Cancer As a Metabolic Disease

Author: This book is written by Thomas Syefried, Ph.D. He has taught and conducted research in the fields of neurogenetics, neurochemistry and cancer for more than twenty-five years at Yale University and Boston College. He has published more than 150 scientific articles and book chapters and is on the editorial boards of Nutrition & Metabolism, Journal of Lipid Research, Neurochemical Research, and ASN Neuro. Supported by evidence from more than 1,000 scientific and clinical studies, Dr. Syefried provided evidence that cancer is primarily a metabolic disease (NOT a genetic disease).

The author dedicated his 438-page-book to: The millions of people who have suffered and died from toxic cancer therapies.

Do you get his message? The present day cancer therapies are toxic! And millions die – from the cancer or from the toxic treatment? Do you ever wonder why the present day cancer treatment has come (or allowed to come) to such a tragic state of affairs?

Mitochonrdia – the Energy Production  Houses of the Cell

The last time I sat in class (Universiti Malaysia) learning about energy production by mitochondria was in early 1970. That’s a long time ago. When I taught Plant Physiology at USM, I dabbled a bit here and there with energy pathways and that too was many years ago! So to fully comprehend what Dr. Seyfried said and then write this article –  trying to put things in layperson’s language –  did take a rather longer-than-usual-time for me. I have to go back to my textbooks again!

Let’s start from the basics!

Mitochondria are unusual organelles found in the cytoplasm and they are the powerhouses that generate energy for the cell. They have their own genome and they can divide independently of the cell in which they reside.  Mitochondrial division is stimulated by energy demand, so cells with an increased need for energy contain greater numbers of these organelles than cells with lower energy needs. http://www.nature.com/scitable/topicpage/mitochondria-14053590

A typical animal cell may have anything from 1,000 to 2,000 mitochondria. Indeed there are a lot of these structures in a tiny cell. http://hyperphysics.phy-astr.gsu.edu/hbase/biology/mitochondria.html.

The mitochondria produce the energy-rich molecule called ATP (adenosine triphosphate). ATP is required to drive all the cellular activities. Indeed ATP is the energy currency of the cells. ATP is like petrol, without it your car cannot move.

The process of energy production in cell is called cellular respiration. It involves a range of metabolic pathways and processes that take place in the mitochondria to convert biochemical energy from nutrients that we eat – sugars, amino acids and fatty acids – into ATP and other waste products.

This energy production (respiration) in cell can take place with or without the presence of oxygen.

If the energy production process occurs in the presence of oxygen it is called aerobic respiration. This process is up to 15 times more efficient than anaerobic metabolism (respiration without oxygen).

This is what happens in aerobic respiration: C6H12O6 (sugar) + 6 O2 (gas) → 6 CO2 (gas) + 6 H2O (water) + heat + ATP

Without oxygen the process of energy production is called fermentation. It is a less efficient way of producing energy because only 2 ATP are produced per glucose molecule (compared to 38 ATP per glucose produced by aerobic respiration).The waste products of fermentation still contains plenty of energy. However, this process creates ATP more quickly. During short bursts of strenuous activity, muscle cells use fermentation to supplement the ATP production from the slower aerobic respiration.

Beside energy production, mitochondria are also involved in the process of cell division and apoptosis (or naturally occurring process of programmed cell death).

In this book, Dr. Seyfried provides us with information saying that mitochondria are also deeply implicated in the initiation, growth and proliferation of cancer.

Energetics of the Healthy Living Cell

In order for cells to remain viable and to perform their functions, they must produce usable energy – and to do so as efficiently and economically (no wastage) as possible.

  • About 88% of total cellular energy is derived from oxidative phosphorylation. This oxidative phosphorylation pathway is probably so pervasive because it is a highly efficient way of energy production than other ways below. In theory oxidative phosphorylation yields 38 ATP molecules per glucose molecule but in reality the current estimate is about 29 to 30 ATP per glucose.

The other remaining 12% of energy is produced about equally by:

  • Substrate-level phosphorylation through glycolysis in the cytoplasm. Substrate-level phosphorylation is the direct transfer of phosphoryl  group (a process called phosphorylation) to ADP to form ATP or GTP. This serves as fast source of ATP. This process takes place in the erythrocytes, which have no mitochondria and in muscles during oxygen depression. In this process only 2 ATP molecules are produced.
  • ATP is also produced through the TCA cycle (tricarboxylic acid cycle or Krebs cycle) in the matrix of the   mitochondria. The net result is production of only 2 ATP molecules.

It is obvious that substrate-level phosphorylation  and TCA  cycle area less efficient method of energy production since only 2 ATP are produced per glucose compared to 38 ATP per glucose by oxidative phosphorylation.

When AT P is  hydrolysed  (hydro =water, lysis = separation) the high energy stored in the ATP is released. The standard free energy change (ΔG) for the hydrolysis of the terminal pyrophosphate bond of ATP under physiological conditions is tightly regulated in cells between -53 to -60 kJ/mole.

The ∆G’ ATP among cells irrespective of how this energy is being produced is similar. For example, the as ∆G’ ATP in heart, liver and erythrocytes are approximately -56 kJ/mol despite of  having very different electrical potentials.

The constancy of the ∆G’ ATP of approximately -56kJ/mol is fundamental to cellular homeostasis. Any disturbance in this energy level will compromise cell function and stability.Cells can die from either too little or too much energy.

Mitochondrial Dysfuction (or Defective Energy Metabolism) May Mean Cancer

Cancer cells produce more energy through substrate-level phosphorylation while normal cells produce most of their energy through oxidative phosphorylation. This goes to say that cancer cells are not efficient energy producers.

A major difference between normal cells and cancer cells is in the origin of the energy produced. Regardless, all cells – normal or cancer cells – require approximately -56 kJ/mol for their survival.

  • A prolonged reliance on substrate-level phosphorylation for energy production produces genome stability, cellular disorder, and increased entropy, i.e. characteristics of cancer.
  • Numerous studies show that tumour mitochondria structure and function is abnormal in cancer cells and they are incapable of generating normal levels of energy.

Against Current Mainstream Thinking

As far back as 1924, Nobel laureate Otto Warburg postulated that cancer was principally a disease of mitochondrial dysfunction. To Warburg, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar.

The question which needs to be asked is: Is it genomic instability or is it impaired energy metabolism that is primarily responsible for the origin of cancer?

Metabolic studies in a variety of human cancers showed that the loss of mitochondrial function preceded the appearance of malignancy. However, the general view over the last 50 years has been that gene mutation and chromosomal abnormalities underlie most aspects of tumour initiation and progression.

Gene theory of cancer would argue that mitochondrial dysfunction is an effect rather than a cause of cancer, whereas the metabolic impairment theory would argue the reverse.

It is suggested that genomic abnormalities found in the majority of cancers can arise as a secondary consequence of mitochondrial dysfunction. Impaired mitochondrial function can induce abnormalities in genes and oncogenes.  Once established, somatic genomic instability can contribute to further mitochondrial defects.  For example, impaired mitochondrial function can induce abnormalities in p53 activation, while abnormalities in p53 expression and regulation can further impair mitochondrial function.

Implications for Treatment and Prevention of Cancer

  • Numerous studies show that dietary energy restriction (DER) is a general metabolic therapy that naturally lowers circulating glucose levels and significantly reduces growth and progression of numerous tumour types to include cancers of the mammary, brain, colon, pancreas, lung and prostate.
  • Dietary energy or calorie restriction (DER) can be considered a broad-spectrum, non-toxic metabolic therapy.
  • It is the amount of the diet consumed rather than the composition of the diet that determines blood glucose levels. Many people have difficulty appreciating this fact because they often think that low carbohydrate diets will produce low blood glucose levels. This is clearly not the case here. Our data show that blood glucose levels are influenced more by the amount of calories consumed than by the composition of the calories consumed.
  • Malignant cells use glucose and amino acids like glutamine as their energy source through the process of fermentation even in the presence of oxygen. So cutting off glucose and glutamine should help in starving cancer cells of their fuel.
  • The cancer research field has drifted off course for too long in my opinion. It is now time for all cancer researchers to pause, and to reconsider the foundation upon which their views rest. In light of the compelling counter arguments against the gene-based theories of cancer together with our extensive in vivo studies in brain cancer, it has become clear to me that genetic theories are wanting in their ability to explain the origin of cancer.
  • I do not dispute the overwhelming evidence that defects in DNA, genes, and chromosomes occur in all cancers. The evidence is massive. What I do question, however, is whether these defects actually cause the disease. I will review evidence showing that most of the genomic defects seen in tumor cells can be linked directly or indirectly to insufficient respiration.

 Interview with Thomas Syefried

Dr. Thomas Seyfried believes that cancer is primarily a metabolic disease and so should be tackled as such. Cancer cells have high metabolic needs and so by manipulating the energy balance in the body through diet restriction, Dr. Seyfried is convinced that these malignant cells would suffer more than normal cells and even be killed. 

Pauline Davies: Well let’s go right back to the beginning, tell me why is cancer a metabolic disease?
Thomas Seyfried: Well, all cancers suffer from the same kind of problem; they have inefficient respiration. The inefficiency of respiration forces those cells to use an alternative fuel which is fermentation, and it can happen in cytoplasm or even in the mitochondria. It’s the fermentation that compensates as an alternative source of energy for damaged respiration. This leads to genomic instability, local inflammation and the features that we see as the hallmarks of the disease.

Pauline Davies: Because cancer cells are growing very rapidly, they need a great amount of energy to respire, to actually grow, and that’s where the stress comes from?
Thomas Seyfried: Well actually they need a great amount of energy because they’re not effectively metabolizing all of the energy in the molecules they take in. Cancer cells release significant amounts of un-metabolized molecules … the cancer cells are wasting this, and this is an indication of an inefficient respiratory system. And it’s the fermentation that drives the proliferation of the tumor cells and also it’s the fermentation that makes the cancer cells drug resistant.

Pauline Davies: Can you, in a very simple way, explain why the fermentation actually drives the cancer. Does fermentation give them more energy to do that?
Thomas Seyfried: Well, you know, we have liver regeneration, the division of normal liver cells to regenerate, they’ll actually grow much faster than a cancer cell and they don’t ferment. The cancer cells are locked into a fermentation profile because they have lost their ability to respire. Cells that can respire will stop their fermentation once the cell becomes more differentiated. The differentiation is also controlled by the energy efficiency of the mitochondria, and if that organelle is damaged in any way, it makes it incapable of using respiratory energy, the cells get locked into a primitive form, the way life was on the planet prior to oxygen. All the organisms were highly fermentative and highly proliferative. The cells were highly proliferative cells in a fermentation reduced environment. Oxygen then brought in stabilization and differentiation and this became the result of having mitochondria in our cells. When those organelles become damaged, these cells revert back to a proliferative condition as they were in ancient times before oxygen came onto the planet. And they will continue to do this now even in the presence of oxygen, because the respiration is deficient and cannot stop this fermentation process. So these cells, as long as they have access to the fuels that drive fermentation, which is glucose and glutamine, they will continue to proliferate and it becomes very difficult to kill them.

Pauline Davies: So you came up with some suggestions for actually controlling cancer. What did you say?
Thomas Seyfried: Our approach to managing cancer will be effective against all forms of the disease, because we view the disease as a singular disease of energy metabolism. So they all suffer from the primary inefficiency of respiration. Now knowing that, can we manage the disease? This becomes not an insurmountable problem. The first step you have to do is you have to treat the whole body, not just the tumor. The body has to be brought into a new metabolic state of metabolic stress where the evolutionary programs for our survival have evolved over millions of years, where we can then tap into alternative fuels due to the genomic flexibility that we have in our systems. Once our body gets into one of these metabolically, or I should say, an energy stress condition, which is actually very healthy, it’s not a painful or harmful situation, the cancer cells now become more stressed than the normal cells because they lack the metabolic flexibility. So the first things we do is put the patients in a state of energy stress by restricting the amount of calories they eat. We bring blood glucose down and ketones up. Blood glucose is the major fuel for the cancer cells and most other cells, especially brain cells. But many normal cells will transition to fat ketones, breakdown product of the fat, which cancer cells have great difficulty utilizing. So putting the patient into a global state of energy stress, puts great pressure on the metabolism of the tumor cell while making the normal cells healthy. The mutations that the tumor cells have, makes them restricted in their ability to adapt to this new energy state. Once we hit those fuels, we can manage the disease; patients can live a lot longer.

Pauline Davies: So what does it actually mean for a patient? How much do they have to restrict their diet?
Thomas Seyfried: Well this is an important point and this is one of the reasons it’s a stumbling block. Some patients have to realize they have to stop eating for several days, and get their blood sugar down to 55 to 65 milligrams per deciliter and their ketones up to about 3 to 2 millimolar and then they know they’re in the state. So we have clear biomarkers for patients to get into this particular metabolic state. The problem is a lot of patients are reluctant, they have other thoughts, the issue of cachexia always comes up and they say, “How could you have a patient who’s losing weight stop eating?” And as I said, they’re losing weight because the tumor cells are mobilizing glucose from their tissues of fats and protein. So by lowering the glucose in the patient, you are actually killing tumor cells that are releasing those cachexic factors, so you will lose additional weight at the beginning, but then the body will regain weight and become far more healthy. So it’s a whole systems physiology that has to be used, together with those drugs that target the ability to use glucose and glutamine. 

Pauline Davies: So what should people do … What sort of food should they be eating after starving themselves for three or four days?
Thomas Seyfried: Well it various from one person to the next; people have to know what their own bodies are capable of doing. They just have to measure their blood glucose and ketone levels which gives them an idea as to, you know, does this food help or not help. You know some people just have to stop eating for a week, it sounds terrible but it works, I know it works, we’ve seen many people benefit from this.

The biggest obstacle to this is the medical establishment is clueless as to how this works. It’s totally different than the way people view the disease; the disease is not viewed as a metabolic disease. If you’re not viewing the disease as the nature of what the disease actually is you’re going to be doing things that are irrelevant to the nature of this. I mean there are some people who are cured by the standard of care and current therapies, but they pay a price for that. They have all kinds of other health issues in those who do survive the treatments. And you know, 60 percent of the people treated with cancer do survive. So you have these many survivors but they pay a price for that survival, they’re debilitated in many ways for the rest of their life if they don’t get a recurrent tumor some other time in the future. We want to eliminate that, we want to eliminate the tumor and keep the body healthy, and that’s what our therapy and understanding will do.

Pauline Davies: Why are we not doing this?
Thomas Seyfried: Because the physicians and oncologists are not trained to do this. If they were trained to do this they would be instituting this. This is not part of the medical practice of the field. Cancer is viewed as a very different kind of disease that needs to be treated with toxic chemicals and radiation. No one is talking about the nutritional metabolic approaches to managing the disease because the physicians themselves are not trained in this. If you’re not being trained to do this, how could you institute this, or even understand the principles and concepts? This is a major stumbling block for the improvement of cancer. We’re not going to make any major advances until the physicians in the field understand that this is a metabolic disease.

Pauline Davies: What I don’t understand is why people haven’t looked at cancer as a metabolic disease so much in the past. Why are they focusing on the nuclear problems?
Thomas Seyfried: Well that took place over a many year period, it really kind of exploded with the discovery of DNA in the 1950’s as being the genetic material, and you find broken chromosomes in cancer. It was a natural connection to say, “Oh this is the hottest area in biology; cancer cells have broken DNA; everybody’s looking at gene transcription,” all this kind of stuff. It was only natural course of action to go that route. But Otto Warburg had clearly defined what the nature of the disease was many years ago, and that was kind of considered not important for a variety of reasons, but it was the core issue here.

Pauline Davies: So is there any way of preventing cancer in the first place? What would you suggest, that people starve themselves for a couple weeks a year?                   Thomas Seyfried: Well I don’t like to call it starving because starving is a pathological condition which is very unhealthy. But if you stop eating for three days, two to three days, and see your blood glucose go down and your ketones go up, you already know you’re enhancing the health and vitality of your mitochondrial system. The inefficient mitochondria undergo autophagy, they’re consumed by the cell for the good of the whole. So the body has an internal control system to purge any cell inefficient in its metabolism. The best way would be to one-week fast once a year, would probably be the singular best way to prevent cancer. This is hard for most people, so maybe three days twice a year, something along this. And as I said you dovetail it in with a religious experience for whatever and it makes everybody feel happy. You can do this with whatever culture or whatever religion; it can be worked in for most people. Let’s put it that way. 

In the foreword of the book, Dr. Peter Pedersen, Professor of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, USA wrote:

  • I have worked in the cancer metabolism field since the late 1960s and have extensively published works on the metabolic basis and properties of cancer.
  • I am very impressed with the excellent job he (Dr. Thomas Syefried) has done in highlighting abnormal energy metabolism as the central issue of the cancer problem.
  • I recognized long ago the privotal role of mitochondria and of aerobic glycolysis in sustaining and promoting cancer growth.
  • A key point made by Seyfried is that most of the genomic instability seen in cancer is likely arises as a consequence rather than as the cause of the disease. Seyfried’s book provide substantial evidence showing how cancer can be managed using various other drugs and diets that target energy metabolism. The restriction of glucose and glutamine, which drive cancer energy metabolism, cripples the ability of cancer cells to replicate and disseminate.
  • The cancer field went seriously off course during the mid-1970s when many investigators began considering cancer as primarily a genetic disease rather than a metabolic disease.
  • The inconsistencies of the gene “only” theory make it clear why little progress has been made in the cancer war and in the development of effective nontoxic therapies.
  • The gene theory had deceived us into thinking that cancer is more than a single disease … cancer is a singular disease involving aberrant energy metabolism.
  • Cancer has remained incurable for many due largely to a general misunderstanding of its origin, biology, and metabolism.
  • If cancer is primarily a disease of energy metabolism, then rational approaches to cancer management can be found in therapies that specifically target energy metabolism.

From the internet I have obtained the following comments:

  • His book is well-written; it has a lot of technical details which are suitable for biochemists and geneticists but at the same time he does a good job in making things comprehensible to the layperson. He has taken apart the official stand on cancer research – one that uses billions of dollars in research grants ultimately coming out of public money – while producing little if any useful results for the millions of cancer patients who suffer and die more perhaps from the toxicity of treatment rather than the disease itself, hoping for the next miracle drug which the drug companies promise to be just around the corner. His anguish at the state of cancer research as well as clinical management comes out quite clearly in the book ~ http://cassiopaea.org/forum/index.php?topic=29102.0
  • It’s (cancer) a huge field and it’s an intimidating field because decades of funding and efforts have resulted in perhaps hundreds of thousands of papers, so it’s impossible to grasp what is known. The good news is that unfortunately most of what we learn does not seem to mean much because we still haven’t made much progress in cancer.
  • I believe that they (mitochondria) play an important role in many diseases including cancer… What I think most people will now agree is that they play some kind of role. Because up to ten years ago most people thought mitochondria just damaged, just a result of the cancer process and therefore if you look at them as damaged, they’re not therapeutic targets whereas if you start looking at them as playing a potentially causal role, then all of the sudden they become therapeutic targets. And since the field is in desperate need for new therapeutic targets, mitochondria provide an extraordinary opportunity for new therapeutic options… I think it’s to break down all the existing biases and dogmas and start looking at what the data shows us, what the information about the mitochondria shows us and take a multidisciplinary approach … Keep in mind that there is this new theory for cancer but it hasn’t been based on dramatically new information, it’s just information that was always there, but people looked at it from a different perspective. So now people are just starting to look at it differently and now you have a metabolic theory for cancer being born. So alternate approaches and new ways of looking at the same data is really needed ~ Evangelos Michelakis, a professor at the University of Alberta in Edmonton, Canada.
  • To me it’s what science is all about; the problem is on the table, you attack it in an intellectually honest way, let the chips fall where they ~Erik Schon, Colombia University, trained as a molecular biologist but have spent the last twenty-six or twenty-seven years working on human mitochondrial genetics and human mitochondrial disease. 
  • It’s clear that the strategy to treat cancer as a genetic disease is not working, but this fuels the pharmaceutical industry. Enormous amounts of money are spent on large cancer genome projects, but this has not advanced our understanding or treatment of cancer. The information from these genome projects has actually created more confusion amongst cancer researchers, and this is very clear if one reads the literature. On the other hand, when cancer is viewed as a metabolic disease the strategies to treat and prevent cancer become incredibly simplistic and economical.
  • Why our own medical profession has not looked into this feature of cancer for therapeutic strategies is also odd.
  • The fact that our PET scans show high glucose uptake in almost all types of cancer proves that cancers have a unique metabolic abnormality unlike normal differentiated cells. Simply put cancer cells require large amounts of glucose, or sugar to survival and multiply ~ Dominic D’Agostino. 

Comments

Let’s again highlight some of the important messages that Dr. Syefried wants us to know:

  • All cancer cells regardless of tissue origin express a general defect in mitochondrial energy metabolism.
  • Cancer can be effectively managed and prevented once it becomes recognized as a metabolic disease.
  • It … became clear to me why so many people die from the disease.
  1. Many of the current cancer treatments exacerbate tumour cell energy metabolism, thus allowing the disease to progress and eventually become unmanageable.
  2. Most cancer patients do not battle their disease but are offered toxic concoction that can eventually undermine their physiological strength and their will to overcome the disease. Cancer treatments are often feared as much as the disease itself.
  • The view of cancer as a genetic disease is based on flawed notion that somatic mutations cause cancer.
  • Substantial evidence indicates that genomic instability is linked to protracted respiratory insufficiency.
  • Once cancer becomes recognised as a metabolic disease with metabolic solutions, more humane and effective treatment strategies will emerge.

A study of medical history tells us that new ideas will be rewarded with toxic reactions by the Vested Interest. I am glad that Dr. Syefried has the guts to speak out. And he spoke with scientific evidence and data.  Of course many self-serving researchers may label him as yet another quack or charlatan! That is the way most scientists behave anyway.

In reading this work of Dr. Thomas Seyfried, I am particularly disturbed with the following findings:

  • Although radiation therapy can help some cancer patients, radiation therapy will also enhance mitochondrial damage and fusion hybridization, thus potentially making the disease much worse.
  • Malignancy and invasiveness of tumours are directly related to vascularity (blood vessel development or angiogenesis). Reduced availability of glucose has been observed to reduce vascularity and cell proliferation. In light of our findings, it is surprising that the cancer field would persist in treating cancer patients with toxic antiangiogenic drugs such as bevacizumab (Avastin)  and cediranib (Recentin), which show marginal efficacy and appear to enhance the invasive behavior of tumor.
  • Compared to bevacizumab (Avastin), which targets angiogenesis, while producing adverse effects and enhancing tumor cell invasion DER (dietary energy restriction) targets angiogenesis, while improving general health and inhibiting tumor cell invasion. 
  •  Is it better for oncologists to target tumor angiogenesis using toxic drugs with marginal efficacy or is it better to use nontoxic metabolic strategies such as DER with robust efficacy? Oncologists should consider this question.

The question I would like to pose is: In the light of Dr. Seyfried work, can we honestly say that chemotherapy and radiotherapy help cancer patients? Will these treatments do more harm than the cancer itself?

They say, ignorance is bliss but I also learnt from my observation that ignorance kills and it kills mercilessly.

To conclude, let me ask you to reflect on the quotations below:

The information in this article are extracted from:
1. Thomas Seyfried & Laura Shelton, Cancer as a metabolic disease http://www.nutritionandmetabolism.com/content/7/1/7

2. Interview with Thomas Seyfried: http://cancer-insights.asu.edu/2012/05/asu-psoc-worksop-wednesday-march-21st-friday-march-23rd-2012-2/

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