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The mountain has labored and brought forth a mouse virus.

Blog entry posted by anciendaze, Oct 1, 2011.

This is hardly a unique event. For perspective on the current controversy over retroviruses in ME/CFS, which continues to generate more heat than light, I want to describe research on human breast cancer in relation to mouse mammary tumor virus (MMTV). You can find surveys of the possible role of mammary tumor virus in breast cancer over 40 years old. Not only does breast cancer remain a serious health problem at significant incidence in the general population, the state of the science on etiology remains murky.

While there is a vast literature on MMTV, there are also reports of virus associated with mammary tumors in rats, dogs, cats, (probably sheep and goats) and cattle. There have even been sporadic reports of mammary tumor virus in non-human primates. The potential for transmission from domesticated animals, included pests domesticated without intent, to humans is large. Rejecting a viral etiology out of hand would be unwise. Why then does the question remain unresolved?

My view is that researchers have spent far too much time trying to force organisms into preconceived roles, and far too little paying attention to what the organisms themselves were telling them.

We now know MMTV has functioning receptor elements in a long terminal repeat (LTR) which respond to progestins, androgens and glucocorticoids. These are all hormones involved in sexual maturity, stress and lactation. This makes sense from the standpoint of viral transmission by milk. What seems less well known is that inserted provirus in non-cancerous breast cells also has a negative regulatory element. What's more, the complete viral genome requires two frame-shift events for efficient production of some proteins. These are facilitated by a pseudoknot in RNA, which frequently causes specific deletions. The provirus could be said to have several "safety" elements like the covers people put on switches that perform dangerous actions. ("Did someone just push the Destruct button for that missile? What do you mean, oops?")

The interaction between endogenous and exogenous virus is also a source of contention. It is well known in other cases that retroviruses commonly, though not always, activate sequences they insert. This says that the best way to activate a gene in an endogenous retrovirus may well be to infect with a very similar exogenous virus. An exogenous virus transmitted by sexual intercourse is the perfect trigger for replication at sexual maturity. A virus could scarcely care less about how it is classified by people.

Why this bizarre and self-contradictory set of properties? It doesn't make sense to people tightly focused on a specific model of pathogenesis developed for use with pathogens which followed a 'strategy' of rapid replication. This made detection convenient. The fact that such pathogens often killed hosts provided plenty of material for morbid pathology. This was convenient for researchers, if not for patients.

At this point I feel compelled to reiterate -- it does not benefit the pathogen to kill the host. All the examples to the contrary are exceptions caused by incomplete evolution following a jump between species, or an unusual burst of pathogen transmission involved in the final stages of disease.

Let me use an example from Ian Lipkin's work on viral hemorrhagic fever. In one outbreak three out of four infected patients died. The survivor only lived because researchers were able to identify a possible treatment in time. Without that intervention the mortality rate would have been 100%. Provided medical workers took adequate precautions that particular pathogen would have become extinct without any intervention at all. (This is not to say that intervention was worthless, just ask the survivor.)

My point is that most epidemics of pathogens following a 'strategy' of rapid replication will burn themselves out. The long-shot chance of one which will consume millions of people first is the driving force behind most epidemiology -- and one current movie.

Rapid replication may benefit a retrovirus when it jumps species, so long as it does not exhaust the pool of susceptible members of the new species before it evolves into a slower replicator depending primarily on vertical transmission and inheritance. The end result would be an endogenous retrovirus without harmful effects on the host, if evolution ever ended.

My point is that the complicated system of promoters, repressors, hormone receptor elements, endogenous and exogenous retroviruses serves a purpose, it keeps the dangerous aspects of the infection to a minimum during the reproductive period of hosts. If negative consequences fall after reproduction, they will have little or no effect on evolution. Infection may even enhance relative reproductive success of infected individuals.

One route is through modulation of immune response. In protecting itself, the virus may also allow more extensive changes associated with host reproduction. Direct immunosuppression in reproductive organs may well offer increased fertility via local immune tolerance. Elsewhere, it may allow more complete development of tissues required for lactation. While breast cancer is a dangerous form of mammary hyperplasia, there are numerous examples on the world-wide web of mammary hyperplasia which seems to contribute to promiscuous, if not reproductive, success.

We no longer have to overcome a 25% infant mortality rate to survive. We don't have to produce a dozen infants to have two survive to take care of us in old age. The effort of raising civilized children who will become more than killer apes is enormous. We could afford lower fertility in exchange for freedom from a dread cancer.

Another 50 years of doubling human populations every 25 years would almost certainly result in a catastrophic collapse. (Even if you support the projection made by the Conference of Catholic Bishops some years back, that the Earth could support 50 billion humans, this only delays disaster by 25 years. If population continues exponential growth, long term projections by planned parenthood are not all that different from opinions expressed by those bishops.)

(Perhaps this is the Gordian knot. Nobody in power dares to present such a stark choice, or even touch these explosive issues.)

Back to my primary topic today, the research muddle in relation to breast cancer. A virus very similar to current MMTV infected human ancestors resulting in a HERV. I don't think we have a good handle on how long this went on, only when it first happened. Numerous papers showing fragments of similar sequences, or activity of similar genes, in human breast cancer have been published. No one has shown a complete sequence of an exogenous virus reliably causing breast cancer.

The point I'm making is that the emphasis is wrong. The virus isn't trying to cause cancer, it is trying to replicate and persist. In the long term it is more useful to the virus to have inserted proviral sequences than active virions. Once similar endogenous sequences exist, exogenous viruses don't have to carry a complete complement of genes, some will already be present in most hosts. This strategy also pays dividends in confusing immune response. It is no longer possible to distinguish pathogens from self. Small wonder if infected hosts develop anti-nuclear antibodies.

When researchers encounter virus in tumors, I'm suggesting all such virus is likely to be defective, and deletions are one easy way to disable long sequences holding back replication. Provirus in somatic cells doesn't need to produce any virions to persist as long as the individual host. Provirus in germ-line cells doesn't need to produce any virions at all to persist and replicate for generations. There will be virions in pathological situations, but these often will not be identical to the originating sequences, which have become partially domesticated.

The search for a pure exogenous virus solely and reliably causing a cancer has resonances for me of an ancient search for "card-carrying communists". I could never figure out why someone devoted to the overthrow of systems of government would handicap themselves with an identifying card. Somehow, I suspect retroviruses are smarter.

I'll have more to say after I check the reception of this post.
anciendaze

About the Author

As the name suggests, I am old and dazed. The avatar illustrates my rule of thumb: "Hang on! This ride isn't over."
  1. Marco
    Hi Alex.

    That must have been fascininating even if you don't swallow the whole Santiago theory whole.

    It looks like my academic history bookends yours in time and subject matter. My undergrad was in Psychology touching on computational vision research and post grad in information systems. Both overlapped with artificial intelligence (an oxymoron if you consider intelligence as an emergent property of the process of living) but not very deeply.

    Ecology seems to be an alien concept to most of the mainstream medical profession; we don't as a species seem to easily get over our own sense of identity and conceive of where we fit in with ecologies inside and outside our own skin.

    As for 'immune psychosis' this was, I believe, what Varela suggested to explain autoimmune diseases. Similarly I've come across papers proposing a model of the immune system as complex, non-linear and with n>1 basins of attraction :

    http://www.scielo.br/scielo.php?pid=S0103-97332009000400015&script=sci_arttext

    (must be something in the water in South America!)

    plus didn't Maes produce a paper on 'kindling' that suggested a similar altered immune state?

    The reason I suggested a simpler alternative was that these concepts are so outside mainstream medical thinking that we are probably talking another 100 years and a major paradigm shift before they are accepted and practical results flow. A little late for me I'm afraid with another 25-30 years ahead of me if I'm lucky:D
  2. alex3619
    Hi Marco, I studied the work of Maturana and Varela in applying systems theory to artificial intelligence. I actually met Maturana and listened to him speak over several days at a seminar. My PhD was based on a symbiotic approach to composite neural network modelling, though I never got far as brain fog was trashing my thoughts at the time.

    The modern view/variant that is gaining popularity is that the immune system and pathogens are an ecology. Sometimes something goes wrong ... a forest fire or some new introduced species that is not normal to the environment. If a pathogen is not well adapted to humans or is located in a place that is not its home it can do a lot of damage.

    This is why disturbing the ecology further with drugs like antibiotics could sometimes be detrimental if the goal is to bring the ecology back into balance. In the ecological sense many bacteria and even viruses are part of the normal ecology and so can be helpful rather than harmful. Linking this back to what Anciendaze was saying, these microbes have an evolutionary adaptive interest in stopping other microbes from colonizing us. We are their host, so evolution drives them to protect us ... but only in the microbe's interest.

    Junk DNA is fodder for evolutionary development ... not junk just underutilized in my view. This is over evolutionary time though. For a given individual much of it is just useless, but some of it may have as yet not understood functions. A big part of what used to be thought of as junk DNA has turned out to have specific functions that don't fit with the central dogma of biology: DNA to RNA to protein. Some are regulatory, and some only make RNA not protein.

    I think many endogenous retroviruses in our genome have indeed been damaged/destroyed over time. However, the extra DNA is additional material that can evolve over many generations. The hypothesis that junk DNA is welcomed by the organism, and therefore that retroviruses are welcomed, is an old hypothesis.

    On amusing potential consequence of adopting Varela's ideas on the immune system (and I am not up to date on current thinking here, I was studying this in the early 90s) is that ME or CFS may be a dysfunctioning immune cognition. In other words, an immune psychosis.

    The systems theory put forward by Maturana and Varela is a high level descriptive view. It does not negate the low level processes, just provides another level with which to consider them. This is important in dealing with complexity .... the low level processes are the same, but the high level complexity of interactions elude us. That is where systems theory has a role. It also has a long way to go both theoretically and in practical applications.

    Bye
    Alex
  3. Marco
    I don't profess any great knowledge of these things and can only add some musings that arise from things I pick up here and there and freely admit to not fully understanding. But these things do interest me and I'd like to encourage anciendaze to expand on this line of reasoning.

    As I understand it, the classical model of the immune response is couched in militaristic terms (a metaphor of the times as our mutual friend often asserts) whereby we have a reactive system that seeks identifies and destroys any invader, presumably spending most of the time in 'stand easy' mode. This response can be clearly seen in experiments where infusions or massive doses of pathogen are met by a similarly massive reactive immune response. Whether this accurately represents the challenges the immune system regularly faces is debatable.

    The immune response depends on the ability to discriminate 'self' from 'non-self'; that is to identify the intruder and not to initiate an 'autoimmune' response against the organism's own tissues. I am aware that there are problems with how this self/non-self distinction might work in practice but not knowledgeable enough to know if they have been fully answered or conveniently ignored.

    An alternative immune model is put forward by Varela and arises from the Santiago theory of cognition (according to which the immune system is an integral part of, if not even a precursor of what we think of cognition - if cognition is considered the ability of an organism to interact with its environment). Under this model it is an immune network not a linear system; it is not 'reactive' but an ongoing process and does not need to discriminate 'self' from 'non-self'. Varela conceives the immune network's function as an :

    'autonomous, cognitive network, which is responsible for the body's molecular identity. By interacting with one another and the body's cells, lymphocytes continually regulate the number of cells and their molecular profiles. Rather than merely reacting against foreign agents, the immune system serves the important function of regulating the organism's cellular and molecular repertoire'

    From this perspective the immune system's role is not to kill any invaders but to maintain the organism's essential identity through multiple encounters with its environment and whatever 'external' organisms it encounters a role which can tolerate the presence of 'non-self' as long as their presence is regulated within certain bounds. Symbiosis is already well known from the billions of bacteria that colonise our gut and which are essential to life (not to mention the structure of eukaryotic cells). Similarly the presence of a virus might be 'tolerated' as long as it does not disrupt the organism's core identity by becoming too intrusive. One question that could be asked is how the immune system determines if the presence of a bacteria or virus is intrusive. Its not as if the immune system has a set of 'lookup tables' of viral titres that are acceptable or unacceptable. One possible answer comes from tumor cells where the immune system appears to react to the rate of change in the number of cells not their mere presence (I can't recall the reference unfortunately). This makes perfect sense if the function of the immune system is not to eliminate invaders but to regulate.

    Getting back to the issue of endogenous retroviruses (eventually), the 'classical' view is that they are the fossil remnants of long forgotten encounters our species has had with exogenous retroviruses - that our immune systems have finally 'defeated' and that, while HERVs may make up 8% of the human genome, their presence represents nothing more than inert, harmless 'junk DNA'. This view is now being moderated with their association with certain (non-lethal) 'autoimmune' diseases and schizophrenia for example.

    Two points occur to me. Firstly from a purely logical perspective 8% of the genome seems to me to be quite a bit of 'junk DNA' baggage to be carrying around analogous to us retaining the ancestral gills or tail that we no longer have any use for. If the presence of HERV's was entirely neutral then you would expect point deletions to the genome to have no detrimental effects and therefore they would be eliminated from the genome over millennia. Has this happened? For arguments sake we could posit that they do cause harm to the organism but not resulting in death. Again you would expect that point deletions would eliminate them from the genome over time and would even result in a general improvement in human health. Or as anciendaze suggests, they may actually confer some reproductive advantage to those individuals that retain the HERV DNA intact regardless of any other non-lethal ill effects they may have.

    Classical immunology would have it that either retroviruses kill us or our immune system 'kills' them leaving only inactivated remnants within the human genome. Alternatively, Varela's immune network model could tolerate the continued presence of a retrovirus (or reactivation of a HERV) within certain parameters as long as the rate of replication is low. Such a presence would not elicit the reactive immune response seen in classical infection experiments.

    Enough rambling. Anyone know how Bridget Huber's work is coming along?

    PS I've never been comfortable with the notion of 'autoimmune' disease which is portrayed as a breakdown of the 'self', 'non-self' distinction. Rather than attacking our own cells, perhaps what is happening is a reaction to these cells replicating outside of the 'regulatory bounds' necessary to maintain the organism's core identity. Why this disregulation would occur is another matter.
  4. alex3619
    Hi Anciendaze, this article can be boiled down to one phrase: Facts over Dogma! Or in other words, what are the endogenous and exogenous retroviruses actually doing, rather than what are they theoretically doing?

    On population growth, the world is heading for a crash. In geological time frames no species that has replicated like humans has failed to suffer a catastrophic crash. The world will not suddenly get bigger to suit human interest. Any closed system has limits to growth ... might have an out at enormous cost if we colonize space, but only a very few could take that route. We either curb population/consumption or the world does it for us, catastrophically. There are no other outcomes that are mathematically possible.

    The good news is that population growth is curbed in highly developed societies, although consumption growth is still continuing. Even if climate change were not an issue, we still need to curb consumption at some point.

    People wonder why we should be interested in space? Why waste money there? Space has more of two things that are limited on Earth - energy and material resources. Its not just about scientific understanding (though there are good arguments for that too) its about how useful space can be if the world wishes to continue to grow.

    Sorry to get off topic, but the point on population growth was raised in the blog.

    Bye, Alex
  5. Enid
    Very interesting anciendaze if I can follow it all - Fine Arts background no match. One wonders if Virologists do go through the "thinking" much needed as well as the science in trying to understand the behaviour etc of viruses. Hope so.