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Warburg Revisited: Maverick Cancer Researcher Questions the Origin of Cancer An interview with Thomas Seyfried, PhD by Michael Uzick, ND, FABNO |
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Page 1, 2 According to Boston College professor and cancer research scientist Thomas Seyfried, the very origin of cancer is in dispute. His recently published book Cancer as a Metabolic Disease is having a dramatic impact on the field of integrative oncology. Michael Uzick: How did you become involved in researching the effects of ketogenic diets in cancer? Thomas Seyfried: We had been doing research on the biochemistry of tumors for decades, particularly lipid metabolism. We knew there were certain kinds of lipids expressed in tumor cells and we were mainly interested in figuring out what kind of function the lipids might have. At the same time, we had a parallel study on the genetics of epilepsy and one of my students talked to me about the ketogenic diet as a therapy for epilepsy. We took the natural models that we had developed and evaluated ketogenic diets for epilepsy and we became very involved in the mechanisms by which ketogenic diets affect epileptic seizures. We found that the majority of the therapeutic benefit of the ketogenic diet came from calorie restriction. One of my other colleagues knew that calorie restriction could be effective against tumors, so we tried this and we saw how powerful it was in blocking tumors. This has been known for a hundred years. Then we just put them together and found out that if you restrict calories on the ketogenic diet you can actually get better therapeutic benefit than either alone. So, it was a fortuitous combination of research activities that were taking place in the lab at the same time. MU: Your book, Cancer as a Metabolic Disease, challenges the current scientific paradigm on the origin of cancer. Can you describe the current paradigm and how you came to question it? TS: The current view now, without any question, is that cancer is a genetic disease. If you go on the National Cancer Institute website or you read any of the major articles published in Nature and Science, often the articles will start with, "Cancer is a genetic disease." I think that this has become dogma. It became clear to us as we did our research that the therapeutic benefits we were seeing from calorie restriction had their origin with Otto Warburg. But if he was correct, why are we talking about genes? The gene theory became predominant following Watson and Crick's evidence that DNA is the genetic material and finding all the mutations in cancer cells. One thing led to another and, among the powers that be, the gene theory won out. The gene theory seemed to be more consistent, and there were mutations that seemed to be either provoking the growth of the tumor or failing to suppress the tumor. The entire field was built on this foundation, that genes are regulating this entire process. But if one goes back in the literature, one can see clear disconnects in the linkage between nuclear genetic problems and the origin of the disease. For example, Darlington had clearly shown that there were carcinogens that did not damage the nuclear DNA, but did cause cancer. He concluded that cancer could not be a nuclear genetic disease. It had to be something in the cytoplasm and he alluded to factors that were related to the mitochondria. That's exactly what Warburg had said, but Warburg's theory had been discredited because it was observed that you could see normal respiration in cancer cells. Of course the genetic argument is that the metabolic issues are due to oncogenes and that's where the big controversy is and I looked at that very carefully and was able to parse it out. It turns out that the oncogenes are responding to the abnormal metabolism of the cell and we were able to show this. It is actually the abnormal metabolism of the cell that's dictating the genetic mutations. This is where my book challenges the field. It provides credible scientific evidence that seriously questions the notion that cancer is a genetic disease. And I think you are not going to make major advances in the field of cancer until this becomes more widely recognized. MU: You mentioned that Warburg was discredited because some cancer cells were found to have normal respiration. Can you explain how this is possible? TS: Most of the work that challenged Warburg's theory was done in culture. When you grow mammalian cells in culture, they take on characteristics that they don't generally have when growing in vivo. For example, if you take normal cells and grow them in culture, invariably they produce lactic acid. This doesn't happen in vivo. Muscle will produce lactic acid when it's under incredible physiologic stress, until there's enough oxygen returning to the system to suppress the formation of lactic acid. So there are a number of artifacts of the in vitro system that compromised the view of cancer as a disease of respiration. Now, when you look in vivo at cancer cells, invariably most cancers will have structural aberrations in their mitochondria. In breast cancer the majority of aggressive breast tumors have no mitochondria. So there's no way that these cells could have normal oxidative phosphorylation. So none of this is discussed in the literature. They just ignore it. I went back and looked at it and I said, "You can't say respiration in cancer cells is normal when there's so much evidence to say it isn't." MU: Let's assume that everyone agrees all cancer cells have damaged respiration. But then the question becomes, which came first – damage to the genes or the abnormal respiration? TS: If you go into the literature, the studies reveal the answer. If oncogenes are the drivers of this disease, why is it that when you take the nucleus from a tumor cell and put it into a normal cytoplasm, the nucleus is no longer capable of producing the disease? And now within the last year people have been able to transplant mitochondria. So if you transplant normal mitochondria into a tumor cell's cytoplasm, you suppress the tumorgenic phenotype. And if you transplant abnormal mitochondria into a normal cytoplasm, you can produce developmental abnormal cells or dead cells. You can actually stimulate oncogene upregulation. So it tells me that the mitochondria are calling the shots. MU: Your research has shown that a CRKD [calorie-restricted ketogenic diet] significantly inhibits brain cancers and in your book you have suggested that this dietary intervention should be effective in every kind of cancer. Can you explain how a CRKD impacts cancer? TS: So why are tumor cells producing lactate if they have normal respiration? We have blood cancers that have plenty of oxygen in the environment, yet they still produce lactic acid. Cancer cells are producing lactic acid because they can't get sufficient energy through normal respiration, and must therefore use fermentation instead. Fermentation usually occurs in the absence of oxygen, not in the presence of oxygen. So what’s going on here? The simplest explanation and the one supported by a variety of different studies, is that their respiration is damaged or insufficient in some way. Now ketones are an alternative fuel, which evolved to substitute for glucose when our food intake was suspended. Our bodies will transition to stored fat for energy, which is broken down to ketone bodies which can then be burned by all of the tissues, especially the brain. But you need good mitochondria to metabolize ketones. These have been shown to be abnormal in many different kinds of cancers. So the tumor cells can't transition to the alternative fuel that normal cells evolved to use. This seems like a very simple way to put pressure on cancer cells without toxicity. MU: I understand how ketones are involved. But where does the caloric restriction come in? Why does that become important? TS: We gave animals unrestricted ketogenic diets and the tumor cells grew just as fast, or even faster sometimes, than a standard high-carbohydrate diet. So we said, what's going on here? There's a diet with zero carbohydrate and the animals are eating as much as they want and when we looked at their blood, their blood sugars were very high. So it turns out if you eat large amounts of fat in a ketogenic diet you get insulin insensitivity, which then increases the level of sugar, and the cancer cells are fat and happy using this. So you have to restrict the diet. Because the glucose is now low and the ketones must be retained to be used for energy. MU: So if caloric restriction is required, how can one maintain this approach in order to target cancer? TS: You know the issue is, how long should you do this? I have to admit in some of my earlier publications, we were pretty hyped on the calorie restriction aspect of it. We were probably going a little overboard on how many calories you need to restrict. Only after we saw rather substantial regression of tumors or stabilization in people who cut down to maybe 1500 calories a day, which is not anywhere near a heavily restricted diet, did we begin to see that each individual is a unique metabolic entity. Some people require minimal restriction and other people require more restriction. If you look in the literature, a lot of people are using ketogenic diets to remain in a healthy state at low weight. And people can maintain this for years and they seem to be very healthy. Now I'm not saying all cancer patients need to maintain for the rest of their lives a state of low glucose and elevated ketones. I suggest they do it until there is clear evidence that the disease has been arrested or stabilized. And then there's a likelihood one could transition off of this, as they would for any kind of therapy. MU: Valter Longo, PhD, will also be speaking at the OncANP conference about his research looking at the benefit caloric restriction during the administration of chemotherapy. Do you have any thoughts on Longo's research and any parallels between your own? TS: You know I agree, I think what he's seeing is real and I think it's important. I have heard of and spoken to people, physicians who have done therapeutic fasting on some of their patients for as much as 30 days and have seen cancer regression in some patients. Water only, you know without any chemo. So if you fast with only water like the Longo group does, the body goes into defense mode. And what I think is happening is a lot of these tumor cells become very compromised under these stressed conditions. Here's where the mutations play an important role in allowing these therapies to work. Many of these cancer cells are loaded with all kind of mutations. And what those mutations do is prevent those cells from making the correct adaptations to the new stressful environment, so they now become in a much more compromised state. So if you give chemo under this therapeutic fasting condition, those cells are going to be less able to deal with the chemo and die faster than the normal cells, which are able to make these adjustments to this new metabolic state. I think it's another view of the same kind of approach. There are metabolic approaches to managing cancer that people need to recognize. MU: Your book opened my mind to the idea of ketones as anticancer agents. I specialize in enhancing the effectiveness of conventional therapies while reducing their toxicity. I was surprised by the number of studies showing that ketones, at least in vitro, enhance the effectiveness of several chemotherapeutic agents. TS: The question is, are they toxic in vivo? We have a paper that's under review now with my colleague Dominic D'Agostino and his graduate student Angela Poff at the University of South Florida. He has evidence that elevated ketones can in fact be toxic to the tumor cells. In my earlier writings, we were considering the ketones to be largely protective of normal cells and basically tumor cells just can't use them. But now we have evidence that they may in fact be toxic to the tumor cells. So it's a one-two hammering of the tumor cells. You're pulling away their glucose, forcing an alternative fuel they can't use, and potentially an alternative fuel that will actually kill them. MU: I see a general fear among cancer patients about losing weight. Medical oncologists for the most part recommend that patients eat ice cream and high carbohydrate foods so as to not lose weight. When you have a patient who is already starting off thin, is there reason to be concerned? TS: For those patients, we know that the ketogenic diet will cause some initial weight loss, but it also maintains muscle mass. Tisdale showed this years ago in England. So, there's a certain way to do this and the patient's weight can be stabilized. Cachexia is a very dangerous situation but you can institute a ketogenic diet, and yes, initially there will be some weight loss, but the weight will stabilize. MU: Currently the NIH (National Institutes of Health) lists eight clinical trials under way or completed examining the effects of ketogenic diets in patients with cancers. Have you been involved with any of studies and do you think your research has played a role in the interest in this topic? TS: Our studies were motivated by Linda Nebeling's 1995 case report on the therapeutic efficacy of the KD in two children with malignant brain cancer. Our research has certainly established the evidence for the current interest and I am excited that some members of the medical community find our approach to cancer management interesting and worthy of patient application. I have helped with protocols for some studies, but not for others. I am not presently participating in any of the studies. I can only hope that the PIs of these studies know what to do, and how to collect and interpret the data. Page 1, 2
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