Changing our perception of diseases

Below is laid out in details the revolutionary new theory of diseases, pathogens of all kinds (viruses, fungi, bacteria and parasites) and their relation to diseases, replacing the germ theory of diseases.

We called this the exogenetic command theory, in which each layer of complexity in the realm of life, are under the genetic and molecular command of the layer above. We do not fight pathogens, we do not cohabit with them in a symbiotic relationships like equals in a partnership. Our genetics commands them, using them to improve the molecular order of our organisms: clean us and as well as share information in our stead.

Viruses, bacteria and multicellular parasites, at least those we meet in our natural environment (with a wide margin over “natural”) serve the need of animal and vegetal species, keeping them fit and genetically strong and partaking in the horizontal transfer of genetic material throughout the whole ecosystem, as recognized today.

In this framework, the definition of life needs to be amended, as it stands to reason that the classical criteria (reproduction, metabolism - difference between the outisde and inside compartiment - and a response to external stimulus) do not matter in this context, as teleology (expected purpose within a system) information and effect.

For practical purpose life should be considered as an enclosed system of information, ultimately only complete taking the whole ecosystem, air land and ocean, into account, hence the link to Gaïa theory.

There also entails profund repercussions as the theory of evolution, hinting at kinds of selective pressures acting on species or groups of them, not out of isolated elements of the natural environment but of the planet:
Since the latter could be considered as alive even by modern standards (tweaking them just a little) without even considering the spiritual aspect it may as well possess a will, expressed as the mathematical integral of all individual interactions, processed through what could be a global neural network. The purpose of this system would be (obviously) to stay alive, hence maintains global conditions conducive to life through its own means and the agency of its constitutive parts, both biotic and abiotic.

While high-end, these speculative ideas aren’t that strange nor new, and with the discovery of a reproductible source of reliable extrasensory phenomena, do come across as fairly natural, intuitive.
What is the new though, is the appplication of the virus theory as the most ancient and prevalent means to transfer horizontally information in the form of genetic material, across individuals and ultimately widely across the species barrier. Such a tool, existing since the dawn of life while not itself living (lacking the characteristic of a metabolism), would be the preferred means of communication inside the system, and its means to influence its components on an evolutionary scale, much like hormones.

Such dynamics are readily apparent in our body as we known now it conveys orders to all the living cells it contains including its bacterial population (of the same order of magnitude, 39 vs 30 trillions), through viruses: Human Endogenous (retro)viruses, exosomes and bacteriophages (which target viruses), helping to control microbial populations, not only by stopping their propagatation but redirect, favor or extinguish species or whole genera. What if such processes were also happening in a vastly different scale, by the Earth on its denizen species ?

On a smaller scale, parasitism - and sometimes epidemics - is an undeniable fact of nature, even in wild animals (though not as much as for domesticated species, cattle etc). All reasonings have limits, don’t they.
Epidemics indeed can be seen in the animal world, animals do fall prey to parasites, to various levels. While others don’t… but still carry the pathogens ? The scientific world doesn’t understand those variations of sensibility and blame genetics whenever it is convenient, to force reality into their prey-predator modelgeneralized to all microbes, parasites, viruses, etc, like forcing a square peg into round holes.
Parasites are extremely varied and numerous, indicating either extremely successful competitors in the battle of life… or an extremely that they fill an extremely important role in ecological equilibriums.
Parasites are a powerful agent of natural selection on a molecular or physiological leve, perhaps greatest that all others factors like predation. That is what biologists now think. This much we do not deny.
However:

If the role of parasites and viruses is to weed out the weak and diseased, the degenerates. Keeping the population fit. The question is, how many weak individuals is a natural population - in a pristine natural setting - supposed to carry, what should be its mean parasitic load ? At what level is the balance attained ?

The answer depends on two things:

• What species are we talking about ?
• Are the parasites out for themselves and fighting against us, or do we actually control them well for our own profit, as long as we fit within the genetic and physiologic norms for a given species ?

we discovered that for mammals parasites (such as tenias) are always regulated. A few days of disciplined instincto suffices to expell in mass any and all resident worms, big or small, through fesces, in animals (pets) and humans alike. Instinctos have sojourned in African countries ridden with malaria-infected mosquitoes, none caught the disease except one - Guy-Claude himself - who thought smart to blend food out of momentary frustration.
None of his twenty others fellows did.

It appeared clear that humans could survive uniquely long with a terribly poor cooked diet. Our resilience and ability to maintain a semblance of health - something of an inner balance - seemed to have evolved further than for any other animals, including chimpanzees, who simply die with cooked fruits, in a short time.

However pets and cattle was also seen capable of gradually eliminating culinary toxins from its body, having similar though less potent mechanisms of molecular exchange when provided with equivalent natural molecules. In short, with all mammals and birds (having no experience with fish) we fed well (ensuring a varied choice not too dissimilar with what they could find on their own in the wild) ever had any issue with epidemics, parasites, nothing. This reality we can not deny, yet it is not the one specialists encounter in the wild.
How to explain cases like this one:

Ommatokoita elongata is a 30 mm (1.2 in) long pinkish-white parasitic copepod, frequently found permanently attached to the corneas of the Greenland shark and Pacific sleeper shark. The parasites cause severe visual impairment,

Or the world-wide scourge of toxoplasmosis in rabbits and hare, also hurting significantly dolphins in the sea, and cats in our house. And cats’ owners too. In all of these species, at least locally the disease’s prevalence and loss of fitness it incurs are high (a big proportion of the population can be infected and show symptoms). Albeit less intelligent than us cats and rabbits are all highly evolved vertebrates, sharing basically the same immune system. This applies obviously all the more to dolphins, in some regards more evolved than us and having a similar lifespan.
I believe the presence of a complex adaptative immune system is the key to differenciate lower lifeforms which tend to die whenever they are polluted (or genetically unfit) to whatever degree, quickly to be replaced by a fitter population.

Such species would need to breed very fast, in large numbers, and typically live short lives. Bacterias being a good exemple, most plants too. Individuals, in those species, do not matter one bit, and the species happily discards them for the greater good. However it seems that the more complex and adaptative the immune system is, the more a species doesn’t need anymore, to discard individuals, instead their capacity to discard the source of the pollution within themselves - natural metabolic waste or in our case an inordinate amount of heat-denatured molecules - grows.
Ecologically, animals with higher lifespans are more likely to show advanced immune systems as loosing individuals for a species (always of slow-breeders) is actually dramatic, an important blow. A species of long-lived, slow-breeders can only be maintained with rather powerful adaptive immune systems, and the ability to maintain homeostasis for the wide range of environmental conditions which necessarily accompany a long life. The two seem to go hand in hand quite well.

On the other hand, once such a system is developped, returning to a fast-breeder lifestyle like rats or mice, should not cancel the advantage of being a mammal, with basically the same body plan and inner organs as a human.

It ensues, that as far as I am concerned I do not believe any mammal should ever be sensitive to viral diseases, nor parasites, in its natural state with the diet it is meant to eat. Wide-spread pollution could have a disproportionate effect. Animals living in degraded environments with a poor food range - and for some reasons can not go elsewhere - are bound to weaken a lot are bound, to show symptoms of deficiencies, not too different from those we get with eating cooked food, to some respect.

We need to draw a line or rather identify two opposite poles, on one hand “evolved” species whose individuals treat parasites and viruses like mere tools, and primitive ones which rather discard the unfit individuals themselves instead of the waste they carry. While our understanding of mammals has reached perfection in this respect, more experiences and studies need to be done with fish, crustaceans, insects, etc, which seemingly possess a much, much wider breadth of variation than we see within vertebrates. Ergo a “harsh” natural selection makes complete sense for primitive species. Primitives in the sense of the capacity for homeostasis, which while only partially coincide with intelligence or we tend to see as evolution. The same goes for lifespan: Living a century can be achieved for lower lifeforms when their metabolic rate is low. Not much happens inside.

On the contrary maintening life and body integrity during a long but very active life despite the constant breaking down of cells and proteins, requires either/or an efficient physiology limiting the turn-over rate to a minimum or incredibly fine-tuned cellular biology, completely reverting the accumulating damages (internal and external).
This, would demonstrate intrinsic genetic complexity. Progress, regardless of environments.

The only way to verify our theories is to take a whole lot of fish we know are sick of whatever pathogen, put them in a safe place with a rich diet, and see how quickly the parasite load dwindles… or not. Same for all the other cases mentioned in the article above.

A New Theoretical Model of the Viral Phenomeon

The following is a booklet published in Mars 1993 by Guy-Claude Burger, introducing a ground-breaking new understanding of the viral phenomena as a purely positive natural mechanism only seldom causing harm because of our unnatural diet.

I hasn’t aged at all, since medicine hasn’t in the slightest in its understanding of the viral phenomena, or human biology for the matter. Ergo, everything written still stands as strong and time could only add more exemples from molecular and genetic studies.
Pasteur was the first to use the term virus to designate the pathogenic action of bacteria that he had discovered in the field of the microscope. At the beginning of the century, increasingly sophisticated filters, followed by ultracentrifugation, X-ray diffraction and electrophoresis techniques, made it possible to establish the existence of very small particles, which carry an indefinitely reproducible infectious power, although they lack autonomous vital functions.

More recently, molecular biology and the electron microscope have made it possible to determine and visualize the exact structures of a large number of viruses, as well as the mechanisms of their multiplication and their action on a molecular scale. Thus, the mystery of these infinitesimal beings which had remained hypothetical for so long, associated with so many illnesses and diseases, and even unbearable tragedies such as smallpox or polio in the past, and AIDS today, seems solved.

This knowledge gives us hope to find ways to fight either preventively by acting on the immune system with vaccines, or curatively by directly inhibiting viral activity by molecular means with antivirals. However, the prolonged failure of these techniques in the case of HIV, despite the importance of the technological apparatus implemented, as well as the contradictions that remain between theory and facts, should prompt us to ask ourselves a number of questions.

The basis of the reasoning behind current research is in fact the legacy of an era when the superstitions attached to the fear of contagion and major epidemics were barely overcome. The image that the medicine of that time gave us of the virus, considered a priori as a pathogenic agent, harmful by definition, is not necessarily the only one possible. The current trend is to consider the disease more as an imbalance between the host and the aggressor, giving more importance to the factors likely to decrease the resistance of the organism. A further step would be to look for the meaning of the viral phenomenon in itself, without any emotional connotation.

There are many viruses in the natural world that do not manifest themselves as a nuisance. Even in humans, many viral diseases occur mostly in a frugal or asymptomatic form. In the case of poliomyelitis, for example, serological studies in epidemic settings have shown that nervous system involvement occurs in only a very small percentage of infected persons.

In children, primary infection with herpes virus usually occurs inapparently, and in adults, complications are exceptional, with the majority of individuals being healthy carriers. In the different classes of viral hepatitis, there are also a large number of completely latent forms; the benign forms usually end with complete regeneration of the hepatocytes, with restoration of a normal architecture thanks to a remarkable conservation of the reticulum during the course of the disease.

Similarly, the Epstein-Barr virus is detectable in most cases only by hematological and serological examinations, and is found in the majority of African children, whereas it causes Burkitt’s sarcoma in only one case in ten thousand, probably in cooperation with various cofactors; when it triggers mononucleosis, this is usually not serious. The rabies virus itself develops the classic symptoms in some people and not in others, and the reasons for these differences are still unknown.

The situation is similar in animals: avian influenza manifests itself in domestic ducks and quails in the form of coughing, sneezing, and swelling around the beak, leading to significant mortality, whereas it remains mild or inapparent in other wild or domestic species. The swine influenza virus, considered dangerous, even fatal for young pigs infected by their mothers, is found in pigs from different regions where it is only sporadically accompanied by clinical manifestations.

Many epidemiologists are of the opinion that most viruses are widely distributed in all living species, including humans, but only occasionally manifest themselves by pathological symptoms, under the effect of triggering factors still not well known.

Insofar as the number of inapparent forms and healthy carriers turns out to be greater than that of the serious forms, there is nothing to prevent, at least from a theoretical point of view, a reversing of the classical model of reasoning. Rather than considering the viral disease as the natural outcome of the invasion by the virus and being surprised that the virus can be present when nothing is happening, one could postulate that the asymptomatic form of the viral invasion is the normal form of a natural phenomenon, the pathological forms being only the result of an accidental evolution due to certain other pathogenic factors.

Moreover, if it is a phenomenon not harmful in itself and belonging to the complex equilibrium mechanisms characterizing biological reality, it should be possible to attribute to it a precise function (a teleological meaning), at the very least a function that is useful to the host, even if this possibility does not yet seem to have been envisaged in the classical conceptions.

To illustrate this in a somewhat trivial way, let us take the case of the rockets used to put satellites into orbit: if the launch fails in one case out of ten, an uninformed observer, struck more by the accidents than by the successes, much less impressive, could think the purpose of the operation is to destroy the satellite and that this purpose is missed in the nine other cases; all the operations conducted by the engineers and technicians would be explained for this observer as well as if he knew their real purpose, apart from the impression of a great quantity of failures and useless efforts; without knowing the real intentions behind the facts he can observe, that is to say, without knowing the satellites can have any usefulness, such an observer would believe it useful to intervene by destroying the satellite with simple explosives rather than to join in the work that represents its launching.

Viruses cause significant problems in about one in a hundred cases. They remain frightening if they have no other meaning than to cause disease. On the other hand, if our postulate were confirmed and if we could attribute a useful function to the viral process on the one hand, while identifying on the other hand the causes of dysfunction causing the accidental danger, a very different direction of research, even therapeutic action, would unveil.

In the case of AIDS, it seemed a priori that the virus had a harmful effect in 100% of cases. It is significant that the best-placed researchers have come to believe, some ten years after its discovery, that the pathogenic activity of this retrovirus is due more to certain co-factors than to its intrinsic characteristics.

Faced with the general failure of the prophylactic and therapeutic means implemented, and faced with the urgency of the situation, all paths certainly deserve to be explored: the very basis of the reasoning on which medical action is founded, as each time a theory leads to failures or contradictions, must be reconsidered in the light of the knowledge acquired in the meantime and, above all, in the light of the facts that can be brought to light by new experiences.

This is precisely another theoretical model of the viral phenomenon Guy-Claude Burger, a former mathematician and theoretical physicist, proposes here for the consideration of researchers open to a multidisciplinary reflection. After thirty years of unprecedented experience on genetic maladjustment to traditional food, he hopes to make a modest contribution to the general effort to curb the threatening epidemic and to advance knowledge.

Classical Model of the Viral Phenomenon

Viruses are generally considered as pathogenic agents, devoid of life of their own and subsisting at the expense of the organisms they infect. The virion (viral particle) attaches itself to the membrane of a cell, introduces its DNA or RNA and hijacks the cell’s genetic machinery in order to reproduce itself.

The new virions spread into the circulating masses and infect other cells. The host’s immune system reacts with varying degrees of success by creating antibodies to stop the process. This is done with a certain delay or falure rate which explain the variable importance of symptoms observed in different subjects.

This process has no other teleological significance than the virus’ multiplication and perpetuation. It is carried out at the expense of a living species that must not, out of necessity, succumb, a fact within limits accounting for a certain balance between the harmfulness of the virus and the resistance of the species.

We know today the sequences of nucleotides of a great number of viruses and retroviruses, as well as the structure of their envelope and the nature of the antigens which allow the immune system to recognize them.

Classical Model of Viral Disease.

Viral invasion triggers an immune system reaction that results in various symptoms: asthenia, hyperthermia, inflammation of the mucous membranes, catarrh, rashes, etc. In addition, in association with the viral process, especially in diseases of the respiratory tract, the multiplication of pathogenic bacteria is often observed.

Normally, this proliferation is slowed down, for example in the case of coryza, by the bacteriostatic action of the nasal mucus, but this balance seems to be broken by the action of the virus. Similarly, viral pneumonia can lead to bacterial superinfection and various complications, hence the systematic use of antibiotic therapy, although this has no effect on the viral process itself.

In the absence of complications, the viral disease converges spontaneously towards recovery. In some cases, it may leave sequelae (e.g., post-liver cirrhosis) or even lead to death.

The classical means of fighting viral diseases are prophylaxis, vaccination, rest, diet, abstention from alcohol, vitamin therapy, and antibiotics to avoid bacterial complications. More recently, various molecules blocking the mechanisms of viral multiplication, or antivirals (such as AZT), have been used, but with inconclusive results. It can be said in general that there is no satisfactory background treatment for viral diseases.

It is accepted that the evolution of a viral disease depends on the general condition of the patient, but the factors characterizing this condition are not yet clearly established. In a significant number of cases, viral diseases develop in a frugal or asymptomatic form. Since the viral information can remain present in infected organisms for a long time without causing any particular symptoms, the a priori contradictory concept of healthy carrier requires definition. This state concerns, for most viruses, the majority of individuals.

Viral Diseases and Burger’s Experiment.

Guy-Claude Burger, a physicist and mathematician, former assistant in theoretical physics at the University of Lausanne, was diagnosed with cancer (lymphoblastic sarcoma of the pharynx) in 1960. For about thirty years, he pursued a dietary experiment consisting of reconstituting a Paleolithic type of diet, in order to demonstrate the influence of a possible genetic maladjustment of the human organism to the data of modern nutrition.

Since the Neolithic period, many artifices have been introduced into food habits, such as cooking, the selection of cereals, the use of animal milk and the manufacture of dairy products, as well as the various processes used in the culinary arts in general. These processes modify the organoleptic qualities of foods so as to increase their palatability (which tends to increase their consumption) and also lead to transformations in the biochemical structures of certain nutrients (oxidation, free radicals attaching themselves to other molecules, heterocycles by heating unsaturated fatty acids, Maillard molecules resulting from the reactions between carbohydrates and protids, etc.)

However, there is no evidence that the genetic data of assimilation, first constituted in contact with primitive foods, could have been adapted in a few millennia to these new food factors. A possible maladjustment of digestive enzymes, of the intestinal barrier, and of the immune system could explain the appearance of numerous disorders and diseases, as a result of the penetration into the circulating masses of molecules foreign to the functioning of the organism.

Paleopathology corroborates this hypothesis by demonstrating that most of the diseases whose traces we know how to recognize on the bones, did not exist or were very rare before the agricultural and culinary era. These few elements may lead us to wonder about the nature of viral diseases: how would they manifest themselves if organisms were fed according to their genetic programming?

Burger’s experiment consisted precisely in observing, over periods of up to twenty years, a large number of subjects fed according to the Paleolithic model, i.e. exclusively with raw food, organically grown, neither prepared nor mixed, excluding all animal milk and all dairy products, and with a minimum of cereals and selected products. The food intake was regulated by a strict observation of the alliesthetic mechanisms (variations of the olfactory and gustatory sensations) so as to reproduce as much as possible the primitive conditions of food.

Burger would have noted, under these particular feeding conditions, that most viral diseases systematically present themselves in a frugal or asymptomatic form. The viral invasion and multiplication of virions, however, seem to occur as under classical conditions. Indeed, Burger claims to have observed in many cases that infected subjects, even though the disease remained inapparent, developed classical symptoms within hours of ingesting traditional foods, i.e. as soon as the foreign molecules of which they could be the vectors had passed into the circulating masses.

Proposal of a New Theoretical Model of the Viral Phenomenon

If, within the framework of a Paleolithic type of diet, in principle in conformity with the genetic data of the organism, the absence or the reduction of the disorders associated with the viral affections were to be confirmed in a systematic way, the very notion of viral disease would have to be called into question.

A first interpretation would be to say simply that a natural diet confers a better resistance to viral aggression. However, it would also be possible to turn the problem around and stop considering the virus as a pathogenic agent in se, the pathogenicity of the phenomenon being sought rather in certain factors of genetic maladjustment to the unnatural diet.

More fundamentally, one should ask whether the viral phenomenon, which is widespread in the natural world, does not possess a biological function whose teleological significance is still poorly discerned by contemporary medicine, at least when it comes to the human being.

Burger points out in this connection that practically all viral diseases are accompanied by effluents: catarrh, perspiration, rashes, diarrhea, heavy urine, seborrhea, particular body odors, etc. Basing himself on these facts of current observation, on the other hand on the current data provided by enzymology, molecular biology, virology and immunology, he proposes the following hypothesis: the viral DNA or RNA would program, in addition to the mechanisms necessary to the multiplication of virions, the synthesis of proteins ensuring the evacuation of certain molecules foreign to the normal metabolism which would have accumulated in the intracellular medium.

It is true that retroviruses have a very restricted genome and that they produce only a small number of different proteins whose functions are already known in most cases. However, it is not excluded that a given protein has two functions, one belonging to the reproduction of the virus, the other to a process useful to the cell, still unknown. Biology has already provided more than one such surprise: many organs have multiple functions, some genes can be read with a shift of one nucleotide and give rise to two different yet functional proteins, etc.

It is no more unreasonable to consider, for example, the hypothesis that a viral protein can, on the one hand, exert a suppressive action on viral replication and, on the other hand, bind to foreign molecules of a given class, in order to ensure their transport outside the cell: viral multiplication would thus be linked to the concentration of foreign molecules, which would explain a self-regulation of the phenomenon such as seems to be apparent from Burger’s clinical observations.

From this point of view, viruses, or at least certain viruses, should be seen as a kind of complement to the traditional immunological system: the latter ensures the synthesis of antibodies responsible for eliminating the antigens present in the circulating masses, whereas viruses would be the agents of a kind of intracellular immunology responsible for maintaining order inside the cells.

In other words, the virus would provide the cell with the necessary genetic complement to recognize and eliminate the molecules that it is not able to control by its own genetics, in particular the molecules that are foreign to the normal mechanisms of assimilation, introduced into the organism by the effect of different environmental factors, in particular as a result of the absorption of food containing molecules that are foreign to the genetic data of metabolism.

The symptoms which appear during the viral process would then reflect the difficulties encountered by the organism to get rid of these foreign molecules, more than a fight against the virus itself.

Discussion

This hypothesis seems to be in agreement with the data already known about the viral process, which it allows us to include in a coherent synthesis.

Origin of the Virus.

It is generally admitted that the virus has adapted to the cell by a series of mutations obeying the laws of chance and natural selection. The virion would thus have become capable of attaching itself to certain proteins present on the cell membrane, or even of integrating into this membrane by using, for example, the mechanisms of phagocytosis to surreptitiously penetrate the plasma, and then of hijacking the cell’s genetic machinery to its advantage.

It is also possible to reverse the reasoning and postulate that the cell has evolved genetically in such a way as to proceed to the synthesis of various viral particles, allowing it to transmit a genetic message to the other cells of the organism and to other individuals of the species.

The selection pressure is probably stronger in this second hypothesis (which would thus appear more probable), if we admit, as Burger does, that the information transmitted by the virus allows the cell to eliminate harmful molecules: in a living species whose representatives are in competition, the individuals best equipped in terms of intracellular immunology obviously have more chances of reproducing than the others.

Membrane Receptors

In the first hypothesis, the virus would have acquired during its evolution the ability to bind to certain proteins present on the cell membrane.

In the second hypothesis, the cell would have evolved to endow the virion with proteins capable of adhering to certain membrane proteins, which it would have taken advantage of to ensure this new function.

The ability of a cell to synthesize a protein capable of binding to a receptor, even a distant one, appears for example in the case of hormones or antibodies, and there is nothing to prevent us from presupposing an analogous phenomenon in the case of the virus.

From the point of view of the quantity of information, it seems more likely that a cell can match a new protein to an element whose synthesis it has already mastered, than the reverse, i.e. that a virus can succeed by chance alone in synthesizing binding proteins corresponding to proteins which would be in no way related to it.

Viral Membrane and Cell Membrane.

Similarly, a series of mutations hardly explains the ability of the virion to integrate its own membrane with that of the cell, which requires rather complex molecular mechanisms. Indeed, no process of natural selection can begin before the virus is able to enter a cell to multiply, and no process of multiplication is possible if the virus is not already able to enter a cell. It is difficult to estimate the probability of such an arrangement occurring, but it is certainly very low.

However, this integration phenomenon is immediately explained if we admit that the membrane of the first virus is derived from a cell membrane. This is also perfectly consistent with some virions leaving the cell where their multiplication took place borrow their membrane from that of their host, or rather: that the multiplying cell uses its own membrane to package the genetic message that it sends to its fellow cells.

Similarity Between Viral DNA or RNA and Cellular DNA.

The remarkable identity between an important portion of the viral nucleotide sequence and that of the cellular DNA, as it is observed in retroviruses, seems difficult to attribute to chance. On the other hand, it is immediately explained if one admits that the retrovirus, in a more or less distant past, originated from the cell.

In DNA viruses, even if we are not dealing with identical sequences, there is nevertheless a relationship that allows the virus to hijack the cellular genetics to its advantage. This homology can be explained either by a genetic adaptation of the virus to the cell, or by an adaptation of the cell to an existing virus, or by assuming that the viral DNA is derived, at least in part, from cellular DNA.

Just as the organism knows how to control the multiplication of useful bacteria, for example in the intestinal flora, it is conceivable that it could have learned to control certain existing viruses in order to take advantage of them: just as intestinal bacteria are useful to it by their enzymes which complete the range of enzymes provided for in the genetic make-up, viruses were able to provide an assortment of proteins useful for maintaining the integrity of the intracellular environment.

Reverse Transcriptase.

The discovery of an enzyme capable of transcribing retrovirus RNA into DNA defied all predictions of biologists at the time. This viral type suddenly proved to be able to predict its copy by synthesizing itself the enzyme necessary to the transcription of its genetic information in the language proper to cellular genetics. Moreover, this fact seemed to contradict everything we knew about the irreversibility of the transcription of DNA into RNA in all living beings.

Such a phenomenon can be better explained if we postulate that the cell, by virtue of a perhaps very old mechanism inscribed in its genetic heritage, has endowed the RNA of the retrovirus with the information necessary for the synthesis of an enzyme capable of retranscribing it into DNA. This allows, on the one hand, the transmitting cell to export information by passing through the classic way of the RNA-polymerase, and on the other hand, the receiving cell to integrate the transmitted information at the level of its own DNA. This reasoning is only meaningful in terms of evolution if one postulates that the transmitted information is useful to the individual and to the species, in accordance with Burger’s hypothesis.

Replication of Viroids.

It seems that viroids, short chains of RNA consisting of only a few hundred nucleotides, studied so far in plants, reproduce thanks to the action of enzymes already present in the host cell.

This fact is difficult to explain if one admits that the viroid is of external origin to the cell: it implies that the viroid is able to divert enzymes in charge of other functions in the cell for its own multiplication. On the other hand, they fit perfectly into the logic of an action programmed by the cell, useful to the individual and the species according to the Burger hypothesis.

In this respect, it should be noted that viroids only cause symptoms in certain sensitive plants of a species, whereas they are also present in others without causing any harmful effects: the problem of the healthy carrier, which concerns the majority of individuals infected by classical viruses, is already present in these simplified viruses. Some researchers consider viroids to be abnormal regulatory molecules: since their action is not systematically harmful, there is reason to look for other factors responsible for triggering a pathology.

Nothing to prevent us from thinking that these rudimentary viral particles are the result of archaic mechanisms of transmission of genetic information, the secrets of which biology has yet to reveal.

Viral Multiplication

It is generally considered that the virus hijacks the cell’s genetic machinery for its own benefit in order to reproduce its own genetic information a certain number of times. This statement is based on the fact that the virus induces in some cases a complete blockage of the cellular machinery, the only genes expressed being then the viral genes.

If one accepts that the expression of viral genes is useful to the organism and the species, one should rather say that certain cells concentrate their activity on the multiplication of viral information, in order to retransmit it to the other cells of the body.

The blocking of the normal activities of certain cells does not pose any particular problem for the organism if their number remains limited. Experience shows that such a limitation is indeed assured in the vast majority of cases.

Cellular Lysis

Some viruses, such as the poliomyelitis virus, are known to cause the destruction of infected cells. As in the previous paragraph, it should be noted that the lysis of a certain number of cells dispersed in the organism does not represent an irreversible lesion if their percentage remains below a certain threshold.

The problem is rather to know which factors can cause this threshold to be exceeded: for example, a deficiency in the immune system, or, in accordance with Burger’s hypothesis, an exaggerated concentration of foreign molecules stimulating the multiplication of the virus responsible for their elimination.

If the viral information is supposed to be useful, it does not appear unfavorable in itself that the organism sacrifices a limited number of cells in order to ensure their multiplication, as long as the phenomenon remains reversible, i.e. the dead cells can be replaced by operational cells. Still in the example of poliomyelitis, the number of patients presenting irreversible lesions of the neurons (alteration of the nucleus of the cells and irreversible paralysis) is about 0.25%, which is obviously insufficient to be able to consider these lesions as a consequence directly linked to the action of the virus.

It should also be noted that the incubation phase, during which the virus multiplies, is generally silent. In Burger’s hypothesis, the symptoms which appear during the state period should be divided into two classes: those which result from possibly irreversible cellular destruction, and those which are caused by foreign molecules released by the cells into the circulating masses. y

In addition, the destruction of certain cells, as in the case of infections by the herpes virus, could be part of a general programming of the phenomenon including, for example, the formation of papules useful for the elimination of substances rejected by the cells.

Genetic Variability

The genetic variability observed in many viruses can be accounted for by the diversity of the classes of foreign molecules whose elimination they are responsible for programming. There would be a certain analogy with the multiplicity of the different antibodies that lymphocytes know how to elaborate to recognize the different classes of antigens likely to penetrate the circulating masses. Similarly, the variability of viruses would allow intracellular immunology to cope with the various classes of foreign molecules capable of accumulating inside the cells. It is therefore questionable whether the mutations we observe are not induced by cellular genetics.

Plant Viruses

The existence of viruses that are obviously harmful to the individual in the plant world can be explained by a kind of homeostasis at the level of the species: the survival of the species is indeed endangered if the biotope becomes unbalanced due to overpopulation. The usefulness for the species seems here to go against the usefulness for the individual. This is undoubtedly due to the fact that the survival of the individual, in the plant world, is much less important for the maintenance of the species than in the animal world, especially in the higher animals where the litters are few.

In this regard, it can be noted that overpopulation causes deficiencies in the humus, which in turn leads to nutritional disorders in plants. Thus, there is already a relationship between nutritional disorders and virosis in the plant kingdom. It is therefore not absurd to think that this same phenomenon could have taken, through the evolution undergone by the animal kingdom, a more elaborate form whose strategy consists in preserving the individual to favor the survival of the species.

The Role of Interferon

The production of interferon during the multiplication of the virion in the first cells, avoiding further multiplication in the other cells, is meaningful if we admit that transmission of the viral information to all the cells of the individual responds to a process of genetic complementation foreseen by the organism.

On the other hand, it is difficult to explain in terms of a defense mechanism as the classical model would have it: if such a defense mechanism is possible at the time of viral invasion, it is not clear why interferon would not be synthesized early enough (at a time when the organism is not yet weakened and would therefore be in a better position to defend itself), as is the case for many immunological mechanisms. Such slowness seems to contradict the laws of evolution, whereas the hypothesis of a collaboration between the virus and the cell, useful for the species, justifies perfectly the presence of a regulation mechanism allowing the virus to multiply within the adequate limits so as to avoid that all the cells of the body are infected.

Even if one accepts that another cause of impairment causes the delay in interferon production, it is still troubling that this production can be completed correctly when the two causes are superimposed (viral infection and external cause), in a manner precise enough to keep the number of virions limited to one or a few copies per cell. On the other hand, the hypothesis of a collaboration between the cell and the virus fully justifies the presence of such a mechanism, which then appears as a regulatory system rather than a defense system.

Autoimmune Mechanisms

The display of certain proteins by cells, which occurs under the influence of interferon (e.g. the p69 protein displayed by pancreatic cells), could have the function of triggering auto-immune mechanisms designed to eliminate cells invaded by excessive quantities of foreign molecules. Thus, letting the virus program the return to integrity of the least affected cells, the immune system would take charge of eliminating the cells that are too severely encumbered and should be replaced. This hypothesis would be confirmed if it could be demonstrated that the display in question is proportional to the concentration of foreign molecules in the cell.

Perfection of Virion Structures

The construction of perfectly structured virions and their expulsion through the cell membrane is the result of a coordinated action, which is very complex if we consider the mechanisms involved. This action is programmed by the viral genome in a surprisingly targeted manner. It seems less risky to attribute its origin to the cellular genome, which has the necessary mass of information, than to a mutation-selection process at the level of the viral particle. This process can only start when the virus is already able to reproduce itself. Insofar as this reproduction can only take place in the cell, it is difficult to see how the phenomenon could have been initiated.

Conservation of Viral Information

The fact that the viral information is stored in the cell and hidden, with the possibility of being reactivated, seems more logical if one postulates that it is useful information, allowing the cell to ensure the evacuation of certain harmful molecules, even if it means reactivating the process at the moment when their accumulation becomes detrimental.

The classical view of the virus as a simple pathogen would suggest that virions and their genetic content are totally destroyed after recovery, at least in the most resistant individuals. However, the persistence of viral information actually is the rule.

If it has not yet been possible to identify the factors likely to trigger the reactivation of the viral process, it is perhaps precisely because they involve not only the biological data of the virus and the cell, but also the biochemical properties of molecules whose existence has not been taken into consideration until now.

Bacterial Symbiosis

The bacterial infections that we often see associated with viral diseases could be explained not only by a weakening of the immune system, but by the presence in the circulating masses of foreign molecules rejected by the cells.

Two hypotheses are therefore possible: either these foreign molecules weaken the organism and open the way to bacterial invasion. Or the multiplication of certain bacteria would also be programmed by the viral information in interaction with the genetics of the organism.

This second explanation is not absurd: the foreign molecules whose presence we postulate escape by definition from the mechanisms of assimilation as well as from the vigilance of the immune system, since they have been able to reach the interior of the cells without ambiguity; their elimination thus requires mechanisms which do not belong to the organism itself, for example bacterial enzymes able to degrade the undesirable molecules.

This model of reasoning is in agreement with what we know about the bacterial flora: there too, the organism seems to have been able to domesticate bacteria whose enzymes allow it to degrade molecules that escape its own enzymes, for example carbohydrate chains like cellulose.

Thus, the virus would induce not only the processes necessary to maintain intracellular integrity, but also the multiplication of bacteria capable of degrading the waste products rejected by the cells. The apparent pathogenicity of these bacteria could be attributed less to the virulence of particular strains than to an excessive level of target molecules in the circulating masses.

Apoptosis

Apoptosis, the process of natural cell death observed, for example, in T4 lymphocytes in the presence of HIV, would have the following meaning in this conception: the virus would program the suppression of lymphocytes in charge of recognizing classes of bacteria, whose enzymes are required to degrade the molecules rejected by the cells, so as to favor the multiplication of these bacteria. The viral genetic information would thus program the transport of foreign molecules out of the cells while bacteries multipliply likely to rid the circulating masses of them on the other.

Under the effect of an exaggerated concentration of target molecules, especially when molecules of the same type are brought in daily by unsuitable food, it would make sense in this hypothesis that apoptosis exceeds the correct limits, and the immune system enters a state of apparent deficiency, letting all sorts of pathogenic elements develop freely.

Autoimmune mechanisms, triggered by the presence of food-borne antigens also bind to lymphocyte membranes, could complicate the phenomenon and aggravate the destruction of these cells.

Difference in Evolution

The more or less severe evolution of the viral process in different individuals can be explained by a more or less important accumulation of foreign molecules, according to the different food anamnesis.

The symptomatic form that it takes more regularly in the human species would be due to the fact that the food proper to the civilization has considerably moved away from the primitive food which could have determined the evolution of our genetics, and it is unlikely that in a few thousand years the human organism could have adapted genetically to all the new molecules brought by the agricultural and culinary artifices established since the Neolithic.

A virus as dangerous as SIV hardly causes any symptoms in monkeys living in their natural environment, nor even HIV in captive chimpanzees fed in a natural way. Since the regulation of viral multiplication depends on the presence of foreign molecules in the body, it is to be expected that additional intake of the same molecules through conventional foods would disrupt the process.
According to Burger, the consumption of certain foods by infected subjects during the incubation period would cause an aggravation of the subsequent symptoms, for example in viral hepatitis. From this point of view, it is understandable that the diet prescribed regularly by family doctors to patients with influenza, coryza, hepatitis, etc., has had enough effect to be maintained in the medical tradition.

Childhood Diseases

The popular wisdom which attributed a utility to the diseases of children, for the majority of viral etiology, is paradoxically justified: the organism equipped with the complements of genetic program brought by the various viruses is better armed against the harmful molecules likely to invade its cells during the existence. This calls into question the fundamental meaning of vaccinations: their usefulness would be to avoid viral invasions that could have serious consequences in the classical food conditions.
On the other hand, if Burger’s hypothesis were to be confirmed, there would be reason to fear that the absence of the genetic complements provided by common viruses would deprive individuals of the mechanisms provided to ensure the maintenance of the integrity of the cellular environment, with the risk of aggravating degenerative processes and compromising various functions of vital importance.

Changes in the Biotope

The expansion of certain viral diseases in wild animals can be explained by changes in the environment, the cultivation of cereals or other mutated plants introducing appreciable quantities of new molecules into the natural food environment (proteins produced following mutations in wheat, for example, accumulating in the body of rodents, then in that of the fox, causing the activation of the rabies virus, which was already present before without causing any particular problems). To this could be added the influence of molecules introduced by industrial waste and pollution.

Antivirals

The relative failure of so-called antiviral molecules can be explained by the difficulty of counteracting vital processes programmed by genetic means. The interactions between the viral genome and the cellular genome take place in the cell nucleus and respond to precise mechanisms, so that it is very difficult to inhibit them without harming the cell at the same time. Such processes probably include self-regulatory or substitution mechanisms intended to guarantee their action, the rebellious nature of which may seem paradoxical as long as their biological purpose cannot be defined.

Oncogenic Viruses

The case of oncogenic viruses occupies a special place; they may always be harmful. However, the multiplication of cells can be useful for various purposes, if only to compensate for cellular destruction due to some cause. It would therefore also be possible to envisage that these viruses provide useful information to the organism, even if this means that they can lead to disastrous results under the effect of certain co-factors.
The Epstein-Barr virus only manifests itself as a sarcoma in a very small proportion of infected children, and only in Africa. In addition to genetic predisposition, it would be appropriate to investigate, on the basis of Burger’s hypothesis, the presence of certain foreign molecules reaching a particularly high concentration, resulting for example from the dietary habits of young Africans.

AIDS

As far as HIV is concerned, it has been admitted that almost all infected persons should develop severe symptoms. Indeed, the evidence so far has confirmed that, with very few exceptions, HIV-positive status will result in a fatal outcome. These facts seem to contradict the previous points. However, the same or similar retroviruses have been found in recent years in many wild animals, which do not seem to show any particular symptoms.

The best researchers have come to believe that the pathogenicity of this virus is due rather to some as yet unknown co-factors than to the nature of the virus itself.

In Burger’s hypothesis, these co-factors could be the molecules that the virus would be responsible for programming the elimination of, present in much greater numbers in human organisms than in wild animals: the latter feed mainly on natural foodstuffs to which their genetics have been able to adapt since time immemorial, whereas humans regularly absorb traditional foodstuffs that did not exist in the primitive environment, and to which human genetics have hardly had time to readjust.

It is therefore to be feared that certain foreign molecules will have the opportunity to accumulate in human cells at concentrations that have never been reached in the history of the species. The viral processes in charge of programming their elimination, in a primitively silent way, would thus be confronted with an unforeseen situation: the abundance of target molecules would disorganize regulatory mechanisms that ensure their proper functioning and would lead to the appearance of dangerous opportunistic infections as a result of an exaggerated multiplication of the associated bacteria.

It remains then to explain why this retrovirus, which was perhaps part of the genetic heritage of humanity without signalling itself, as it is the case in animals, would be suddenly out of the shadow of the cellular nuclei to cause a serious epidemic. Among the reasons to be considered are the changes in eating habits, which have been considerable in the last decades, especially in the Third World countries, where Western eating habits spread quite suddenly, as well as new causes of contagion. Once viral multiplication has been triggered, the virus could only improve its performance: the most contagious virions and those causing the most mucous lesions are the ones that multiply preferentially.
In addition, organisms no longer in possession of the virus or in which it was more deeply inactivated, had the time to accumulate a particularly high quantity of target molecules. This would explain the particular violence of the viral process, further increased by the daily intake of foodstuffs carrying molecules of the same classes.

Theoretical and Empirical Verification.

A new theoretical model, in a field as complex and charged with emotional factors as disease and contagion, can only be verified with sufficient hindsight, through the coherence of the reasoning to which it provides the starting point, and above all through the facts.

Unfortunately, it is not easy to obtain the publication of new ideas not yet endorsed by the scientific corpus, even if it is only a matter of submitting them to the criticism of specialists. Burger therefore invites all interested researchers to criticize his proposed model in the light of their theoretical knowledge, and all practitioners to observe whether the presumed relationships between patients’ diets and the evolution of classical viral diseases correspond to possible predictions. He would be glad if those who observe either significant contradictions or concordances could take the trouble to communicate them to him.

If Burger’s viral model proves successful, it could open up a new avenue of research, especially in the field of AIDS. It would not only be a matter of looking for a vaccine or developing antiviral molecules to deal with the most urgent problems, but also of identifying the molecules of food origin potentially responsible for disrupting the viral process.

Dietary measures applied as a preventive measure could consequently improve the future prospects of current seropositive people. The daily intake of foreign molecules may also play a role in the regulation of the viral process. A correction of the food hygiene could, in this hypothesis, improve the fate of the persons already contaminated, and perhaps limit the evolution of the symptoms even after their appearance.

It is regrettable that no epidemiological research has been done so far to establish the possible existence of a relationship between the dietary history of HIV-positive persons or the daily diet of AIDS patients and the severity of symptoms.

Furthermore, the identification of food-borne xenobiotics could lead to a better understanding of the cause of many dysfunctions affecting metabolism or other functions involving biochemical mechanisms, such as the transmission of nerve impulses, DNA replication, etc. Certain proteins contained in wheat gluten (gliadins) seem to aggravate the symptoms of schizophrenia, various Maillard molecules have been shown to be mutagenic, and there are certainly many pathogenic factors still to be discovered in this field.

In the same perspective, the heuristic proposed by Burger would lead to a more systematic search for food-borne antigens involved in the genesis of autoimmune diseases. The recent discovery of a peptide in cow’s milk, apparently responsible for the reversal of the immune system against the B cells of the pancreas, and opening the way to juvenile diabetes, as well as various experiments on rheumatoid arthritis, improved in some 80% of cases by a diet excluding cow’s milk, wheat and their derivatives, go in the same direction.

Summary

Burger et al. propose a model of the viral process that integrates current data from genetics, immunology, virology and dietetics and attempts to bring them together in a coherent theory.

The viruses and bacteria involved in most of the so-called infectious diseases are considered as vectors and partners of genetically programmed symbiotic processes, intended to carry out the elimination of molecules foreign to the functioning of the organism, accumulated in particular in the cells.

The pathological aspect of these processes would come from an excessive concentration of foreign molecules in cells and in circulating masses, mainly linked to an inappropriate food hygiene and the inadaptation of metabolic data to the modifications in eating habits since the Neolithic period.

The systematization of antibiotics and vaccinations, by inhibiting these processes, could contribute to the development of degenerative, auto-immune and cancerous diseases as a result of the accumulation of foreign molecules, antigens or xenobiotics, which could disrupt the biological and immunological functions necessary to maintain health.

Exosomes and Viruses

The text under this heading is an essay I wrote for an exam in biology.

I propose here to postulate, in the light of the latest data on these molecular mechanisms, that the viral processes are in reality in most cases, under the control of the body, and that exosomes and viruses are all variations of an universal mailing system shared by all of nature for billions of years.
I gathered evidences from cell biology demonstrating our ignorance of the fundamental nature of retroviruses or viruses in general, and exosomes in particular. This is what I will try to show by using studies that have been done on the dynamics and behavior of the different structures or molecules that will serve my purpose (prion, various vesicles, within the cell or between cells.

Among viruses, those that interest us are the enveloping viruses because they cover their protein capsid (if they have one) and their genetic material by one (or more) lipid bilayer. They can derive either from nuclear membranes like the envelopes of Herpesviridae or from plasma membranes for Orthomyxoviridae. The genetic material of these viruses can be of any type: RNA, DNA, single or double stranded.

In theory, these vesicles are not related despite their similarity because unlike viruses they do not reproduce. However, contemporary virology has moved away from this strict definition by its wide use of the terms non-infectious and defective virus. Therefore, extracellular vesicles generated by retrovirus-infected cells that carry viral proteins and even fragments of viral genomes essentially fall into this category of non-infectious viruses.

The vesicles are surrounded by a lipid membrane that also contains cell membrane proteins. Like those of viral envelopes, these proteins can determine adhesion to the plasma membrane of specific target cells. In addition to DNA polymerase activity, tumor vesicles also showed endogenous reverse transcriptase activity more commonly associated with viruses.

Despite the important differences in membrane morphology, recent research has revealed a variety of similar mechanisms in bacteria, pointing to an identity of form and function of vesicular formations between the three domains of life (bacteria, archaea and eukaryotes or cells with nuclei including animal, plant or fungal organisms, unicellular or multicellular). I will only mention them here in the spirit of completeness.

Bacteria have on their inner membrane a layer of peptidoglycan, a rigid substance giving very particular conditions for the budding of vesicles on the surface. The vast majority of bacteria also have a layer of external lipopolysaccharide (LPS) and underneath a little peptidoglycan located in the periplasmic space. They are generally referred to as Gram-negative or bidermic bacteria.
In contrast, most bacteria in the phylum Firmicutes have a single membrane covered by a thick layer of peptidoglycan. The phylum Actinobacteria is quite distinct from the classical types, their thin peptidoglycan layer is directly covered by a thick polysaccharide layer. Many bacteria also contain a protein S-layer.

Several types of extracellular vesicles have been described¹, the most studied being formed by budding from the LPS-containing outer membrane (OM) and containing mainly periplasmic components, however, some formed from the outer and inner membranes of didermatid bacteria have been identified in several species, and contained elements of the whole bacterium. Finally, vesicles have been observed in Gram+ bacteria with thick envelopes, crossing the thickness according to a mechanism that is still unknown and thought to be impossible.

The same functions are found as in eukaryotes and viruses: resistance of vesicles to enzymatic attack, allowing the delivery of contents at long distance, with the same specificity towards a target cell of the host organism, and to foil the immune system of the latter² for example, by carrying specific antigens serving as decoys. They can also help bacterial colonization by selectively killing or promoting the growth of other bacterial species³, by exchanging genetic material (transformasome). And as in the animal case, increased vesiculation may aid in removal of toxic by-products after exposure to stress⁴.

These nanotubes (membranous structures 50-200 nm in diameter and up to several cell diameters in length) often contain membrane-surrounded vesicle arrays, suggesting that they may be involved in vesicle production, particularly by some cancer cells.
Although studies are already piling up, we still know a lot more about eukaryotes.

Due to the small size and heterogeneity of vesicles, their detection and classification is difficult. Although different types of vesicles have been identified, widely used terms such as exosomes ectosomes and microparticles are often inconsistent, especially in the older literature.
In addition, the extent to which the various morphologies contribute to the processes studied is largely unknown. For practical reasons, the various terms are to be considered here roughly interchangeable. Electron microscopy remains the gold standard technique for determining vesicle morphology and size.

Exosomes can cross biological barriers (such as the blood-brain barrier) and penetrate cells with a high degree of specificity. Hence their significant interest as drug delivery agents and diagnostic biomarkers.

In general, their diameter does not exceed 120 nm, which is smaller than the maximum theoretical resolution of a conventional optical microscope. The fate and interactions of exosomes inside cells are therefore difficult to study, which limits investigation in the field⁵.

Several studies have shown that the populations of extracellular vesicles are very heterogeneous, even in pure cell culture, each cell type being able to produce different types. However, it seems that some are produced exclusively by certain cells. To further complicate matters, the content of extracellular vesicles varies depending on the source and the original isolation or enrichment technique.

In 2007, Lötvall demonstrates that eukaryotic extracellular vesicles (exosomes) contain large amounts of RNA of all kinds and transfer these to target cells⁶. After that, it was found that the RNA content was highly specific, and sometimes enriched several thousand times relative to their host cells, even between different subpopulations of the exosomes which suggests an active RNA packaging mechanism⁷.

Although there is intact mRNA and long non-coding RNA present in EVs, most RNAs are fragmented or small in size. As mentioned above, these RNAs encapsulated in vesicles can have a profound impact on recipient cells, transferring between different cell types a signal causing transient transformation of recipient cells e.g. leading to the production of new proteins (case of mRNA transfer), or regulation of gene expression in the case of miRNAs.

The same researcher, in 2013 found that RNAs isolated from apoptotic vesicles (forming after programmed cell death), membrane vesicles and exosomes have very different profiles. Membrane vesicles have the least amount of RNA, apoptotic vesicles the most. This could reflect an active process of communication to other surrounding cells informing about the causes and conditions of apoptotic cell death.

Vesicle Formation

The classical pathway involves the formation of intraluminal vesicles (ILVs) in MVEs (Multivesicular endosomes). In turn, the MVE membrane fuses with the plasma membrane, resulting in the release of VILs. When secreted, VILs are called exosomes. Alternatively, the direct pathway involves the release of vesicles, indistinguishable from exosomes, directly from the plasma membrane.
In most cases, the classical pathway is controlled by the proteins of the ESCRT pathway (for endosomal sorting complexes required for transport), and the Rab-GTPases proteins for addressing the cell surface. An influx of intracytoplasmic calcium coupled with cytoskeletal remodeling will lead to externalization of phosphatidylserine and budding.

In addition, ESCRT-independent pathways are probably involved in exosome formation, although they are less well understood. Indeed, depletion of key proteins in different ESCRT complexes does not abolish the formation of multivesicular bodies (temporary organelles of common vesicle formation).

These ESCRT-independent mechanisms are thought to involve HSPs (Heat Shock Proteins),lipids, and tetraspanins: the lipid composition of small vesicles is different from that of the mother cell, although it is related to cell type. As for structural lipids, small EVs are enriched in cholesterol and sphingolipids, indicating a membrane composition similar to that of the lipid rafts floating on the surface of the mother cell, and involved in a large number of interactions. In addition to structural lipids, extracellular vesicles also contain active lipids such as prostaglandins and lysophospholipids.

Redundant pathways are a common phenomenon in biology, and thus multiple non-exclusive mechanisms may be responsible for sorting various proteins for exosomal export.

Little or nothing is known about the loading of nucleic acids.
In one study, it was shown that double-stranded DNA would rather be adsorbed on the outside of vesicles and large vesicles carry most of the tumor double-stranded DNA circulating in the plasma of prostate cancer patients. Because of their oncogenic potential much data on extracellular vesicles in the context of tumors have been collected, but this also reflects the fact that the spread or functions of endogenous exosomes in vivo or data on adult tissues under healthy i.e. homeostatic equilibrium conditions are pretty much unknown, in comparison.

The existence of sorting mechanisms is assumed but not known. Several sequence motifs highly enriched in exosome-associated miRNAs (an important class with a ubiquitous role as a negative regulator of gene expression), compared to cellular miRNAs, have been determined, along with a specific protein ⁸ binding to these EXOmotifs, thus trigerring RNA loading.

Sequence motifs on messenger RNAs lead to vesicle enrichment via a mechanism involving interactions between mRNAs and microRNAs, sometimes involving specific transcription factors binding degenerate consensus sequences in the upstream untranslated region (UTR) of the RNA⁹.

The general rules governing RNA loading efficiency are not well understood. Therapeutic uses are limited to applying an empirical method that works more or less, without knowing why, nor what will be the fate of said mRNA once the target cell is reached. But there is no longer any doubt that certain species of molecules are recruited in a selective and controlled manner.

Virus Formation

Conceptually, virus budding can be divided into two steps:

1. membrane deformation, when the membrane is wrapped around the assembling virion,
2. membrane fission, when the neck of the bud is severed.
   The structural proteins of enveloped viruses generally bind to membranes and form spherical or helical assemblies. Thus, assembly and budding are often inextricably linked processes. These fusion proteins undergo dramatic conformational changes, converting the free energy released by fusion protein folding into energy that is used to fuse viral and cellular membranes.

Budding is usually tightly coupled to virion assembly, so most viruses use their structural proteins to recruit the ESCRT pathway. They can also use host factors¹⁰, for example in the GAG polyprotein (the main structural element of retroviruses. In HIV-1, the energy released is not required for Gag polymerization but for detaching nascent virions from the plasma membrane. Subsequent studies identified two different short peptide motifs in p6 Gag that contributed to the efficiency of HIV-1 budding.

In parallel, others have identified distinct short peptide motifs in the structural proteins of other viruses, called late assembly domains of which at least five distinct but interchangeable classes have subsequently been identified, often leading to the identification of analogous motifs within cellular proteins, recruiting ESCRT factors, an interaction verified experimentally. Funny system where thieves and bankers agree on a common system of semaphores to keep each other in sight…
In other cases, budding seems more complex or entirely independent of known cellular pathways.

Exosomes in the Facilitation of the Viral Process

Exosomes and viruses share, in addition to budding, probably the mechanisms of specific cargo packaging and membrane budding for cell release. Most surprisingly, different viruses with very different evolutionary pathways seem to converge in their use of the endocytic pathway for entry and exit of their host cells.

Similarly, the hepatitis C virus has been shown to incorporate its entire RNA genome into exosomes without surface proteins, leaving them infectious. Most of these data on the function of extracellular vesicles such as exosomes, however, are collected from transformed cancer cells and depend on the use of a heterogeneous population of vesicles purified from supernatant or liquid cell cultures. Therefore, the spread of endogenous exosomes in vivo is largely unknown, and data on their biogenesis and role in normal development of tissues and adult tissues under homeostatic conditions are clearly lagging and understanding their transfer and fate in recipient cells is crucial.

The Trojan exosome hypothesis, which has since been proven, proposed that HIV evolved to use the exosomal system (more precisely ESCRT and Rab GTPases), in the absence of a receptor-based system. It is known that this is not unique to HIV, but common to both enveloped and non-enveloped viruses. This mechanism was demonstrated using HIV-infected dendritic cells, which were able to transfer the virus to closely associated uninfected T cells via exosomes… Furthermore, infectivity is reduced in the absence of exosomes, assuming that both are integral parts of the same mechanism.

It seems sound to me to consider the possibility that the viral process is only one aspect of intercellular communication, including between different organisms, although in ecological ways that are not yet understood. Through microRNAs, some viruses can modulate cellular processes as diverse as immune evasion, apoptosis, proliferation, and even viral infectivity. These viral miRNAs, in conjunction with endogenous miRNAs, are thought to play a role in modulating the expression of target genes in recipient cells. In addition to RNAs, infected cells may also excrete specific viral proteins via exosomes, thereby modulating cellular processes in surrounding cells (cytokines, interferons).

For example: exosomes released from HTLV-1 (human T-lymphotropic virus 1) infected cells contain not only viral mRNA transcripts, such as those of Tax, HBZ and Env, but also the biologically active trans-activator protein Tax. In addition, the HTLV-1 Tax protein was shown in exosomes isolated from cerebrospinal fluid of patients with HTLV-1-associated tropical spastic paraparesis myelopathy, suggesting that HTLV-1 may modulate its microenvironment by selective secretion of specific viral cargoes.

Substantial evidence indicates that many different types of pathogens, including bacteria, viruses, and protozoa¹¹(and prions, see below) can exploit the exosomal pathway, for secretion or movement.

These parasites can also influence exported cellular products. A body of evidence indicates that exosomes in virus-infected cells can induce processes as diverse as immune evasion, apoptosis, angiogenesis, proliferation, trans-cellular spread and cytokine modulation. The molecular details of how these processes are triggered are poorly understood, and they differ between tissues, cell states, viruses…

Another well-known mechanism by which some viruses can evade immune responses is by down-regulating viral lytic gene expression and persisting in infected cells in a latent state, where the absence of viral antigen in infected cells means that the immune response cannot be triggered, but also simply that the virus is paused.

For example, herpes simplex type 1 (HSV-1) replicates in mucosal epithelial cells during primary infection and then enters the sensory neurons where it establishes a lifetime latency. During the latent state, although no viral protein is expressed, numerous miRNAs (viral microRNAs) have been detected, and some of these miRNAs appear to play a central role in suppressing viral gene expression and maintaining latency. And transmit antiviral factors, to the same effect.

There is some evidence that EVs, although less efficient than virions themselves, can transfer cytosolic proteins involved in antiviral responses, such as APOBEC3G and cGAMP (33-36), to recipient cells. In addition to miRNAs, extracellular vesicles also contain a wide variety of other small noncoding RNAs, such as fragments of protein-coding regions and repeat sequences, which could also act as regulatory RNAs by influencing gene expression.

In some viral infections, such as hepatitis B and herpes as well, non-infectious subviral particles are released into the serum, in some cases without viral capsid or viral DNA, often at levels 1000-fold higher than mature infectious particles. One hypothesis is that these subviruses would lure the immune system. In addition to immune modulation, exosomes released from some virus-infected cells may promote viral infection and spread as discussed with HIV-1.
In a similar vein, T cells can produce vesicles containing the HIV CD4 receptor, allowing them to bind to viral particles as antibodies would, thereby decreasing the number of virions that would otherwise affect CD4+ T cells.
Thus, the cells are able to selectively exchange antigens with each other, certainly to direct the process of clonal selection in secondary lymphoid organs.

Conversely, in vivo, exosomes can interact with viruses and each other directly or via modulation of host responses, thus participating in a war and peace between viruses and the host.
In 2014, exosomes derived from infected cells containing Tax proteins and pro-inflammatory factors, as well as viral mRNA transcripts including Tax, HBZ and Env (viral envelope protein) were found. In addition, giving these Tax-expressing exosomes to other cells improved their cell survival to Fas antibody treatment, indicating induction of NF-kB and activation of AKT (2 anti-apoptotic factors).
Another study found similar processes for HIV. When transferred via exosomes, TAR RNA can increase the population of susceptible target cells. Inside EV target cells, full-length TAR RNA is transformed into miRNAs, which quench the mRNA encoding the Bcl-2 interacting protein (involved in induction of apoptosis).

Viruses of several different species commonly were found ¹² to travel in the same exosomes throughout the body, and thus were (contrary to what was thought) in physical proximity, which would allow for increased exchange.

The mentioned article still talks about exploitation of vesicular trafficking and genetic cooperation between viral species, as if it were a criminal alliance with a will to do harm. But viruses have no more will than they have metabolism, they are only molecular robots, and they are entirely passive.
In particular the content of HIV is very limited, known at the tip of one’s fingers. One could well compare it to a computer whose program in assembler has so well elaborated to take part of the instruction set of the CISC processor (for Complex Instruction Set Complex, hard to imagine more complex than an animal cell!). And to keep this extreme syntony, in spite of this same enormous mutation rate which allows it to escape the immune system and vaccine attempts.

So there is no reason why the interaction between viral proteins of different species should produce anything other than disorder: putting a helical gear there instead of a normal straight road is not known to improve a mechanism, and a cell is several hundred times more complex than a machine, in fact scientists compare it more to a whole city than to a factory. What kind of miracle of improbability does it take to make virologists question their view?

This proximity and this traffic, is one more proof of the arranged and programmed nature of the viral phenomenon, in concert with the cellular dynamics. And not the blind product of a mutative process still much more chaotic on average than our cells. Typically, influenza, HIV and coronaviruses mutate several dozen times. And yet the information necessary for proper functioning is maintained.
So we invoke, as always… the sacrosanct natural selection. But since it is an article of faith without the slightest statistical justification or mathematical model (the complete life cycle involving the whole cell, thus exceeding our computers by several millions or billions) we don’t need to ask ourselves any questions, and we will put forward the same argument no matter what the facts are that go against the grain and the enormity of the claim.

Simply, because there can be no other explanation: it is a dogma, a religion.

Other functional studies of exosomes released from infected cells have shown that infected cells release not only infectious virions, which are capable of spreading infection, but also a variety of non-replicative particles, which are difficult to classify, as they could be considered either as defective viral particles or vesicles containing viral elements, such as viral proteins and viral regulatory double-stranded DNA.

These non-replicating particles typically include cytidine deaminase, degrading retroviral RNA by random mutation, inhibiting viral replication. Exosomes containing host miRNAs produced by virus-resistant cells can confer resistance to other cells. This has been demonstrated for trophoblasts, which are largely resistant to infection by various viruses, including HIV, likely contributing to fetal protection in vivo. Exosomes produced by these cells in vitro carry host miRNAs and deliver them to virus-susceptible cells, making them resistant to virus infection.

One can see the analogy with the aforementioned virus defectives indistinguishable from exosomes, which confer resistance AND at the same time reduce the immune response. It seems to me that these are two sides of the same phenomenon.

Exosomes and the Removal of Denatured Proteins in Neurodegenerative diseases

In humans, prion disease occurs in sporadic, familial and acquired etiologies. However, all forms of the disease are transmissible, with possible routes of infection through dietary exposure, medical procedures and blood transfusion. The isoform of the normal prion protein, PrP C, is encoded by PRNP and is expressed in all tissues of the human body, with the highest levels of expression observed in central nervous system and brain tissues.

• PrPC and PrPSc have been isolated in association with exosomes, and PrPSc-containing exosomes were infectious in both animal and human cell bioassays.
• Alzheimer’s disease (AD) is the most common form of dementia in humans and is pathologically characterized by the extracellular deposition of insoluble amyloid plaques consisting of β-amyloid peptide (Aβ), a 39-43 amino acid peptide produced by proteolytic cleavage of the amyloid precursor protein. APP is cleaved from Aβ, left intact as a membrane associated fragment (β-CTF). These fragments accumulate intracellularly in multivesicular bodies and are incorporated into exosomes and released into the extracellular environment.

The identification of Aβ in association with exosomes is an important finding, especially since other exosomal proteins such as Alix and Flotillin-1 have been shown to accumulate in the brain plaques of Alzheimer’s patients.

Exosomes could also provide an explanation for the transport of equally toxic Aβ and APP-CTF around the body to the brain, where they contribute to amyloid deposition.

Underlying causes of neurodegenerative diseases are the folding and aggregation of specific proteins , such as amyloid β peptide (Aβ) in AD, scrapie associated prion protein (PrPSc) in prion disease, α-synuclein in PD, and superoxide dismutase 1 (oxidoreductase catalyzing the dismutation of superoxide anions O2–, involved in the neutralization of oxidative stress) in amyotrophic lateral sclerosis.

And all of these enzymes seem to be moving in the same direction: cleaning up, removing metabolic waste. Even if the theory still lacks precision, it seems clear that prion and prion-like diseases are neither infections or diseases, but essential vital clean processes of eliminating denatured molecules, AGEs in particular.

Alongside or at the same time as prions, the main proteins associated with these neurodegenerative disorders are found to colocalize on/in exosomes, containing binding sites for copper, zinc, iron and manganese. All of these have an obvious role in what would normally be detoxification: a dozen zinc transporters, ferroportin, transferrins, serotransferrin, several metalloreductases, ferritins, aconitate hydratase (sequester iron), ferroxidase, for iron.

We have already seen the role of AGEs and ALEs in disorders as varied as cancer, diabetes, aging. They are found colocalizing with AGEs receptors (RAGEs) in exosomes with Alzheimer’s disease ¹³.

RAGEs also bind the amyloid substance responsible for plaques, stimulating its production in the brain and regulating its influx across the blood-brain barrier. RAGE also promotes senile plaque formation via tau hyper-phosphorylation, synaptic dysfunction and neuronal death.

It is clear that prions were an extensive set of proteins with several functions unique to the brain (insofar as it is largely cut off from the normal blood and immune circulation), one being the sequestration of denatured molecules. However, the formation of plaque, linked to age and therefore to the level of intoxication, is not their property: rather, it is the consequence of a rate of intoxication completely unforeseen by nature and reaching such a peak in old people that the body is overwhelmed.

So we have seen infectious exosomes that are not viruses, and viruses that are not infectious, not quite infectious. Since the purpose of the phenomenon is not negative for the organism (beyond the individual cells), is it logical to always consider these viruses as foreign when we observe a whole continuum between self and non-self?

As far as the DNA content in eukaryotic extracellular vesicles is concerned, less is known than the RNA content. Single-stranded, mitochondrial, plasmid, and double-stranded DNA have been observed. The DNA seems to be present in the form of small fragments (about 10 to 20 kb) covering the whole genome including mitochondria without apparent order for the moment. However, it is important to note that some EV-associated DNA fragments contain entire genes with promoter and terminator regions. This DNA can be transported from cell to cell by endocytosis or fusion and this transfer can affect the transcriptional pattern of recipient cells, inducing both up- and down-regulation of many genes¹⁴.
Finally, not only RNA from enveloped retroviruses but also non-enveloped DNA viruses, such as herpesviruses, export their products and genetic material in the same way.
Many aspects of this mechanism remain to be clarified.

Just as the majority of viral infections are said to be frustrated, the detection of the pathological PrPSc isoform is not a sign of a disease, there would be thresholds, and an excess of normal forms would be able to trigger the conversion.

Conclusion

The consequent increase in resistance to apoptosis is said to allow the cell to produce a virus for a longer period of time, thus facilitating the spread of HIV. This is true, but the process is not automatic or a priori undergone by the cells and one can decently ask the question: why in the same package, incorporate virions at the same time as deaminases decreasing the efficiency of the viral load?

If we exclude this disturbing fact, the official theory of the pathogen already holds little when we consider that HIV for example would contain only 10 genes…

What an incredible compaction of information, if viruses can with so little orchestrate a whole set of cellular and intercellular reactions, and program exosomes to target specific cells or organs!

Well, essentially the same characteristics must be attributed to a simple deformed protein (the prion), having evolved according to the official theory to take control to the point of pushing distant organs to send their own quota of proteins to the brain.

We urgently need to change our perspective and see it as simply an information exchange protocol, just like sex hairs, more classical viruses, tunnels, circulating RNAs and maybe something else yet to be discovered. From my search of the literature, no one has thought of tracking the movement of a single AGE molecule, for example cells in the gut wall, from a nutrient solution that mimics the natural nutrient concentrations from a meal.
However, this would be technically feasible ¹⁵.

It is important to be able to show directly a correlation between reciprocal behavior in case of infection by different viral agents, and the treatment of this xenobiotic load and/or the packaging in the exosomes themselves. Similarly, tracking a prion or Aβ protein as it travels through the body would provide crucial information about how cells process the signal and pass it on, as on potentially several meters of transit there is a chance that the exosome carrying them will be contacted or even captured by cells for which they are not intended.

A Few Recent Confirmations

Viruses

The latest research cemented the notion of animals - people - literally swimming in a sea of viruses:

• Deposition rates of viruses and bacteria above the atmospheric boundary layer, Reche, D’Orta, Mladenov, M. Winget and A. Suttle

  Aerosolization of soil-dust and organic aggregates in sea spray facilitates the long-range transport of bacteria, and likely viruses across the free atmosphere. Although long-distance transport occurs, there are many uncertainties associated with their deposition rates. Here, we demonstrate that even in pristine environments, above the atmospheric boundary layer, the downward flux of viruses ranged from 0.26 to >7 billions per squared meter per day. These deposition rates were 9–461 times greater than the rates for bacteria, which ranged from 0.3 × 10^7 to >8 × 10^7 per squared meter per day.
  Virus deposition rates were positively correlated with organic aerosols <0.7 μm, whereas, bacteria were primarily associated with organic aerosols >0.7 μm, implying that viruses could have longer residence times in the atmosphere and, consequently, will be dispersed further.
  These results provide an explanation for enigmatic observations that viruses with very high genetic identity can be found in very distant and different environments.

• Coastial Wikia relates:

  In a drop (one millilitre) of seawater, one can find 10 million viruses, one million bacteria and about 1,000 small protozoans and algae (called “protists”). In addition to their high abundance, microbes play a crucial role in most biogeochemical processes occurring in the marine environment: they account for almost half of global primary production and form a major part of ecosystem respiration and nutrient recycling.

That makes 10 billions viruses per cubic meter !

So we see viruses circulate throughout the the entire biosphere, from near-space to several kilometers under the sea. As Steele hypothetised, it also makes sense that epidemics could travel this way, through clouds, sharing genetic information everywhere on the planet without a need for migrations.
What consequences this might possibly have on evolution, potential similarities between unrelated groups or animal species without actual hybridization and the validity of our models, can only be guessed.

The total biomass of viruses has been estimated¹⁶:

The sum of the biomass across all taxa on Earth is ≈550 Gt C, of which ≈80% are plants, dominated by land plants (embryophytes). The second major biomass component is bacteria, constituting ≈15% of the global biomass. Other groups, in descending order, are fungi, archaea, protists, animals, and viruses, which together account for the remaining <10%.

So 10% of everything, is viral. Perhaps it’s about time we understand it ?

Giant Viruses

Since 2013, a slew of new giant viruses were discovered, who size exceed that of a lot of bacteria and whose genome is actually bigger than a number of single-celled eucaryotic organisms. The biggest giant virus so far, Pithovirus sibericum, is large it can be seen in an optical microscope with its 1.5 micrometres in length. Most viruses measure around 20 nm, while the common E.Coli bacteria is 1 micrometer. That makes this virus 75 times bigger than the average.

More interestingly, the DNA content includes a lot of genes pertaining to metabolism and protein synthesis, one even including the necessary transfer RNA for all 20 ribonucleotides, which makes no sense from the point of view of viruses not being alive: in fact they still don’t use these genes alone, they need to cells to replicate otherwise they’re inert. And most of those genes come from either other viruses or a range of hosts. Some species are packed with ribosomes, whose recipe they include and which they use once within a host cell. Some even carry their own viruses, hijacking their hijacking their future hosts…
Since then the have been found in a variety of places, in all environment, including at our feet. Not yet in humans though, but it shouldn’t take long until they are.

Why they carry this package is unknown. Their most obvious useful to us to however, is the horizontal transfer of enormous amounts of genes among all protozoas and bacterias alike.

Not much can be said as of now, but these discoveries did sparkle a hot debate about the definition of life: these viruses while sharing most viral traits include genes strictly related to metabolism which we ignore how they would profit from in their infectious cycle, which we ignore everything as of yet. But they still do not show internal activity or independence. What if they did though ? What if we did find some intermediary between a bacteria and virus, an obligate intracellular parasite of extremely limited metabolism in a mostly inert shell ? What would that change ?

Not a lot. Without involving the presence of consciousness (whose simpler substrate could well be DNA itself as far as we know !) thus without extrasensory to perceive it, the definition of life is mostly a matter of convention, as stated above. Defining the nature of these new viruses still depends on their observed relationships with the collective of their hosts, as species or individuals.

From the standpoint of superior species (in term of complexity), bigger viruses or using bacteria or whatever vector instead as part of their exogenome, just means bigger and sturdier postcards, eventually with its own dedicated postman.