On Thursdays at noon Yhouse holds a lunch meeting at the Institute of Advanced Study, in Princeton. The format is a 15 minute informal talk by a speaker followed by a longer open-ended discussion among the participants, triggered by, but not necessarily confined to, the topic of the talk.  In order to share I am posting a synopsis of the weekly meetings.

Synopsis of Michael Solomon’s YHouse Lunch talk 10/26/17

Cancer As A Metabolic Disease

Speaker:  Michael J. Solomon, MD

Present:  Michael Solomon, Piet Hut, Olaf Witkowski, Yuko Ishihara, Steven Lin

TITLE:  Is cancer a metabolic disease caused by mitochondrial dysfunction?

ABSTRACT:  For the past 40 years we have thought of cancer as the result of somatic mutations in nuclear DNA that either block tumor suppressor genes or unblock oncogenes resulting in malignant transformation.  But our success in understanding or in treating cancer has been sadly limited. Thomas Seyfried and others have made a strong case that, in fact, cancer results from the loss of the cell’s ability to obtain energy (ATP) via oxidative phosphorylation, resulting in the cancer cell’s reverting to more primitive metabolic pathways and fermenting glucose (and the amino acid glutamine) even in the presence of adequate oxygen (aerobic glycolysis).  This theory was originally suggested by Otto Warburg in the 1940’s, the so-called Warburg effect.  I will offer evidence supporting the possibility that malignant transformation in all cancer is a metabolic disease resulting from mitochondrial dysfunction and is not a genetic disease caused by nuclear DNA changes which occur secondarily.  This leads to alternative management strategies for cancer without toxic radiation or chemotherapy.  Michael Solomon, MD


     PRESENTATION:  Finding a cure for cancer is almost a cliché, like hoping for world peace.  But I’m reminded of the old joke about looking for your keys under the lamppost when you dropped them elsewhere, because the light is better under the street lamp.  For the past 50 years, cancer research has been focused on the somatic mutation theory that changes in nuclear DNA result in activation of oncogenes and inactivation of tumor suppressor genes.  But we have made limited progress in curing cancer. We still see 1500/day deaths from cancer in the USA with minimal change from 1990 (1,040,000 new cases, 510,000 deaths 1397 deaths/day) to 2010 (1,529,560 new cases, 569,490 total deaths/year, 1560 deaths/day).  While some argue that the incidence of cancer has grown faster than the deaths per day, we are still a long way from a cure.

What makes cells get uncontrolled proliferation, limitless replicative potential, evade apoptosis, become insensitive to antigrowth signals, sustain angiogenesis, and acquire tissue invasion and metastasis?

     Otto Warburg received the Nobel prize in physiology and medicine in 1931. He headed the Kaiser Wilhelm Institute in Berlin under Hitler despite being one quarter Jewish. His mother was Presbyterian and his paternal grandparents were observant Jews, but his father converted from Judaism. Warburg was a friend of Einstein but was apparently a true supporter of Nazi ideology.

Warburg’s theory was that Cancer is the result not of nuclear mutations but of Mitochondrial dysfunction, specifically loss of ability for Aerobic Respiration. He found elevated lactate levels in cancer cells even when adequate oxygen was available.  We will need to look at cell metabolism.

       Energy Metabolism:  Life originated with compartmentalization in cell membranes, coding for replication in RNA/DNA, and use of redox reactions to store and use energy (eventually as ATP).  Reduction/Oxidation reactions in chemistry are coupled reactions in which one molecule donates an electron to another molecule.  One way of thinking about this is that electrons that are further from the nucleus of an atom have greater energy than those closer to the nucleus. By donating an electron, a molecule becomes Oxidized while the recipient molecule gains energy and becomes Reduced. (Piet: the electrons climb out of the energy well.) The nomenclature is a bit confusing here, but a reduced molecule has higher energy.

     For the first billion years of life on Earth, eubacterial and archaebacterial prokaryote (without a cell nucleus) unicellular organisms developed glycolysis.  We know now there are 10 steps (the first 5 require 2 ATP to add energy and the next 5 are exergonic, i.e. release energy) to convert glucose to pyruvate, with substrate phosphorylation (i.e. coupled reactions that do not require oxygen) yielding 2 ATP and 2 NADH and FADH2. NAD+ and FAD are electron carriers that can accept a high-energy electron to become reduced to NADH and FADH2 and carry those electrons for a brief time. Fermentation of pyruvate to either lactose or ethanol occurs in the absence of oxygen in order to recycle NADH and FADH2 to NAD+ and FADH. If you run out of NAD+ then glycolysis stops.  In the presence of Oxygen, the electron carriers move into the mitochondria, as does pyruvate, to enter the Krebs cycle and Electron Transport Chain.  It is of note that the A in FAD and NAD is Adenosine, a nucleotide that is a component of DNA and RNA.  Biology made use of what molecules were available for multiple purposes.

     At some early point photosynthesis arose, providing autotrophs (organisms that can obtain energy from sunlight or from inorganic molecules) instead of heterotrophs (organisms that must ingest organic compounds to obtain energy). Chlorophyll and other pigments (Quinones with an Iron molecule as the center of the electron receptor) trapped sunlight in the light reaction and stored that energy in high energy electrons. The electron carrier in photosynthesis is NADP rather than NAD or FAD.  An electron transport chain evolved in the cell membrane of these photosynthetic cells to store energy as ATP. Then the dark reaction evolved within the cell to convert CO2 + H2O + light energy -à Glyceraldehyde-3-phosphate + O2.  The G3P could be made into Glucose. Thus, carbon based molecules could be made and could store energy for later use.

     A different electron transport chain evolved in the cell membrane of heterotrophs as well, creating a chemical gradient of hydrogen ions, and the amazing complex of ATP Synthase allowed that chemical gradient to be converted to kinetic energy to add a phosphate to ADP to make ATP. ATP is the molecule used by all living cells to provide energy.  ATP fuels all endergonic reactions, DNA replication, cell division, maintaining membrane electrical gradients, muscle contraction, nerve action potentials, and all other activities.  We utilize our body weight in ATP daily! The enzymes used for photosynthesis are not the same as those in the electron transport chain in mitochondria, but both use the same ATP Synthase complex.

     Photosynthesis led to the O2 catastrophe as the atmosphere changed (and the amount of oxygen in sea water increased) and was toxic to many (not to all) anaerobic prokaryotes. 

   Eventually (maybe some 1.5 to 2 billion years ago) eukaryotes evolved, nucleated cells.  Either these eukaryotes or possibly other prokaryotes incorporated archeobacteria as endocytic symbionts that became mitochondria.  This allowed the Krebs cycle (citric acid cycle) to make additional ATP and NADH and FADH2 in the matrix of the mitochondria. Also eventually, the electron transport chain in the cell membrane dramatically improved the efficiency of metabolism.  The only enzyme in the Krebs cycle that is membrane bound is succinate dehydrogenase to oxidize succinate to fumarate. This enzyme is also Complex II in the electron transport chain.  It uses FAD and not NAD+ as the electron carrier.

     Photosynthetic prokaryotes became chloroplasts in plant cells with the cell membrane forming the Thylakoid membrane in stacks in Grana.  Chloroplasts use different proteins in the electron transport chain from those used in mitochondria, but both use ATP synthase to convert kinetic energy from the proton gradient created to make ATP.  The proton gradient in chloroplasts is from inside the thylakoid membrane to the stroma outside. In mitochondria, the protons are pumped into the intermembrane space.

     The Key point is that glycolysis using substrate phosphorylation yields net 2 ATPs, Krebs cycle yields another 2 ATP, but OxPhos using the electron transport chain and oxygen yields 36 ATP. So over 80% of the cells energy comes from OxPhos. (Aerobic Respiration includes Krebs + electron transport chain, but often refers only to electron transport.)  OxPhos is dramatically more efficient than glycolysis in providing energy from glucose and allowing evolution of multicellular organisms and processes that require more energy.  In fact, OxPhos captures about 40% of the energy in glucose.  While this may not appear good at first, the best cars are about 20% efficient.  And while obtaining only 2 ATPs from glycolysis may seem minimal compared with the 38 from aerobic respiration, glycolysis was sufficient to sustain life for one billion years, no small feat.

      Oxygen is the ultimate electron receptor.  In Hypoxia, signals from the mitochondria to the nucleus turn on adaptive genes and turn off OxPhos genes.  Normally cells resume OxPhos when oxygen returns.  But cancer cells CANNOT, and continue glycolysis and fermentation even in the presence of oxygen. 

       This inability of cancer cells to perform oxidative phosphorylation (aerobic metabolism) and reliance solely on glycolysis to meet all the cell’s energy needs, leads to a treatment strategy by restricting Glucose and Glutamine (an amino acid that can be converted to glucose and used for energy).  All noncancerous cells (even brain cells, which normally use 20% of the body’s total glucose) can use alternative fuels including ketones for aerobic respiration in the mitochondria.  A ketotic diet along with Dietary Calorie Restriction to 60% of daily calories calculated for height and weight can slow down or stop the growth of cancer cells. 

     To stop the growth of cancer you must become Ketotic.  Ketones (Beta Hydroxy Butyrate and Acetaldehyde) are breakdown products of fat and can be measured in the blood. They spill into urine also.  Blood glucose must fall to the 50 – 60 mmole range instead of 100.  Ketosis is not Ketoacidosis.  The latter occurs in type 1 and some type 2 diabetics due to lack of insulin so glucose cannot enter cells and blood glucose gets very high.  The liver makes ketones from fat as an alternative energy source for cells that cannot get glucose in and blood ketone levels become extremely high (in the hundreds to thousands). Ketones are acids and exceed the buffering capability of the body leading to dangerous acidosis.  On the ketotic diet, ketone levels are about 4 or 5 in blood.  Humans did not evolve to eat three meals a day, but to eat one meal every three days.

     What evidence do we have for this theory?  In nuclear transfer experiments, when you remove the nucleus from a cancer cell and put it in a mouse ovum, you get a normal blastocyst and embryo.  If you take the nucleus from a normal ovum and put that nucleus into an enucleated cancer cell, you get cancer cells in tissue culture.  It’s not in the nucleus! Nuclear gene changes are secondary to metabolic dysfunction.  That’s why we see no consistent gene mutations even in metastatic sites from a single patient. There is a problem with “Personalized treatments” aimed at which mutations are detected.

     Look at Renal Cancer:  Marston Linehan and his team at the NIH have made amazing progress in identifying the genes associated with the four subtypes of kidney cancer.  The most common form of kidney cancer is clear cell carcinoma. Von Hippel Lindau syndrome is a familial syndrome in which members get hemangioblastomas (vascular tumors), pancreatic and other tumors, and clear cell renal carcinomas.  The gene for VHL was identified on chromosome 3.  But surprisingly, this same gene mutation was found in 90% of clear cell renal cancers occurring in patients without VHL. If you look at what the VHL gene does, you find that it codes for a protein complex that turns off Hypoxia Inducible Factor.  HIF is intended to turn on when oxygen is gone and then turn off rapidly when oxygen returns.  When the tumor suppressor VHL gene is mutated, the Alpha HIF remains active and blocks OxPhos in favor of glycolysis.  The gene associated with papillary renal cancer (familial leiomyomatosis and papillary renal cell cancer) is Fumarate Dehydrogenase, a Krebs cycle enzyme that converts fumarate to malate.  It is likely that the nuclear changes seen are not primary but are secondary to damage to the mitochondria which signal the nucleus to compensate for inability to get sufficient energy.

     We use for PET scanning FluroDeoxyGlucose and see increased uptake in cancer tissues that are taking more glucose.  This is often misinterpreted, but is not because there is increased blood flow, but because the cancer cells require much more glucose for energy production.

      Because there were few attendees at the talk, we modified the format, and questions and discussion were incorporated within the presentation.  This discussion has been included in the synopsis. However, some additional discussion was held regarding Mitochondrial structure and function. We have 100 to 10,000 mitochondria per cell depending on the energy requirements of that cell.  Mitochondrial DNA is in a ring as in bacteria and not in linear chromosomes, and each mitochondrion has 10 to 100 mitochondrial DNA copies per mitochondria instead of just two copies of the DNA in the cell nucleus.  Mitochondrial division is not linked to nuclear replication. Also, like bacteria, mitochondria can perform both fission (dividing into two cells) and fusion (two cells becoming one) to mix the mitochondrial DNA.  When the mitochondria replicate the mtDNA rings migrate randomly to the two daughter cells, so if some of the mtDNA contain mutations, those may or may not lead to phenotypical findings depending on the threshold for gene expression. The mtDNA triplet code is somewhat different from nuclear.  Only maternal mitochondria are passed on in sexual reproduction.  In sperm, the mitochondria all fuse into one giant unit, the NEBENKERN, and attach to the flagellum and are then destroyed by lysozymes in the egg once fertilized. Why this occurs and provides an advantage is not at all clear.  More mutations occur in mtDNA partly from different DNA replicase and repair enzymes and partly from increased Reactive Oxygen Species. We see recognized mitochondrial diseases now, the first was Lebers Retinopathy.  A common misconception is that plants have chloroplasts and animals have mitochondria.  In fact, while only plants have chloroplasts, both all plants and all animals have mitochondria.

     Why most cancer researchers have not pursued this proposal, that mitochondrial damage and inability to preform aerobic respiration even in the presence of adequate oxygen is the hallmark of malignancy, is not clear to me.  The book “Tripping Over The Truth” by Travis Christofferson is a worthwhile read in this regard.  So is the textbook Cancer As A Metabolic Disease by Thomas Seyfried.  The amazing progress in nucleotide sequencing and in the technology for understanding genetics has led to more funding and research.  There is little financial incentive for the pharmaceutical industry for discovering a dietary treatment.  The Fall 2017 Penn Medicine, U. Of Penn School of Medicine periodical, included an article entitled Symbiosis Inside Our Cells on Douglas Wallace, PhD and some 250 staff actively researching mitochondrial diseases.  It should be emphasized that the calorie restricted ketogenic diet does not cure cancer, but only slows or stops the growth of cancers that cannot meet their energy requirements other than by glycolysis.  Additional treatments in conjunction with the diet are needed. Hyperbaric oxygen has shown some benefit in brain cancers.  It is also true that compliance with the ketogenic calorie restricted diet is extremely difficult.  It is only in comparison to treatments that will surely be considered barbaric in the future:  mutilating surgery, toxic chemotherapy, and the use of radiation that is somehow both a cause and a cure for cancer, that this dietary regimen may seem preferable.  Hopefully, further investigation of the role of mitochondria in cancer as well as in other presently idiopathic diseases will result in future cures.

     We ended our discussion here.

Michael J. Solomon, MD