the inhibitory effect of the castania sativa extracts on ...

THE INHIBITORY EFFECT OF THE CASTANIA SATIVA EXTRACTS ON THE MALIGNANT CELL CULTURES©1 Czimbalmos-Kozma, Ferenc, MD.(1), and Papp, Erika, MD.(2) (1) – DCH MED Ltd. 7695-Mecseknadsd, Mezo 13., HUNGARY (2) – Mohacs City Hosp., Dept. of Internal med. 7700-Mohacs, Szepessy T. 7., HUNGARY 7695-Mecseknadsd, Mezo str. 13., P. O. Box 24., HUNGARY

E-mail: [email protected] ; [email protected] ; website: www.cancer.uw.hu 1 - Because of the inter-disciplinary character of this study, and because not all readers have advanced mathematical and medical knowledge, the authors deemed useful to include some references and citations of classic knowledge from easy accessible sources, with the indication of origin and furthermore a bibliography index to render text understanding easy. Sources and bibliography data are indicated with [“number”] symbols.

THE MITOCHONDRIAL THEORY OF CANCER© The use of the Turing-Machines in the Modelling of the Malignant Cell Behaviour© ABSTRACT: Considering the cell like a system [1], in the mathematical sense of the wording, we introduce the concept of the non-virtual, “biological" Turing-machines [2] in the modeling [3] of cell and malignancy [4]. The programmed cell death [5] can be described like a "self-stopping program" of the cell. The cell is modeled like a non-virtual, “biological" Turing-machine. The process of the programmed cell death rules in the interest of the living organism, described like the set [6] of cells, thus achieving in our activity the cooperative model of the game theory [7]. This mathematical model has unexpected consequences in understanding malignancy processes. The programmed cell death process of some cells operates in the interest of the living organism, and “disconnects" the wrong element of the set in the interest of the persistence of the cooperative model in the set. This cooperation is the basis of the life functions of the living organism. Because the mitochondria [8] are “included" type non-virtual “biological" Turing-machines within the elements of the set, included like archaic endosymbionts [9] before the development of multi-cell organisms, they, like the endosymbiont bacteria [10], are cooperative only with the “including" host cells and not with the set of this cooperative “includer" host cells – they are isolated “inside" within the “includer" host cells and are cooperative with hosts only when such cooperation serves the interests of the “included" elements too. The programmed cell death is the death of the ”included" mitochondria too, and thus the defense reaction of these included elements is expectable, as they try to survive said process in disagreement with their own interests. Normally, the mitochondria are under severe control inside in the host cells, but in pathological situations we cannot rule out their "escape" and respective change of their cooperative pattern of behavior into a non-cooperation [7], intracellular parasite pattern, probably achieving supra-regulation of host cell processes, and thus blocking programmed cell death and causing host cells to multiply and assure their own reproduction, transforming host cells into “zombie" malignant cells (such cells in this model can be the outcome, but not the cause of malignancy) serving only the interests of these agents, resulting from endosymbionts intracellular parasites (intracellular parasitism and cell multiplication-induction like the EBV in the Burkitt's lymphoma[44]). The used basic mathematics-based model, which is useful in the life sciences also, was originally described by Alan Turing [2] and is now adapted to modeling malignancy. We used mathematical notions from the game theory also; they are the notions described by John von Neumann and John Nash [7] and the NKS of Stephen Wolfram (the basic concept of this work is the algorithm-like pattern of malignancy). The deductions arising from the mathematical modeling of malignancy may have unexpected consequences in practice, too. Some microorganisms (Mycoplasma [13], Phytoplasma [14], etc.) are very similar with the archaic proto-mitochondria [11] (and, probably, with the non-cooperative mitochondria of the tumor cells [12]. Some plants, like the sweet chestnut, contain defence substances against microorganisms, like Mycoplasma, and some bacteria develop antibiotic [15] substances having such destination (see the analogy with the penicillin [15] of the Penicillium), serving in ecosystem competition. In the authors’ preliminary laboratory tests [16], these substances manifested inhibitory effect on some tumor cell cultures [17] (these results are based yet on initial tests, and need to be confirmed by independent sources). In theory, it is possible to see the similar effect of some antibiotics, like the macrolides [18] used against this micro-organisms (Mycoplasmas [13], Phytoplasmas [14], etc.) today in therapy: this plant extracts bacterial toxins, antibiotics – targeting [19] the non-cooperative mitochondria of the tumor cells – hypothetically can be (in combination with classic anti-tumor drugs) a useful adjuvant in cancer therapy [19]. KEYWORDS:

Turing-machines [2], Malignancy [4], Mitochondria [8], Anti-mitochondrial target [16].

CONTENTS:

subsequent to the emergence of the problems in the set theory [35] and the formulation of the Gödel article [36] about the un-decidable problems, today we cant hope that the Langlands program and the NKS can at last shed the much desired light. The situation in the medicine, particularly in cancer research, is even worse as compared to mathematics. We cannot speak today about any long-term, mathematically-based, serious and logical strategies that can constitute useful guidelines for the future. Over the past 100 years of the cancer research, one can refer only to short-term tactics, and, sometimes, only fashion modes. Ideas about bacterial and viral origin of malignancy [37], the research for hidden embryonic cells [38] are the moments of these heroic but strategically uncoordinated efforts. The situation is complicated with controversies about the complexity of the cancerdevelopment process: involving some delimited cell clones or biochemical mechanisms are declared reductionism ideas by the believers of multi-aetiology and multi-step development process of malignancy [39]. All too many people forgot the awareness-creating example of Robin Warren (treatment of peptic ulcer is possible with antibiotics, without resection involving drastic operations; the aetiologic role of the saprophyte-believed Helicobacter pylori is NOT reductionism but is the simple but useful reality) [40], and are involved in the jungle of the no-end complicated research of molecular biology [41] processes; moreover, do not forget the new trends of the oncogene [42] hunting and multiple 6 cancer therapies with monoclonal antibodies [43]. We can see heroic, expanded and expensive tactic efforts, but the long-term, mathematically founded, logical, serious strategies and real, logically acceptable guidelines for the future simply fail to exist as yet. Important questions about cancer are still lacking response. The malignant process kills the host organism. Could it be that evolution developed a complex, self-destructive code? The behavior of the malignant cell clone in the host's organism involves clone evolution [23], multiple, complex, developed, targeted processes with the capacity of adaptation and development [4]. Can be this be the outcome of wrong, faulty processes and loss of functions? With the apparition of the malignant clone in the host organism, new patterns and processes emerge, in contradiction with the host's interests. Can this appear in the absence of the participation of an alien code in the system, as we don't know any example of action of any alien code in the organism [44], very similar with the malignant processes? Evolution begins with unicellular organisms in the ancient ocean [45]. Sure isn’t there present any alien, hidden code, coming the very beginnings of evolution, in the host organism? It is mathematically possible to answer "yes" to all this questions, modelling mathematically the cancer behaviour process, working only with strictly logical principles? Can have any long-term, mathematics-based, serious strategies being useful guideline for the future without responding first to this questions? Sure NOT. By understanding the processes of the life we open a door to treat diseases. Biochemistry, molecular biology, genetics, immunology are the tactics in the war with cancer. But only short-time tactics. Today, we lack strategy. Trendy approaches, such as embryonic cells once were and oncogenes are today, fail short of being a serious long-term strategy in this war (which is in the defensive now). The long-term strategy can be only a mathematics-based long-term strategy. In all serious sciences long-term strategies rely on mathematics. This is not as yet the case in medical sciences, in which said role is pretty small. We have questions and must come up with answers. We need to decide, using “high-end mathematics,” what cancer may be and what it is not for sure. First, we need to reflect about modelling cancer. We can model cancer via formulas [46]. The cancer process is a dynamic [47], rolling process, not a static stage. In this study we use algorithms [48] to describe the aspects of the malignancy. Using algorithms is not a new idea. We know a very developed and modern system of thinking, using algorithms: the NKS [34]. A New Kind of Science is a book by Stephen Wolfram, published in 2002. It contains a study of computational systems such as cellular automata. Wolfram calls these systems simple programs and argues that the scientific philosophy and methods appropriate for the study of simple programs are relevant to other fields of science [34]. The thesis of A New Kind of Science is twofold: that the nature of computation must be explored experimentally, and that the results of these experiments have great relevance to understanding the natural world [34]. What is THE NEW KIND OF SCIENCE? See: http://en.wikipedia.org/wiki/A_New_Kind_of_Science ; Wolfram, Stephen, A New Kind of Science. Wolfram Media, Inc., May 14, 2002. ISBN 1-57955-008-8 Wolfram, Stephen, "Quick takes on some ideas and discoveries in A New Kind of Science". Wolfram Media, Inc. NKS 2004 conference. Wolfram Media, Inc. ; InformationSpace. Causal set exploration tool which supports 1 dimensional causal sets such as those found in the book. Wolfram's NKS Conference blog, June 2006. An other very important question in the modelling the behaviour of the cancer cell is the flow and the pathways of the information during the multiplication of the cell, and the informatic pathways of the regulation of the processes in the cell. We use for this the Turing machines. In the conception of this study, the cell is the materialisation of the hypercomplexe, but logic, non-virtual Turing machine. What is THE TURING MACHINE? See: http://en.wikipedia.org/wiki/Turing_Machine ; http://en.wikipedia.org/wiki/Alan_Turing Stephen Wolfram, A New Kind of Science, Wolfram Media, ISBN 1-57955-008-8 Turing, Alan (October 1950), "Computing Machinery and Intelligence", Mind LIX (236): 433–460, doi: 10.1093/mind/LIX.236.433, ISSN 0026-4423, http://loebner.net/Prizef/TuringArticle.html, retr. on 18 August 2008 Hodges, Andrew (1983). Alan Turing: The Enigma. New York: Simon & Schuster. p. 5. ISBN 0-671-49207-1. The living cell as Turing-machine [16]. Normal cell as multi-input, multi output, non-virtual, analogue, autoreproductive, „includer” „biological Turing-machine” with informatic pathways and with the mitochondrion, as multi-input, multi output, non-virtual, analogue, autoreproductive, „included” biological Turing-machine with informatic pathways (ITM) and the correspondent parts of the virtual Turing-machine:

1. Introduction (1) (2) 2. History and some references to the classic knowledge (1) 3. About the mitochondria in cancer cells (1) (2) 4. Modeling cancer (1) 5. Ecology-related aspects of the endosymbiosis of the mitochondria (1) (2) 6. Cancer therapy and mitochondria (1) (2) 7. Practical consequences of the study (1) (2) - The components of the Castanea sativa Mill., as possible cancer cell inhibitors (1) (2) - Results of the laboratory tests with Castanea sativa Mill. extracts (1) (2) - Effects of bacterial toxin in malignant cell culture (2) 8. Conclusions (1) (2) 9. Bibliography (1) (2)

4. MODELLING THE CANCER Modelling the malignant processes by mathematical methods is based in this study on the next principles: - Whatever exists, can be modelled by mathematics - What is mathematically modellable, may be possible - Something that surely cannot be modelled (to be more precise: when the contrary is modellable) simply not exist - Something existing may exist upon an unknown model - If something exists upon an unknown model, and we find such a model, which can be reproduced, such a model can be true also in case there are unexpected properties.

(1) by Czimbalmos-Kozma, Ferenc, MD. (2) by Papp, Erika, MD. 1. INTRODUCTION Life should be logical. Because life is a part of the Universe, and “the mathematics of the Universe should be beautiful” (Garrrett Lisi) [20], the life should have a beautiful mathematics [21] too, and, naturally, all the processes of the life should be logic [21]. Life processes lacking reason simply does not exist. Another question is the usefulness of various biological processes. A process should be useful only for the party making the rules in its own interest. Exceptions are biological communities: symbioses [22], co-habitant groups, populations organized in societies and organisms. Yet the sacrifice of a member of the community is useful for such members too: without living in such a community where the need to assume the risk of the sacrifice arises, they have no possibility to stay alive - the risk assumed behaviour is in the end the only way to survive in some conditions. The processes of life must be logic and mathematically modellable [3]. If we see something we fail to understand in life processes, we search for the logics of such phenomena. Thus, when we come to know some details of the process, parts apparently suggesting being parts of the one puzzle image, we try to predict the entire image. But finally the puzzle can be built only in one logical structure: the reality is only one and cannot be divided – something cannot be true and not true simultaneously. When we have something for sure, verified pieces and partial knowledge about the puzzle image, we then have ideas about what can the image be (we may have not only one concept in the initial stage). But only when we gather some additional knowledge we can make progress in assembling the puzzle image, and come to know what the final puzzle image may be. Only now we have some guidelines on how to build the puzzle, but we have too some ideas referring to what we shouldn’t try to do with the puzzle pieces, because it’d surely translate into a mistake. Thus we arrive to a situation which points out that certain facts force us to depart from the current ideas about the possible puzzle image and to pursue some other approach that apparently looks weirder, yet nevertheless the mathematical possibilities and the output of the working models suggest that no other solutions are allowed. Today we have a lot of pieces of the final puzzle image of malignancy [4]. The guidelines to assemble the puzzle is based on the idea that malignant tumours emerge because of multiple causes, in steps, because of wrong mechanisms and loss of control of processes, which results in cells having lost functions and non-limited capacity of reproduction [4]. But here we encounter problems: the resultant malignant tissues have new, special, complex functions [23], useful for themselves only – from the loss of function and wrong mechanisms cannot arise special, developed, targeted functions having the capacity of adaptation. And the resultant malignant tissues make something exactly contrary to the interests of the organism: apparently the organism poses a non-logical program and operates with a loss of reason. But this is not probable. We think all the processes of life should be logical, and life processes with loss of reason simply do not exist. In this piece of work we try to find a logical model for rationally assembling the known parts of the malignancy puzzle. This study examines the mathematical considerations of the possible mitochondrial (exactly: the mutant-mitochondrial) aetiology of the malignancy, in part based on finding the logically possible and not possible models of the cells, as systems, in the structural concept of the Turing-machines, in part based on the logically possible information pathways in the cell division and classic knowledge in life evolution [24] theory, cell biology [25], genetics (specially mitochondrial genetics of the different species, from the point of view of evolutionary biology [26]), and presents the authors’ original theories as to mathematical modelling of malignant processes, describing the algorithms of the possible actions of the mutant-mitochondria (arising from endosymbionts to intracellular parasites) in the process of the malignization; in short, it presents some preliminary results from the authors’ original experimental lab works [16] with possible anti-mitochondrial agents (elected thanks to the results of mathematical modelling) under malignant cell culture lines. 2. HISTORY AND SOME REFERENCES TO THE CLASSIC KNOWLEDGES

We accept the theory of endosymbiosis, by Linn Margulis [9]. We deem the mitochondria are endosymbiotic bacteria, included in the beginnings of the evolution by the includer host cells (like the chloroplasts in plant cells, which too are the energy and bio-synthesizing centers of the plant cells, responsible for photosynthesis, like the adenosine triphosphate generating mitochondria in the animal cells). The mitochondria are under control of the host cells if the mechanisms of the host cells are undamaged (ex.: the fecundated ovocyte kills the mitochondria from the sperm, and in the fetus we see only the mitochondria with maternal origin). In the normal cases, the irreparable damages of the cell trigger the cell death processes, like the apoptosis – the protective mechanism of the organism aiming at eliminating the wrong cells. But the programmed cell death kills the mitochondria too, and we think they try to prevent this by becoming endocellular parasites arising from endosymbionts - the behavior pattern changes mathematically from cooperative Nash-equilibrium to non-cooperative game models. In this study, we think this mutant mitochondria activates different active and inactive parts of their genome (specially some parts of the variable region of the mitochondrial DNA and possible other parts of their genome) and tries to achieve the supra-regulation of the host cell. If they are successful, apoptosis is blocked (apoptosis is a process that can be described mathematically like a dynamic unstable system, [47] maintained in balance [59] by external forces – like a pen, perpendicular to the desk plane: if the hand stops aiding the pen, balance is lost and the system is destroyed: apoptosis cannot be stopped by damage - damages normally start the cascade of the apoptosis, in a domino-like development). In the view of this study, cancer cell multiplication is not the outcome of the damaged mechanism of cell death, one “wrong apoptosis”, because these processes are “cascade” mechanisms, which rule (like the domino) if they are in the beginning: the aggressive external agents and programmed cell death signals damage the normal cell mechanisms, maintaining the cell death in an inactive stage and after the episode the cell death rules. The pathologic process of the malignant transformation (in part) is exactly the blockage of the cell death and maintaining it in an inactive stage, by the mutant mitochondria escaped under host cell control, trying to survive the process; otherwise the cascade mechanism rule and different substances, like the caspase enzymes, emerge, and they destroy cell and mitochondria too. In the view of this study, the malignancy process can be modeled mathematically. We deem, by examining the only possible mathematical models of the patterns of the behavior of cancer cells and their processes and phenomena in living organisms and in the human body, that the process is NOT the result of activity of the damaged cells, because this malignant cells have new, alien, complex functions, serving the interests of the an alien, non-self code-controlled entity (the phenomena of the “clonal evolution”: metastasis, angiogenesis, immuosuppression, and other phenomena, are useful only for the alien code directed agent) – mathematically is not possible to model a different process pattern. We think that something that cannot be mathematically modelable simply does not exist. In malignant processes we see not the signs of an altered cell activity, but the signs of an developed and complex activity of the non-self agent. The properties of the malignant cells are: blocking of apoptosis, unlimited growth and unlimited capacity to divide, production of the growth factors for themselves, increased speed of division, changed capacity of differentiation, loss of contact inhibition, invasion of local tissues, forming of metastases in distant tissues, angiogenesis, etc. These properties are not compulsory present in all malignant cells, but their descendants form clones manifesting them. This is the clonal evolution in the malignant process and this cannot be modeled with an altered cell function model, but can be modeled only with the model of the developed and complex activity of the non-self agent [16] (NOT cited from [2]). We know various research works trying to find the external, viral or bacterial agent of cancer. Some mycoplasmas were involved, and we remember the publications about Progenitor cryptocides [60]. Cancer is a disease appearing very similar in some mechanisms with some infectious diseases produced by intracellular pathogen bacteria and tissular neoformation inducer bacteria. Malignancy is suspected to be induced by mutant mitochondria trying to survive cell death, escaping damaged host cell control, achieving supra-regulation of host cells, transforming them into “zombie” cells, used for the multiplication of these mutant mitochondria, which changes their endosymbiont behavior into intracellular parasitism. In this study we describe some mathematical models of malignancy, we reveal arguments for mitochondria capacity to achieve the described processes, arising from the mitochondrial genetics data; we refer to the mitochondrial genetics of sharks and other species affected by malignant tumors. The frequency of malignancy increases “going up phylogenetically” after the emergence of thermoregulation, thanks to the rise of some new mitochondrial pathways, possible with changing or acquiring genetic information with or from the includer host cells. We consider this phylogenetic moment of development like the beginning of the capacity of mitochondria to arise from endosymbionts intracellular parasites. We various different animal and vegetable pathologic processes with tissue neo-formation with known and unknown agents, and we compare them with malignant tumors, in order to present the joint characteristics of these patterns of behavior of living matter. In the experimental section of the work [16], we present the first results of our studies and laboratory works with the Castanea sativa Mill. (chestnut) [61, 16] extracts and streptolysine: we think that as the classic process of antibiosis described by Fleming works - in some other conditions too some plants develop in the process of evolution various substances used to combat competing microorganisms like the ancestral mitochondria (ex. Phytoplasmas, phylogenetically not very far away from proto-mitochondria, etc.,) – especially some highly evolved and cultivated, comestible Mediterranean plants, which extend their habitat areas into North, in some subMediterranean areas (sometimes with the aid of man's farming work), where they are highly exposed to various parasites (like the Phytoplasmas, 20 very similar with the ancestral mitochondria); some bacteria develop also, in the process of the evolution, substances used to combat other competing micro-organisms, to protect themselves and ensure their access to food sources by fighting competitors. Such is the example of penicillin, produced by Penicillium, to fight the Streptococcus, for example. These substances (in part non toxic for human cells, but toxic for the cells and mitochondria with a very different – and archaic – metabolism) kill or damage the different cancer cell lines, and we know documented cases of the disappearance of metastases in patients with severe Streptococcus septicaemia – we can not exclude the antibiotic effect of Streptococcus toxins, blocking the mitochondria of the cancer cells [16]. We present the data and some considerations about cancer therapy using classic cytotoxic and citostatic drugs, and the possibility of the use of the chestnut's active substances and different antibiotics used today in the therapy of the infectious diseases caused by different pathogens, similar with the mitochondria, considering the mutant mitochondria as a new target of the anti-tumor therapy. This, the “number eight target” works in line with the “three principles of anti-mitochondrial cancer drugs”: 1. not tumor-specific, 2. not host-cell specific, 3. specific for the ancestral mitochondrial expressions. We hope there is a fourth principle too: not toxic for the unaltered host cells [16].

Upper drawing part: Input: d=direct, r=receptor, p=pore; CDP: cell data processing, N: nucleus, I: information, DNA: deoxyribonucleic acid, mRNA: messenger RNA, R: ribosome, P: proteins, CBM: cell biochemical machinery, M: mitochondrion, MBM: mitochondrial biochemical machinery, Im: internal medium, Em: external medium, C: cell, red MDNA: blocked, latent mitochondrial DNA. The included-includer relation mathematically is the co-operative Nash-equilibrium (author's picture included). Lower drawing part: Principles of the function of the Turing-machine: (author's picture included) P: processor, M: memory, W: writer, R: reader, < >: moving mechanism , D: data binding medium.[16]. (NOT cited from [2])

3. ABOUT THE MITOCHONDRIA IN THE CANCER CELL In cell biology, a mitochondrion [8, 9, 11] is a membrane-enclosed organelle, with range from 1–10 µm in size, found in most eukaryote cells. Mitochondria are "cellular power plants" because they generate adenosine triphosphate. In addition to supplying cellular energy, mitochondria are involved in further processes, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. In cancer cells we see a highly increased number of hyperactive, enlarged mitochondria. Thus, we wonder: could this be the cause, and not the effect of malignancy? We deem the answer could be yes. In this study we come up with the idea of having mutant mitochondria as potential etiology of cancer. Mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins. A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 total genes, 24 tRNA and rRNA genes and 13 peptide genes. The 13 mitochondrial peptides in humans are integrated into the inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus. And furthermore do not forget the variable region of the mitochondrial DNA (used today for describing different ways of genetic condescension and heredity). This variable region of the mitochondrial DNA is one of the possible sections of mitochondrial genetic code, which might bind some ancestral information (originating from before the time when in the ancient ocean the mitochondria was included as endosymbionts by the includer host cells and they lived independently) and some acquired information (during the long period of the evolution of the life), information in part inhibited and inactive in physiologic conditions, and possibly activated in mutant mitochondria (maybe with some other parts of the mitochondrial DNA), during their attempt to escape from cell death, possible by blocking apoptosis, turning into intracellular parasites from endosymbionts and achieving supraregulation of the host cell, transforming it into a “zombie” cell with infinite multiplicative capacity, an ideal “home” for the mutant mitochondria transformed now in intracellular parasites (otherwise, the reciprocity in the regulation of symbiotic communities is a known fact).

Fermat, Willes, Hilbert, Laglands, Clay, Wolfram – despite these heroic efforts, mathematics still fails to be a coherent, united science, lacking contradictions and serious problems [28, 29, 30]. Nevertheless, long time

In this study we talk about the theory of endosymbiosis of the mitochondria. We present the development in the biological evolution [24] of this cell organelles [62] [16].

Input: d=direct, r=receptor, p=pore; CDP: cell data processing, N: nucleus, I: information, DNA: deoxy-ribonucleic acid, mRNA: messenger RNA, R: ribosome, P: proteins, CBM: cell biochemical machinery, M: mitochondrion, MBM:mitochondrial biochemical machinery, Im: internal medium Em: external medium, C: cell, red MDNA: blocked, latent mitochondrial DNA. The included-includer relation mathematically is the co-operative Nash-aequilibrium. (author's picture included).

The “included” is the mitochondrion inside in the “includer” from the beginning of the biological evolution, the inclusion are produced in the archaic ocean. The included is an endosymbiont bacteria like the chloroplast in the plants. The inclusion is the beginning of the endosymbiosis. Normal cell as multi-input, multi output, nonvirtual, analogue, autoreproductive, „includer” „biological Turing-machine” with informatic pathways and with the mitochondrion, as multi-input, multi output, non-virtual, analogue, autoreproductive, „included” biological Turingmachine with informatic pathways (ITM): Input: d=direct, r=receptor, p=pore; CDP: cell data processing, N: nucleus, I: information, DNA: deoxyribonucleic acid, mRNA: messenger RNA, R: ribosome, P: proteins, CBM: cell biochemical machinery, M: mitochondrion, MBM: mitochondrial biochemical machinery, Im: internal medium, Em: external medium, C: cell, red MDNA: blocked, latent mitochondrial DNA. The included-includer relation mathematically is the cooperative Nash-aequilibrium (author's picture ).

Cancer cell as multi-input, multi output, non-virtual, analogue, autoreproductive, „includer” „biological Turing-machine” with informatic pathways and with the mitochondrion, as multi-input, multi output, non-virtual, analogue, autoreproductive, „included” biological Turing-machine with informatic pathways: Black arrow: normal way,dark arrow: blocked way, red arrow: mutant way. Blue MDNA: activated latent mitochondrial DNA. Input: d=direct, r=receptor, p=pore; CDP: cell data processing, N: nucleus, I: information, DNA: deoxyribonucleic acid, mRNA: messenger RNA, R: ribosome, P: proteins, CBM: cell biochemical machinery, M: mitochondrion, MBM: mitochondrial biochemical machinery, Im: internal medium, Em: external medium, C: cell. The included-includer relation mathematically is the non co-operative intracellular parasite model (author's picture included).

The mitochondria in the evolution (author's pictures included). The scientist who produced the endosymbiont http://en.wikipedia.org/wiki/Endosymbiont

The simple representation of the Turing-machine: (author's picture included) P: processor, M: memory, W: writer, R: reader, < >: moving mechanism , D: data binding medium [16].

If we consider the concept of the Turing-machine and we extend it to the living cell, the living cell can be understood like a hyper-complex, multi-input, multi-output type, analogue, non-virtual, self-reproductive, biological Turing-machine, which responds to the excitations coming from the environment, communicates with the other similar entities, cooperates with them, if necessary, makes the “self-disconnection” in the interests of the cooperative set of the similar entities (programmed cell death) and produces functions in the interest of this cooperation. This biological Turing-machine has a delimiting membrane, which maintains homoeostasis and isolates the internal environment from the external environment, has an internal program and memory, has “readers” (receptors and other mechanisms transforming the inputs) and “writers” (ribosome and other mechanisms, achieving the outputs). By executing this program, internal homoeostasis is maintained, the changing of the parameters of the external environment is felt, and reactions to this changes are produced, materializing in the outputs given in the internal and external medium. The biological Turing-machine assimilates

theory

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[9].

Sérgio Luiz Pereira: Mitochondrial genome organization and vertebrate phylogenetics Genetics and Molecular Biology, 23, 4, 745-752 (2000). Abstract: With the advent of DNA sequencing techniques the organization of the vertebrate mitochondrial genome shows variation between higher taxonomic levels. The most conserved gene order is found in placental mammals, turtles, fishes, some lizards and Xenopus. Birds, other species of lizards, crocodilians, marsupial mammals, snakes, tuatara, lamprey, and some other amphibians and one species of fish have gene orders that are less conserved. The most probable mechanism for new gene rearrangements seems to be tandem duplication and multiple deletion events, always associated with tRNA sequences. Some new rearrangements seem to be typical of monophyletic groups and the use of data from these groups may be useful for answering phylogenetic questions involving vertebrate higher taxonomic levels. Other features such as the secondary structure of tRNA, and the start and stop codons of protein-coding genes may also be useful in comparisons of 40 vertebrate mitochondrial genomes. Proc Natl Acad Sci U S A. 2006 Dec 26; Parasitic inhibition of cell death facilitates symbiosis. Pannebakker BA, Loppin B, Elemans CP, Humblot L, Vavre F. Laboratoire de Biometrie et Biologie Evolutive, Unite Mixte de Recherche 5558, and Centre de Genetique Moleculaire et Cellulaire, Unite Mixte de Recherche 5534, Centre National de la Recherche Scientifique, Universite Claude Bernard Lyon 1, IFR 41, 69622 Villeurbanne Cedex, France; Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Ashworth Laboratories, King's Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland, United Kingdom. Proc. Nati. Acad. Sci. USA Vol. 85, pp. 7288-7292, October 1988: Genetics Plasmids can stably transform yeast mitochondria lacking endogenous mtDNA (Saccharomyces cerevisiae/oxil/rhol-/high-velocity microprojectile bombardment) THOMAS D. FOX*t, JOHN C. SANFORD*, AND THOMAS W. MCMULLIN* *Section of Genetics and Development, Cornell University, Ithaca, NY 14853; and tDepartment of Horticultural Sciences, New York State Agricultural Experiment Station, Cornell University, Geneva, NY 14456 Communicated by Gerald R. Fink, June 10, 1988 Mitochondria: More than Mitochondrial DNA in Cancer: Bora Baysal In their PLoS Medicine article, entitled “A critical reassessment of the role of mitochondria in tumorigenesis,” Salas et al. [1] reviewed reports describing identifi cation of mitochondrial DNA (mtDNA) mutations in several tumors. They identifi ed many instances where the purported mutations in tumors corresponded to certain populational haplotypes, suggesting that contamination or sample mix-up could be a better explanation for these mtDNA variations found in tumors. This manuscript has important implications for this research fi eld by questioning the validity of conclusions drawn in several high-profi le publications that laid foundations for the role of mtDNA in cancer. While it is essential to investigate the origin of mtDNA variations found in certain tumors, the conclusion in the abstract that “the role of mitochondria in tumorigenesis remains unclarifi ed” is simply incorrect. March 2006 | Volume 3 | Issue 3 | e167 | e156 PLoS Medicine | www.plosmedicine.org

Mereschkowsky C (1905). "Über Natur und Ursprung der Chromatophoren im Pflanzenreiche". Biol Centralbl 25: 593–604. Inoue, K (2007). "The chloroplast outer envelope membrane: the edge of light and excitement". Journal of Integrative Plant Biology 49: 1100–1111. Margulis, Lynn and Dorion Sagan, 2007, Dazzle Gradually: Reflections on the Nature of Nature, Sciencewriters Books, ISBN 978-1-933392-31-8 Margulis, Lynn and Eduardo Punset, eds., 2007 Mind, Life and Universe: Conversations with Great Scientists of Our Time, Sciencewriters Books, ISBN 978-1-933392-61-5 Margulis, Lynn, 2007, Luminous Fish: Tales of Science and Love, Sciencewriters Books, ISBN 978-1-933392-33-2 Margulis, Lynn and Dorion Sagan, 2002, Acquiring Genomes: A Theory of the Origins of Species, Perseus Books Group, ISBN 0-465-04391-7 Margulis, Lynn, et al., 2002, The Ice Chronicles: The Quest to Understand Global Climate Change, University of New Hampshire, ISBN 1-58465-062-1 Margulis, Lynn, 1998, Symbiotic Planet : A New Look at Evolution, Basic Books, ISBN 0-465-07271-2 Margulis, Lynn and Karlene V. Schwartz, 1997, Five Kingdoms: An Illustrated Guide to the Phyla of Life on Earth, W.H. Freeman & Company, ISBN 0-613-92338-3 Margulis, Lynn and Dorian Sagan, 1997, What Is Sex?, Simon and Shuster, ISBN 0-684-82691-7 Margulis, Lynn and Dorion Sagan, 1997, Slanted Truths: Essays on Gaia, Symbiosis, and Evolution, Copernicus Books, ISBN 0-387-94927-5 Sagan, Dorion and Lynn Margulis, 1993, The Garden of Microbial Delights: A Practical Guide to the Subvisible World, Kendall/Hunt, ISBN 0840385293 Margulis, Lynn, 1992, Symbiosis in Cell Evolution: Microbial Communities in the Archean and Proterozoic Eons, W.H. Freeman, ISBN 0-7167-7028-8 Margulis, Lynn, ed, 1991, Symbiosis as a Source of Evolutionary Innovation: Speciation and Morphogenesis, The MIT Press, ISBN 0-262-13269-9 Margulis, Lynn and Dorion Sagan, 1991, Mystery Dance: On the Evolution of Human Sexuality, Summit Books, ISBN 0-671-63341-4 Margulis, Lynn and Dorion Sagan, 1987, Microcosmos: Four Billion Years of Evolution from Our Microbial Ancestors, HarperCollins, ISBN 0-04-570015-X Margulis, Lynn and Dorion Sagan, 1986, Origins of Sex : Three Billion Years of Genetic Recombination, Yale University Press, ISBN 0-300-03340-0 Margulis, Lynn, 1982, Early Life, Science Books International, ISBN 0-86720-005-7; Margulis, Lynn, 1970, Origin of Eukaryotic Cells, Yale University Press, ISBN 0-300-01353-1

The neoformation-generating behavior is a common phenomenon in parasite systems. Various neoformations in the plant and animal organisms, they can be classified by origin: parasitic, bacterial, viral, etc., specially referring to the “mitochondria-like” agents in plants and animals. Left: plant tumor (author's photo included).

For understanding this theory we must refer to the Last Universal Ancestor or Last Universal Common Ancestor: LUA – LUCA., citation from Wikipedia:

The special form of the neoformations can be considered different manifestations of atherosclerosis (ref. original work of the author, referring to the correlations within the Helicobacter pylori positivity and cardiovascular diseases, see bibliography) [16]. As the Besnier-Boeck-Schaumann sarcoidosis [67] and the Kweim-test [68] suggest, one might suspect the potential role of mitochondriareleased factors in the growth of neoformed, but not malignant tissues, characteristics for sarcoidosis. Right: a cladogram linking all major groups of living organisms to the LUA (the black trunk at the bottom). This graph is derived from ribosomal RNA sequence data. (source: Wikipedia.org) [63]. An alternative tree based on the model of neomuran evolution from eubacteria. (source: Wikipedia.org) [63]. Left: LUCA: Last Universal Common Ancestor (source: Wikipedia.org) [63]. The last universal ancestor (LUA), also called the last universal common ancestor (LUCA) or the cenancestor, is the hypothetical latest living organism from which all organisms now living on Earth descend. Thus it is the most recent common ancestor of all current life on Earth. It is estimated to have lived some 3.6 to 4.1 billion years ago (sometime between the Basin Groups and Paleoarchean eras)[1] .

2. HT 1080 Human fibrosarcoma (malignant cell culture).

- more effective in combination and in high dosage, - have variable and transitory effects, - have serious toxicity - the selective activation of these highly effective drugs make them specifics in different tumours.

Cell Line Name: HT 1080, ECACC No. 85111505, Human fibrosarcoma. Cell Line Description: Established from a fibrosarcoma arising adjacent to the acetabulum of a 35 year old caucasian male. The cells can give rise to tumours in immunosupressed NIH Swiss mice. Susceptible to infection by RNA tumour viruses including RD114 feline endogenous virus and FeLV.

Classification of the anti-tumor drugs 1. Cytotoxic drugs with low anti-tumor effectiveness: 1.1. Antimetabolits, inhibitors of the synthesis of the nucleotides (5-fluoruracil, methotrexat, citozin-arabinosid, gemcitabin, capecitabin, etc.) 1.2. DNA acting drugs (alkylating drugs, platina, nitrozoureas, temozolomid, dacarbazin, actinomycin D, bleomycin) 1.3. Topoisomerase inhibiting drugs (irinotecan, etoposid, antracyklines) 1.4. Mitosis inhibiting drugs (vinca alkaloides, taxanes, estramustin) 2. High therapeutic effective (citostatic) anti-tumor drugs: 2. 1. Anti-tumor drugs modifying the signal transmission 2.1.1.Inhibitors of the receptors of the surface of the tumor cell (EGF-R, inhibitors of the tirosyn-kinase: trastuzumab, gefitinib, erlotinib) 2.1.2.Intracellular inhibitors of the tirosyn-kinase (imatinib) 2.1.3.Serin-treonin-kinase inhibiting drugs (flavopiridol) 2.2. Proteosoma and HSP inhibiting drugs (bortezomib, geldanamycin) 2. 3. Chromatine-function inhibiting drugs (isotretinoin) 2.4. Protein synthesis inhibiting drugs (asparaginase, rapamycin) 2. 5. Other citostatic anti-tumor drugs (Celecoxib) 3. Hormone derivates 3. 1. Antiandrogens (flutamid) 3. 2. Antiestrogens (tamoxifen, toremifen) 3 3. Aromatase inhibiting anti-tumor drugs (exemestan, letrozol) 3 4. LH-RH substances (goserelin, buserelin, triptorelin) 3. 5. Somatostatine derivatives (octreotid) 4. Cytokines (interferons, interleukins) 5. Neovascularisation inhibiting anti-tumor drugs (endostatin, angiostatin, bevacizumab) 6. Antimetastatic anti-tumor drugs (bisfosfonats, marimastat) 7. Others (chemoprotective modulators, vaccines) - citation from classic knowledges

In this study, becoming from the deductions of mathematical modelling, the authors proposes a new group to these: 8. DRUGS BLOCKING THE METABOLIC PROCESSES OF MUTANT MITOCHONDRIA OF THE TUMOR CELLS [16]. We suggest a “group eight” of the anti-tumor drugs, and advocate the use of anti-mitochondria targetting in therapy. The anti-mitochondria target in the cancer therapy and the anti-mitochondria anti-tumoral chemotherapy has 3 principles:

Left: HT 1080, control cell culture, no Castanea sativa extract added. Univ. Pécs, PTE OEC ÁOK Inst. of Pharmacology, Feb. 2008. Center: HT 1080 Human fibrosarcoma (malignant cell culture), 800 mcg Castanea sativa Mill. extract added, massive tumor cell necrosis in 24h. Univ. Pécs, PTE OEC ÁOK Inst. of Pharmacology, Feb. 14, 2008, right: enlarged detail of the central image.

2. ND-C (Mouse neuroblastoma x Rat neurone hybrid, malignant cell culture). Cell Line Name: ND-C, ECACC No. 92090913, Mouse neuroblastoma x Rat neurone hybrid Cell Line Description: ND-C hybrid cells were derived after fusion of primary neonatal-rat dorsal-root-ganglion (DRG) neurons with N18Tg2, a mouse neuroblastoma (C1300) derived azaguanine resistant line. HAT sensitive hybrids were selected and cloned by limiting dilution. The cells express rat Thy 1.1 marker and the sensory neuropeptide substance P. The cell line has been mycoplasma eradicated at ECACC. Left: ND-C (Mouse neuroblastoma x Rat neurone hybrid) control cell culture. Univ. Pécs, PTE OEC ÁOK Inst. of Pharmacology, Feb. 2008. Center: ND-C (Mouse neuroblastoma x Rat neurone hybrid) malignant cell culture. 400 mcg / ml Castanea sativa extract added, massive tumor cell necrosis in 24h. Univ. Pécs, PTE OEC ÁOK Inst. of Pharmacology, Feb. 14, 2008. Right: etail of the central photo.

Effects of bacterial toxin in malignant cell culture [16]. We remember some ecological [65] considerations: the concurrence of the micro-organisms in the biological systems, like the penicillin mediated inhibition of Streptococcus [66] by Penicillium [15]. We tested the possible streptolysine mediated inhibition of the mutant mitochondria of the tumour cells by Streptococcus. If the mutant mitochondria of the tumour cells manifest archaic bacterial expressions, may be inhibited by Streptococcus, on the analogy of the penicillin mediated inhibition of Streptococcus by Penicillium. We infected sterile tumour cell culture medium with Streptococcus ß-haemolytic., and we filtered it sterile after an incubation during 24h. The sample of filtered solution remain sterile after 3 days of incubation.

-not tumor specific -not host cell specific -mitochondrial primitive expression specific -we furthermore hope there also is a fourth principle: non-toxic for the host cell.

Left: The infected medium. Univ. Pécs, PTE OEC ÁOK Inst. of Imunol. Biotechn., Feb. 2008. (left), and the filtered, sterile medium. Univ. Pécs, PTE OEC ÁOK Inst. of Imunol. Biotechn., Feb. 2008. (right). Center: SP2 malignant control cell culture, no Streptococcal toxins added, laboratory of the authors, water immersion, 2008 Mar. 03. Right: Inhibition of the SP2 malignant cell culture, after incubation (24h) with 25% filtered, sterile, Streptococcustoxins containing medium, laboratory of the authors, water immersion, 2008 Mar. 03. 7. CONCLUSIONS [16].

ALH 84001 (Allan Hills 84001) - From Wikipedia Left: classic figure of the pathways of incretin actions. Cited from [69]. Right: Incretins are released when food arrives in the intestines, before of the insulin secretion. This is in correlation with the hypothesis: the antiapoptotic agent acts against the tumour by reducing the number of the programmed cell death processes, which results in the decrease of the number of situations requiring defence of mitochondria (authors picture included).

Left: Non-caseating granuloma (colon of a patient with Crohn's disease), center: tuberculous process, right: sarcoidosis

Up: The complexity of the human mitochondrial genome

Left: Langhans cell in tuberculous process, right: ultinuclear malignant cell The behaviour of some “mitochondria-like” pathogens (Mycoplasma, Chlamydia, etc.) in the human body and the aspects of the antimicrobial chemotherapy of the diseases induced by these pathogens are informative too in relation with the possible role of mutant mitochondria in carcinogenesis. These pathogens, of different categories, are as follows:

Simple, little mitochondrial genes: Left: Mitochondrial gene map of the echiuran Urechis caupo, right: he Complete Mitochondrial DNA Sequence of the Shark Mustelus manazo. All genes are transcribed from the same DNA strand. Scaling is only approximate. Genes are designated by standard nomenclature except for tRNAs, which are identified only by the one-letter code for the corresponding amino acid, with the two serine and two leucine tRNAs differentiated by numeral as identified in Fig. 3. "nc" indicates the largest non-coding regions; it may be that

Left: Control malignant cell culture, no Castanea sativa extract added. Right: Malignant cell culture, Castanea sativa extract added - massive tumor cell necrosis and degeneration (Castanea sativa Mill. subst. sicc. 10,0 g, in 100 ml aq. dest. 20°C, boiled 5 in 5min. to 100°C, bioled 60 sec., after 5 min. centrif., filtr. 0,2 sterile. To 15 ml cell culture 0,250 ml added. 8,2 + 0,02 mg/ml, subst. sicc., 2,05 mg in 15 ml = 136 mcg/ ml in the culture. Added 2008. Feb. 07. 13:00. Univ. Pécs, Inst. Immunol. Biotechnol. In 2008. Feb . 08. 13:00. we see massive tumor cell necrosis and degeneration.

The cytotoxic drugs are:

To understand this theory, we need to refer to further knowledge about archebacteria and special forms of life, like the “black smokers” from the depth of the oceans, the nanobacteria and the life forms from meteorites, like the famous ALH 84001 (Allan Hills 84001).

1. Left: Normal cell division: The cell C1 dividing in the C2x and C2y cells: he I1, I2x, I2y information is identical and self . 2. Center: Division of the cell C1 with homoeostasis H: The cell C1 dividing in the C2x and C2y cells: the I1, I2x, I2y information is identical and self, the structure S1, S2x, S2y and the function F1, F2x, F2y is identical and self, the internal and the external homoeostasis is self directed and persistent. 3. Right: Cancer cell division: The effect of the non-self information I (N) on the division of the cell C1: the I1, I2x, I2y information is in part identical and in part self, the structure S1, S2x, S2y and the function F1, F2x, F2y is in part identical and in part self, the internal and the external homoeostasis is non-self directed and non persistent (author's pictures included).

Cell Line Name: SP2/0-Ag14, ECACC No.: 85072401, Mouse x Mouse hybridoma, non-producing. Cell Line Description: Sp2/0-Ag14 is a non-Ig-secreting or synthesising line derived from a cell line created by fusing a BALB/c mouse spleen cell and the mouse myeloma P3X63Ag8. Resistant to 8-azaguanine at 20ug/ml and does not survive in HAT containing media.

In this study, in compliance with specific literature [19], we call cytotoxic drugs the substances damaging the molecular processes of the cell proliferation (damaging the synthesis of the nucleotides, genetic substance, mitosis and topoisomerase) and citostatic drugs the substances aimed at modifying the perturbations of the tumour cell regulation or for diminishing tumour progress. Another important group is the group of the hormone derivates, destined for action under endocrine regulation of tumour.

Vol. 95, Issue 12, 6854-6859, June 9, 1998, http://www.pnas.org/cgi/content/full/95/12/6854

Mitochondrial genomics: Duong, C. A., Sepulveda, C. A., Graham, J. B. and Dickson, K. A. (2006). Mitochondrial proton leak rates in the slow, oxidative myotomal muscle and liver of the endothermic shortfin mako shark (Isurus oxyrinchus) and the ectothermic blue shark (Prionace glauca) and leopard shark (Triakis semifasciata). J. Exp. Biol. 209, 2678-2685: Proc Natl Acad Sci U S A. 2006 Dec 26; Parasitic inhibition of cell death facilitates symbiosis. Pannebakker BA, Loppin B, Elemans CP, Humblot L, Vavre F. Laboratoire de Biometrie et Biologie Evolutive, Unite Mixte de Recherche 5558, and Centre de Genetique Moleculaire et Cellulaire, Unite Mixte de Recherche 5534, Centre National de la Recherche Scientifique, Universite Claude Bernard Lyon 1, IFR 41, 69622 Villeurbanne Cedex, France; Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Ashworth Laboratories, King's Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland, United Kingdom. Proc. Nati. Acad. Sci. USA Vol. 85, pp. 7288-7292, October 1988 Genetics Plasmids can stably transform yeast mitochondria lacking endogenous mtDNA (Saccharomyces cerevisiae/oxil/rhol-/high-velocity microprojectile bombardment) THOMAS D. FOX*t, JOHN C. SANFORD*, AND THOMAS W. MCMULLIN* *Section of Genetics and Development, Cornell University, Ithaca, NY 14853; and tDepartment of Horticultural Sciences, New York State Agricultural Experiment Station, Cornell University, Geneva, NY 14456 Communicated by Gerald R. Fink, June 10, 1988

(PLEASE SEE THE ENLARGED IMAGES TOO FROM THE NEXT POSTER!)

1. SP2, (malignant cell culture).

5.CANCER THERAPY AND MITOCHONDRIA

Woese, Carl, The universal ancestor, Proceedings of the National Academy of Sciences,

What is Allan Hills? See: http://en.wikipedia.org/wiki/Allan_Hills_81001 ALH 84001 (Allan Hills 84001) is a meteorite found in Allan Hills, Antarctica in December 1984 by a team of US meteorite hunters from the ANSMET project. Like other members of the group of SNCs (shergottite, nakhlite, chassignite), ALH 84001 is thought to be from Mars. On discovery, its mass was 1.93 kg. It made its way into headlines worldwide when scientists announced that it contained evidence for microscopic fossils of Martian bacteria.

IMAGES

We consider some possible relations in the problem of the mitogen effect of the insulin administration: insulin has a growth-factor-like effect and this proliferate effect has a corespondent in physiological situations: the known anti-apoptotic effect of the incretins [69].

We compare the histology of the granulomas induced by different agents, and some malignant processes, in As to mitochondrial genetic considerations, we refer to the different results of the research concerning mitochondrial genome, and the differences of the mitochondrial genome in evolution. The sharks, animals order to present the possible common pattern of tissue neoformation: similar tissue responses for different agents practically without cancer are the phylogenetic “limit” of the apparition of the malignancy, and this may be in – neoformation, like a modality of tissue behaviour. Only for the sake of visualizing the aspects, we hereby present relation with the apparition of the mitochondrial membrane mechanism components used in thermoregulation: some pictures with cell proliferation, a very common phenomenon in biology: from this point, the mitochondria have (probably imported from the host cells genome) the capacity to try the above-mentioned supra-regulation of host cells. Organisms with simple mitochondrial genomes are practically “protected” from cancer. The answer for the question of the problem of malignancy may lie in the evolution of the mitochondria [64]. We keep in mind some ecology issues: symbiosis and parasitism, as patterns of behavior, in order to understand parasitism; and as to parasitism with tissue proliferation, we refer to the neoformationgenerating behavior in the parasite ecology relations.

The programmed cell death cannot be “wrong”. Cancer is not the consequence of the damaged mechanism of cell death, one “wrong apoptosis”, because these processes are a “cascade” mechanism, which rules (like dominoes) if they begin: the aggressive external agents and programmed cell death signals damage the normal cell mechanisms maintaining the cell death in an inactive stage and after the episode rules the cell death. The pathological process of the malignant transformation (in part) is exactly the blockage of the cell death and maintaining it in an inactive stage, by mutant mitochondria escaped of host cell control, trying to survive the process; otherwise the cascade mechanism is executed and different substances, like the caspase enzymes, emerge, and this destroys the cell and the mitochondria too. The apoptosis mathematically is an unstable dynamic system maintained in balance by external effects: when the inactivity maintaining effect ceases to exist, the process is activated like a cascade. This is a result of biological evolution: the sets of cooperative cells lacking the capacity of “self-disconnection” of the “wrong” cells fail to have success in the competition of the evolution. The loss of balance of the programmed cell death inactivating processes, which is the trigger of destruction, can be blocked only by an non-self code directed agent, which can be the old cooperative endosymbiont, now a mutant intracellular parasite, by way of changing the behavior from cooperative to non-cooperative, and thus turning the host cell into a non-cooperative “zombie” cell too, from the viewpoint of the sets of cooperative cells. Information about a phenomenon must be coherent if true. The problem of contemporary cancer theories is the loss of a point of view at system level: the malignant tissue is not simply a sum of the malignant cells, but an organized system. This organized system - with multiple and complex new functions - mathematically simply cannot be directed by some wrong functions. Logically there is a need for a non-self directed programming system to explain the blocking of apoptosis, unlimited growth and unlimited capacity to divide, production of the growth factors in their own interest, increased speed of division, changed capacity for differentiation, loss of the contact inhibition, invasion of the local tissues, forming metastases in the distant tissues, angiogenesis, etc. (the clonal evolution) in the malignant process. This cannot be modelled with an altered cell function model, but is modellable only with the model (non-cooperation in the mathematical game theory) of the developed and complex activity of the non-self agent. Looking at cancer from the “upper perspective”, with the mind of the mathematician, and applying synthetic and system theory oriented approximations, searching intuitive ideas on the principles of cancer guidance processes, one can see some suspect patterns and correlations, which come in contradiction with current cancer theories: we see the idea of the latent bacteria, sleeping in the human cells from the archaic times. Really, this may be the mitochondrion, showing its “Ianus-face”. We know some similar processes with external agents, e. g. the Burkitt's lymphoma [44].

substances with such goals (see the analogy with the penicillin [15] of the Penicillium), serving in ecosystem competition. Said substances in the authors’ preliminary laboratory tests [16] manifest inhibitory effects on some tumour cell cultures [17] (this results are based on initial tests, and require confirmation from independent sources). In theory, it is possible to see some effect similar to that of certain antibiotics, like the macrolides [18] used against this micro-organisms (Mycoplasmas [13], Phytoplasmas [14], etc.) today in therapy: this plant extracts, bacterial toxins, antibiotics – targeting [19] the non-cooperative mitochondria of the tumour cells. They might be (in combination with classic anti-tumour drugs) useful adjuvant in cancer therapy [19].

What is the Last Universal Common Ancestor? See: http://en.wikipedia.org/wiki/Last_universal_ancestor

John von Neumann2 [7]., and John Forbes Nash3 [7]. We introduce the concept of the non-virtual “biological” Turing-machine in modelling malignancy [16]. The programmed cell death can be described like the self-stopping program of the cell. The cell is modeled like a nonvirtual “biological” Turing-machine. The process of the programmed cell death rules in the interest of the living organism, described like an ordinate set of cells, which achieves the cooperative model of the game theory. The process of the programmed cell death rules in the interest of the living organism, and “disconnect” the wrong element of the set in the interest of the persistence of the cooperative model of the game theory in the set. This cooperation is the basis of the life functions of living organisms. Since mitochondria are “included” type nonvirtual “biological” Turing-machines within the elements of the set, working in the cooperative model of the game theory, this mitochondria, like the endosymbiont bacteria, are cooperative only with the “includer” host cells and not with the set of this cooperative “includer” host cells – they are isolated “inside” by the “includer” host cells and are cooperative with hosts only when this cooperation serves the interests of the “included” elements too. The programmed cell death is the death of the “included” mitochondria too, and is expectable the defence reaction of these elements, trying to survive a process in opposition with their interests. Normally, the mitochondria are under severe control of the host cells, but in pathologic cases they can “escape” and change such cooperative behaviour pattern into an intracellular parasite model, achieving the supra-regulation of host cell processes, and blocking the programmed cell death and causing host cells to multiply, ensuring their reproduction, transforming host cells into “zombie” cells serving only the interests of these agents, turned into intracellular parasites from endosymbionts. The basic mathematical model, useful in the life sciences too, originally was described by Alan Turing [2].

transcription initiates here, but this is not known.) The Complete Mitochondrial DNA Sequence of the Shark Mustelus manazo: Evaluating Rooting Contradictions to Living Bony Vertebrates, Ying Cao,*† Peter J. Waddell,* Norihiro Okada,† and Masami Hasegawa* *The Institute of Statistical Mathematics, Tokyo, Japan; and †Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan A remarkable example of a misleading mitochondrial protein tree is presented, involving ray-finned fishes, coelacanths, lungfishes, and tetrapods, with sea lampreys as an outgroup. In previous molecular phylogenetic studies on the origin of tetrapods, ray-finned fishes have been assumed as an outgroup to the tetrapod/lungfish/coelacanth clade, an assumption supported by morphological evidence. Standard methods of molecular phylogenetics applied to the protein-encoding genes of mitochondria, however, give a bizarre tree in which lamprey groups with lungfish and, therefore, ray-finned fishes are not the outgroup to a tetrapod/lungfish/coelacanth clade. Some important citations to the subiect:

2 - John von Neuman, know for: ** von Neumann algebras** von Neumann architecture** Game theory** Von Neumann universal constructor** Von Neumann entropy** Von Neumann–Bernays–Gödel set theory** Utility theory** Von Neumann universe** Von Neumann conjecture** Von Neumann's inequality** Stone–von Neumann theorem** Minimax theorem** Von Neumann extractor** Direct integral** 3 - John Forbes Nash, Jr., (born June 13, 1928), is an American mathematician and economist whose works in game theory, differential geometry, and partial differential equations provided a basis for successive scientific research across a number of disciplines and mathematical insight into the forces that govern chance and events inside complex systems in daily life; his theories are still used today in market economics, computing, accounting and military theory. Serving as a Senior Research Mathematician at Princeton University for the latter part of his life he shared the 1994 Nobel Memorial Prize in Economic Sciences with game theorists Reinhard Selten and John Harsanyi. Nash is also the subject of the Hollywood movie, A Beautiful Mind , which was nominated for eight Oscars (winning four), and was based on the biography of the same name about him, his mathematical genius and his struggle with schizophrenia .

Alan Turing [2]

(Left: Source: http://www.microscopyu.com/galleries/fluorescence/cells/cho/cho.html Fluorescence Microscopy Digital Image Gallery, Chinese Hamster Ovary Cells (CHO-K1 Line), MitoTracker Orange CMTM Ros was utilized to fluorescently label the active mitochondria in a culture of Chinese hamster ovary cells (illustrated above). [12] (Right: Source: http://www.buckinstitute.org/site/index.php?option=com_content&task=view&id=116&Itemid=45 Picture above is a field-effect scanning EM of a single mitochondrion from a HeLa cell (courtesy of Angus Lamon, University of Dundee). [12]

5. ECOLOGY RELATED ASPECTS OF THE ENDOSYMBIOSIS OF THE MITOCHONDRIA

Normal cell as „biological Turing-machine” with informatic pathways:

In contemporary advanced science there are some mathematical systems yet not enough used in biology and medicine. From the somewhat new systems we recall the NKS (A New Kind of Science) by Stephen Wolfram, which is revolutionary, unexpected and insufficiently employed in life sciences. The NKS says that physical reality is described not by formulas and equations, but by algorithms, modelled by mathematical cell-automatons. Other, older, not sufficiently used mathematics in life sciences are the mathematics of chaos processes and the We can distinguish different situations in the flow of information during the cell division, from point of view of mathematics of the non-linear equations, fractals, Turing-machines, game theory, which describe the extraordinary the transmission and the effect of the information in the normal and in the cancer cells: but ordinate variety of life processes.

All sciences, in their approach aimed at solving fundamental issues, are in need of long-term strategies [27], i.e. guidelines for the future. In mathematics, for example, we can recall David Hilbert's problems [28], and today the Robert Langlands-program [29], the Landon T. Clay founded ClayMath's Institute's Millennium-problems [30] and the philosophy of the Stephen Wolfram's NKS [34]. The Langlands program is a very important example for other sciences: partially it is based on the extremely daring, but absolutely seriously founded logic and expectable conjectures and predictions (some without proof yet!), which rendered their first, extraordinary results: the proof Illustration: much, enlarged, hyperactive mitochondria in the cancer cell: of the Fermat's conjecture [31] by Andrew Willes [32], the proof of the Taniyama–Shimura conjecture [33].The Stephen Wolfram's NKS [34], is something absolutely revolutionary: existing reality is described via algorithms, cell automatons, and not by formulas! [34].

Fermat, Willes, Hilbert, Laglands, Clay, Wolfram

and eliminates substances (used for structure and function reasons) and energies from and into the environment. This biological Turing-machine is capable to self-replicate, based on division, and can increase the number of the individuals of their population. A special case is the cooperative association of these biological Turing-machines, when co-operation is achieved from simple symbiosis to the mammal animal living organism. Modelling of such complexity is apparently impossible, but some mathematical models looking at the flow of information at the “macro”-level of the cell activity are applicable, and this may suffice to decide whether a damaged system is able for some very complex, aggressive functions or this is possible only with the action of an alien, non-self code. To understand malignancy, we need to understand the mathematical pattern which, like an algorithm, guides the process. For this we need some notions from the mathematical game theory too. First we present some information pathways in the normal and cancer cells [16].

- obligate intracellular (or only sometime extra-cellular) pathogens - have no peptydoglicane capsule - are not, or difficult to cultivate on the acellular mediums (exclude Mycobacteria) - are evolutionary primitive in comparison with other, developed pathogens having capsules - have small dimensions - are inactivated by molecules with entirely different structures in comparison with the drugs active in infections with other, developed pathogens having capsules The deductions arising from mathematical modelling of malignancy may have unexpected consequences in the practice too. Some micro-organisms (Mycoplasmas [13], Phytoplasmas [14], etc.) are very similar with the archaic proto-mitochondria [11] (and, probably, with the non co-operative mitochondria of tumor cells [12]. Some plants contains defensive substances against this micro-organisms, certain bacteria develop antibiotic [15]

The place of the antimitochondrial drugs in the cancer therapy – author's image included Red arrow: inhibition, green arrow: activation, Gray arrow: destruction. [16]. 6. PRACTICAL CONSEQUENCES OF THE STUDY The components of the Castanea sativa Mill. [61], like possible cancer cell inhibitors You can read in these chapters of this study about the use of the Castanea sativa extracts in the experiments of the in vitro cancer cell culture inhibitions [16]. Why the chestnut? The target of the cancer therapy today is the cancer cell, which, in the view of this study, is the result, and not the cause of the process: the “zombie” host cell, controlled by the mutant mitochondria. In compliance with the idea of this study, mathematically the cancer cell is an “included in the includer” type, included-controlled, nonvirtual, biological Turing-machine, and, to block it, we need to neutralise the controller, the included. Today we shoot the zombie and we fail to kill the devil from the zombie. The malignant, pseudo-self includer is very similar with the self, and damaging the pseudo-self, we damage the self too. And the activated included is very different from the included endosymbiont, because of the activation of the archaic mechanisms, originating before the inclusion and the beginnings of endosymbiosis (the included cooperative endosymbiont works in a highly specialized mode, without the use of the important sequences of the mtDNA). The activation of these archaic mechanism is the point, where we have possibility to damage these mechanisms because of the differences in comparison with the includer host's mechanisms: the selective toxicity might possibly be used against the noncooperative included: in the language of the game theory, only the neutralization of the non-cooperative included can damage the pseudo-self includer, without damaging the self. For this, we need to distinguish the cooperative included from the non-cooperative included. This is possible considering the difference of the outputs of the included, non-virtual, biological Turing-machines. The non-cooperative included, non-virtual, biological Turing machine has the output with the archaic expressions, inactive in the cooperative included, non-virtual, biological Turing-machine. The non-cooperative included, non-virtual, biological Turing-machine has specialized, limited functions, and partially works with information outsourced from the includer, boasting a petite self-management because of all that is necessary is ensured through endosymbiosis, the regulation of the co-operative included, non-virtual, biological Turing-machine is under control and supraregulation of the information system of the includer cell. In opposition with this, the non-cooperative included, non-virtual, biological Turing-machine escaped under control and supraregulation of the information system of the includer non-virtual, biological Turing-machine, in case of diminution of the sources, due to the activation of the cell death mechanisms, tries to activate sleep functions, and upon obtaining control of regulation, causes the host to multiply. But, here, inside the pseudo-self cell, are some eukaryote patterns and mechanisms: this is the point of the selective damaging of this system, with some substances, not toxic for the self. Some plants, especially Mediterranean plants cultivated in subMediterranean areas, have serious pathogens, like the fungi, and the phytoplasmas. But, the phytoplasmas are very similar in some respects with the non co-operative mitochondria from the cancer cells, because of their phylogenetic relations (see the LUA – LUCA theory), and we can expect anti mutant-mitochondrial effects from the substances of these plants, effective against the phytoplasmas. Maybe we witness a duplication of the story of penicillin: the Penicillium kills the bacteria to protect the sources of food from the ambient. Here, the plant kills the other prokaryotes to protect itself. But these prokaryotes are similar to the mutant mitochondria from the cancer cell. We tried to identify non toxic, preferable food plants to try to obtain substances active against mutant cancer mitochondria, in the hope of damaging the cancer cell with something non toxic for the normal cell [16]. Results of the laboratory tests with Castanea sativa Mill. extracts In this part of the study we refer to the documentation of the following patent: „The use of the extracts and the other drug forms (infusions, solutions, injections, tablets and other drug forms) obtained from Castanea sativa (and subsp.) or obtained from the components of the extracts of the Castanea sativa (and subsp.) in the in vitro inhibition of the malignant cell line cultures and in the preparation of the drugs used for the treatment of malignant tumours” [16] . patent registered with: PAT. № P0800453., REG. № 0816705., REG. DATE: 07. 22. 2008., CZIMBALMOS-KOZMA, FERENC MD., PAPP, ERIKA MD., at the Hungarian Patent Office [16]. In this part of the study we refer to the documentation of the following book: “The Mitochondrial Theory of Cancer” © ARTISJUS № 080722001T, DATE: 07. 22. 2008. CZIMBALMOSKOZMA, FERENC MD., PAPP, ERIKA MD., REG. BY THE HUNGARIAN ARTISJUS OFFICE FOR COPYRIGHT PROTECTION ASSOCIATION.

According to this study, the malignancy process can be mathematically modelled. We deem, upon examining the only possible mathematical models of the behaviour patterns of the cancer cells and their processes and phenomena in living organisms and in the human body, that such processes are NOT the result of activity of the damaged cells, because this malignant cells have new, alien, complex functions, serving the interests of the an alien, non-self code controlled entity (the phenomenon of “clonal evolution”: metastasis, angiogenesis, immunosuppression, and other phenomena, useful exclusively for the alien code directed agent). Mathematically is not possible to model another pattern of the process. We believe that something that cannot be mathematics-based modelled simply cannot exist. In malignant processes we can see not the signs of an altered cell activity, but the signs of a developed and complex activity of the non-self agent. The properties of the malignant cells are: blocking apoptosis, unlimited growth and unlimited capacity to divide, production of the growth factors for themselves, increased speed of division, changed capacity for differentiation, loss of contact inhibition, invasion of local tissues, forming of metastases in distant tissues, angiogenesis, etc. These properties are not compulsory present in all malignant cells, but their offspring form clones manifesting them. This is the clonal evolution in the malignant process and this is cannot be modelled with an altered cell function model, but can be modelled only with the model of the developed and complex activity of the non-self agent. In the cancer cell we can see a highly increased number of hyperactive, enlarged mitochondria. Thinking about this phenomenon, we wonder: could be this the cause, and not the consequence of the malignancy? We think the answer is yes. In cell biology, a mitochondrion is a membrane-enclosed organelle, ranging from 1–10 µm in size, found in most eukaryote cells. Mitochondria are "cellular power plants" because they generate adenosine triphosphate. In addition to supplying cellular energy, mitochondria are involved in other processes, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. In this study, The Mitochondrial Theory of Cancer©, we present the hypothesis of the possible aetiology of cancer by the mutant mitochondria. The mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins. A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 total genes, 24 tRNA and rRNA genes and 13 peptide genes. The 13 mitochondrial peptides in humans are integrated into the inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus. And we shouldn’t forget the variable region of the mitochondrial DNA (used today for describing different ways of genetic condescensions and heredity). This variable region of the mitochondrial DNA is possibly part of the mitochondrial genetic code, which might bind some ancient information (originating before the time when in the ancient ocean the mitochondria was included as endosymbionts by the includer host cells and they lived independently) and some acquired information (during the long period of the evolution of the life), information which is inhibited and inactive in physiologic conditions, and possible activated in the mutant mitochondria (maybe with other parts of the mitochondrial DNA), during their attempt to escape from cell death by blocking apoptosis, thus becoming intracellular parasites from endosymbionts and achieving supra-regulation of the host cell, transformed in a “zombie” cell with infinite multiplication capacity, an ideal “home” for the mutant mitochondria transformed now in intracellular parasite. We accept the theory of endosymbiosis, by Linn Margulis. We believe the mitochondria are endosymbiotic bacteria, included at the beginnings of evolution by the includer host cells (like the chloroplasts in the plant cells, who are too the energy and biosynthetic centers of the plant cells, responsible for photosynthesis, like the adenosine triphosphate generating mitochondria in animal cells). The mitochondria are under control of the host cells if the mechanisms of the host cells are undamaged (ex.: the fecundated ovocyte kills the mitochondria from the sperm, and in the fetus we see only the mitochondria with maternal origin). In the normal cases, the irreparable damages of the cell are the trigger signal of the cell death processes, like the apoptosis – the protective mechanism of the organism to eliminate the wrong cells. But the programmed cell death kills the mitochondria too, and we think this is how they can try to prevent it: from endosymbionts, they can become endocellular parasites – the model of their behaviour changes mathematically from cooperative Nash-equilibrium to non-cooperative game models. In the mitochondrial theory of cancer, we believe this mutant mitochondria activates different active and inactive parts of their genome (especially some parts of the variable region of the mitochondrial DNA and possible other parts of their genome) and tries to achieve supraregulation of the host cell. If they are successful, apoptosis is blocked (the apoptosis is a process that can be described mathematically like a dynamic unstable system, maintained in balance by external forces – like a pen, perpendicular to the desk plane: if the hand ceases to aid it, the pen loses its balance and the system is destroyed. Apoptosis is not stopped by the damage; damages normally start the cascade of the apoptosis, somewhat like the “domino principle”). In the view of The Mitochondrial Theory of Cancer©, the multiplication of cancer cells is not the outcome of the damaged mechanism of cell death, one “wrong apoptosis”, because these processes are a “cascade” mechanism, which develop (like the dominoes) if begun: the aggressive external agents and programmed cell death signals damage the normal cell mechanisms maintaining the cell death in an inactive stage and after the episode the cell death rules. The pathologic process of the malignant transformation (in part) is exactly the blockage of the cell death and maintaining it in inactive stage, by the mutant mitochondria escaped under host cell control, trying to survive the process, otherwise the cascade mechanism rules and different substances, like the caspase enzymes, emerge, and they destroy cell and mitochondria too. Thus we deem that cancer is a disease very similar in some mechanisms with some infectious diseases produced by intracellular pathogen bacteria and tissue neoformation inducer bacteria, induced by the mutant mitochondria trying to survive cell death, escaped from damaged host cell control, and which achieves the supra-regulation of the host cells, transforming them into “zombie” cells, used for the multiplication of these mutant mitochondria, which change their endosymbiont behaviour to intracellular parasitism. Some substances, like the Castanea sativa extract (and some components of this extract) and other substances, toxic for phytoplasmas and “mitochondria-like” organisms (Mycoplasma, Chlamydia, etc.) can be used to inhibit cancer cells and thus in cancer therapy. In this study we describe some mathematical models of the malignancy, we present the arguments concerning the capacity of the mitochondria to achieve described processes, and, upon data coming from mitochondrial genetics, we refer to the mitochondrial genetics of sharks and other species, which are rarely affected by malignant tumours. The frequency of malignancy increases “phylogenetically-speaking” above the emergence of thermoregulation, by the emergence of some new mitochondrial pathways, possibly involving sharing or acquiring genetic information with or from the includer host cells. We consider this phylogenetic moment of development as the beginning of the mitochondria capacity to turn into intracellular parasites from endosymbionts. We describe various animal and plant pathologic processes with tissue neoformation involving known and unknown agents, and we then compare them with the malignant tumours, with a view to present the common characteristic of these patterns of behaviour of living matter. In the experimental part of work, we present the first results of our studies and laboratory works with the Castanea sativa Mill. (chestnut) extracts and streptolysine: we believe the classic process of antibiosis described by Fleming works in some other conditions too – some plants develop in the process of the evolution various substances used to fight competing microorganisms, like the ancient mitochondria (ex. Phytoplasmas) – especially some highly evolved and cultivated, edible Mediterranean plants, which extend their habitat areas to the North, in some sub-Mediterranean areas (sometime relying on man’s farming activity) and here they are highly exposed to different parasites (like the phytoplasmas, very similar with the ancestral mitochondria); some bacteria develop too in the process of the evolution substances used to fight other competing micro-organisms, to protect themselves and ensure their access to food sources by fighting competitors. These substances (in part non toxic for human cells, but toxic for the cells and mitochondria with a very different – archaic – metabolism) kills or damage different cancer cell lines, but does not damage under similar conditions and concentrations the sensitive not-malignant fibroblast cell cultures in laboratory conditions. We present the data and some considerations about cancer therapy using classic cytotoxic and citostatic drugs, and the possibility of the use of the chestnut's active substances and different antibiotics used today in the therapy of the infectious diseases caused by different pathogen agents, similar with the mitochondria, considering the mutant mitochondria as a new target of anti-tumour therapy. This, the “target number eight” works in line with the “three principles of anti-mitochondria cancer drugs”: 1. not tumour-specific, 2. not host-cell specific, 3. specific for the ancestral mitochondria expressions. We hope there is a fourth principle in force also: not toxic for the unaltered host cells. Some micro-organisms are very similar with the proto-mitochondria (and, probably, with the non-cooperative mitochondria of tumour cells (Mycoplasma, Phytoplasmas, etc.). Some plants containing defence substances against these micro-organisms, some bacteria develop antibiotic substances with this destination (like the penicillin of the Penicillium). These substances in the authors preliminary tests manifest inhibitory effect on the tumour cell cultures. In theory, it is possible to have an effect similar to some antibiotics used against micro-organisms today in therapy: these plant extracts, bacterial toxins, antibiotics – targeting the non-cooperative mitochondria of the tumour cells - can be (in combination with classic anti-tumour drugs) useful adjuvant in the cancer therapy [16].

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