{"id":615,"date":"2017-10-01T19:32:44","date_gmt":"2017-10-01T19:32:44","guid":{"rendered":"http:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=615"},"modified":"2017-10-01T19:32:44","modified_gmt":"2017-10-01T19:32:44","slug":"is-cancer-a-mitochondrial-disease","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2017\/10\/01\/is-cancer-a-mitochondrial-disease\/","title":{"rendered":"Is Cancer a Mitochondrial Disease?"},"content":{"rendered":"

\u201cCancer is a genetic disease. \u00a0Its primary cause is mutagens in the environment, abetted by time and bad luck. \u00a0A cell is controlled by the chromosomes in its nucleus, and when just the wrong combination of mutations happens to occur, a cell can begin to grow and multiply uncontrollably. \u00a0The next crucial step occurs when the cell acquires the ability to travel through the bloodstream and implant somewhere else. \u00a0The whole pathway from errant cell to malignant cell proceeds via chance mutations. From inception to metastasis, cancer is driven by genetics.\u201d<\/p><\/blockquote>\n

This theory of cancer is more than 100 years old<\/a>, but it didn\u2019t become the dominant view until the 1950s, when, after Watson and Crick, genes assumed an exalted position in the study of biology. \u00a0The \u201csomatic mutation theory\u201d continues to dictate the course of cancer research and treatment today.<\/p>\n

It is uncontested that cancer cells have abnormal chromosomes. \u00a0Dozens of different mutations have been found in malignant cells. \u00a0They have been catalogued as different oncogenes<\/a>, and because they are so different in their functions, cancer has been re-conceived from a single disease to a category containing many different diseases with similar symptoms.<\/p>\n

Are mutated genes the root cause of cancer? \u00a0Toxins that commonly break DNA (teratogens) are also found to cause cancer (carcinogens). \u00a0Radiation, ditto. \u00a0\u201cIonizing\u201d radiation packs enough wallop in each photon to break a chemical bond, and is associated with cancer, while non-ionizing radiation (visible, infrared, and radio waves) is not mutagenic and generally not carcinogenic*. \u00a0This has been taken as powerful circumstantial evidence for the prevailing theory.<\/p>\n

A direct answer to the question of whether cancer originates in the nuclear DNA is available from an experiment that is simple in principle: Swap nuclei between two cells, one normal and one malignant. \u00a0Take the mutated DNA out of a cancer cell and put it in a normal cell, to see if it becomes malignant. \u00a0Take the un-mutated DNA out of a normal cell and put it in a cancer cell to see if the cell is rescued and restored to health.<\/p>\n

This experiment has been technically feasible for more than 30 years, and indeed Barbara Israel and Warren Schaeffer actually performed both experiments at UVM and wrote them up in 1987 [ref<\/a>, ref<\/a>]. \u00a0The results were exactly the opposite of what was expected: The cell with normal cytoplasm and cancerous nucleus was normal; the cell with normal nucleus and cancerous cytoplasm was cancerous. \u00a0This result has been confirmed in other labs<\/a> [reviewed by Seyfried, 2015<\/a>].\u00a0 Still, the genetic paradigm has a stubborn grip on cancer research and treatment to this day.<\/p>\n

An alternative theory of cancer as a metabolic disease was put forth by the Nobel polymath Otto Warburg<\/a> in the 1930s. \u00a0The principal proponent of this theory today is Thomas Seyfried<\/a> of Boston College. \u00a0Seyfried cites evidence<\/a> that damage to the nuclear DNA, conventionally thought to be a root cause of cancer, is actually an effect of the damaged mitochondria and irregular metabolism. \u00a0\u201cThe metabolic waste products of fermentation can destabilize the morphogenetic field of the tumor microenvironment thus contributing to inflammation, angiogenesis and progression.\u201d<\/p>\n

 <\/p>\n

Respiration and Fermentation<\/strong><\/p>\n

Every cell in our bodies (and almost every cell in all eukaryotes everywhere) makes uses of energy in the form of ATP, adenosine triphosphate. \u00a0ATP is manufactured in the mitochondria<\/a>, usually by a controlled burning of sugar to form CO2<\/sub> and H2<\/sub>O. Highly energy-intensive cells such as muscles and nerves have thousands of mitochondria in each cell. \u00a0The word \u201crespiration\u201d in this context is used to mean burning sugar in an efficient energy conversion process, yielding 38 ATPs for every sugar molecule. \u00a0But when oxygen is scarce, perhaps because you\u2019re breathing as fast as you can or sprinting in deep anaerobic mode, another process can be used to rapidly convert available sugar stock to lactic acid, requiring no oxygen at all, but yielding only 2 ATPs per sugar molecule. \u00a0The latter process is called \u201cfermentation\u201d. \u00a0(This observation explains the extraordinary effectiveness of interval training (sprints) for weight loss<\/a>.)<\/p>\n

Warburg was among the first to notice [1931<\/a>] that most cancer cells use fermentation rather than respiration as an energy source. \u00a0Metabolic studies pointed to damaged mitochondria in tumor cells that had become inefficient in producing sufficient energy through respiration. \u00a0He theorized that impaired mitochondrial function is the root cause of cancer. \u00a0In fact, Warburg did some of the early work establishing the role of mitochondria as cellular energy factories.<\/p>\n

So most cancer cells are sugar addicts. \u00a0They consume enormous amounts of sugar, both because they are actively growing and dividing, and also because they use sugar so much less efficiently than normal cells. \u00a0A PET scan can be used to visualize concentrations of sugar in the body, and PET technology is often used to locate tumors.<\/p>\n

<\/p>\n

Sugar is easily made from carbohydrate foods, and when you eat a diet containing carbs, sugar is the fuel of choice. \u00a0Ketones are an alternative fuel used by the body when burning fat, either stored fat or ingested animal fat or vegetable oils. \u00a0(Medium chain saturated fatty acids like coconut oil seem to be most effective in inducing metabolic ketosis.) \u00a0Unlike sugar, ketone bodies cannot be fermented.\u00a0 They generate ATP energy only through oxidative respiration in the mitochondria.<\/p>\n

The logical question:<\/p>\n

Are zero-carb diets an effective treatment for cancer?<\/strong><\/p>\n

Some well-known cancer drugs (Gleevec<\/a>, Herceptin<\/a>) already target the fermentation metabolism.\u00a0 Acarbose has been proposed but not yet tried.\u00a0 But might it be safer and more effective to starve cancer cells by cutting carbohydrates in the diet to zero?\u00a0\u00a0There is a robust literature suggesting, \u201cyes\u201d [e.g., ref<\/a>, ref<\/a>, ref<\/a>, ref<\/a>, ref<\/a>, ref<\/a>, ref<\/a>] but so far the results have been less than earth-shaking.<\/p>\n

A search of ClinicalTrials.gov<\/a> yields 25 trials<\/a> of ketogenic diet variants for cancer treatment. \u00a0Most are in early stages, 5 have been completed, 2 have results. \u00a0In this study<\/a>, the ketogenic diet, with or without chemotherapy, did not cure glioma. \u00a0This small study<\/a> found modest benefits in a variety of advanced cancers. \u00a0These results are consistent with many mouse studies, in which some benefit was recorded from the ketogenic diet, but not a dramatic difference. \u00a0The most encouraging results I have found was a study<\/a> in which 9 of 11 mice treated with a combination of radiation and a ketogenic diet were cured of brain cancer. \u00a0Clearly, this is no miracle cure, but it\u2019s too early to give up–we\u2019re just figuring out how to make the diet work, and it has not yet been tried except at late stages, after all else has failed.<\/p>\n

Fasting shows more promise than ketogenic diets. \u00a0(Perhaps fasting lowers blood sugar even more than ketogenic diets.) \u00a0A series of studies<\/a> by Valter Longo make the case that fasting simultaneously sensitizes cancer cells to chemo or radiation and de-sensitizes normal cells.<\/p>\n

Seyfried has proposed a \u201cpress-pulse<\/a>\u201d system based on this vulnerability, targeting the glucose metabolism and the glutamine metabolism with hyperbaric oxygen. \u00a0Besides glucose, glutamine is also a major fuel for tumor cells.\u00a0 Drugs will be required to target glutamine, as glutamine is the most abundant amino acid in the body and can be easily synthesized from glutamate.\u00a0 Hyperbaric oxygen requires a patient to be enclosed in a pressurized oxygen chamber or room filled with pure oxygen at 2.5 x atmospheric pressure. \u00a0There is\u00a0one highly encouraging case report<\/a> for the success of this triple combination\u2014hyperbaric oxygen, glucose inhibitors, and low-dose chemo\u2014in which a late-stage, resistant breast cancer is driven to total remission.<\/p>\n

Last week, a research paper<\/a> from Duke U suggested a target for attacking the fermentation metabolism of cancer cells, and a marker for identifying which cancers are likely to be sensitive to it. \u00a0The research group of Jason Locasale<\/a> found a protein called GAPDH which switches to the fermentation metabolism, and a compounded called koninjic acid, extracted from fungi, that inhibits GAPDH. \u00a0They have tested koninjic acid extensively in cell lines, and have begun testing in live mice.\u00a0 Whether such drugs are more effective than simply restricting glucose is a topic for investigation.<\/p>\n

\"\"
Explanatory diagram from the Duke study of GAPDH<\/figcaption><\/figure>\n

 <\/p>\n

Mito-targeted Cancer Prevention <\/strong><\/p>\n

\u00a0<\/strong>Supplements that promote mitochondrial health include CoQ10, PQQ, mitoQ\/SkQ, alpha lipoic acid (ALA), carnitine, and melatonin.\u00a0 Can they lower risk of cancer?\u00a0 So far, we have just a few hints; this is a promising area for research<\/a>.<\/p>\n

CoQ10 was studied in the 1990s as a cancer treatment, with some encouraging results [ref<\/a>].\u00a0 PQQ has been shown to kill cancer in vitro [ref<\/a>].\u00a0 One mouse experiment looked at ALA as part of a cancer treatment [ref<\/a>].\u00a0 Use of carnitine remains theoretical [ref<\/a>].\u00a0 Most has been written about melatonin [ref<\/a>, ref<\/a>, ref<\/a>], but even here, there is no epidemiological evidence.<\/p>\n

\u00a0<\/strong><\/p>\n

The Bottom Line<\/strong><\/p>\n

All the evidence for radiation and other mutagens causing cancer might be re-interpreted in terms of mutations to mitochondrial DNA.\u00a0 (Mitochondria<\/a> live in the cytoplasm, outside the cell nucleus, but they have a bit of their own DNA and ribosomes for transcribing it.)\u00a0 Damaged mitochondria can also cause cancer even when their DNA is intact, and Seyfried (after Warburg) makes a strong case that mitochondrial damage is the root cause of cancer. \u00a0Inflammation is probably the single worst source of mitochondrial damage. Do we need one more reason to minimize inflammation? \u00a0Viruses often target mitochondria<\/a> for their own ends, and this may explain cases in which viral infections are associated with etiology of cancer.<\/p>\n

The insight that mitochondrial damage is the root cause of cancer (preceding nuclear mutations) also has broad implications for cancer prevention.\u00a0 As for treatment, there have been a few disappointments and also some promising pilot studies, especially in combining glucose deprivation with radiation or chemo to finish the job (\u201cpress-pulse\u201d).\u00a0 This is a research field that deserves much more attention.<\/p>\n

__________<\/p>\n

*There are exceptions to both these generalizations.\u00a0 There is controversy whether ionizing radiation at low dosages causes cancer [ref<\/a>]; and cell phones (non-ionizing) have been linked convincingly to cancer risk, presumably by a different mechanism than breaking chromosomes [my column last year<\/a>].<\/p>\n

I sent a draft of this column to Thomas Seyfried, who was kind enough to edit it in detail and add references of which I was unware.<\/em><\/p>\n

I was led to this subject by my co-author\u2019s publisher, Chelsea Green, publishers of<\/em>
\n Tripping over the Truth<\/a>, by Travis Christofferson.\u00a0<\/em><\/p>\n","protected":false},"excerpt":{"rendered":"

\u201cCancer is a genetic disease. \u00a0Its primary cause is mutagens in the environment, abetted by time and bad luck. \u00a0A cell is controlled by the chromosomes in its nucleus, and when just the wrong combination of mutations happens to occur, a cell can begin to grow and multiply uncontrollably. \u00a0The next crucial step occurs when … Read more<\/a><\/p>\n","protected":false},"author":65,"featured_media":616,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-615","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-uncategorized"],"yoast_head":"\nIs Cancer a Mitochondrial Disease? - Josh Mitteldorf<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2017\/10\/01\/is-cancer-a-mitochondrial-disease\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Is Cancer a Mitochondrial Disease?\" \/>\n<meta property=\"og:description\" content=\"\u201cCancer is a genetic disease. \u00a0Its primary cause is mutagens in the environment, abetted by time and bad luck. \u00a0A cell is controlled by the chromosomes in its nucleus, and when just the wrong combination of mutations happens to occur, a cell can begin to grow and multiply uncontrollably. \u00a0The next crucial step occurs when ... 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The surprising fact that our bodies are genetically programmed to age and to die offers an enormous opportunity for medical intervention. It may be that therapies to slow the progress of aging need not repair or regenerate anything, but only need to interfere with an existing program of self-destruction. Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for vigorous self care, including exercise, meditation and caloric restriction. After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle and Temple University. He is presently affiliated with MIT as a visiting scholar. In private life, Mitteldorf is an advocate for election integrity as well as public health. He is an avid amateur musician, playing piano in chamber groups, French horn in community orchestras. His two daughters are among the first children adopted from China in the mid-1980s. Much to the surprise of evolutionary biologists, genetic experiments indicate that aging has been selected as an adaptation for its own sake. This poses a conundrum: the impact of aging on individual fitness is wholly negative, so aging must be regarded as a kind of evolutionary altruism. Unlike other forms of evolutionary altruism, aging offers benefits to the community that are weak, and not well focussed on near kin of the altruist. This makes the mechanism challenging to understand and to model. more at http:\\\/\\\/mathforum.org\\\/~josh\",\"sameAs\":[\"http:\\\/\\\/AgingAdvice.org\"],\"url\":\"https:\\\/\\\/scienceblog.com\\\/joshmitteldorf\\\/author\\\/joshmitteldorf\\\/\"}]}<\/script>\n<!-- \/ Yoast SEO Premium plugin. -->","yoast_head_json":{"title":"Is Cancer a Mitochondrial Disease? - Josh Mitteldorf","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/scienceblog.com\/joshmitteldorf\/2017\/10\/01\/is-cancer-a-mitochondrial-disease\/","og_locale":"en_US","og_type":"article","og_title":"Is Cancer a Mitochondrial Disease?","og_description":"\u201cCancer is a genetic disease. \u00a0Its primary cause is mutagens in the environment, abetted by time and bad luck. \u00a0A cell is controlled by the chromosomes in its nucleus, and when just the wrong combination of mutations happens to occur, a cell can begin to grow and multiply uncontrollably. \u00a0The next crucial step occurs when ... 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The surprising fact that our bodies are genetically programmed to age and to die offers an enormous opportunity for medical intervention. It may be that therapies to slow the progress of aging need not repair or regenerate anything, but only need to interfere with an existing program of self-destruction. Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for vigorous self care, including exercise, meditation and caloric restriction. After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle and Temple University. He is presently affiliated with MIT as a visiting scholar. In private life, Mitteldorf is an advocate for election integrity as well as public health. He is an avid amateur musician, playing piano in chamber groups, French horn in community orchestras. His two daughters are among the first children adopted from China in the mid-1980s. Much to the surprise of evolutionary biologists, genetic experiments indicate that aging has been selected as an adaptation for its own sake. This poses a conundrum: the impact of aging on individual fitness is wholly negative, so aging must be regarded as a kind of evolutionary altruism. Unlike other forms of evolutionary altruism, aging offers benefits to the community that are weak, and not well focussed on near kin of the altruist. 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