Systemic Complexity for human development in the 21web.univ-pau.fr/~bricage/slidesplanches/ues/pbCancerDataLisboa20… · hosting and our capacity to be hosted (governed by our endophysiotope

Systemic Complexity for human development in the 21st centurySystemic Complexity : new prospects to complex system theory

7th Congress of the UES Systems Science European Union Lisbon, Dec. 17-19, 2008

CANCER isa Breaking of the Cell's Association for the

Reciprocal and Mutual Sharing ofAdvantages and Disadvantages

Through an Aggressionthat Results in a Lack of Non-Autonomy.

Complementary Data, Figures & References.http://www.minilien.com/?oUtHBBpz46 (file: UESlisboaPBcancerRef.pdf )

Pierre BRICAGE, Social and Health Sciences Engineering

[email protected]

PLAN

Abstract & key words p. 3/26

1. Origins.1.a. Cancer is a disease of disfunctioning cellular genes and unwanted viral gene

expression. p. 41.b. Cancer is the result of modifications of “the capacity «to be welcomed»“ of the

endophysiotope of cells for which the “capacity of «hosting»“ of the body (our endophysiotopewhich is the ecoexotope of survival for these cells) becomes unfitted. p. 5

1.c. Cancer is the result of modifications of the “capacity of «hosting»“ of our ecoexotope(EXT), unsustainable by the limited “capacity «to be welcomed»“ of our endophysiotope (ENT).

1.d. Cancers can be induced by the agents of cellular provirus lysis: the UV andionizing forms of radiations and the harmful chemicals that alter DNA. p. 6

1.e. The genome of any organism is hosting viral sequences.1.f. In addition to viruses, a connection has been noted between bacteria & certain cancers.

2. Susceptibilities.2.a. The individual susceptibility results from interactions between our capacity of

hosting and our capacity to be hosted (governed by our endophysiotope heritage). 2.b. These constrained dangers can be released by the "failure" of the regulation

processes. p. 72.c. These constrained dangers can be freed depending on the sex & the hormonal status.

3. Toxicity of the usual treatments.3.a. Chemotherapy: advantages & disadvantages.3.b. Radiotherapy.

4. Resistances to the usual treatments. p. 8

4.a. Chemotherapy resistances4.a.1. «Survivre c’est “manger“ ET “ne pas être mangé“, pour SE survivre.»4.a.2. «Survivre, c’est “transformer les inconvénients en avantages“ ET

“éviter que des avantages deviennent des inconvénients“, pour SE survivre».4.b. Radiotherapy resistances.4.c. Diversions of the normal defences for the benefit of cancer cells resistances.

APOCOSIS Associação Portuguesa de Complexidade Sistémica Faculty of Science & Technology, LisbonCancer curative vaccine p. 1 /26



5. A biological partnership to struggle against freed or de-constrained dangers. 5.a. What advances in a vaccine designed to prevent cancer are available?5.b. The use of another non-hosted danger to destroy a settled pre-existing one.

5.b.1. To restore apoptosis by the reversion of the phenotype to the normality.5.b.2. Tumour cell assassination through viral lysis. p. 115.b.3. Curation of an endo- provirus or a pseudo-virus, with an antagonistic one.5.b.4. Curation by the death of the sick cells after they returned to non-autonomy:

vanishing the cancerous state with re-creation of the infectious viral state.5.c. Application: a new ex-vivo curative auto-vaccination strategy. p. 12

ConclusionReferences p. 13

Tables & Figures p. 18

TABLES & FIGURES

FIGURE 1: Ergodicity and modularity : juxtaposition, superposition & encasement ofall levels of organisation to make a “fitted” Association for the Reciprocal and MutualSharing of Advantages and DisAdvantages (ARMSADA). p. 18/26

FIGURE 2: The structural & functional ergodicity of the living systems. Juxtaposition& encasement at the all levels of the living systems: ecoexotope (EXT) & endophysiotope(ENT). Advantages/DisAdvantages & cancerisation. p. 19

FIGURE 3: Cancerisation is a response of better survival of the aggressed ENT of acell. Apoptosis is a response of best survival of the organism's stressed ENT. The onlyresponse for the survival of all partners (cells, organism & virus) is to re-born into a new“constrained” ENT, an ARMSADA. p. 20

FIGURE 4: The percolation network of the adjacent levels of organisation.

FIGURE 5: Cancer curative vaccine: the paradigm & the process. p. 22

FIGURE 6: The fates of (healthy or cancerous or infected) cells (or bacteria) andviruses (or bacteriophages) is depending on their “percolating” interactions.

FIGURE 7: Regulation of genes' activity. Dormant, constitutive, repressed &activated genes' expressions: the processes. p. 24

TABLE 8: The costs for each type of genes' regulation: the regulation load. Controlelements of genes' governance. p. 25

FIGURE 9: Evaluation of the risk of disfunctioning & of the cost of the prevention ofthe risk: costs, disadvantages or risks versus gains, advantages or robustness of asystem. In a real network of regulation, 1 cause has more than 1 effect. Why?




ABSTRACT

Cancer (malignant neoplasm) may affect people at all ages, even foetuses, and risk tendsto increase with age. A group of cells (Sigma 2008 a) displays the traits of “uncontrolled growth,division beyond the normal limits”, invasion and destruction of adjacent tissues and spreading toother locations via lymph or blood. These properties differentiate cancers from benign tumours,which self-limited stay under control. Cancer is the result of the failure of the capacity of “tobe hosted”, of the endophysiotope of cells, in response to the failure of the hostingcapacity of their ecoexotope, the organism. There is only one rule of survival: "to transformdisadvantages into advantages" and "to prevent advantages from turning to disadvantages".When the ecoexotope is changing, a disadvantage can turn to an advantage and conversely(Dolberg & al. 1985). For stressed endangered cells, cancer is the way not to die. Cancer isa survival response of damaged cells! How is that process of retrogression working?

Viruses were the first proved cancerous agents. Viruses are the second most importantrisk factor for cancer development in humans, exceeded only by tobacco usage. The amount ofcancers linked to AIDS or other viral sources is continuously increasing (Routes & al. 2000). Thegenome of all organisms is inhabited by viral genomes. The presence of these controlled“constrained“ risks is usually an advantage for the survival of both the inhabited cells and theirinhabitant viruses (Feng & al. 2008): the genetic material of a cancer virus is inserted into thehost cell genome without any production of virus particles and with no cell death. Cancer is adisease of disfunctioning cellular genes due to unwanted viral gene expression. How,when and why do these silenced killing dangers reborn?

Cancer is induced by agents of cellular provirus' lysis: radiations & chemicals alteringDNA. The same that are used in chemotherapy and radiotherapy. Dose-dependence effects andthreshold concentration dependencies may impaired or reversed the activity of protective orcurative agents. The stability of a cancerous cell is in the key fact that the virus does not kill thecell and reciprocally the cell prevents the virus to be killed by other cells. The result is themerging of a new spatiotemporal network, a new mode of integration into an Association forthe Reciprocal and Mutual Sharing of Advantages and of Disadvantages “ARMSADA“(FIGURE 1) within the cell: an advantage for the “new” cell but a dis-advantage for the organisminside which the re-autonomy of the cancer cells disrupts the previous steady-state’s controls. Inorder that one survives, it is necessary that the others survive first, and reciprocally (FIGURE 2).The fate of a cancer cell, like the fate of a bacterium infected with a phage, is depending on theinteractive “percolation“ with its invading virus (Bricage 2005 a1 & a2). That explains theheterogeneity of the disease, its evolutions and the diversity of the potential hosts: "the way isboth the cause and the consequence of the history" (Sigma 2008 b). Cancer is a disease of thebreakage of the Association between the “parceners”. Usually (FIGURE 3) that leads toapoptosis (Bricage 2005 b1 & b2), but sometimes to cancer (Ishikawa & al. 2008).

Key words: apoptosis (FIGURES 2 & 3), association (FIGURE 1), cancer, cancerisation(FIGURES 2 & 3), curative vaccine (FIGURE 5), governance (FIGURE 8), hosted viruses,integrated dangers (FIGURE 6), regulation (FIGURE 7), risk (FIGURE 9).

Definitions: organisation, integration, ergodicity, fractal, symmetry breakage,contingency (p. 10 In Bricage 2001), percolation (p. 10 In Bricage 2001, p. 22-23 & 31 In Bricage2003, p. 33 In Bricage 2006 a & b, p. 4 In Bricage 2007).

This work is dedicated to Évelyne Andreewsky, AFSCET's vice-President & Founder of theEuropean Union of Systemics, who died 1 year ago, in December 2007, after a lot of pain, from ageneralized cancer. http://www.afscet.asso.fr/Archives/andreewskyDeces.html

(accepted 18 June 2008, revised 21 Sept. 2008)




Yesterday, with plague, tuberculosis and leprosy, men were killed by bacterial diseases.Today, the killers are "the” viral diseases (Hannoun 1980a), and particularly cancers

(Beaulieu 1980, Jasmin 1980), AIDS and flu (Hannoun 1980b).

CANCERSCancer (malignant neoplasm) is a class of diseases in which a group of cells display the

traits of “uncontrolled growth and division beyond the normal limits”, “invasion and destruction ofadjacent tissues”, and sometimes “spread to other locations via lymph or blood” (metastasis).These 3 properties of cancers differentiate them from benign tumours, which are self-limited, anddo not invade or metastasise.

Cancer may affect people at all ages, even foetuses, and risk tends to increase with age.http://en.wikipedia.org/wiki/Cancer

1. OriginsCancers are caused by abnormalities in the genome of the transformed cells.These abnormalities may be due to the effects of chemicals (such as tobacco smoke),

radiations (Lehnert 2007), infectious agents, may be acquired through errors in DNA -replication,-repair or -methylation, or are inherited (and thus present in all cells from birth) (FIGURE 2).

Complex interactions between carcinogens and the host genome may explain why onlysome develop cancer after exposure (Han 2008).

1.a. Cancer is a disease of disfunctioning cellular genes and unwanted viralgene expression.

The first cancerous agents that were found were viruses (Tambourin 1989). Virusesappear to be the second most important risk factor for cancer development in humans,exceeded only by tobacco usage. The International Centre for Cancer Research of the WorldHealth Organization was created in 1965 to study a viral induced cancer : the Burkitt Lymphomawhich is associated with the Epstein-Barr Virus. The main viruses associated with human cancersare Human PapillomaVirus HPV, Hepatitis viruses B and C, Epstein-Barr Virus EBV, and Human T-Lymphotropic Virus HTLV.

In acutely-transforming viruses, the viral particles carry a gene that encodes for anoveractive viral-oncogene and the infected cell is transformed as soon as the gene isexpressed (Kamiyama & al. 1993). In slowly-transforming viruses, the virus genome is insertednear a proto-oncogene in the host genome. Transcription regulation elements (Latchman 1991)cause over-expression of that proto-oncogene, which in turn induces uncontrolled cellularproliferation. Because viral genome insertion is not specific slowly-transforming viruses have verylong tumour latency compared to acutely-transforming viruses.

The genetic material of a cancer virus is inserted into the host cell genome withoutany production of virus particles and with no cell death (Feng & al. 2008). Repressors orinducible factors like transcription factors facilitate adaptation to deprivation by regulating theexpression of genes that control metabolism, angiogenesis, cell proliferation, and apoptosis(Rankin & Giaccia 2008). Cancer is a micro-evolutionary response for best survival of adamaged cell ! (FIGURES 3 & 7)

Normally DNA viruses (probability 0,999999) are not integrated in the cell genome and theviral infection results in cell death: lysis and burst of a new viral generation. Rarely (probability0,0000009), if a mutant virus or an unusual phenotype of cell, the viral DNA is integrated into thecell DNA into a new whole (FIGURE 2).

RNA viruses (retroviruses) normally integrate the cell DNA to subvert the cell genome tomake a new generation of RNA viruses. Rarely there is no cell death, if a defective virus or anappropriate unusual genome change as a whole. The viral integration into the cell DNA promotes adis-regulation of the ago-antagonist mechanisms of the number growth control (Gaurenne 1995).




Retroviruses are cell transforming viruses. All transforming signal ways are present:amplification of the number of a gene, activation of a silent gene (or hyper-expression of itsactivity), repression of an active gene (or hypo-expression of it), and normal expression but at thewrong place and at the wrong time.

MicroRNAs (miRNAs) play critical roles in development, and disregulation of miRNAexpression has been observed in human malignancies. Recent evidence suggests that theprocessing of several primary miRNA transcripts (pri-miRNAs) is blocked post-transcriptionallyin embryonic stem cells, embryonal carcinoma cells, and primary tumors (Viswanathan & al.2008). A developmentally regulated RNA binding protein is a negative regulator necessary andsufficient for blocking microprocessor-mediated cleavage of miRNAs in embryonic stem cells andin certain cancer cells. It functions with 3 other factors to reprogram human fibroblasts topluripotent stem cells. This suggests that the regulation of miRNA processing may be critical inthe dedifferentiation that occurs in both reprogramming and oncogenesis.

In cancer cells promoting oncogenes are often activated, giving those transformed cellsthe new properties of hyperactive growth and division, protection against programmed cell death,loss of respect for normal tissue boundaries, and the ability to become established in diverse tissueenvironments. Tumour suppressor genes are often inactivated in cancer cells, resulting in theloss of normal functions in those cells, such as accurate DNA replication, control over the cellcycle, orientation and adhesion within tissues, and interaction with protective cells of the immunesystem.

1.b. Cancer is the result of modifications of “the capacity « to be welcomed »“of the endophysiotope of cells for which the “capacity of « hosting »“ of the body(our endophysiotope which is the ecoexotope of survival for these cells) becomesunfitted.

It is the only answer which allows these “assaulted“ cells to survive, by changing theirmode of integration within the organism (Tyson & al. 2008), through the return to a previousless differentiated phenotype. This retrogression is the usual answer to violence (Bricage 2000b),whatever is the level of organization (FIGURES 1 & 2) of the considered alive systems (Bricage2000c). Tumours have been shown to be inducible at sites of wounding (Dolberg & al. 1985).Repeated wounds may be at the origin of stem cells’ tumour emergence (Beachy & al. 2004,Rakoff-Nahoum 2006).

1.c. Cancer is the result of modifications of the “capacity of « hosting »“ ofour ecoexotope, unsustainable by the limited “capacity « to be welcomed »“ of ourendophysiotope.

It is a disease of dis-functioning resulting of the inadequacy of our “to be welcomed“capacity with the available limited “accommodation facilities“. It is the consequence of the"collateral" damages of our industrial societal “habitus“.

Whatever is the modification of the “capacity of hosting“ of the ecoexotope (for exampleeither with carcinogenic insulating asbestos (Golberine & al. 1995) or with phenolic antioxidants ofcigarette smoke, hair dyes, and industrial catechol derivatives, with tumor-promoting activity(Furihata & al. 1993)) or of the “capacity of to be welcomed (or hosted)“ of our endophysiotope(for example with substitute hormonal treatments: the hormonal treatments of the menopauseimprove the quality of the life and prevent osteoporosis but they increase the risk of breast cancer(This 2004)), there is no advantages without inconveniences (dis-advantages) and since a longtime the risks are identified. And the best treatment is prevention. For example, tobacco andalcohols are the greatest risk factors for the oral and pharyngal cancers. For all the cancers, the epidemiological studies have allowed to point to -the hazards inlabouring tasks, -the influence of the addiction to smoking, -the fats in the nutrition diet, and todetermine the carcinogenic agents. The causes and the mechanisms of their actions are identified.Thus, the wisdom is to emphasize the prevention, because no curative treatment is withoutdanger and frequently no efficiency, outside the total surgery, is guaranteed (Schwartz 1996)!




The curation is a failure, in particular, as for the (HIV induced) AIDS, with the unwantedeffects of medicines (Girard 1987).

1.d. Cancers can be induced by the agents of cellular provirus lysis: the UVand ionizing forms of radiations, the harmful chemicals that alter DNA.

Cancers are activated by the same factors as those who start the bacterial proviruslysis: -the mutagen & teratogen ionizing radiations (Hiroshima, Nagazaki, Tchernobyl) (Reuillon2005), -the UV radiations (particularly UV A ones which penetrate into the skin 1000X more thanUV B ones. And, in a "sunbath" there is 100X more UV A than UV B (Legac 1995)).

And, there is no curative treatment of the evolved melanoma.

1.e. The genome of any organism is hosting viral sequences.Genes of fly were identified in the genome of the man species, in 1992! Several hundreds

of "jumping" genes of the mariner type are hosted in it, among which at least one is active (Hart &al. 1999). At least 10 % of our genome is constituted by genes of viral origin. Theseendogenous “constrained“ viruses (Bénit & al. 1999) are still active (Stoye & al. 2001), they notonly do express themselves, but indeed they usually confer a resistance against similar parentedviruses (Esnault & al. 2005) or against other dangers. A protein, APOBEC3G, prevents the liberation of these endogenous viruses: -it introducesmutations into the genomes of the retrovirus which make them unable to reproduce, -it blocks thereplication of the HIV.

Many genes can be controlled by viral promoters or activated by viral transcriptionfactors (Latchman 1995).

Many genes that are nowadays indispensable for the survival of the cell may have originatefrom ancient viral lytic genes, particularly from retroviruses, like RNA coding genes ? (Marshall &al. 2008)

1.f. In addition to viruses, a connection has been noted between bacteria andcertain cancers. The papilloma viruses' infections are involved in the cervical cancer but they are alsoassociated with cancer of the pharynx (Gillison & al. 2000). The most prominent example is thelink between chronic infection of the wall of the stomach with Helicobacter pylori and gastriccancer. Even if a sharp decline in mortality due to AIDS has followed the introduction ofantiretroviral tri-therapy, although the prevalence of HIV infection has not increased, in the USA,the amount of cancers linked to AIDS or other viral sources is continuously increasing(Data from UNAIDS and the US Center for Disease Control and Prevention).

Within the superior plants genomes, at least a gene (an intron), inhibits the tumorisationby the bacterium Agrobacterium tumefaciens (Azmi & al. 1997, Sales & al. 2002).

An external danger can be constrained by an internal danger!Many bacteria species genomes are hosting genomes of viruses (FIGURE 9), which

give them an increased, and inherited, greater survival aptitude (FIGURE 6). Cancer results froma "de-control" of constrained dangers, which are free released or badly repositioned, orfrom the bad integration of new not-constrained dangers (FIGURE 7).

It is a new way of looking at proviruses: they are not sources of viruses but at leastshields against the invading (invaders coming from the ecoexotope) or even active defencesagainst the evading (evaders from the endophysiotope) of viruses!

2. SusceptibilitiesCancer is the result of epigenetic phenomena that alter the regulation mechanisms of

transcription (FIGURES 7 & 9 TABLE 8). These mechanisms not necessarily are the results ofmutations (Marty 2006). Their emergence is the result of the failure of the buffering role of theecophysiotope (Bricage 2002), which is the space-time of the interactions between theendophysiotope and the ecoexotope of the cells.




In 1980 more than 150 viruses were connected with cancers (Daudel 1980).

2.a. The individual susceptibility results from interactions between thecapacity of hosting and the capacity to be hosted (in the endophysiotope heritage).

Breast cancers (Stoppa-Lyonnet & al. 1997) have a genetic determinism. Numerousalterations (Tassin 1996) predisposing to cancers are autosomal (independent from the sexheritage) and dominants (http://www.nci.nih.gov/cancer_information/prevention), and neverthelessthey are frequent (1 %). Why?

Because it exists also an ecological determinism ( quality dependence ) depending on ourenvironmental heritage (“ecoexotope's load”). And the phenotypical determinism ( dose dependence ) results (Simone 1996) from interactions between the ecoexotope's load and theendophysiotope's limits (FIGURE 1).

In the case of breast cancers, the answer of the body is at the same moment theconsequence of its genetic predispositions (genotype), its hormonal status (phenotype) and itslifestyle, especially the food customs (interactions between phenotype and environment) (Bertière& al. 1995) (genetic, ecological and physiological determinism: ecophysiotope (Bricage 2002)).

2.b. Constrained dangers are released by the failure of regulation processes.Tandem simple sequence repeats (SSRs) are abundant across the genome, but their

distribution, preferentially inside centromeric, telomeric and intronic sequences, is nonrandom.SSRs locate preferentially in regulatory genes related to transcription and signal transductionand are under-represented in genes of structural proteins. Changes of SSRs within and betweenthe genomes of the cell (the hosting inhabited partner) and the endo-virus (the hosted inhabitingpartner) can result in changes in transcriptional (or post-transcriptional) activity (FIGURE 7). SSRsinstability is frequent in human cancers and other genetic disorders (Li & al. 2002).

2.c. These constrained dangers can be freed depending on the sex & thehormonal status.

It runs as well into the man: breast cancer (Julian-Reynier & al. 1998), prostate cancer(Woolf 1995), colorectal cancer (Winawer & al. 1997), as it runs into plants (Azmi & al. 1997).

Man is not an exception!

3. Toxicity of the usual treatmentsOnce diagnosed, cancer is usually treated with a combination of surgery, chemotherapy

and radiotherapy. But, Treatments are so aggressive that the doctors sometimes hesitate tooperate them (Garnick 1994), because of the risks of collateral damage or therapeutic hazard (LeTaillanter 1996)? The best treatment is the prevention (Darnis 1980).

“We are what we eat.” The breastfeeding protects both the mother and the child againstcancer (Coll. GHFBC 2002). To avoid the risks, recommendations are “listed“ in order to reduce theprobability of cancerisation. Symptoms are “listed“ which permit to detect, as soon as possible, theappearance of cancers (Daudel 1980).

3.a. Chemotherapy: advantages & dis-advantages.The DMSO has the advantage "to target" only the cancer cells (?) and it is used as

(toxic!) "solvent" (Brachat & al. 2002) of the usual anti-cancerous drugs (camptothecin,methotrexate, paclitaxel). But cancer cells "look like" the embryonic cells and the stem cells, andthe DMSO is teratogenic (Caujolle & al. 1965). The DMSO also has the advantage (AND theinconvenience!) to diffuse across the blood-encephalic barrier (Tucker & Carrizo 1968). The DMSOis also used as a solvent during drug tests against auto-immune diseases (Rosloniec & al. 2006).

The most effective of all anti-cancerous substances is the cisplatin, but its efficiency islimited. And its great renal toxicity and its "other" side effects are "very heavy". The only newdrug is the taxol, a "poison" the cellular target of which is the tubulin (Schwartz 1996).




The chemotherapy with arsenic derivatives (arsenic is a highly toxic poison!) can restorethe normal cell state by resumption of the differentiation of a false differentiated cancer cell(Lallemand-Breitenbach & al. 2008).

Thus, chemotherapy addresses healthy subjects “which can bear very aggressivetreatments“ (Rougier & al. 1997).

The efficiency of the chemotherapy is limited by the capacity of the tumoral cells todevelop an always bigger resistance and by the risk of change of healthy cells becoming inturn tumoral!

Cancer cells are fast dividing cells (Gaurenne 1995). Thus new drugs are elaborated toabort cell's division. But healthy cells, particularly stem cells, must also sometimes divide to renewdead cells (Sonigo 1995). Cytotoxic chemicals are rarely specific because they act on everydividing cell (Gatard 1995). No more are growth regulators for the same reason (Soufflet 1995).Thus drug treatments must be done not heavier or more frequently, but more targeted (Jean 1996),into the space (of the organism and the cell) and at the best moment of the body and cells timings(Bricage 2005c1).

3.b. Radiotherapy.It is even more the case for the radiotherapy that pulls massive cellular deaths in the bowel

and the blood fabric tissue. The dose which would be totally effective is not delivered because itwould give too many side effects:

" the treatment's pain would be too load than the disease's pain! " (Schwartz 1996).

4. Resistances to the usual treatments.Some dose dependence effects and threshold concentration dependencies may

impaired or reversed the activity of protective or curative chemicals.« Survivre c’est “manger“ & “ne pas être mangé“, pour SE survivre » (Bricage 2000a).« Il n’y a pas d’avantage(s) sans inconvénient(s). » (Bricage 1998)« Survivre, c’est “transformer les inconvénients en avantages“ ET“éviter que des avantages deviennent des inconvénients“, pour SE survivre »

(FIGURES 2, 3 & 6)

4.a. Chemotherapy resistances.4.a.1. « To survive it is "to eat" AND "not to be eaten", to allow life goes on. »

(Bricage 2000 a & b) (FIGURES 2 & 6).Angiogenesis, the growth of new blood capillaries, is an usual phenomenon during the

development of the body, during the menstrual cycle or during the healing. To eat, cancer cellscontrol angiogenesis by secreting the Vascular Endothelium Growth Factor VEGF (Coisne 2008).The advantage of the angiogenesis for the healing of the normal organism becomes adisadvantage for the survival of the body when cancer is installed.

But, anti-angiogenesis drugs (in combination with usual chemotherapy), which are anadvantage for the survival of the cancerous body, have inconveniences for the cardiacfunctioning.

"There is no an advantage without any disadvantages." (Bricage 1998)4.a.2. To survive, it is "to transform disadvantages into advantages" AND "to

avoid advantages turning to disadvantages", in order to live on... “To survive itself“(Bricage 2000 a & b).

The resistance in a product for a strain is an advantage only when the product ispresent. When the product is missing, the resistance is usually a disadvantage with regard to thenon-resistant strains. But disadvantages do not sum necessarily and even 2 disadvantagescan be an advantage with regard to 1! A second disadvantage can cancel the cost of the firstone (Berticat & al. 2008).




Fundamental to living cells is the capacity to differentiate into subtypes with specializedattributes. How cells adopt a particular fate is usually thought of as being deterministic, and in thelarge majority of cases it is. That is, cells acquire their fate by virtue of their lineage or theirproximity to an inductive signal from another cell.

In some cases, however, cells choose one or another pathway of differentiationstochastically, without apparent regard to environment or history. Stochasticity isadvantageous, and even critical in some circumstances, to the individual, the colony, or thespecies (Losick & Desplan 2008). Even the biotherapy with natural substances did not hold itspromises (Jasmin 1987).

4.b. Radiotherapy resistances.A molecule, which has just been discovered, defends the healthy cells from the noxious

effects of the radiotherapy, but activates a metabolic way usually used by the tumour cells toprotect themselves from apoptosis (Burdelya & al. 2008).

4.c. Diversions of the defences for the benefit of cancer cells & antiviral drugsresistances.

Interferons are rarely effective (Ferrara 1984).How to distort the abnormality of cancer cells without altering the normality of

healthy ones? (FIGURE 5)The interleukin 3, which infers a fluidity of the plasma membrane, is indispensable to the

survival and to the number growth of normal hematopoiesis stem cells, just as much as of those ofthe stem cells of myeloblastomes (Laskay & al. 1988).

Interleukins are numerous, polymorphic, and pleiotropic. They act in interaction, through avery weak occupation of the cellular receptors (Nicola & al. 1988), and with very weak active doses(their level of secretion is of the order of 2 ng/million cells/12h). They have opposite or synergiceffects. For example, the mitogenic bFGF and the inhibitive TGFb together control angiogenesis(ago-antagonism). They are secreted at the same moment both by healthy endothelial cells of thecapillaries, under the organism's self-control, and by the de-controlled cancer cells (Hannan & al.1988).

The normal events of the cellular metabolism (a stream of calcium, a change of pH, achange of potential of the plasma membrane or the phosphorylation of its proteins), withoutselection, and at the same moment, activate both the expression of the healthy genes and theoncogenes (Amagai & al. 1989) or the viral constrained dangers (FIGURES 5, 6 & 7).

How to activate some without activating the others? (FIGURE 5)

5. A biological partnership to struggle against “freed“, non- orde-constrained dangers.

In the plant Arabidopsis thaliana, operon-like gene clusters (like the thalianol pathwayoperon) are built of unrelated genes but with related functions. The clustered genes are co-expressed, as in bacterial operons. The gene cluster has been assembled from plant genes bygene duplication, neo-functionalization, and genome reorganization, independently in divergentplant lineages (Arabidopsis and oat). Thus, selection pressure may act during the formation ofmetabolic pathways to drive gene clustering (Field & Osbourn 2008).

5.a. What advances in a vaccine designed to prevent cancer are available?In 2006, the US FDA approved a human papilloma virus vaccine, called Gardasil. The

vaccine protects against 4 HPV types, which together cause 70% of cervical cancers and 90% ofgenital warts.

Our endophysiotope owns (and inherits) both a “hosting“ capacity (it is an ecoexotope ofsurvival for other living organisms) and a “to be welcomed“ capacity (into an ecoexotope whichis shared with other organisms). The "balance" advantages versus disadvantages is dependingon the considered level of organisation (into the space and through the time: FIGURE 2).




The cell's transformation is the result of a variety of metamorphoses depending on theplace of integration of "the danger" (the unwanted gene) and the moment of its expression ornot. The stability of the association is in the key fact that the virus does not kill the cell andreciprocally the cell does protect the virus of the killing by other cells. Infectious particles are notliberated following the fusion of some transformed cells with non-transformed permissive ones.

The shuttle (Bricage 2002) of a step of organisation “i” to a higher adjacent one “i+1” is theresult of the merging of a new spatial and temporal network, whatever its mode of integration,through the birth of an Association for the Reciprocal and Mutual Sharing of Advantages andof DisAdvantages (like a Lichen Organism). But, all the partners must loss simultaneously thecapacity to destroy the others. Each advantage for a partner is always a disadvantage for all theothers and reciprocally. No one partner is a winner, all are “winner and looser”: the symbiosis is anassociation " for the best and the worst " . The gain is only for the wholeness !

There is only one rule to survive : "to transform disadvantages into advantages" and"to prevent advantages turning to disadvantages". When the ecoexotope is changing, adisadvantage can turn to an advantage and conversely. To survive it is "to eat and not to beeaten". Preys or hosts and predators or parasites (like immune cells and HIV) struggle each otherin a war without mercy. Each defensive innovation of a prey is followed by an aggressive one of itspredators. “To attack” is never the best defence, but “to change” of trophy network. Only themetamorphosis of the endophysiotope makes possible to contain the dangers (Bricage 2005 b2).In order that one survives, it is necessary that the others survive first, and reciprocally. Duringthe ontogeny of a leguminous nodule, the host plant part metamorphoses into a tumour and theBacteria metamorphose simultaneously into bacteroids.

Like that of a bacterium infected with a phage, the fate of a cancer cell is depending on theinteractive percolation with its invading virus (FIGURES 4 & 6).

That indeed explains the heterogeneity of a disease (cancer or AIDS), its evolutions and thediversity of the potential hosts:

"the way is, both, the cause and the consequence of the history."As the previously proposed AIDS curative vaccine, built with HIV engineered stem cells

(Bricage 2005 b1 & b2), the application of this systemic paradigm will allow us the design of newtypes of vaccines, like a cancer curative vaccine, like a preventive leprous vaccine.

5.b. The use of another non-hosted danger to destroy a settled pre-existingone (FIGURE 5).

The injection of a viral vector is commonly used to restore a damaged or absent gene,for example to control circadian rhythms "2 clocks are better than 1" (Fuller & al. 2008)

5.b.1. To restore apoptosis by working to the reversion of the phenotype tothe normality.

Adult mouse and human fibroblasts can be reprogrammed to a pluripotent state afterthe viral integration of 4 transcription factors. However, questions remained as to the origin ofthose cells, whether specific genomic integration sites are needed, and how tumorigenicitymight be reduced (Bang & Carpenter 2008).

Embryonic stem cells and cells of human malignancies are characterized by lowlevels of microRNAs (miRNAs), a phenomenon thought to be functionally linked topluripotency and oncogenesis. Precursors are detectable but processing to the miRNA matureform is inhibited (Viswanathan & al. 2008).

In vivo restoration of RhoB expression, through recombinant adenovirus transduction, witha single 108 p.f.u. of the reporter gene vector virus (Couderc & al. 2008), leads to ovarian tumorregression, through the activation of the intrinsic apoptotic caspase cascade.

But, at the cell body, an incoming virus stimulates its own uptake (Darland-Ransom & al.2008) by mimicking the uptake of apoptotic cell corpses (Mercer & Helenius 2008).

But as the requirements for reprogramming different somatic cell types to apluripotent state may not be equivalent, the same for reverting cancer cells to normal ones(Bang & Carpenter 2008).




5.b.2. Tumour cell assassination through viral lysisA tumor killing virus may be loaded into a cell type that houses to tumors (Harrington & Vile

2006). Parvoviruses do stop the tumours' progress into the man. They infect all the cells, but theymultiply only in the cancer cells which they destroy, 1 cell producing 500 viral particles in 48 hours(Stéhelin & al. 1999).

Around half of all cancers have mutations in the p53 gene that controls cell division anddeath. A harmless human virus kills only cells with this mutation (Raj & al. 2001).

5.b.3. Curation of an endo-provirus or pseudo-virus, with an antagonistic one.In plants, fungi and worms, RNA interference functions to silence endogenous repeated

and parasitic DNA, including transposons, in somatic cells (Ghildiyal & al. 2008).Silencing of oncogenes, or other genes, contributing to tumor malignancy or progression,

has been done by RNA interference in mice (Takahashi & al. 2005) using viral plasmid vector(Takahashi & al. 2006).

5.b.4. Curation by the death of the sick cells after they returned to non-autonomy: “vanishing“ the cancerous state with re-creation of an infectious viralstate.

But, the interaction between a virus and its host cell, like that between a predator andits prey, is an arms race, with each new viral attack parried by the host and each newdefence by the host one-upped by the virus: a rapid escalation characterises virus/hostarms race.

The merging of a new living system, like a cancer clone, is always a transgression of olderones. It is achieved by the juxtapositions and encasements of previous systems (FIGURE 1). Thenew wholeness is both more and less than the sum of its parts. It merges from the simultaneousmetamorphoses of the partners that maintain their identity and their half-autonomy by thepreservation of their individual and collective boundaries and their self-organisation, like theeukaryotic cell which merged from Monera (Bricage 2005a1).

The cancer is a disease of the breakage of the Association for the Reciprocal andMutual Sharing of Advantages and DisAdvantages (ARMSADA) between the partners(named “parceners”). Usually the breakage leads to apoptosis, but sometimes to cancer: mutationsin mitochondrial DNA can spur metastasis and mtDNA in tumor cells tends to be riddled withmutations -and far more than in normal tissues- (Ishikawa & al. 2008).

On the short duration, the cell lysis (probability 0,9999) is an advantage for the virus anda disadvantage not only for the permissive cells but and the whole organism. But virus codedproteins are usually expressed on the surface of the host cell, making the cell a target fordestruction by the immune system. Thus, on the long duration, the hosted cells are killed with thevirus, it is a disadvantage for the virus, and an advantage for the organism as a whole if now"vaccinated" against the virus and its other relatives.

But at the long duration, if the cells' deaths result in the organism's death without itsreproduction, it is a disadvantage for the both species: the virus and the organism.

At the short duration, the cancerous state, the transformation without lysis of non-permissive cells (probability 0,0001), is an advantage both for the virus and the cell.

Because, the transformed cancer cells have lost the contact inhibition of growth and gainedthe immortality. Not only they are not killed but also they survive and multiply indefinitely and thewhole endophysiotope of the organism is their permissive ecoexotope. Simultaneously the virussurvives indefinitely within the endophysiotope of the cell, which is its permissive ecoexotope. Andno killed cells of the tumour can elicit immune protection against live cells of a second tumour. Butat the long duration, even if it is a disadvantage for the organism, it is an advantage for theboth species if the organism ("the prey") has given birth a new generation of preys for "thepredator" (the virus).




5.c. The ex-vivo curative auto-vaccination: FIGURE 5.In its principle it is similar to that proposed to fight against the HIV (Bricage 2005b2) :- 1. taking of cells only from sick patients,- 2. then putting them in culture,- 3. in order to the in vitro selection of cells having integrated into their genome, a

"harmless" transducing retrovirus,- 4. then in vivo re-implantation of these modified cells. But it is different in its purpose:- 5. to reveal the expressed, but not-recognized, dangers, so that he can be

recognized and destroyed. Some viruses cause a cancer, some others not, because theirpresence is recognized and they are destroyed (Routes & al. 2000), because the viral genomeallows to express proteins associated with the tumor, and the antigenic presentation of theseproteins activates the immune system (Andujar 2006).

ConclusionInto an aggressive ecoexotope (Rohr 1991 a & b), soon or late, the liberation of the

“constrained“ dangers that are homing the endophysiotope is unavoidable. It is a collateral damageof the evolutive “hasard et nécessité”. “Unusual gene therapies“ also are not without risks(Cartier 2006). But curation needs to take some risks to go out of the no-success of the currentvaccine situations.

“A good virus is not a dead one!“ But a "very alive" one and the endophysiotope of which is"integrated" ("juxtaposed and encased"), and not only structurally, but also functionally, into theendophysiotope of the cell, as well as the mitochondrial genome (of prokaryotic origin) is integratedinto that of the nucleus of the eukaryotic cell (Bricage 2005 a1 & a2). The sheep needs a retrovirus(Dunlap & al. 2006) to reproduce. To reproduce itself it has to reproduce an other self, anendogenous virus (Palmarini & al 2000). The survival of the 2 species is depending on thesurvival of each parcener species (Xiao & al. 2008): FIGURES 1 & 4.

Why have the meristematic cells of the apexes of stalks and roots of vegetables anindefinite growth ? And why do they resist to the infection by exogenous viruses? Because, as anystem cell, they do have the characteristics of unlimited growth of a cancer cell. Because, likein many plant species (Jakowitsch & al. 1999), they do contain integrated endoviruses .

Their properties of tumorisation, a "constrained disadvantage", or of regeneration, anadvantage of that disadvantage, are connected. During the floral differentiation (acquisition ofthe capacity of reproduction: an advantage for the species), the meristematic cells lose their owncapacity of growth (the vegetative reproduction). They lose the eternity! What is a greatdisadvantage for themselves but an advantage for the preservation of the alive sort (the species)of which their organism is a part : FIGURE 3.

This breakage is not a failure but a progress! (FIGURE 6)And it is controlled by constrained (controlled) cancer genes (Ausin & al. 2004).The genome of Chlamydomonas reinhardtii is hosting genes of both plant and animal

origins (Merchant & al. 2007) that may have been transduced by plant and animal viruses. Likebacteria have their bacteriophages, viruses also have their virophages (La Scola & al. 2008). Likein verbal evolution (Cowen 2007), “The more you use a virus, the less likely it will change.” “Theless you use it, the more it will change.” The best protection and curation against viruses damagesis to host and to express their genes (FIGURES 7 & 9), in order to stop their evolution asparasites: “the full usage will make invariance and security, while no usage is making troubles”.

A danger may be constrained by an other one! (FIGURE 5)Two dangers which separately lead to great disadvantages, together may be a great

advantage! (TABLE 8)Dangers are unavoidable but they are sustainable and may aid to the sustainability.




References

Afscet (2007) La gouvernance dans les systèmes. Polimetrica International, Monza, 182 p.Amagai M. & al. (1989) Cloning of TPA-Inducible Early (ITE) Genes by Differential Hibridization Using

TPA-Nonresponsive Variant of Mouse 3T3-L1 Cells. Somatic Cell & Molecular Genetics 15: 153-158.Andujar G. (2006) Des lymphocytes T génétiquement modifiés éradiquent des tumeurs. Biofutur 271:

9.Ausin I. & al. (2004) Regulation of flowering time by FVE, a retinoblastoma-associated protein.

Nature Genetics 36: 162-166.Azmi A. & al. (1997) Bud regeneration from Eucalyptus globulus clones and seedlings through

hormonal imbalances induced by Agrobacterium tumefaciens strain 82.139. Plant Sci. 127: 81-90.Azouaou N. & al. (1997) Mycobacterium avium infection in mice associated with time-related

expression of Th1 and Th2 CD4+ T-lymphocyte response. Immunology 91: 414-420.Bang A.G. & M. K. Carpenter (2008) Development: Deconstructing Pluripotency. Science 5872: 58-

59.Beachy P.A. & al. (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432: 324-331.Beaulieu E.E. (1980) Cancer du sein. La Recherche 115: 1078-1087.Bénit L. & al. (1999) ERV-L elements: a family of endogenous retrovirus-like elements active

throughout the evolution of mammals. J. Virol. 73:3301–3308. Berticat C. & al. (2008) Costs and benefits of multiple resistance to insecticides for Culex

quinquefasciatus mosquitoes. BMC Evolutionary Biology 8: 104-112.Bertière M.C. & al. (1995) Nutrition et Cancer. impact médecin Hebdo pages spéciales 268, 14 p.Brachat A. & al. (2002) A microarray-based, integrated approach to identify novel regulators of

cancer drug response and apoptosis. Oncogene 21: 8361-8371.Bricage P. (1998) La Survie des Systèmes Vivants. Atelier fondateur de MCX20 “Prendre soin de

l’homme”, Centre Hospitalier Général de Pau, 19 oct. 1983, 3 p. http://minilien.com/?pyYTSP76nY- Bricage P. (2000a) La Survie des Organismes Vivants. Atelier fondateur groupe AFSCET “Biologie &Systémique“ , Fac. Médecine St Pères, Paris, 4 fév. 2000, 44 p. http://www.afscet.asso.fr/SURVIVRE.pdf

Bricage P. (2000b) La nature de la violence dans la nature. Déterminismes écophysiologique etgénétique de l'adaptation aux changements dans les écosystèmes végétaux. “ La violence “, Journées AFSCET d'Andé, 6 p. http://www.afscet.asso.fr/pbviolW98.pdf

Bricage P. (2000c) Systèmes biologiques : le "jeu" de la croissance et de la survie. “ La décision systémique: du biologique au social. ” Atelier AFSCET Institut Internat. Administration Publique, Paris, 6 p. http://www.afscet.asso.fr/JdVie1.pdf

Bricage P. (2001) Les caractéristiques du vivant biologique et sociétal ? Pour survivre et se survivre,la vie est d’abord un flux, ergodique, fractal et contingent, vers des macro-états organisés de micro-états, àla suite de brisures de symétrie. “ L’évolution, du vivant au social. “ Atelier AFSCET , I.I.A.P., Paris, 11 p., 2figures. http://www.afscet.asso.fr/ergodiqW.pdf

Bricage P. (2002) The Evolutionary “Shuttle” of the Living Systems. 5 th ECSS (Heraklion, Creta,Greece), 6 p. http://www.afscet.asso.fr/resSystemica/Crete02/Bricage.pdf

Bricage P. (2003) Organisation, intégration et espace-temps des systèmes vivants. Intégration duvivant et du social: Analogies et différences . Journées AFSCET d'Andé , 17-18 juin 2003, 31 p. http://www.afscet.asso.fr/pbAnde03.pdf

Bricage P. (2005a1) The Cell originated through Successive Outbreaks of Networking and Hominginto Associations for the Mutual and Reciprocal Sharing of Advantages and of Disadvantages, between thepartners, with a benefit only for their wholeness. 6 th ECSS (Paris, France) , 11 p. http://www.afscet.asso.fr/resSystemica/Paris05/bricage3.pdf

Bricage P. (2005a2) Les Associations à Avantages et Inconvénients Réciproques et Partagés.L'origine endosyncénotique de la cellule : avantages et inconvénients partagés entre partenairesindissociables et bénéfice global pour le nouveau tout émergeant. 55 p. http://minilien.com/?MKOkk2v5NvIn 6 th European Systems Science Congress Proceedings: workshop 1 Ago-Antagonism

Bricage P. (2005b1) The Metamorphoses of the Living Systems: The Associations for the Reciprocaland Mutual Sharing of Advantages and of Disadvantages. 6 th ECSS (Paris, France) ,10 p. http://www.afscet.asso.fr/resSystemica/Paris05/bricage.pdf

Bricage P. (2005b2) Les Métamorphoses du Vivant : Les Associations à Avantages et InconvénientsRéciproques et Partagés. 9 p. http://minilien.com/?LUeZbdsNCHIn 6 th European Systems Science Congress Proceedings: workshop 4 BioSystemics.

Bricage P. (2005c1) The Modelling of the Time Modularity of the Living Systems: the Time Delay, theTime Duration, the Time Lag, and the Rhythms. 6 th ECSS (Paris, France) ,10 p.

http://www.afscet.asso.fr/resSystemica/Paris05/bricage2.pdf




Bricage P. (2005c2) La Modélisation de la Modularité Temporelle du Vivant: Le Temps est à la foisPlus et Moins que la Somme de ses Parties. 3 p. http://minilien.com/?X8Db8nnL16In 6th European Systems Science Congress Proceedings: workshop 19 Gouvernance Sanitaire & Sociale.

Bricage P. (2005d) La durabilité contractuelle du vivant. Seules perdurent les associations àavantages et inconvénients réciproques et partagés. Anthropo-politique et gouvernance des systèmescomplexes territoriaux. Presses de l'Université des Sciences Sociales de Toulouse, p. 111-117. http://www.afscet.asso.fr/PBtlseMCX33.pdf

Bricage P. (2006a) Danger des représentations non-systémiques et pouvoir de prédiction desreprésentations systémiques en sciences de la vie. “Les représentations au crible de l'approche systémique“Journées Afscet Andé, 13 mai 2006, 39 p. http://www.afscet.asso.fr/pbAnde06txt.pdf

Bricage P. (2006b) About the dangers of the use of non-systemics concepts & the testability ofsystemics designs through their predictions in the life's sciences. Unity through production, consumption,growth and surviving: the symbiosis, a "unity through diversity" partnership of mutual sharing of profits and ofinjuries. Journées Afscet Andé, 13 mai 2006, 7 p. http://minilien.com/?IlzFET9WhX

Bricage P. (2007) Comment les systèmes biologiques mettent-ils en place (team building) desorganisations, juxtaposées et imbriquées en réseaux (networks), "groupwares" robustes et durables ? Quelssont les facteurs limitants de ces processus ? “ Intelligence des systèmes & action collective “. Journées Annuelles Afscet, Andé, 42 p. http://www.afscet.asso.fr/Ande07pb.pdf

Bricage P. (2008a) La démarche scientifique expérimentale, un langage "systémique" : mise enévidence d'une phase critique d'apprentissage. “Systémique & Langage “ Jour nées AFSCET, Andé , 30 p. http://www.afscet.asso.fr/Ande08/pbAnde08ExpSci.pdf

Bricage P. (2008b) Associations for the Reciprocal and Mutual Sharing of Advantages andDisadvantages: Applicative Insights in Prevention or Cure of AIDS, Cancer and Leprous Diseases. 7 th ECSS , Lisboa, Portugal, dec. 2008, 10 p. http:// minilien.com /?gEHtVdd60o

Burdelya L.G. & al. (2008) An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouseand Primate Models. Science 5873: 226-230.

Cartier N. (2006) Thérapie génique, un peu d'optimisme dans un monde de risque... Actualités,Innovations, Médecine 117: 11.

Caujolle F. & al. (1965) Pouvoir tératogène du diméthylsulfoxyde et du diéthylsulfoxyde. C. R. Acad.Sc. Paris 260: 327-330.

Chouard T. & M. Yaniv (1994) Le contrôle de l’expression des gènes. La Recherche 266: 626-635. Coisne S. (2008) Affamer les tumeurs pour mieux les cibler. La recherche 420: 46-49.(Coll. GHFRC) Collaborative Group on Hormonal Factors in Breast Cancer (2002) Breast Cancer

and breastfeeding: collaborative analysis of individual data from 47 epidemiological studies in 30 countries,including 50,302 women with breast cancer and 96,973 women without the disease. Lancet 360: 187-196.

Couderc B. & al. (2008) In vivo restoration of RhoB expression leads to ovarian tumor regression.Cancer Gene Therapy 15 (7): 456.

Cowen R.C. (2007) Verbal evolution: the more you say a word, the less likely it will change. TheChristian Science Monitor, October 25. http://www.csmonitor.com/2007/1025/p14s01-stgn.html

Darland-Ransom M. & al. (2008) Role of C. elegans TAT-1 Protein in Maintaining Plasma MembranePhosphatidylserine Asymmetry. Science 5875: 528-531.

Darnis F. (1980) Rôle de l'alimentation dans la genèse du cancer primitif du foie et de certains autrescancers humains. Rev. Palais Découverte 8(80): 38-51.

Daudel R. (1980) Vaincre le cancer. Prévention et traitement. Rev. Palais Découverte 8(80): 4-37.Dolberg D.S. & al. (1985) Wounding and Its Role in RSV-Mediated Tumor Formation. Science 250:

676-678.Dunlap K.A. & al. (2006). Endogenous retroviruses regulate periimplantation placental growth and

differentiation. Proc. Natl. Acad. Sci. USA 103: 14390-14395.Esnault C. & al. (2005) APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous

retroviruses. Nature 433: 430-433.Farnham P.J. & al. (1993) The role of E2F in the mammalian cell cycle. Biochimica Biophysica Acta

1155: 125-131.Feng H. & al. (2008) Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma. Science

5866: 1096-1100.Ferrara J. (1984) Les interférons: efficaces et de moins en moins chers. Science & Vie 800: 50-53.Field B. & A. E. Osbourn (2008) Metabolic Diversification-Independent Assembly of Operon-Like

Gene Clusters in Different Plants. Science 5875: 543-547.Fuller P.M. & al. (2008) Differential Rescue of Light- and Food-Entrainable Circadian Rhythms.

Science 5879: 1074-1077.




Furihata C. & al. (1993) Possible Tumor-initiating and -promoting Activity of p-Methylcatechol andMethylhydroquinone in the Pyloric Mucosa of Rat Stomach. Jpn J. Cancer Res. 84: 223-229.

Garnick M. (1994) Comment traiter le cancer de la prostate. Pour La Science 200: 86-93.Gatard M. (1995) Quels critères pour la chimiothérapie ? Actualités Innovations médecine 18: 24.Gaurenne R. (1995) Multiplication cellulaire et cancers. Rev. Palais Découverte 226: 37-42.Ghildiyal M. & al. (2008) Endogenous siRNAs Derived from Transposons and mRNAs in Drosophila

Somatic Cells. Science 5879: 1077-1081.Gillison M.L. & al. (2000) Evidence for a Causal Association Between Human Papillomavirus and a

Subset of Head and Neck Cancers. Journal of the National Cancer Institute, 92(9): 709-720.Girard M. (1987) Les effets indésirables des médicaments. La Recherche 185: 234-241.Golberine G. & al. (1995) Mortel amiante. Une épidémie qui nous concerne tous. Sciences & Avenir

580: 28-44.Han J.-D.J. (2008) Understanding biological functions through molecular networks. Cell Research

18: 224–237.Hannan R.L. & al. (1988) Endothelial Cells Synthetize Basic Fibroblast Growth Factor and

Transforming Growth Factor Beta. Growth Factors 1: 7-17.Hannoun C. (1980a) Les maladies virales. La Recherche 115: 1140-1146.Hannoun C. (1980b) Les grippes humaines. La Recherche 115: 1147.Hao Y. & al. (2004) Repression of AGAMOUS-LIKE 24 is a crucial step in promoting flower

development. Nature Genetics 36: 157-161.Harrington K. & R. Vile (2006) Virus smuggling, tax evasion and tumor assassination. Nature

Medicine 12: 507-509.Hart D.L. & al. (1999) Regulation of the transposable element mariner. Genetica 100(1-3): 177-184.Iba H. (2000) Gene transfer into chicken embryos by retrovirus vectors. Development, Growth &

Differentiation 42(3): 213-218.Ishikawa K. & al. (2008) ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell

Metastasis. Science 5876: 661-664.Jakowitsch J. & al. (1999) Integrated pararetroviral sequences define a unique class of dispersed

repetitive DNA in plants. Proc Natl Acad Sci USA 96(23): 13241-13246. Jasmin C. (1980) Cancer des os. La Recherche 115: 1088-1095.

Jasmin C. (1987) Le traitement biologique des cancers. La Recherche 189: 844-847.Jean C. (1996) Des progrès tous azimuts. Actualités Innovations Médecine 32: 16-18.Julian-Reynier C. & al. (1998) Cancer genetic clinics: why do women who already have cancer

attend ? Europ. J. Cancer 34: 1549-1553.Kamiyama T. & al. (1993) B-raf Oncogene: Activation by Rearrangements and Assignment to Human

Chromosome 7. Jpn J. Cancer Res. 84: 250-256.Kim H.-J. & al. (2004) A genetic link between cold responses and flowering time through FVE in

Arabidopsis thaliana. Nature Genetics 36: 167-171.La Scola B. & al. (2008) The virophage as a unique parasite of the giant mimivirus. Nature 455: 100-

104.Lallemand-Breitenbach V. & al. (2008) Arsenic degrades PML-RARalpha through SUMO-triggered

RNF4/ubiquitin-mediated pathway. Nature Cell Biology 10(5): 547-555.Laskay G. & al. (1988) Interleukin-3-Specific Modification of Cell Membrane “Fluidity“ of

Hematopoietic Cells. Growth Factors 1: 67-73.Latchman D. (1995) Gene Regulation. A eukaryotic perspective. Chapman & Hall, London, 271 p.Legac S. (1995) Cancers cutanés. Du "capital soleil" au mélanome. Panorama du Médecin 4250: 11.Lehnert S. (2007) Biomolecular Action of Ionizing Radiation. CRC Press, Atlanta, 372 p. Le Taillanter M. (1994) L'aléa thérapeutique. Panorama du médecin, jeudi 13 juin 1993, p. 23.Li Y.C. & al. (2002) Microsatellites: genomic distribution, putative functions and mutational

mechanisms: a review. Molecular Ecology 11: 2453-2465.Liang R. & J. Liu (2008) In-frame deletion of Escherichia coli essential genes in complex regulon.

BioTechniques 44: 209-215.Losick R. & C. Desplan (2008) Stochasticity and Cell Fate. Science 5872: 65-68.Marshall L. & al. (2008) Elevated tRNAi

Met Synthesis Can Drive Cell Proliferation and OncogenicTransformation. Cell 133: 78-89.

Marty M. (2006) Cancérologie. Actualités Innovations Médecine 117: 12-13.McGrath S. & al. (2002) Identification and characterization of phage-resistance genes in temperate

lactococcal bacteriophages. Molecular Microbiology 43(2): 509-520.




Mercer J. & A. Helenius (2008) Vaccinia Virus Uses Macropinocytosis and Apoptotic Mimicry to EnterHost Cells. Science 5875: 531-535.

Merchant S.S. & al. (2007) The Chlamydomonas genome reveals the evolution of key animal andplant functions. Science 5848: 245-250.

Nicola N.A. & al. (1988) Cellular Processing of Murine Colony-Stimulated Factor (Multi-CSF, GM-CSF, G-CSF) Receptors by Normal Hematopoeitic Cells and Cell Lines. Growth Factors 1: 41-49.

Owens G.P. & al. (1985) Brain “Identifier Sequence“ Is Not Restricted to Brain: Similar Abundance inNuclear RNA of Other Organs. Science 229: 1263-1265.

Palmarini M. & al. (2000) Molecular Cloning and Functional Analysis of Three Type D EndogenousRetroviruses of Sheep Reveal a Different Cell Tropism from That of the Highly Related ExogenousJaagsiekte Sheep Retrovirus. Journal of Virology 74(17): 8065-8076.

Raj K. & al. (2001) Virus-mediated killing of cells that lack p53 activity. Nature 412: 914-917.Rakoff-Nahoum S. (2006) Why Cancer and Inflammation? Cancer Issue Yale J Biol Med. 79(3-4):

123-130.Rankin E.B. & A.J. Giaccia (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death

& Differentiation 15: 678–685.Reuillon C. (2005) Cancer de la thyroide : rare mais en progression. Valeurs Mutualistes 240: 23.Rohr R. (1991a) Peut-on encore se nourrir sans risque ? Valeurs Mutualistes 139: 24-26.Rohr R. (1991b) Peut-on encore se nourrir sans risque ? Valeurs Mutualistes 140: 20-21.Rosloniec E.F. & al. (2006) Second-generation peptidomimetic inhibitors of antigen presentation

effectively treat autoimminue diseases in HLA-DR-transgenic mouse models. J. Autoimmunity 27: 182-195.Rossignol J.-L. & G. Faugeron (1994) Gene inactivation triggered by recognition between DNA

repeats. Experientia 50: 307-317.Rougier P. & al. (1997) Indications de la chimiothérapie dans les cancers digestifs. Cancer de

l'oesophage et de l'estomac. Le Concours Médical 119-08: 529-532.Roussenq J. (2001) Percolation. CD-ROM Encyclopedia Universalis, 1773 mots.Routes J.M. & al. (2000) Dissimilar Immunogenicities of Human PapillomaVirus E7 and Adenovirus

E1A Proteins Influence Primary Tumor Development. Virology 277: 48-57.Sales E. & al. (2002) Plant hormones and Agrobacterium tumefaciens strain 82.139 induce efficient

plant regeneration in the cardenolide-producing plant Digitalis minor. J. Plant Physiol. 159: 9-16.Schwartz L. (1996) Le cancer résiste à la science. La Recherche 284: 54-60.Sigma (2008a) The Cancer Stem Cell Hypothesis. BioFiles 3(5): 4-7.Sigma (2008b) Carcinogenesis and Epigenetics. BioFiles 3(5): 18-20.Simone D. (1996) Le thé à la bergamote est-il cancérigène ? J. Français Santé 31: 6.Sonigo P. (1995) Nouveaux concepts en chimiothérapie. Actualités Innovations Médecine 23: 59-61.Soufflet E. (1995) Le lanréotide, analogue de la somatostatine: 2 I.M. par mois au lieu de 3 par jour!

Actualités Innovations Médecine 19: 10-11.Stéhelin D. & al. (1999) Un virus contre le cancer. Pour La Science 256: 28.Stoppa-Lyonnet D. & al. (1997) Cancer du sein : évaluer le risque. Les tests génétiques donnent

naissance à une médecine de l'incertain. La Recherche 294: 72-76.Stoye J.P. (2001) Endogenous retroviruses: still active after all these years? Curr. Biol. 11: R914-

R916. Takahashi Y. & al. (2005) Gene silencing in primary and metastatic tumors by small interfering RNA

delivery in mice: Quantitative analysis using melanoma cells expressing firefly and sea pansy luciferases. J.Control Release 105: 332-343.

Takahashi Y. & al. (2006) Suppression of tumor growth by intratumoral injection of short hairpin RNA-expressing plasmid DNA target beta-catenin or hypoxia-inducible factor 1. Journal of Control Release 116:90-95.

Tambourin P. (1989) Les prix Nobel 1989. Médecine. La percée des gènes du cancer. La Recherche216: 1517-1519.

Tassin J.P. (1996) Allergique à l'aspartame. J. Français Santé 31: 6.This P. (2004) Les traitements hormonaux remis en question. Pour La Science 315: 28-34.Tucker E.J. & A. Carrizo (1968) Haematoxylon Dissolved in Dimethylsulfoxide Used in Recurrent

Neoplasms. International Surgery 49: 516-527.Tyson M. & al. (2008) Metabolic Oligosaccharide Engineering and the Staudinger Ligation: Tools for

Monitoring Sialic Acid Expression. Life Science Innovations Sigma 23: 21-22.Vile R. (1990) Cancer and Oncogenes. New Scientist Inside Science 32: 1-4.Viswanathan S.R. & al. (2008) Selective Blockade of MicroRNA Processing by Lin28. Science 5872:

97-100.




Vukov N. & al. (2003) Functional regulation of the Listeria monocytogenes bacteriophage A118 holinby an intragenic inhibitor lacking the first transmembrane domain. Molecular Microbiology 48(1): 173-186.

Wenzel J. & al. (2005) The role of cytotoxic skin-homing CD8+ lymphocytes in cutaneous cytotoxicT-cell lymphoma and pityriasis lichenoides. J. Am. Acad. Dermatol. 53: 422-427.

Winawer S.J. & al. (1997) Colorectal cancer screening: guidelines and rationale. Gastroenterology112: 594-642.

Woolf S.H. (1995) Screening for prostate cancer with prostate-specific antigen: an examination of theevidence. New England J. Medicine 333: 1401-1405.

Xiao R. & al. (2008) Identification and Classification of Endogenous Retroviruses in Cattle. J. Virol.82: 582-587.

For basic “general” references, look at:for a review of the susceptibilities to the diseases:

http://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Leprosy

for a review of the properties of the pathogens (with the key words : HIV, AIDS, cancer, leprosy): http://en.wikipedia.org/wiki/Infection

http://en.wikipedia.org/wiki/Mycobacterium_lepraehttp://en.wikipedia.org/wiki/Virus

For complementary references about the application to health sciences of the paradigm of theAssociation for the Reciprocal and Mutual Sharing of Advantages and DisAdvantages, look at:

UESlisboaPBaidsRef.pdf http://minilien.com/?USaw1HHJ4ZUESlisboaPBcancerRef.pdf http://www.minilien.com/?oUtHBBpz46UESlisboaPBlepraeRef.pdf http://minilien.com/?iUZluv4lpLUESlisboaPBsymbiosisRef.pdf http://minilien.com/?gEHtVdd60o

For complementary references about the paradigm of ARMSADAAssociation for the Reciprocal and Mutual Sharing of Advantages and DisAdvantages, look at:

en français : Bricage P. (2003) Les associations à avantages et inconvénients réciproques et partagés: intégration,

contingence et résilience des systèmes vivants. mémoire HDR en Sciences Sanitaires et Sociales, UPPA, 1CD (mai 2003) & 1 manuscrit 89 p. http://minilien.com/?H0FY0mvaGO

in English:Bricage P. (2006b) About the dangers of the use of non-systemics concepts & the testability of

systemics designs through their predictions in the life's sciences. Unity through production, consumption,growth and surviving: the symbiosis, a "unity through diversity" partnership of mutual sharing of profits and ofinjuries. Journées Afscet Andé, 13 mai 2006, 7 p. http://minilien.com/?IlzFET9WhX




FIGURE 1: Ergodicity and modularity : juxtaposition, superposition & encasement of alllevels of organisation to make a “fitted” Association for the Reciprocal and Mutual Sharing

of Advantages and DisAdvantages (ARMSADA).

1. The law of fitness: to make an other different alive form through the superposition and encasement of twoprevious ones (for examples: genes), in order to reduce the load (e.g. “to make from 1 hit 2”). J juxtaposition, Ssuperposition, E encasement (and into a “white box”, which is into a “black box”), the Whole being a “grey box”.

2. The time course of evolution: juxtaposition and encasement... from a step to an other. At each level oforganisation, both the structures and their associated functions are spatially and temporally repeated in modules, likegenes are into the genome (1.), Monera are into the cell, cells are into the organism, organisms are into ecosystems...

3. The result: an Association for the Reciprocal and Mutual Sharing of Advantages and DisAdvantages(for example: i+1 organism, i cell, i-1 monere-like compartment, i-2 virus (bacteriophage-like), i-3 viroid-like) allows themerging of new “blueprints”: exaptation (Bricage 2006 a & b).

4. The functioning: modules are both juxtaposed and encased, in the same space or in different spaces, in thesame time or in different times, and they interact for the same control or in different ones, with their actions beingdifferent (unrelated) or antagonistic (opposite) or agonistic (synergic) or complementary (cooperative) or ago-antagonistic. Depending on their related relative roles in the survival of their whole, modules are more or less expressedthan other ones, and their hyper- or hypo- expressions are linked to the fitness of the iso-expression of the Whole.

Figure's key words: “inhabitant” the one which is “hosted” through its capacity “to be welcomed”,“inhabited” the one which is “hosting” through its capacity of hosting (playing the role of an ecoexotope),the endophysiotope of “the Whole” (i+1) is hosting, encasing, juxtaposed inhabitants (i).

Figure's key reference: Bricage P. (2001) Les caractéristiques du vivant biologique et sociétal ? Pour survivre etse survivre, la vie est d’abord un flux, ergodique, fractal et contingent, vers des macro-états organisés de micro-états, àla suite de brisures de symétrie. L’évolution, du vivant au social. atelier AFSCET, I.I.A.P., Paris, 11 p., 2 figures.

http://www.afscet.asso.fr/ergodiqW.pdf




FIGURE 2: The structural & functional ergodicity of the living systems.Juxtaposition & encasement at the all levels of the living systems:

ecoexotope & endophysiotope. Advantages/DisAdvantages & cancerisation.

The structural & functional ergodicity of the living systems runs through the juxtaposition &encasement of the all levels of the living organisations. 2 . 1. To survive it is “to eat and not to be eaten” :every living form, and its inside or outside predators too, soon or late, is a prey. The endophysiotope of a preyis the ecoexotope of survival of its endogenous predators. 2.2. Cancerisation is a mean to survive to viralaggressions at the cell level. Cells (i level) are usually eaten by viruses, like Monera (i-1 level) are eaten bybacteriophages: lysis, probability 1 (0.999999). Rarely, probability -6 (0.000001), infected cells are not killedand “resist” through autonomy: cancerisation. Exceptionally, but soon or late, even with a probability -12(0.000000000001), viruses are definitely integrated into ARMSADAs, because it is the only way “to turndisadvantages into advantages” simultaneously at all the levels (from i-2 to i+1). Thus this way is favoured.We do not know, how, when, why, and with what probability (-?) the simultaneous metamorphosis of thefuture parceners begins but it does. 2.3. Every alive system forms through the superposition and encasementof previous ones. Monera are inhabitants of the cell, cells (i level) are inhabitants of the organism (i+1 level),and viruses are inhabitants of every organelle (monere-like compartment, i-2 level) of the cell. Usually thevirus infected cells are killed and the organism survives (probability 1). Rarely, probability -3 (0.001), when theinfected cells are keystone actors of the survival of the organism, the cells' death (in black) leads to theorganism's death (in black). But the survival of cancer cells, soon or late, always leads to the death of theorganism.




FIGURE 3: Cancerisation is a response of better survival of the aggressed ENT of a cell.Apoptosis is a response of best survival of the stressed ENT of an organism. ARMSADA isthe only response for the survival of all partners: cells, organism and virus into a new ENT.

1. Encasement : the endophysiotope (ENT) of a system at a i+1 level of organisation is also the ecoexotope (EXT) ofsurvival of adjacent (sub-)systems (in yellow) with a i level of organisation. 2. Apoptosis is the usual response of aninfection (by viruses, or bacteria, in blue), the suicide of the infected cell (in orange) kills the future viral generation butpreserves the other cells (in green) from being eaten by the virus, and the organism (in pink) survives (2a.). Apoptosis isusually induced by the ancient (inferior i-1) adjacent systems (monere-like compartments, in yellow, for examplemitochondria or nucleus) which ENTs are nowadays integrated into the ENT (superior adjacent level i) of the cell(Bricage 2005 a1 & a2, b1 & b2). Rarely, if the robust mechanism of apoptosis fails (2b.), the viral genome (its ENT)incases into the cell genome, like do the temperate bacteriophages in their invaded bacterial host (their EXT) (FIGURES1, 2 & 6). The transformed hosting cell (in blue) survives with “its” “constrained” hosted viral partner (in black). And,soon or late, the organism is killed by the invading autonomous cancer cells, which eat the ENT of the organism, which istheir EXT of survival. 3. Only if the selfishness of the whole cell-virus system is constrained into the organism, e.g. if thevirus is constrained (half-selfishness) into the cell, and the cell is (re-)constrained into the organism, through theirsimultaneous metamorphosis into an Association for the Reciprocal and Mutual Sharing of Advantages andDisAdvantages (ARMSADA), the 3 would survive (virus+cells+organism). The merging and maintaining of an ARMSADAresult from the half-selfishness of all the partners through constraints of subsidiarity and non-autonomy. Due tothe modularity of the ENT of the Whole, each parcener (in pink, blue, green and orange) have transfered parts of theirself-regulation paths in one of them (for example genes transfers from mitochondria and plastids into the nucleus of theplant cell: black arrows). How to fit within an ARMSADA ? (FIGURE 4)




FIGURE 4: The percolation network of the adjacent (inferior, superior) levels of integration.1. An example of percolation within a neurones' spatial network (Bricage 2001, 2003).

If the intercalation of new actors change the activity of the previous ones, a new network merges.

before then after a previous 2D network of actors but, only “actors that fire together “exaptation“

wire together“, and reciprocally (Bricage 2008a), may survive into a new network

2. Percolation runs both through the space and through the time (Bricage 2005 b1 & c1).

1 Only 3 partners may share all the possible interactions between each other in a 2D space-time cyclic network, andwith the same relative temporal position (in green the time arrow): a rhythm is born! Each interaction is allowed, and isunique, with no repetition, through an eulerian cycle. 2 2a Comes a new “unwanted“ partner n (or a new step ofdevelopment: exaptation). The structure of the time network does no more allow the interactions to be free, but to beconstrained in a unique cycle, with a start point 1 (or the day of the birth) and a end point n (or the day of the death).Nevertheless at least 1 rhythm (in green) is allowed: 2b, with a variant 2c, but it is not an eulerian one. 3 But, to maintaina rhythm (3a), some partnerships are excluded (O in blue: not allowed link), or privileged (in red), with supplementarylinks (1/1 equal inputs and outputs, 1/2 more outputs than inputs, 2/1 more inputs than outputs). To structure an euleriancycle (3b) with these 4 partners, an other one is necessary to build a new 3D space-time, with an ordered sequence andwith the same interaction weight for each one (red partner at the start & at the end of the cycle, black one the last one).




Figure 5: Cancer curative vaccine: the paradigm & the procedure.

- the paradigm: de-constraining of integrated dangers in cancer cells, either to restore apoptosis or to induce immunization or to select controlled dangers hosting cells (ARMSADA).- the procedure: t1 picking (black arrow) of both healthy (in yellow) and sick (in orange) cells, t2 eventually killing of cancer cells by in vitro lytic provirus induction by aggressiveagents: de-masking of eventually evading dangers (black points), and multiplication of not-killed cancer cells, t3 thus eventually using these same de-controlled dangers (blackpoint •: endogenous freed viruses) to now destroy in vivo cancer cells (in red) either with production of viruses to be recognized by the immune system (immunization) or throughapoptosis and without virus production (in blue), t4 ex vivo culture of both persisting together healthy cells (if any) and cancer cells, t5 tests of induction of the lysis of cancer cells byother viruses (black x: exogenous added viruses), either directly (in blue) or indirectly with the evading of other “defective” dangers (black point •) or through their complementation, t6mixing of the healthy surviving cells, if any (in green), with heathy normal cells (in yellow) and test of their no-cancerous controlled growth in vitro, t7 in vivo engraftment of the mix.




C Cell (i level): S Stem cell, D Differentiated cell, O state of transition, gal-/gal+ genome without/with the possibility to use galactose T Tumour cell, origin: arrows in white (retrogression), fates: A Apoptosis, lyse lytic viral cycle: big black arrow, in yellow : coexistence of V Virus (i-2 level, development cycle: arrows in blue): I viral Infected cell, the bacterial (gal-) & viral (gal+) genomes (juxtaposition), in blue L Lysis, i+1 level of the organism, i+n merging new level: E emergence integration of the viral genome into the bacterial one, but, in green (adapted from Bricage 2003, Bricage 2005 a1 & b1). inhibition breakage of the viral danger, de-constrained through UV irradiation.

Figure 6: The fates of cells (or bacteria) and viruses (or bacteriophages) is depending on their “percolating” interactions.Figure's key words: the endophysiotope of i is the ecoexotope of i-1, exaptation's failure, integration's breakage, metamorphosis, retrogression, shuttle.Figure's key references: Bricage P. (2005b1) The Metamorphoses of the Living Systems: The Associations for the Reciprocal and Mutual Sharing of Advantages and of

Disadvantages. 6th ECSS (workshop 4: BioSystemics), 10 p. http://www.afscet.asso.fr/resSystemica/Paris05/bricage.pdf,Bricage P. (2002) The Evolutionary “Shuttle” of the Living Systems. 5th ECSS (Heraklion, Creta, Greece), 6 p. http://www.afscet.asso.fr/resSystemica/Crete02/Bricage.pdf




FIGURE 7: Regulation of genes' activity.Dormant, constitutive, repressed & activated genes' expressions: the processes.

1b 1a 1c 1d

The interpretation of genome sequences and the exploration of their functions or the localization of their proteininteractions is now possible in tissue culture. During the cell cycle of survival (circle) there are 4 types of genes'expression: sometimes expressed genes depending on either their “activation” (+ activated expressed genes) or“repression” (- inhibition breakage expressed genes), “never expressed” genes (no activation, no inhibition, “locked”,“dormant” + ), “ever expressed” genes (independent, “freed”, “constitutive” expression ••). If a gene has to be expressedevery time (circle in black), the cost of its regulation is null, the cost is only that of the expression of its encoded protein(in yellow): 1a. But if a gene is under an activation control (+) the cost of its expression is the sum of the cost of theexpression of its encoded protein (in yellow) plus that of the synthesis of the regulator protein (in green): 1b. Thus thecost for an activation will be reduced if the gene will be expressed only over a short duration of the life cycle (the blackpart of the white circle). If a gene is never expressed (1c) there is no cost in protein synthesis, but their is a cost in themaintain of its corresponding gene sequence. However only 1 sequence needs to be maintained, like in constitutiveexpression (1a). But 2 genes must be maintained in the case of activated (1b) and repressed (1d) expressions. But whya dormant information would be conserved in the genome? In the case of a repressive control (1d) all over the cell cycleonly 1 protein is expressed, either the repressor protein (in pink, during the black part of the cycle) because that of thecontrolled gene is not (in white) or the “de-controlled” protein, if inhibition breakage (in yellow, during the white part of thecircle). Actually the situation of “up & down” regulation of gene expression (Vile 1990, Latchman 1995) is far morecomplex (FIGURE 9) because the same regulator can have an inhibitory or a repressive action depending on the operonwith which it binds (Iba 2000, Ishikawa & al. 2008) and the regulon (Latchman 1995, Liang & Liu 2008) it is a part.

Repression.The expression of the structural gene !! of the enzyme beta-galactosidase is controlled by 2 other genes in

Bacteria. One is producing a “repressor“ protein, the other one producing an “activator“ protein (Chouard & Yaniv1994). In the absence of an "inductor" (external stimulus of the ecoexotope, or internal one of the endophysiotope), therepressor blocks permanently the “operator“ (zero level), there is no transcription. In the presence of an inductor(lactosis), there is de-repression (inhibition breakage) and the synthesis of the enzyme takes place at the highest levelin absence of glucose (maximal or amplified level), or at a reduced level in its presence (base level), the absence ofglucose playing the role of an activation (Chouard & Yaniv 1994). The lambda bacteriophage repression is governed byseveral repressor proteins which have to join (to juxtapose & to encase) in a repression complex.

Up-regulation through the down-regulation of down-regulations.The flowering in Arabidopsis thaliana is initiated through the negative regulation of a gene encoding a

protein that itself inhibits other genes of flowering (Hao & al. 2004, Kim & al. 2004). Flowering starts (up-regulation)when its active inhibition (down-regulation) is actively suppressed (down-regulation) through an oncogene expression(up-regulation) (Ausin & al. 2004).

Up- OR Down-regulation through summation of Up- & Down-regulative ways.Not only a gene can control several regulating proteins, but still every regulating protein can control several genes(Chouard & Yaniv 1994): « loi systémique constructale » (Bricage 2007). Several regulating sequences are situated near,or remotely, by the same gene. All the regulating proteins, and with their co-factors, are necessary to interact with theDNA, but they do not still act simultaneously and have effects which can be synergistic or antagonistic. The global effectarises from a spatial and temporal summation of opposing & conflicting effects (Hao & al. 2004), exactly as is bornthe action potential into a "perceptron", as a neurone, by spatial and temporal summation of activating and inhibitory"pre-potential" (Bricage 2003): “Actors that fire together wire together, and reciprocally”.

Up- AND Down-regulative pathways are themselves Up- & Down-regulated.In non-tuberculous-non-leprous mycobacterial diseases interferon has been shown to stimulate the

mycobacteriostatic activity of macrophages, but this effect is dependent upon the macrophage population and themycobacterial strain. Interleukin 10 has been shown inversely to impair the ability of macrophages to respond and asignificant increase in its production only occurs after a 3 weeks time delay after infection (Azouaou & al. 1997).




TABLE 8: The costs for each type of genes' regulation: the regulation load.The control elements of genes' governance.

Any protein (like an enzyme or a regulator) has a limited time of action, depending on its concentration and itshalf-life. There is always a concentration threshold below which the inhibitor or the activator is not active. Thus (FIGURE7), in the case of an activated expression (-7.1b- activation), the activation starts after a latent phase (lag duration)which is the sum of the latent period of the synthesis of the activator plus that of the synthesis of the regulated protein.Reversely, when the activation stops (de-activation) the lag duration is the sum of the duration of the latent period of thedisappearance of the activator plus the disappearance of the regulated protein (1+1). In the case of a repressedexpression (7.-1d- repression), the repression starts after a lag (depending from dose-dependence threshold effects)which is thus equal either to the latent period of the synthesis of the regulator or that of the disappearance of theregulated protein (1 or 1). When the repression stops (de-repression = inhibition breakage) the latent period is alsoonly the longest duration of either the latent period of the disappearance of the activator or that of the disappearance ofthe regulated protein. Thus, from an economic point of view, a repressed control must be twice favoured, because itscost (in duration, in information and in use of this information) is lower than that of an activated control. With fewermodules expressed in the same time (only 1 protein is active at a time: 1 or 1), it is more reactive (repression needs thesynthesis of only 1 regulator protein), it is far more speedy than activation (which needs 2 proteins: the regulator plusthe controlled protein) and thus it is more robust. The natural selection does indeed, soon or late (Bricage 2005 a1 & b1),facilitate the repressive controls (with only 1 protein expressed, even during all the cycle, versus 2 proteins expressedeven during a short part of the cycle).

If we compare the genome with a book every page of which would be a gene.All the cells have the same book, but each can read only some pages.The mode of reading the book is strictly controlled (Chouard & Yaniv 1994). The agents of the checking are

(DNA or RNA) genes or their products (DNA, RNA or proteins), who are themselves checked back by other regulatinggenes (feedback controls).

Control elements governing a specific gene expression (Chouard & Yaniv 1994) often form a family of repeatedsequences in DNA (Bang & Carpenter 2008). These elements occurs frequently in introns of a lot of growth controllinggenes (Owens & al. 1985). Proteins contain repeated sequences with a three times higher abundance of repeats ineukaryotes compared to prokaryotes (Li & al. 2002). And, prokaryotic and eukaryotic repeat families are clustered tonon-homologous proteins (Li & al. 2002). The centromeric and telomeric regions of the chromosomes are composed ofnumerous highly clustered tandem repeats (Li & al. 2002). The repetitive sequences alter the DNA structure and stronglystimulate the formation of multiple crossovers (Li & al. 2002). A repeat can enhance gene activity from a distanceindependent of its orientation (Li & al. 2002). Repeats are preferentially located in regulatory genes related totranscription and signal transduction and under-represented in genes for structural proteins (Li & al. 2002). Thepromoters of many genes contain binding sites for the transcription factor E2F, a cellular DNA-binding protein which wasfirst identified in HeLa cancer cells as a transcriptional activator of the adenovirus E2 promoter (Farnham & al. 1993).Gene inactivation may result from the presence of repeated gene copies (Rossignol & Faugeron 1994). Gene silencingresulting from introduction of one (or several) transgene(s) “co-suppression“ is common in plants and fungi (Rossignol &Faugeron 1994), organisms where percolated interactions (FIGURE 4) are more easily buffered (FIGURE 9), becausethey can not escape from aggressors by moving.

Figure's key words: ago-antagonism, cost, contingency (FIGURE 4), epigenesis (FIGURE 6), ergodicity(FIGURE 1), exaptation (FIGURE 9), governance (Afscet 2007), inhibition breakage, up & down regulation(FIGURE 7).




FIGURE 9: Evaluation of the risk of disfunctioning & of the cost of the prevention of therisk: costs, disadvantages or risks versus gains, advantages or robustness of a system.

1. A real network of regulation in a plant material. Why are there 2 juxtaposed systems of inhibition (- in pink &salmon)? Why the same system (in blue) has 2 opposite (antagonistic) effects (+ in green & - in pink)?

2. Mostly 1 cause has more than 1 effect. Why?When there are 2 effects (pleiotropy) for 1 cause (1 cost), the modularity of the system is lowered and the cost of itsmaintenance decreases: it is an advantage. But the risk of its alteration increases (because “1 cause makes to effects”):it is an inconvenient, a dis-advantage. Any abnormality of the target (or of the effect) is a risk, but the existence of 2targets lowers the risk (it is an advantage), and different ways of retro-control (separate feed-backs or additive ones) areallowed, new ways may appear (3.2.): it is an “evolutionary” advantage (exaptation). When the cause is endogenous(from the ENT), any abnormality of the coding gene or of its product(s) may be a risk. In the case of a dormant gene(FIGURE 7.1c) the only risk is activation. When it is an exogenous cause (from the EXT), the cost of maintenance islowered (advantage) but both activation and repression are possible risks (it is a disadvantage). There is noadvantage(s) without disadvantage(s): to survive it is “to avoid advantages from turning to disadvantages” andsimultaneously “to turn disadvantages into advantages”. In the case of repression (FIGURE 7.1d) during the repressionphase the risk is similar to the sum of that of a constitutive expression (expressed regulator) plus that of a dormant one(no-expressed protein), conversely during the de-repression phase the risk is that of the dormant no-expression (no-expressed regulator) plus that of constitutive expression (expressed protein). In the case of activation (FIGURE 7.1a)during the activation phase the risk is the sum of 2 risks of the constitutive type (which is the greatest risk), during the de-activation phase the risk is the sum of those of 2 dormant states (like in provirus dormancy!). The risk is continuous. Arepressive system is less risky, easier to maintain and more robust, than an activator one, thus the juxtaposition andencasement of repressive regulatory systems (3.1.) has been selected through the merging of ARMSADAs... which hasfavoured recurrently the merging of ARMSADAs of ARMSADAs “in the risky ways of life survival, the way isconstructed during the way”. For a review about the paradigm of ARMSADAs (Bricage 2005 a1, b1, d) look at:http://minilien.com/?IlzFET9WhX. Activator systems are convenient only to initiate or modulate inhibitory ones. Duringdevelopment, the way from a step to an other one (metamorphosis) is initiated by activator systems, or in a better waythrough inhibition breakage. The maintenance of a step of development (growth) is insured by inhibitory ones whichblocks the other steps' expressions, and modulated by the interactions between activator and inhibitor ones. The lowestcost to contain a danger it to make it dormant (FIGURE 7.1c). A lot of cancers merges from abnormal activation of adormant gene: “hip-hop” from a dormant state to a constitutive one. But this risk usually is very rare. And, a dormant viralgene, if “domesticated” may be used, if re-activated at the right time and into the good place, to selectively lyse a cancercell. In the case of a constitutive expression (FIGURE 7.1a) the risk of abnormality is everlasting. The “to be constrained”danger has to be very big to run such a risk. The best way of survival is the hosting of dangers which are repressedby their own regulatory system, like bacteriophages which are integrated into bacteria (FIGURE 6): the hosting ofdangers which are limited in their expression to proteins that confer an immunity of their hosting cell (FIGURE 5). All thatexplains the evidence of a HIV curative vaccine (Bricage 2005 b1 & b2). Usually a repressor protein is constitutivelyexpressed for over-infection exclusion (McGrath & al. 2002). But viral antigen proteins can induced misguided activationof antiviral pathways (Wenzel & al. 2005). The same repressor/activator protein inhibits/permits the translation ofdifferent regulatory antagonistic protein effectors. The same protein, depending on its length, may be an activator or arepressor (Vukov & al. 2003). Risks are everlasting but they are sustainable.


ON LINE TALKS:

http://www.minilien.com/?tK6VbNQI8h

http://www.minilien.com/?ZIBO8i3w6b

Documents

Systemic Complexity for human development in the 21web.univ-pau.fr/~bricage/slidesplanches/ues/pbCancerDataLisboa20… · hosting and our capacity to be hosted (governed by our endophysiotope