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June 2017 Volume 13: Issue 2 Introduction Afterwards, it is believed, he feared causes of cancer. He said, “Cancer, the development of cancer. This prob- above all other diseases, has countless Louis Pasteur observed two types ably saved Warburg’s life. He was the seconday causes. Almost anything of energy production in the world of most prominent cancer researcher in can cause cancer, but even for cancer, single cells. The most primitive form Germany during the Second World there is only one prime cause. The of energy production is anaerobic and War. Hitler turned a blind eye to his prime cause of cancer is the replace- does not use oxygen. This process is Jewish ancestry and ordered him to ment of oxygen in normal body cells also called fermentation and is utilized continue his research on cancer. by fermentation of sugar.” in manufacture of beer and wine. This is considered a more primitive form In 1944, Warburg was nominated Reference: of energy production. for a second by Albert https://en.wikipedia.org/wiki/Otto_Heinrich_ Szent-Gyorgyi, the scientist who iso- Warburg The second form of energy produc- http://www.nobelprize.org/nobel_prizes/medi- lated vitamin C, for his discovery of tion noted by Pasteur is aerobic which cine/laureates/1931/warburg-bio.html the involvement of nicotinamide (vi- means that it utilized oxygen. This Christofferson, Travis, Tripping Over the Truth, tamin B3) and flavin in fermentation. North Charleston, SC: CreateSpace Independent process is also called respiration. It is Flavin is a yellow pigment found in Publishing Platform, 2014, 32. the form of energy production used by and vitamin B2. Hitler for- https://commons.wikimedia.org/wiki/DNA#/ most multicellular organisms. media/File:Dna-split.png bade Germans from accepting Nobel Otto Warburg Prizes in 1937. Warburg showed that normal body The DNA Hypothesis Otto Warburg greatly admired cells turned to cancer cells when they Louis Pasteur. He became convinced Percivall Pott was the first scientist are deprived of oxygen for even a few that a defect in energy to show that cancer could be caused hours time. There was no need to in- was central to the development of by an environmental carcinogen. In troduce carcinogens, radiation, or vi- cancer. He believed this because of 1775 Pott associated chimney soot as ruses to achieve this transformation. the nonspecific nature of the disease. a direct contact carcinogen leading This led Warburg to conclude and to scrotal cancer in chimney sweeps. Warburg won a Nobel Prize in promote the idea that the creation of The primary carcinogen in chimney 1931 for his discoveries relating to cancer cells was due to a defect in cel- soot is also a prime energy production in cells. One of his lular energy metabolism which later suspect in various observations was that cancerous cells came to be identified with the -mito caused by can live and develop in the absence of chondria or energy factories of the smoking cigarettes. oxygen. Today the ability of cancer cells. Pott’s work result- cells to ferment glucose even in the Warburg never gave up his convic- ed in the Chimney presence of oxygen is known as “the tion that the primary cause of cancer Sweepers Act of Warburg effect.” was alterations in glucose metabolism 1788 which sought Warburg had a Jewish father and and energy production. In 1966 at age to reduce the risk lived in Germany throughout the Sec- 82 near the end of his life Warburg of cancer among ond World War. In 1935 Hitler had a summarized his belief about cancer as the young boys polyp removed from his vocal cords. he discussed primary and secondary who were working

Copyright © 2017 by Jim McAfee. All rights reserved. 1 specific. the voracious appetite of cancer cells fir glucose. Warburg Continues II binds with a protein Pete Pedersen of Johns Hopkins called VDAC preventing suicide of worked in a laboratory run by Albert cancer cells () and making Lehninger. Leninger had discovered cancer cells immortal. Hexokinase II that mitochondria were the site of also positions itself in the in such the cells’ energy production. He also a way that it can steal ATP (the energy as chimney sweeps. knew Warburg personally. Like a dog produced by the cell). In 1966 Francis Peyton Rous was after a stick, Pedersen became fixated In 1991 a brilliant South Korean awarded a Nobel Prize for his work on the metabolism of cancer cells. He scientist, Young Hee Ko, came to showing that could cause found that the cancers that grew the work in Pedersen’s laboratory. She cancer. In 1911 a woman walked fastest and were most aggressive had discovered that a molecule called 3BP into the Rockefeller Institute in New a smaller number of mitochondria and (3-bromopyruvate) could enter the York City carrying a chicken with a fermented more glucose. Tumor cells cell and mortally damage hexokinase large tumor on its breast. Rous surgi- that grew the fastest invariably had II. Ko demonstrated that this com- cally removed the tumor, sliced it into about half the mitochondria of normal pound was much more effective than pieces and placed it into the bodies of body cells. traditional chemotherapeutic agents at other chickens which subsequently Mitochondria of cancer cells were killing cancer cells in virtually every developed cancer. Later Rous filtered also abnormal in structure. They were type of cancer cell tested. Over 100 out bacteria and cancer cells showing missing important internal mem- tissue studies demonstrated the ef- that viruses were causing the cancers. branes and had abnormal protein and fectiveness of the compound against In 1953 and Fran- content. Pedersen has discovered cis Crick discovered the structure why the Warburg effect takes place. of DNA. It became obvious that the In 1977 Pedersen and a graduate stu- DNA stored information. The scien- dent, Ernesto Bustamante, identified tific community moved away from a chemical messenger, mitochondrial Warburg’s focus on the mitochondrial hexokinase, responsible for pushing origin of cancer and concluded that cells into utilization of fermentation defects in the DNA caused by chemi- for energy production. cal carcinogens, viral infection, or ra- Hexokinase exists in four differ- dioactivity. ent forms (isozymes). The cancer cell It did not take long to trace the produces vastly more hexokinase II, cancer-causing Rous had found normally present in only tiny quanti- in chickens to a defect in a specific ties in the normal cells of the body. gene triggered by the virus. It was This form of the forces glu- named src for sarcoma. This gene was cose down the fermentation pathway found to regulate kinases, key signal- and ignores the regulatory signals of ing molecules in the cell. The viral the cell to slow down. version of the src gene was stuck in The fact that cancer cells stuff the on position causing cells to divide themselves with glucose due to high over and over again. Science began a levels of hexokinase II became the ba- largely fruitless search of DNA for the sis for the PET scan, one of the most cause of cancer. accurate means of identifying where The association of cancer with cancer tumors exist in the body. A DNA led to chemotherapeutic treat- glucose molecule is combined with a ments targeted at preventing replica- fluoride molecule. This “tagged - glu tion of DNA. These treatments kill cose” (FDG or gluorodeoxyglucose) cancer cells, but they also have a can be easily detected by the PET devastating effect on healthy cells. scan. The PET scan is utilized in vir- In other words, the treatments are not tually every cancer center in the world and provides powerful illustration of

Copyright © 2017 by Jim McAfee. All rights reserved. 2 Evans, Josie M., et al., Metformin and reduced as a Metabolic Disease. It this book risk of cancer in diabetic patients, BMJ, June 4, 2005,330:1304-1305. he argues that epigenetic signaling https://en.wikipedia.org/wiki/Percivall_Pott travels from damaged mitochondria https://en.wikipedia.org/wiki/Chimney_Sweep- to the nucleus of the cell altering the ers_Act_1788 expression of the genes which have https://commons.wikimedia.org/ the potential to cause cancer. This sig- wiki/Category:Mitochondria#/media/ File:Blausen_0644_Mitochondria.png naling by the mitochondria is called By Kuebi = Armin Kübelbeck - Own work, CC the “retrograde response.” BY-SA 3.0, https://commons.wikimedia.org/w/in- The signals from the damaged mi- dex.php?curid=17398088 tochondria alter the energy production cancer cells. https://commons.wikimedia.org/wiki/ Ko then tested the compound on File:Ketogenic_diets_pie.png of the cell from aerobic metabolism to rabbits. The compound killed cancer fermentation of glucose as a source of cells in living rabbits without killing Caloric Restriction energy for the cell. the animals. Rat studies produced Caloric restriction and fasting In other words, the mitochondria similar results. have been repeatedly shown to reduce are sending a message to the DNA of Ko also was able to sucessfully the risk of cancer and retard cancer the cell: “We cannot produce energy treat one human subject with her growth in both animals and humans. in a normal way and need to alter the compound. At this point the promis- These practices promote improved functioning of this cell to ferment glu- ing new compound became tied up in energy production and rejuvenation cose. Let’s become a cancer cell.” The legal battles and politics. of mitochondria in cells. changes in the DNA are secondary to damage to the energy producing mito- Bert Vogelstein at Johns Hopkins Barrett and associated wrote, “Cal- chondria and the messages they send University achieved recognition when orie restriction (CR) is the most effec- to the DNA of the cell. his laboratory identified mutations of tive and reproducible intervention for the p53 gene in cancer. Mutations of increasing lifespan in a variety of ani- Seyfried’s hypothesis is support- p53 are the most common of all alter- mal species, including mammals. CR ed by research conducted by Warren ations in the DNA of cancer cells af- is also the most potent, broadly acting Schaeffer. Shaeffer placed the DNA fecting over 50% of cancers. In 2003 cancer-prevention regimen in experi- of cancer cells into normal cells. The Vogelstein was recognized as the most mental carcinogenesis models.” DNA tended become normal. He then frequently cited scientist in the world Dr. Thomas Seyfried was drawn placed normal DNA into cancer cells. during the previous 20 years. to research fats. His particular focus The normal DNA was altered by the damaged mitochondria. The research- Voelstein’s research led to the con- was on gangliosides which look like ers wrote, “...we have found evidence cept of intratumoral heterogeneity. In a blooming flower on the outer mem- to support the theory that the cyto- other words, most tumors have a wide brane of cells. These fats relay signals plasm from a normal cell can suppress variety of different mutations for cell and are central to cell to cell commu- tumorigenicity.” to cell making treatment with a sin- nication. They constitute 6% of all the gle drug almost impossible. In 2008 phospholipids in nerve cells. The implications are enormous. It Voelstein linked a mutated oncogene When Seyfried fed these to shifts the focus of cancer treatment direcly to defective energy produc- animals with tumors he was surprised and prevention from the DNA to the tion. In 2006 metformin which alters to see a slowing of the growth of the energy production of the cell in the energy metabolism in diabetics was tumors. A grant to study gangliosides mitochondria. The key to addressing shown to reduce cancer risk. as a cancer treatment found that the cancer becomes focusing on the en- ergy production of the cell in the mi- Research on the energy metabo- primary reason these lipids slowed tochondria. lism of cancer cells appears to be cancer development was because they bearing fruit, while targeting changes decreased appetite and promoted ca- References: in the DNA has met with only limited loric restriction. Seyfried concluded Barrett, J. Carl, Calorie restriction, aging, and cancer prevention:Mechanisms of action and ap- success. that many of the drugs being tested plicability to humans, Annual Review of Medicine, References: to treat cancer did nothing more than Feb. 2003; 54:131-152. Pedersen, Peter L., Ko, Young H., et al., Hexoki- make animals and people lose their Weindruch, Richard, et al., Caloric restriction nase-2 bound to mitochondria: Cancer’s stygian link appetites. The question was why ca- delays disease onset and mortality in rhesus mon- keys, Science, July 10, 2009; 325(5937):201-204. to the “Warburg effect” and a pivotal target for ef- loric restriction inhibited cancer. fective therapy, Semin Cancer Biol, Feb. 19, 2009; https://en.wikipedia.org/wiki/Ganglioside 1:17-24. In 2012 Seyfried published Cancer Israel, Barbara A., and Schaeffer, Warren I., Cy-

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toplasmic supression of malignancy, In Vitro Cel- evaluates this study. lmed.3003293. lular & Developmental Biology, September 1987; Longo, Valater D., et al., Fasting: Molecular 23(9):627-632. It appears that fasting and a ke- mechanisms and clinical applications, Cell Metabo- togenic diet may not be effective in lism, February 2014; 19(2):181-192. Ketogenic Diet and curing cancer, but they can be useful Safdie, Fernando M., et al., Fasting and cancer Cancer adjuncts to other treatments that in- treatment in humans: A case series report, Aging, December 2009; 1(12): 1-20. terere with the ability of cancer cells A ketogenic diet tends to put pres- to utilize oxygen or treatments that sure on cancer cells. It upregulates place oxidate stress on cancer cells. A glutathione in normal cells, but not in number of food substances such as al- Web Resources cancer cells. This makes normal cells lium and cruciferous vegetables have www.imageawareness.com more resistant to oxidative damage proven anti-cancer properties. These www.yourbodyssignlanguage.com and cancer cells less resistant. nutrients could be incorporated into a In a study by Seyfried and associ- www.jimmcafee.com ketogenic dietary regimen as well. As Disclaimer ates the combination of a ketogenic far as I know, no one has conducted a This publication contains the opinions diet and hyperbaric oxygen increased test along these lines. the survival time of mice with sys- and ideas of its author. It is intended to pro- References: temic metastatic cancer by 77.9%. vide helpful and informative material on the Seyfried, Thomas N., et al, The ketogenic diet subjects addressed in the publication. It is The ketogenic diet alone increased and hyperbaric oxygen therapy prolong survival survival time by 56.7% in mice with systemic metastatic cancer, PLoS provided with the understanding that the au- thor and publisher are not engaged in render- Safdie reported in 2009 that fast- One,June 5, 2013; 8(6):e65522. Jarrett, Stuart G., et al., The ketogenic diet in- ing medical, health, or any other kind of per- ing decreased the side effects of che- creases mitochondrial glutathione levels, Journal of sonal professional services in this newsletter. motherapy without interfering with Neurochemistry, August 2008;106(3):1044-1051. The reader should consult his or her medical, the effectiveness of the treatment. Lisanti, Michael P., et al., Ketones and lactate ‘fuel” tumor growth and metastasis, Cell Cycle, health or other competent professional before Fasting and a ketogenic diet de- 2010; 9(17): 3506-3514. adopting any of the suggestions in this news- crease insulin levels and IGF-1 (in- http://livinlavidalowcarb.com/blog/do-ketones- letter or drawing inferences from it. sulin-like growth factor 1). Both of fuel-cancer-the-low-carb-experts-respond/10124 The author and publisher specifically dis- these substances increase the risk of Longo, Valter D., et al., Starvation-dependent differential stress resistance protects normal but not claim all responsibility for any liability, loss, developing cancer cancer cells against high-dose chemotherapy, PNAS, or risk, personal or otherwise, which is in- June 17, 2008; 105(24):8215-8220. There is one flawed study by curred as a consequence, directly or indirectly, Lisanti which suggests that ketones Longo, Valter D., et al., Fasting cycles retard growth of tumors and sensitize a range of cancer of use and application of any of the contents of fuel cancer growth. A reference is cell types to chemotherapy, Sci Transl Med, Mar this newsletter. provided (livinlavidalowcarb) which 7, 2012; 4(124): 124ra27. doi:10.1126/scitrans-

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