Mainstream Science’s Dogma Reversal: Aerobic Glycolysis/ Metabolic Alterations are finally seen as Necessary for Cancer Cell Initiation/ Maintenance.
Gregory S. Bambeck Ph.D. and Michael Wolfson J. D., M.B.A
After a half of a century, mainstream big science has completely reversed its dogma on how it is necessary that cancer cells partition their nutrient resources, in a specific way, between material for cell growth and energy production. A thirty years ago modified version of the originally rejected Warburg theory, now has powerful support from newly integrated metabolic pathway studies and core system therapies. This theory was worse than ignored, as it was actively squelched by a small, but elite group, controlling the publication and funding philosophy of cancer during this whole time span. Only the future will tell how much human suffering, could have been prevented, if just honest inquiry and scrutiny had also been allowed to flower, instead of the exclusionary and prejudicial pursuit of personal influence over pet investigative paradigms. Much precious time, knowledge and human life were lost enforcing such preconception, assumption, and opinion upon the course of scientific investigation. Fortunately, but belatedly, data and fact finally triumphed over politics and elevated position. Newly discovered metabolic control systems may benefit us all, not only in the medical area of cancer, but in therapeutic arenas of some other major diseases of aging, as well. A brief human, scientific, data and fact history is contained, herein.
In a watershed reversal of an entrenched fifty four year old dogma, Science magazine published a Special Section issue on 12/03/10 devoted to metabolic energetics; and more so to the diseases of aging, such as heart disease, diabetes II and especially, cancer. Most important, from a historical (and this document’s) standpoint, is the article on p.1340 by Levine and Puzio-Kuter, which concludes that key elements of the Warburg aerobic glycolysis hypothesis are critical to and necessary for the initiation and maintenance of the transition from the normal cell to cancer cell metabolic pattern. In most of our previous (and this) papers, we refer to this conversion as the cancer ‘metabotype.’ This publication did not surprise us, as our prediction that such a ‘revelation’ would happen soon, has its basis not just in new, but in firm, and very old, evidence. From 1956 to near present times, such a pronouncement would have been considered heretical, and so taboo as to be refused publication in any major scientific journal or to have received any research funding by any respectable granting agency. This sorry story goes back to the mid twentieth century. Although science itself may be impartial, scientists, being all too human, are not. Their organizations and institutions consist of hierarchies of power, influence and opinion no different from that of any other political system. Sometimes, even the ‘show me’, ‘replicate to prove’, and peer review crosscheck and verification safeguards of scientific inquiry can be swept away in the emotional heat of the moment. As such, was the fury and wholesale rejection surrounding the towering influence of the Nobel laureate, Otto Warburg and his aerobic glycolysis hypothesis. Fortunately, for science and the rest of us, blunders of this magnitude are rare.
Science, for all its outward appearances of rational intelligence and progresses that have arisen from its aggregate achievements, can obscure the view from inside individual laboratories or in narrow areas of specialization, where it can be actually shown that science moves forward more so in fits and starts, lurches and bounds and often in haphazard random walks. Scientific disagreements usually take place without much beyond a few political ripples, as friendly (or otherwise) combatants ruffle each other’s feathers on a one to one, or small group basis. In short, things do not normally get out of hand.
Such is not the case with the Warburg hypothesis, or the refinements of its one and only significant shortcoming. For over a half of a century, the subject of aerobic glycolysis has been verboten; sealed with skull and crossbones. In 1956, Warburg’s two valid hypotheses went down the same drain used to flush down his third imperfect hypothesis. More significantly, even the study of general intermediary metabolism, itself, has moved into similar backwaters for the last 30 years. How and why did this happen? What has caused such a profound reversal in our thinking? How have we, (science and medicine) been hurt by this? Can we, or do we resolve the inequities of the past and/or give credit where credit is due? What are the medical implications of our newly found logical reversal? Where do we go from here?
Answers to some of these questions, in part or more fully, are available in the Science article referenced in the second sentence of this paper. We highly recommend that the reader look into this article, because it (ever so quietly) represents probably the biggest biomedical upheaval, reversal and revolution in more than a half century. This is no small potatoes. We are looking at a genuine historical paradigm shift of momentous dimensions, the historical importance, of which, aerobic glycolysis naysayers would wish to remain hidden in the attic, like a senile grandparent, because the ‘unquiet’ story version is simply just too embarrassing. We know this is true, because one of us was there; lived it. We take a little different tack than Science, when answering such questions and while remembering the fifty-four year aformentioned history. We are going to talk a little science, but the real heavy stuff we will leave to the reader to find in our short, but highly informative reference list. Regardless, it helps to have a basic background in metabolics, nutrition and bioenergetics or biochemistry 101. For the less technically initiated, scan over the science stuff, paying deeper attention to the human narrative woven throughout this document, as it is instructive in its own way.
About 70 years ago, Otto Warburg, a highly prestigious paragon of theoretical metabolics, hypothesized that aerobic glycolysis, lactic acid production and mitochondrial respiratory deficiency were a triple requirement for the conversion from a normal to a cancer cell. This cellular state completely changed the way a cell made the vital energy carrier molecule, ATP, which is required to power most cellular functions. In a normal cell, glucose is the primary fuel burned to make ATP. This occurs in two stages. The first stage, called glycolysis, burns without oxygen, produces two ATP and feeds its product, pyruvate, into the second stage, called the Kreb’s-OX/PHOS system, which burns with oxygen and produces 32 ATP. The second system also makes two ATP without oxygen. Thus, in total, four ATP (12%) result from burning without oxygen (substrate phosphorylation) and 32 ATP (88%) are made by burning to carbon dioxide, with oxygen (oxidative phosphorylation-OX/PHOS). Glycolysis occurs in the cell cytoplasm, while Kreb’s-OX/PHOS occurs in the cellular organelles called the mitochondria. When oxygen concentrations are limiting (hypoxia), mitochondria cannot burn all the pyruvate that glycolysis produces. So instead, the pyruvate, is converted to lactate and exported from the cell. Rather than dying an energy death due to lack of ATP, the cell elevates glucose importation and the rate of glycolysis increases dramatically (often exceeding 1000%) to make up for the ATP energy production shortfall. When oxygen levels rise, the normal cell system returns back to its efficient 12/88% ATP production ratio. This we call the Pasteur affect. This return to normal does not occur in cancer cells when adequate oxygen supply returns to normal, once again. Thus, Warburg used the term aerobic glycolysis, when ascribing this phenomenon to cancer cells. Warburg stated that cancer cells were different from normal cells in that they were ‘stuck’ in a state of 1) elevated glycolysis, 2) elevated lactate production and 3) mitochondrial oxygen consumption deficiency.
It was postulate number three that became the fly in the ointment. Scientists successfully attacked his mitochondrial respiratory defect concept because many cancer cell mitochondria had normal respiration. Warburg countered that low mitochondrial numbers, on a per cell basis, could yield the results seen, as it is the cell, which is the unit of life. This whole debate came to a head in 1956-1959, in a duel between Warburg and Weinhouse, Chance and others. Warburg’s third hypothesis was upended, when it was demonstrated that more than just a few types of cancer cell mitochondria have normal respiratory chains and that a small number of cancers even show elevated respiration on a ‘per cell’ basis (Warburg, Science 123, 309-314, 1956. Weinhouse, 124, 267-269, 1956. Chance, 128, 700-708, 1959). When Warburg shifted his emphasis toward mitochondrial ATP production deficiency, Weinhouse countered by assuming that normal carbon dioxide production and oxygen consumption were a proof of adequate ATP production. Weinhouse was wrong on this one, but it was before the days of the chemiosmotic hypothesis of Mitchell, and the concept of respiration being uncoupled from ATP was unknown and not readily measurable with the technology of the times, so his knowledge error can be overlooked, but his assumption cannot, because it was no more proven than its antithesis. Even though Weinhouse was very wrong, he won the day. In fact, he won the next four decades, and even in 1999, metabolism was still not considered in Hanahan and Weinberg’s highly touted ‘six hallmarks of cancer’, even though by
Everything that the human race has done and thought is concerned with the satisfaction of deeply felt needs and the assuagement of pain. One has to keep this constantly in mind if one wishes to understand spiritual movements and their development.Everything that the human race has done and thought is concerned with the satisfaction of deeply felt needs and the assuagement of pain. One has to keep this constantly in mind if one wishes to understand spiritual movements and their development.
