Respectful Insolence

If this looks a bit familiar to some of you, let’s just say that it’s grant crunch time again. This should be over after today. I hope.

In the meantime, one of the difficult things about science-based medicine is determining what is and isn’t quackery. While it is quite obvious that modalities such as homeopathy, acupuncture, reflexology, craniosacral therapy, Hulda Clark’s “zapper,” the Gerson therapy and Gonzalez protocol for cancer, and reiki (not to mention every other “energy healing” therapy) are the rankest quackery, there are lots of treatments that are harder to classify. Much of the time, these treatments that seemingly fall into a “gray area” are treatments that have shown promise in animals but have never been tested rigorously in humans or are based on scientific principles that sound reasonable but, again, have never been tested rigorously in humans. (Are you sensing a pattern here yet?) Often these therapies are promoted by true believers whose enthusiasm greatly outstrips the evidence base for their preferred treatment. Lately, I’ve been seeing just such a therapy being promoted around the usual social media sources, such as Facebook, Twitter, and the like. I’ve been meaning to write about it for a bit, but, as is so often the case with my Dug the Dog nature—squirrel!—other topics caught my attention.

I’m referring to a diet called the ketogenic diet, and an article that’s been making the rounds since last week entitled “Ketogenic diet beats chemo for almost all cancers, says Dr. Thomas Seyfried.” Of course, when I see a claim such as that, my first reaction is, “Show me the evidence.” My second reaction is, “Who is this guy?” Well, Dr. Seyfried is a professor of biology at Boston College, who’s pretty well published. He’s also working in a field that has gained new respectability over the last five to ten years, namely cancer metabolism, mainly thanks to a rediscovery of what Otto Warburg discovered over 80 years ago. What Warburg discovered was that many tumors rely on glycolysis for their energy even in environments with adequate oxygen for oxidative phosphorylation, which generates the bulk of the chemical energy used by cells. I described this phenomenon in more detail in a post I did four years ago about a drug that looks as though its anticancer properties come from its ability to reverse the Warburg effect.

What not to do if you want your hypothesis to be taken seriously

So on the surface, Dr. Seyfried’s argument that cancer is primarily a metabolic disease (an argument I’ll look at in more depth shortly) is well within the bounds of current oncologic science. Indeed, a few years ago it was all the rage, and I remember attending several sessions and lectures on the Warburg effect and cancer at the AACR meetings three or four years ago, although, oddly enough, I don’t recall as many the last couple of years. In any event, if that’s all I looked at, I probably would have shrugged my shoulders and moved on, as in, “Nothing to see here.” But there are quite a few red flags. The first red flag is a claim that a ketogenic diet can treat cancer better than chemotherapy. The second, even bigger, red flag is on Dr. Seyfried’s Boston College web page:

In addition, Dr. Seyfried has worked with noted alternative health advocate Dr. Mercola to provide a thought-provoking discussion on the benefits of a ketogenic diet. Dr. Mercola provides a thorough synopsis of the talk on his website, and also includes the original audio recording of their conversation.

Über-quack Dr. Mercola? Oh, dear. His evident pride at having been interviewed by Dr. Mercola does not reflect well on Dr. Seyfried’s critical thinking skills and knowledge of medicine. Dr. Mercola sells quackery. He has promoted antivaccine views, breast cancer pseudoscience, and the rankest cancer quackery, such as that of Tullio Simoncini, who believes that all cancer is a fungus and that baking soda is the way to treat it, and the twice-a-day coffee enemas. Seriously, this is not the sort of person a legitimate scientist wants to associate himself with—ever—if he wants to be taken seriously. I can see a naive researcher making a mistake and, not realizing who Dr. Mercola is, agreeing to an interview, but that’s the sort of thing that a reputable scientist would do his best to disavow and distance himself from.

Neither is the American College for Advancement in Medicine (ACAM), which bills itself as the “voice of integrative medicine,” where he’s given a major talk, the sort of organization a legitimate scientist wants to associate himself with if he wants to be taken seriously. Don’t believe me? Just peruse the ACAM website, where you will find lots of chelation therapy, including a program to “certify” in chelation therapy and detoxification, as well as other quackery. There’s a good reason that ACAM is so disreputable. I emphasize again, this is not an organization with which a scientist who wishes to be taken seriously by oncologists associates himself.

Also, if a scientist wishes to be taken seriously, he shouldn’t say things like this:

The low-carb, high-fat ketogenic diet can replace chemotherapy and radiation for even the deadliest of cancers, said Dr. Thomas Seyfried, a leading cancer researcher and professor at Boston College.

In an exclusive interview, Dr. Seyfried discussed why the ketogenic diet has not been embraced by the medical community to treat cancer despite its proven track record both clinically and anecdotally.

“The reason why the ketogenic diet is not being prescribed to treat cancer is purely economical,” said Dr. Seyfried, author of Cancer as a Metabolic Disease. “Cancer is big business. There are more people making a living off cancer than there are dying of it.”

And don’t associate yourself with Ralph Moss, the number one promoter of laetrile quackery and make easily refuted claims such as the claim that “chemo and radiation do not cure cancer or extend life, although cancer physicians often make this claim” and that radiation “often does more harm than good to the patient.” Given that all Dr. Seyfried has is a couple of case studies as clinical support for his treatment (see below) and I can produce reams of studies over nearly 50 years demonstrating that chemotherapy can cure specific cancers and prolong life when used appropriately, the “2% gambit” notwithstanding, it’s not a winning proposition, and it sure doesn’t help your credibility to use the language of cancer quacks to promote your idea.

So, what, exactly is Dr. Seyfried’s hypothesis?

Cancer as a metabolic disease

Red flags or no red flags, it is, of course, possible that Dr. Seyfried is on to something and has let his enthusiasm overwhelm his judgment with respect to whom he associates with and the sorts of statements he makes, many of which sound as though they could have come from Stanislaw Burzynski, Ralph Moss, or Joe Mercola. In actuality, he isn’t totally wrong, but he isn’t totally right, either. As is typical of someone without a medical background, in particular an oncology background, he is, basically, putting the cart before the horse, as you will see.

In his talk, Dr. Seyfried begins with what he refers to as a “provocative question”: Is cancer a genetic or metabolic disease? Actually, whether he realizes it or not, his question is not quite as provocative as he thinks it is, nor is the answer anywhere near as clear-cut as he thinks it is or as he characterizes oncologists and cancer researchers as thinking it is. I’ll tell you what I think the answer to the question is after I’ve discussed Dr. Seyfried’s hypothesis. In the meantime, not surprisingly, his answer is that cancer is a metabolic disease, while everyone else’s answer—according to him, at least—is that it is a genetic disease, making him the brave maverick doctor, who says things like:

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.

Except that it really isn’t, at least not anymore. If you do a Pubmed search on “targeting cancer metabolism,” which is what Dr. Seyfried is talking about, you’ll find over 22,000 articles, with over 3,000 in 2013 alone, with a sharply increasing curve since 2000 that only now appears to be leveling off. A search on “cancer metabolism” brings up 369,000 references, with 28,000 in 2013 alone. Cancer metabolism is an incredibly important topic in cancer research and has been for several years now, and finding means of targeting the common metabolic abnormalities exhibited by cancer cells is currently a hot area of research. From my perspective, Dr. Seyfried is exaggerating how hostile the cancer research community is towards metabolism as an important, possibly critical, driver of cancer, although, to be fair, one prominent cancer researcher, Robert Weinberg, has been very skeptical. To me, Seyfried just appears unhappy that genetics is currently thought—for good reasons, I might add—to be the primary driver of most cancers. Note that I intentionally used such phrasing, because Dr. Seyfried, in my readings, appears all too often to speak of “cancer” as if it were a monolithic single disease. As I’ve pointed out many times before, it’s not. Indeed, only approximately 60-90% of cancers demonstrate the Warburg effect.

There are three components to glucose metabolism: glycolysis, which feeds the Krebs citric acid cycle, which in turn feeds oxidative phosphorylation. The issue with the Warburg effect is that it leads to a shift in metabolism that favors glycolysis. As a result of this shift, tumor cells tend to use a lot more glucose than normal cells because glycolysis is much less efficient at converting glucose into ATP molecules used for cellular energy than oxidative phosphorylation. One reason that this is thought to provide a growth advantage to cancer cells is because oxidative phosphorylation requires oxygen while glycolysis does not and cancers frequently outgrow their blood supply such that they often live and grow in tissue spaces where there is not much oxygen. In any case, the avidity of cancer cells for glucose has been known a long time and is the basis for positron emission tomography (PET) scanning, where a radiolabeled derivative of glucose is the most commonly used tracer for exactly that reason: Tumor cells take it up much more avidly than do normal cells, leading to ugly black blobs (old-fashioned PET scans alone) or pretty bright blobs (PET-CT) where there are tumor masses in the scans.

The idea behind ketogenic diets is very simple. If glucose is the primary fuel for cancer, then lower carbohydrate intake and replace carbohydrates with other sources of fuel, such as fats, in order to push the body’s metabolism into ketosis. It actually turns out that ketogenic diets are probably useful in the treatment of intractable epileptic seizures in children. Unfortunately, their mechanism of action in preventing seizures is unclear, although four potential mechanisms, including carbohydrate reduction, activation of ATP-sensitive potassium channels by mitochondrial metabolism, inhibition of the mammalian target of rapamycin (mTOR) pathway, or inhibition of glutamatergic synaptic transmission (glutamate as a neurotransmitter), have been proposed. Interestingly, the mTOR pathway is an important signaling pathway in many cancers that couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and growth factors. It’s a commonly overactive signaling pathway in cancer.

It’s also interesting that the cancers used to produce the basic science cited by Dr. Seyfried are virtually all brain cancers and that virtually all the evidence comes from rodent tumor models. For one thing, if there is a tumor type that exhibits the Warburg effect and a high degree of metabolic derangement, it’s brain tumors. It’s no coincidence that dichloroacetate was first tested in brain tumors. In this study, VM/Dk mice were used, and a mouse histiocytoma cell line resembling human glioblastoma multiforme with macrophage/microglial properties derived from that same mouse strain (VM-M3) was implanted subcutaneously. This cell line has the property of metastasizing quickly and widely when implanted under the skin and allowed to grow, which actually makes it not very much like brain tumors, which seldom metastasize and usually kill through local invasion and taking up increasing volume in the closed space of the skull, something the brain most definitely does not like. The results showed that a ketogenic diet increased mean survival time by over 56%, while a combination of a ketogenic diet and hyperbaric oxygen therapy (HBOT) increased survival time 78%. The result is interesting, but it is a mouse tumor model, not a human tumor model, and that makes its applicability to humans tenuous, particularly given the nature of the murine tumor, but probably worth investigating further.

Another mouse study cited by Seyfried is one in which dietary restriction was reported to promote vessel maturation in a mouse astrocytoma model. Given that tumor angiogenesis is one of my scientific interests and I have a fair number of publications on the topic, I was interested. Unfortunately, I ended up being disappointed. This was another syngeneic model (i.e., a mouse tumor implanted in mice of the same strain from which the tumor was isolated as a cell line, like the one discussed above). Although it showed increased tumor vessel maturation (which is one mechanism by which inhibitors of angiogenesis work), I wasn’t quite convinced, because there was a distinct lack of quantification of the phenomenon, and the microscopy appears not to have been blinded, something that’s critical to avoid unconscious bias in the results. It’s not surprising that this result, which, if more convincing evidence had been obtained, could easily have appeared in Cancer Research, was published in a low tier journal. It’s an OK study, but not fantastic. Certainly it didn’t lead me to smacking myself in forehead and saying, “Of course!”

Throughout his talks, both here and elsewhere, Dr. Seyfried presents mouse studies that are interesting and suggestive that there might be something to this whole ketogenic diet thing, at least in brain tumors, such as this one. However, this is what we in the oncology biz would call pretty preliminary data, worthy of further investigation but not supporting the grandiose claims that Dr. Seyfried makes.

We need more beef. We need clinical studies. Unfortunately, they’re in short supply.

Clinical evidence for ketogenic diets as a cancer treatment

It’s not as though Dr. Seyfried doesn’t cite clinical evidence. It’s just that the evidence is so darned thin and unconvincing thus far. For instance, in this talk, the first study he presents is a very small case series (two patients, actually) performed in 1995 in which two girls with inoperable astrocytomas were placed on a ketogenic diet in order to “determine if a ketogenic state would decrease glucose availability to certain tumors, thereby potentially impairing tumor metabolism without adversely affecting the patient’s overall nutritional status.” Interestingly (to me, at least) these case reports came from University Hospitals of Cleveland, where I did my general surgery residency. In fact, I was still there in 1995. Unfortunately, I don’t have access to the journal back to 1995; so I’m stuck with just the abstract. However, the abstract is pretty clear:

Within 7 days of initiating the ketogenic diet, blood glucose levels declined to low-normal levels and blood ketones were elevated twenty to thirty fold. Results of PET scans indicated a 21.8% average decrease in glucose uptake at the tumor site in both subjects. One patient exhibited significant clinical improvements in mood and new skill development during the study. She continued the ketogenic diet for an additional twelve months, remaining free of disease progression.

One notes that the patient who didn’t survive 12 months wasn’t much mentioned; so I assume she didn’t demonstrate any clinical improvement. In any case, this study doesn’t really show anything, other than that a ketogenic diet might decrease glucose uptake in some brain tumors. It’s like a Burzynski case report, in which we have no idea whether the patient did better than expected because of the intervention or because she had less aggressive disease.

The next case report is from 2010. It describes the case of a 65-year-old woman who presented with progressive memory loss, chronic headaches, nausea, and a right hemisphere multi-centric tumor seen with magnetic resonance imaging (MRI). Following incomplete surgical resection, the patient was diagnosed with glioblastoma multiforme (GBM). Now here’s the kicker: The patient underwent standard therapy plus the ketogenic diet. A day after her surgery, she underwent a two-day fast, followed by a three day fast beginning a week after surgery, followed by a restricted ketogenic diet (only 600 Cal/day). Three weeks after her surgery (and two weeks after starting the ketogenic diet) she began standard of care treatment, concomitant radiation plus chemotherapy (temozolomide), “according to standard procedures,” which lasted six weeks. The patient also had a gene mutation in her tumor that produces increased sensitivity to temozolomide. The conclusion? Fortunately for the patient, she had what appears to have been a complete response, after which she went on a less restrictive ketogenic diet. Unfortunately, the patient recurred eight months later. By that point, the patient was off of the ketogenic diet. The authors’ conclusion? Because it was “unlikely” that the tumor would have responded this well on standard therapy alone, it must have been adding the ketogenic diet that done it. Worse, in the talk, Dr. Seyfried strongly implies that the tumor recurred because she had gone off the ketogenic diet two and a half months before her recurrence.

Irritatingly, during the same talk, Dr. Seyfried refers to having done a “biopsy” on the GBM when the case report clearly says that the patient underwent a partial excision of the temporal pole with incomplete debulking of the tumor, which is a different thing. When a surgeon tries to debulk a tumor, he is trying to remove as much of it as possible. When a surgeon biopsies a tumor, he is trying only to get enough tissue to make a diagnosis. He also heaps scorn on the hospital for insisting that the patient undergo standard of care therapy, clearly demonstrating that he has no understanding of clinical trial ethics. What most likely happened with this patient is that the debulking was significant, and the remaining tumor was small enough to be eliminated by the combined chemotherapy and radiation therapy—at least to the point of no longer being detectable on PET scan. Also, just because the diet appears to have decreased glucose uptake by the tumor doesn’t mean that the tumor was dying. In fact, it might have even made the PET scan less sensitive to whatever remaining viable tumor cells might still have been around, a possibility that I don’t see Dr. Seyfried as having considered.

There are other studies, but little or nothing in the way of randomized clinical trials. For instance, a recent retrospective study of 53 patients, of whom only six followed a ketogenic diet while being treated for GBM, concluded that the diet was safe, but no suggestion of efficacy was noted. More recently, a German group examined the effect of a ketogenic diet on 16 patients with advanced cancer of various types who had exhausted all therapeutic options. The treatment didn’t result in any serious side effects, although subjects found it very difficult to maintain the diet, particularly in the context of family life. Only five were able to complete the three month treatment period, and it was reported that these five didn’t have progression while on the diet. Of the remaining 11, two died early, one was unable to tolerate the diet and dropped out very quickly, two dropped out for personal reasons, one couldn’t continue the diet for more than a month and three had disease progression within less than 2 months of starting the diet and one dropped out to resume chemotherapy. As a whole, this study was well-nigh uninterpretable due to the different kinds of cancer, other than to conclude that less than 50% of patients with advanced cancer could adhere to the diet, and that those who could generally had no significant side effects. Of course, it’s unclear whether the diet helped the five who could adhere to it or whether those who adhered to it could do so because they had more indolent, less aggressive disease.

None of this stops Dr. Seyfried from concluding:

  1. Preclinical and case report studies indicated that the restricted ketogenic diet (R-KD) can be an effective “metabolic therapy” for managing malignant brain cancer in children and adults.
  2. The therapeutic effects of the R-KD against brain cancer can be enhanced when combined with drugs or HBOT that also target energy metabolism.

Uh, no. Not exactly. Preclinical experiments are intriguing but fairly limited in applicability, and the case reports demonstrate nothing of the sort. There’s more to Dr. Seyfried’s hypothesis, for example, his idea that metastatic cancer comes about because of alterations in glutamine metabolism, but unfortunately he appears to misunderstand the genetics of metastasis when he bases part of his conclusion on observations that metastatic cancers often have the same genetic derangements as the primary tumor. It’s been a longstanding question whether clones of tumor cells possess the ability to metastasize as an intrinsic part of the process of becoming cancer cells or whether they acquire it later. Given that evolution is a major force driving cancer cells to become more invasive and that tumors are very heterogeneous, full of lots of different clones with different sets of genetic mutations, Dr. Seyfried’s hypothesis is at best simplistic. Also disappointingly, the evidence for any diet as a treatment for cancer is weak at best.

Putting the cart before the horse

Clearly, ketogenic diets are not ready for prime time as a treatment for cancer, either alone or in combination with conventional therapy. Unfortunately, that hasn’t stopped it from being touted by all manner of alternative cancer practitioners (i.e., quacks) and others as a cancer cure that “they” don’t want you to know about or saying things like, “…it’s nothing short of medical malpractice and negligence to fail to integrate this type of dietary strategy into a patient’s cancer treatment plan,” as Joe Mercola did. Dr. Seyfried himself has contributed to the hyperbole quite a bit as well. For example:

These studies are all in combination with either radiation or chemotherapy. My preference is to start metabolic therapy with GBM (glioblastoma multiforme). This is a devastating type of brain cancer. Metabolic therapy with a restricted KD could be done with a few tumors where you know the conventional standard of care doesn’t work at all. You would choose those kinds of patients and do a clinical trial based on historical controls and see what the outcome would be and see if you could get some level of survival that would match or be better than the conventional standard of care.

Regular readers of SBM should know the problem with this sort of approach. No IRB worth its salt would approve such a trial because it would be ethically dubious, but, even worse, it would be ethically dubious and it wouldn’t really tell us anything unless those few patients either had near-miraculous responses or died very quickly. Anything else would simply tell us that the diet is probably doing no harm. More numbers would be needed, particularly if the comparison is to historical controls, to get even an inkling of whether there might be benefit. In that case, you might as well do a proper phase I/II clinical trial, which is what is happening. For instance:

In other words, clinical data should be rolling in fairly soon, and that’s a good thing. In the meantime Dr. Seyfried and other advocates who so passionately believe that ketogenic diets will greatly help patients with brain cancer do no one any favors by claiming unequivocally that cancer is a metabolic disease and saying that ketogenic diets are more beneficial than chemotherapy for patients with brain tumors.

This brings me back to the question of whether cancer is a metabolic disease or a genetic disease, y answer to which I promised early on. The likely answer? It’s both! Indeed, a “chicken or the egg” argument continues about whether it is the metabolic abnormalities that cause the mutations observed in cancer cells or whether it is the mutations that produce the metabolic abnormalities. Most likely, it’s a little of both, the exact proportion of which depending upon the tumor cell, that combine in an unholy synergistic circle to drive cancer cells to be more and more abnormal and aggressive. Moreover, cancer is about far more than just the genomics or the metabolism of cancer cells. It’s also the immune system and the tumor microenvironment (the cells and connective tissue in which tumors arise and grow). As I’ve said time and time and time again, cancer is complicated, real complicated. The relative contributions of genetic mutations, metabolic derangements, immune cell dysfunction, and influences of the microenvironment are likely to vary depending upon the type of tumor and, as a consequence, require different treatments. In the end, as with many hyped cancer cures, the ketogenic diet might be helpful for some tumors and almost certainly won’t be helpful for others. Dr. Seyfried might be on to something, but he’s gone a bit off the deep end in apparently thinking that he’s found out something about cancer that no one else takes seriously—or has even thought of before.

Comments

  1. #1 Dangerous Bacon
    June 24, 2014

    What would cause a scientist with respectable credentials to go off the deep end, associating with Mercola and whining about how his proposed dietary intervention isn’t standard care because “cancer is big business”?

    There are enough red flags raised by Dr. Seyfried to furnish an entire May Day parade in Red Square.

    Curiously, I was just reading remarks by a laetrile advocate who approvingly quotes G. Edward Griffin* about how cancer is a vitamin deficiency disease (the “vitamin” is “vitamin B-17 a.k.a. laetrile).

    *Griffin is also big on the “cancer business” angle – at least, when he’s not going on about chemtrails, the 9/11 conspiracy and Jews promoting the New World Order.

  2. #2 Helianthus
    June 24, 2014

    The current view now, without any question, is that cancer is a genetic disease.

    My former colleagues, with whom I was looking for cancer protein biomarkers, would have said the current view on cancer is a bit more nuanced than that.
    Especially the “without any question” part.

  3. #3 Eric Lund
    June 24, 2014

    a very small case series (two patients, actually)

    This reminded me of a snippet from an old joke about translating paper speak to plain English.
    “In my experience”: It happened once.
    “In case after case”: It happened twice.
    “In a series of cases”: It happened three times.

    It sounds so far as though ketogenic diets are mostly harmless.

  4. #4 Mu
    June 24, 2014

    What would cause a scientist with respectable credentials to go off the deep end
    The guy is a biologist. As such, his potential media exposure is very limited. Being suddenly all over the news, even, if only as “maverick researcher” , might be too much to resists after 30 years in an academic cubicle.
    If he’d only taken up blogging like Orac’s alter ego.

  5. #5 Eric Lund
    June 24, 2014

    As [insert scientific field here], his potential media exposure is very limited.

    That’s true of most scientists. Most scientists don’t go off the deep end. And of those who do, a disproportionate number seem to be scientists who are already well-known. Think of Nobel Prize winners like Linus Pauling or Brian Josephson. Or for that matter Dr. Oz, who already was a well-respected surgeon with his own TV show before he embraced woo.

    I’d like to know the answer to DB’s question, too, but I think you’re on the wrong track here.

  6. #6 Todd W.
    http://www.harpocratesspeaks.com
    June 24, 2014

    The danger in Dr. Seyfried’s hyperbole is that he looks to be a respected researcher at a fairly well-known, somewhat prestigious university. By making the claims the way he does (diet can cure cancer where chemo can’t), he might sway people to just skip conventional treatment altogether.

  7. #7 Shay
    June 24, 2014

    Were we playing quack bingo, Seyfried’s card would be full. Claims of BigPharma conspiracy? check. Guaranteed to work? check. Association with Mercola? check. Hyped claims based on no real clinical trials? check….

  8. #8 kruuth
    June 24, 2014

    Question for Orac and others, but is 2 patients allowed to be called a series or is he using the Dr. Oz “flowery language?”

  9. #9 The Grouchybeast
    June 24, 2014

    Most scientists don’t go off the deep end. And of those who do, a disproportionate number seem to be scientists who are already well-known. Think of Nobel Prize winners like Linus Pauling or Brian Josephson

    Or perhaps it’s that scientists who are already well known have a much higher chance of attracting wider interest in their woo.

  10. #10 KeithB
    June 24, 2014

    When I got my chemo orientation, the Navigator back-handedly mentioned that I might want to avoid sugar. She indicated that there was no science behind it, but it might help.

  11. […] the patients. this article breaks down the various studies regarding ketogenic diets and cancer. http://scienceblogs.com/insolence/20…ts-for-cancer/ __________________ You can't out-exercise poor eating […]

  12. #12 Yodelady
    June 24, 2014

    I hear a lot of hype about this on cancer message boards, but somehow the proponents never mention articles like this one, which says ketones can promote metastasis. http://www.ncbi.nlm.nih.gov/pubmed/20861671

    I’ve tried to educate myself on the science of it and it’s well beyond me. I notice, though, that the popular theory could be effectively written up as a comic book while the other theories can’t.

  13. #13 Woo Fighter
    June 25, 2014

    So here’s a sincere question from a non-science person (I’m not JAQ’ing, just confused):

    All the cancer quacks seem to say the same thing: “sugar feeds cancer” and they cite Otto Warburg and the Warburg effect as their “evidence.” They claim if you cut off the sugar supply in the diet, the cancer “dies.”

    I know that claim has been refuted many many times over by people I trust, including a video of a presentation by Orac’s friend last year at TAM.

    I realize these quacks are talking about eliminating sugar from the diet, but I also understand that a lot of food turns into sugar in the body when metabolized. So is the Warburg effect a result of the unavoidable glucose that results from ALL food? And is sugar in the diet irrelevant as far as the Warburg effect is concerned?

    I’d like some rational, science-based responses when I’m told by some woo-sympathetic friends that “sugar causes cancer.” When I refute this, they stammer “…but Warburg said…”

  14. #14 Irène Delse
    Somewhere without cats
    June 25, 2014

    Well, if Dr. Seyfried wanted media exposure, ketogenic diets are the way to go these days. And big business too! In addition to the cancer quacks and the fungus scaremongerers, there’s the whole world of “paleo” proponents. Low-carb diets are apparently good for everything, from weight loss to spiritual connection with your hunter-gatherer ancestors… Or something.

  15. #15 Narad
    June 25, 2014

    Low-carb diets are apparently good for everything, from weight loss to spiritual connection with your hunter-gatherer ancestors… Or something.

    Atkins ripped off Robert Cameron’s “The Drinking Man’s Diet.” I wish I knew when or why I disposed of my copy.

  16. #16 Yodelady
    June 25, 2014

    Woo Fighter, I hope the others will answer because I’m no expert. As I understand it, all of the cells in our bodies use sugar (specifically glucose) for energy. Our healthy cells use oxygen to convert the glucose to energy. That’s a very efficient process, producing lots of energy per molecule of glucose. Many cancer cells don’t use oxygen. They convert the glucose to energy by an inefficient process which produces only a little energy from each molecule of glucose. That’s presumably why cancer cells are so greedy for glucose — they have to consume a lot to produce the energy a normal cell could get from just a little bit. The failure of the cancer cells to use oxygen and follow the more efficient system is called the Warburg effect.

    All of the carbohydrates we eat break down into simple sugars, and if we eliminate all carbs from our diet our bodies can break down muscle to create sugars.

    This is pure anecdote, but the cancer patients I’ve known who follow keto diets die off just like everyone else.

  17. #17 Lawrence
    June 25, 2014

    RE: going off the deep end

    I think it’s human nature. Evolution has programmed us to be excellent at pattern recognition, even when no pattern actually exists. Along the same lines, we dislike randomness and seek out order and cause and effect relationships. It’s hard to wrap our heads around the fact that cancer is a complicated set of diseases that can strike anybody at anytime. This is why 100% of people ask me what caused my cancer. So if there’s something like a diet that could potentially “cure” cancer, don’t we all want to believe that’s true?

    We’re also strong motivated reasoners; we develop conclusions and afterwards seek out information to justify it. Dr. Seyfried probably developed some sort of cautious hypothesis, and the more he thought about it, the more he wanted it to be true, and the more he sought out support to justify it. Throw in the spotlight of news interviews, and he wants to be right even more. Imagine the celebrity of being the doctor to cure cancer, or the humiliation of being shown to be a huge fraud. He wants this to be true as much as anyone, so it skews his perception of the research.

    I read a site on weightlifting with articles from tons of competitive athletes and trainers, so their exercise advice is usually top notch. Unfortunately, the site is also run by a supplement manufacturer, so the articles are constantly pimping these products that have limited to no research justifying them. Do I think all of the writers are shills selling snake oil they know doesn’t work? No. More often than not, I think they genuinely do believe, or at least want to believe, for all of the reasons mentioned above. Dr. Seyfried is no different.

  18. #18 Daniel Corcos
    France
    June 25, 2014

    The problem is not the woos, but what became of science with the advent of impact factor driven research.
    http://www.nature.com/nature/journal/v510/n7505/full/nature13264.html
    In this paper, it is suggested that, as a metabolite can mimic dietary restriction, it is possible to manipulate lifespan pharmacologically.
    And the paper begins with:
    Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms1, 2.
    However, the article cited in reference 2 just showed no effect of caloric restriction on the lifespan of monkeys.
    Therefore, a drug that, when found, would have some effect on this metabolite is very unlikely to extend lifespan. The editor could not ignore the negative results, as they have been reported and commented in Nature. So that’s how science works now, and this a much more serious issue.

  19. #19 Brook
    June 25, 2014

    doesn’t seem to have done the wellness warrior any good

  20. #20 AdamG
    June 25, 2014

    Speaking of our favorite ‘warrior,’ a post from last week reveals she’s going into ‘hibernation’ indefinitely to focus on “self-care.”
    I bet her arm’s taken a turn for the worse.

  21. #21 herr doktor bimler
    June 25, 2014

    In this paper, it is suggested that, as a metabolite can mimic dietary restriction, it is possible to manipulate lifespan pharmacologically.

    The capacity of modern science to extend the lifespan of nematodes is truly amazing.

  22. #22 Narad
    June 25, 2014

    The problem is not the woos, but what became of science with the advent of impact factor driven research.

    That’s a peculiar variation on the normal complaints about the metric.

  23. #23 Narad
    June 25, 2014

    However, the article cited in reference 2 just showed no effect of caloric restriction on the lifespan of monkeys.
    Therefore, a drug that, when found, would have some effect on this metabolite is very unlikely to extend lifespan.

    “Therefore”? One narrow and qualified negative result, and you pull a sweeping conclusion out of your tokhes?

    The editor could not ignore the negative results, as they have been reported and commented in Nature. So that’s how science works now, and this a much more serious issue.

    I honestly cannot parse the first sentence, much less figure out what the second is for.

  24. #24 TBruce
    June 25, 2014

    The capacity of modern science to extend the lifespan of nematodes is truly amazing

    It looks like Mercola and Null are in luck.

  25. #25 Helianthus
    June 25, 2014

    @Woo fighter #13

    So is the Warburg effect a result of the unavoidable glucose that results from ALL food? And is sugar in the diet irrelevant as far as the Warburg effect is concerned?

    Not a cancer specialist either, but as I understand it, saying “glucose/sugar causes cancer” is very likely a case of putting the cart before the horse (although there may be a grain of truth in linking over-eating and cancer).
    What Warburg showed was that cancer cells are degrading glucose/sugar without the benefit of oxygen. To be fair, Otto Warburg himself did indeed postulate that this switch in sugar degradation may be a cause for cancer. We believe now he was overreaching.

    Your liver and pancreas conspire in maintaining the blood concentration of glucose around 1 gram/liter, degrading muscles and eventually fatty tissue to create glucose as needed. Ketones (as in “ketogenic”) are a by-product of these alternative ways of creating glucose.
    In a RI thread a few years back, a misled proponent of ketogenic diet linked to an article (which I didn’t find back), which showed how a keto diet in rats may reduce the blood sugar concentration at first, but in a matter of weeks the sugar level returned to normal level.
    So, to my mind, there is no question, whatever you eat, your body is going to adapt and have glucose circulating everywhere; glucose which cancer cells will be free to use any way they want, Warburg style or otherwise. I’m highly skeptical a keto diet may make any lasting difference in the cancer cells’ glucose intake. Now, this diet, or the metabolic changes it induces, may have other benefits I’m unaware of.

    About the reason for the Warburg effect: one hypothesis a colleague of mine explained to me, is that the oxygen-using path is hosted by the cell’s mitochondria, little organelles in charge of using oxygen in conjunction with high-energy biochemical reactions.
    There are dozens of proteins whose role is to control the cell replication cycle, slowing it, or in extreme cases ordering the suicide of the cell (apoptosis) if it looks like the cell is going rogue. A number of these proteins are interacting on the surface or inside mitochondria. Since one step of the tumorisation process is the override of these controls, mitochondria may be turned off during the takeover. In this case, the Warburg effect is merely collateral damage: the cell has to do without its power plant because the furnace has been turned off.

    Another hypothesis is based around the pyruvate kinase, the enzyme at the crossroad between anaerobic (no-oxygen) glycolysis and the Krebs cycle (which ends up using oxygen). This enzyme is responsible (among other factors) of the switch between the anaerobic and aerobic degradation of glucose; moreover, the switch by this enzyme to the anaerobic pathway may have other beneficial effects for the tumor cell, like directly or indirectly activating other biochemical pathways encouraging proliferation and cell survival. Notably, by not fully degrading each glucose molecule (as it would happen if using the oxygen-linked pathway), the tumor cell is accumulating molecules it could be using as building blocks for its proliferation. For the tumor cell, these benefits are worth the loss in energy production.

    Or it could be another reason altogether. Or a mix of the above.

    Actually, the Wikipedia article on Warburg effect explains it way better than me.

  26. #26 Vicki
    June 25, 2014

    Herr Doktor–I would like to quote the remark about the lifespan of nematodes. Is this cool, and if so, how would you like it attributed?

  27. #27 herr doktor bimler
    June 25, 2014

    Go for it! I have no idea what is the proper attributional style for semi-anonymous commenters.

  28. #28 Daniel Corcos
    June 26, 2014

    Narad, why don’t you content yourself with copying/pasting my sentences?
    Herr Doktor:
    Good remark, and I will quote your pseudo. Some of mine are much more famous than me.

  29. #29 Narad
    June 26, 2014

    Narad, why don’t you content yourself with copying/pasting my sentences?

    That’s not much of a reply to the observation that they comprised a dumb conclusion, an incoherent one, and a bizarre generalization with no discernible referent.

  30. #30 Daniel Corcos
    June 26, 2014

    Narad, if you don’t understand, ask Herr Doktor. Maybe he can do something for you.

  31. #31 Narad
    June 26, 2014

    Narad, if you don’t understand, ask Herr Doktor. Maybe he can do something for you.

    No, I suggest you give it a try. I understand what the reference that you’re making a grandiose stink about is doing there; it’s not at all clear that you do, or how on earth one footnote supports any of your assertions.

  32. #32 Daniel Corcos
    June 26, 2014

    Narad
    http://www.ncbi.nlm.nih.gov/pubmed/22932268?dopt=Abstract&holding=npg
    We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes.

  33. #33 Narad
    June 27, 2014

    Narad
    http://www.ncbi.nlm.nih.gov/pubmed/22932268?dopt=Abstract&holding=npg
    We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes.

    Did you not understand any part of my original comments? The submitted manuscript is open-access.

  34. #34 Narad
    June 27, 2014

    Actually, mentioning “open access” is likely to have been a very wrong choice of squirrel. Allow me to rephrase.

    Why do you think I said “one narrow and qualified negative result”?

  35. #35 Daniel Corcos
    June 27, 2014

    “Did you not understand any part of my original comments?”
    No

  36. #36 Narad
    June 27, 2014

    Have you taken this smoking-gun footnote to PubPeer?

  37. #37 Daniel Corcos
    June 27, 2014

    Maybe I should do, but I have the impression it’s mainly a loss of time, what do you think?

  38. #38 Narad
    June 27, 2014

    Maybe I should do, but I have the impression it’s mainly a loss of time, what do you think?

    OK, I’ll do it from scratch. Let’s travel back in time.

    The problem is not the woos, but what became of science with the advent of impact factor driven research.

    I have heard many complaints about IF. They have not inclued the assertion that it drives research.

    [http]:/[/www.nature.]com/nature/journal/v510/n7505/full/nature13264[.htm]l
    In this paper, it is suggested that, as a metabolite can mimic dietary restriction, it is possible to manipulate lifespan pharmacologically.

    Of nematodes.

    “Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan.”

    And the paper begins with:
    Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms1, 2.

    Yes, you have successfully copied and pasted.

    However, the article cited in reference 2 just showed no effect of caloric restriction on the lifespan of monkeys.

    No, it didn’t. I will stick to the abstract for your convenience.

    “Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies.”

    Therefore, a drug that, when found, would have some effect on this metabolite is very unlikely to extend lifespan.

    This is where I initially came in and tried to make the point that this is either a hopelessly sloppy or frankly insane use of the word “therefore.” I’m going with the former explanation, as what follows doesn’t make any sense anyway.

    The editor could not ignore the negative results, as they have been reported and commented in Nature.

    I will reiterate that this did not even parse upon first viewing. As far as I can tell, you are asserting that “the editor” must have noted that footnote 2 utterly destroyed the sentence and thence the paper. But had to keep quiet, because… random, contradictory citations are fine so long as they somehow drive the IF of Nature?

    This is insane. Were you to spend more than a moment fixating on some shiny object, you’d realize that there are two large-scale studies of CR going on. And that Nature doesn’t exactly go with lengthy literature reviews as introduction.

    So that’s how science works now, and this a much more serious issue.

    By means of conspiratorially placed footnotes to drive the journal’s IF? This is “how science works now”?

  39. #39 Daniel Corcos
    https://www.researchgate.net/profile/Daniel_Corcos2/?ev=hdr_xprf
    June 28, 2014

    OK, I see your point. Therefore, I should have written: “Therefore, a drug that, when found, would have some effect on this metabolite is very unlikely to extend lifespan OF HUMANS”.
    This was implicit in my comment, since I don’t believe that drug companies would invest money for extending C. Elegans lifespan.
    If there is anything else that I’ve written that you don’t understand, please tell me, I will try to make it accessible to you.

  40. #40 James Peters
    June 28, 2014

    @AdamG#20 That’s beyond low!

  41. #41 AdamG
    June 28, 2014

    Low?

  42. #42 Mephistopheles O'Brien
    June 28, 2014

    @AdamG – I presume James Peters was reading your comment as somehow wishing Ms. Ainscough ill.

  43. #43 AdamG
    June 28, 2014

    I certainly don’t wish her ill, I just wish she’d be honest about her disease progression and whether she’s stuck with purely alternative treatments in the wake of her mother’s death.

  44. #44 john
    london
    July 11, 2014
  45. #45 Daniel Norris
    London
    July 12, 2014

    John, Thank you for posting from Nature – dont believe what you see on this website or any of the following websites:

    sciencebasedmedicine.org/
    scienceblogs.com/
    quackwatch.com
    quackwatch.org/
    skepdic.com/

    These websites have an AGENDA and that is to bash ANYTHING alternative or natural that will help people. They likely are funded by big Pharma.

    here is the original work by Warburg:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2140820/pdf/519.pdf
    http://mosao2.org/Article%20-%20Medicine/cancer_Otto_Warburg_00.pdf

    Also, check out these website
    http://www.cancertutor.com
    http://www.cancure.org/

  46. #46 Lawrence
    July 13, 2014

    @Daniel – yes, go ahead and reject anything that doesn’t fit into your very narrow-minded worldview & most certainly ignore actual science, evidence, and by all means, just go ahead and reject reality….go outside, look up, and declare the sky is orange today.

  47. #47 Sarah A
    July 13, 2014

    @ john – Interesting, but notice that the authors of this paper discuss ketogenic diets for cancer in the category “emerging evidence” rather than “strong evidence.” Their conclusion is actually quite conservative: “ketogenic diets show promise as an aid in at least some kind of cancer therapy and is deserving of further and deeper investigation—certainly the evidence justifies setting up clinical trials.” Orac acknowledges as much in his post; what he’s criticizing is someone who is making claims that far exceed the evidence, associating with known snake oil salesmen, and untruthfully implying that “conventional” oncology has some huge blind spot regarding the metabolic nature of cancer. Also…

    Don’t believe anything you see posted by Daniel Norris. He has an AGENDA and that is to bash ANYTHING evidence-based that will help people. He is likely funded by Big Supplement.

    See? Two can play at that game.

  48. #48 novalox
    July 13, 2014

    @Sarah A

    Actually, considering the quack websites that daniel norris put on hhis post, you probably are much close to the truth than daniel ever can be.

  49. #49 Krebiozen
    July 13, 2014

    Daniel,

    dont believe what you see on this website or any of the following websites […]

    Please give examples of factual inaccuracies on each, or any, of those websites. If you are also unable to do so I will assume you are telling deliberate lies as part of an agenda. Do you sell some kind of alternative medicine by any chance?

  50. #50 Narad
    July 14, 2014

    Also, check out these website

    It’s not every day that one encounters shilling for R. Webster Kehr.

  51. #51 herr doktor bimler
    July 14, 2014

    Ah. So R. Webster Kehr has proven that Einstein was wrong (but SCIENCE has suppressed his work because FREE ENERGY and CONSPIRACY), and that Darwin was wrong about evolution (because DNA), and that Goedel was wrong about transfinite numbers. He is such a Renaissance man, no wonder Daniel Norris wants us to attend to his equally radical discoveries about cancer.

  52. #52 squirrelelite
    July 14, 2014

    I knew the cancer tutor website was BS from just reading, but I didn’t realize how bad it was until I checked out his reference paper:
    http://www.burtongoldberg.com/home/burtongoldberg/contribution-of-chemotherapy-to-five-year-survival-rate-morgan.pdf

    It’s a sort of interesting survey of the percentage incremental survival benefit of chemotherapy. But, the survival numbers are calculated estimates based on studies for various types of cancer. Then those estimates are turned around and lumped in with thousands of cancer cases for which there is no incremental benefit from chemotherapy to get the very low 2.1 US / 2.3 Australia percentages.

    Then the website makes the idiotic statement that

    If you studied the charts, the 5-year cure rate in America is 2.1%. In other words, in five years after diagnosis, 97.9% of the cancer patients treated with traditional cancer treatments, meaning those who trust the media and pharmaceutical industry, are dead.

    In other words, if you survived due to surgery alone, or surgery plus radiation therapy, you are “dead”.

    The stupid, it overflows my screen !!!

  53. […] might argue otherwise, claiming that atavism suggests treatments based on targeting the Warburg effect, DNA repair mechanisms, ABC transporters (which can function as drug efflux pumps), […]

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