleus has been removed), this does not produce cancer cells (McKinnell 1969; Mintz 1975; Howell 1978; Harris 1988; Shay 1988; Li 2003; Hochedlinger 2004). But if you transplant a normal nucleus into a cancerous cell, the cell can now form tumors – again, presuming that the original nuclear material has been removed (Israel 1987; Israel 1988). These results show that nuclear gene mutations alone cannot produce tumors and that normal mitochondria can suppress tumor formation.
Seyfried also has a great deal to say about how this new-old conceptual view of cancer affects the proper idea of cancer, particularly a novel dietary treatment.
Seyfried's book opens the door to a discussion of cancer as a metabolic disease. We now need a wide-ranging discussion of the fundamental nature of cancer. Is it genetically driven, as most believe, or in fact does mitochondrial insufficiency, followed by compensatory fermentation, drive genome instability? Seyfried makes a powerful case that, in effect, "Warburg rules," and that control of cancer will come about by controlling fermentation.
In the tradition of Otto Warburg, Dean Burk, and Peter Pedersen, Thomas Seyfried has attempted to inform the world about the nature of cancer and of more effective ways that this scourge can be brought under control. I highly recommend Cancer as a Metabolic Disease to all readers who want the clearest statement yet of the metabolic cause and control of cancer. I look forward to a debate over its arguments, for this will almost certainly revolutionize the entire war on cancer.
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Ralph W. Moss, PhD, is the author of 12 books on cancer-related topics. The former science writer at Memorial Sloan-Kettering Cancer Center, for 35 years Moss has investigated the validity of many cancer treatments. He currently directs the Moss Reports, a library of reports for patients on over 200 different cancer diagnoses.