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Subversive Literature

Blog entry posted by anciendaze, Feb 27, 2012.

People who complain that my last post was overly mysterious should know that I just read Mikhail Bulgakov's The Master and Margarita. They should be thankful to have escaped references to Faustian bargains, Gnostic Christianity and comparative demonology. These pieces of misdirection make sense in Bulgakov's case, because he was writing a highly subversive novel in Stalin's Moscow during the Great Terror. Remarkably, he managed to complete the work and die of natural causes in 1940. It was first published, in censored form, 26 years after his death. In Eastern Europe it is a cult classic.

My own subversion is far less ambitious, as are any pretensions to literary immortality. All I want to do is break down the walls in research thinking between endogenous and exogenous retroviruses. This shouldn't be hard because there have been cracks visible from the inception of the concept of ERVs.

Conventional wisdom in virology treats endogenous retroviruses (ERVs) as ancient and defective junk which is best ignored in the search for causes of active diseases. At the same time, we have a surprising number of putative triggers which may activate ERVS: chemicals, other viruses (generally not retroviruses), light, heat, electrical stimulation, immune compromise, etc. This professional attitude appears schizophrenic to me, (which must mean I have insufficient indoctrination to be considered professional.)

From a purely theoretical viewpoint I am interested in any clues to how defective microbes incapable of reproduction might evolve into replication-competent ones, because this bears on the subject of autopoiesis (terminology of Maturana and Varela) and the origin of life. General opinion in that field is that such changes take place on such long time scales that we are unlikely to observe complete progressions in the laboratory. This stands in sharp contrast to the surprising number of reports of results often attributed to resurrected ERVs. It also bears upon questions which arise when retroviruses jump species, a possibility of interest to most readers here.

A major cause of preexisting diseases jumping from one species to another is typically predation. Domestication of animals used for food enormously accelerated this natural process. Not only does this affect humans, domestication also vastly complicates interaction with other domesticated species. (For example, "in the wild" sheep and pigs occupy rather different territory, yet some diseases of sheep do affect domestic pigs.)

The first retrovirus which caught my eye in this regard was bovine leukemia virus, a delta retrovirus. Only Denmark has been able to eliminate this from its herd. Existing tests used in veterinary medicine may be off by an order of magnitude in sensitivity. Since many infected animals are asymptomatic, this means BLV is definitely in our food supply. Agricultural workers who drink unpasteurized milk often show antibodies to BLV, when sensitive tests are used. (Earlier tests were simply not sensitive enough.)

Whatever is being done to limit exposure now was certainly not being done over a century ago. Many human infants were fed unpasteurized cows milk. Once a retrovirus is in an individual it stays there for life. Even if other methods of transmission disappear transmission by bodily fluids remains possible. This includes transmission through repeated sexual contact as well as transmission from mother to offspring via milk or colostrum. (This also turned up in work on XMRV in mus pahari.) BLV is on my list of suspects because it also has demonstrated potential to jump species and infect primates.

Avian reticuloendotheliosis virus (REV) was a surprise suspect. Normally, I would put the probability of a retrovirus jumping between different classes of animals so low as to be negligible. In that particular case, we have a virus causing disease in chickens and turkeys which shows remarkable similarities to mammalian gamma retroviruses: MLV and GALV. This especially concerns me because gibbon apes are primates, distant cousins to humans.

Another potential suspect is HERV-Fc1 which has surprised researchers by also turning up in the first complete dog genome. Unless a statistical miracle has taken place it would appear a gamma retrovirus has jumped between dogs and humans since dogs were domesticated. This HERV has also been implicated in multiple sclerosis, though that debate is far from over. There are questions here on the relationship between HERV-H, HERV-F and HERV-W which I will leave to experts. I will however note that active HERV-W is already suspect in schizophrenia and affective disorders.

In discussions elsewhere I have mentioned Jaagsiekte sheep retrovirus/enzootic nasal tumor virus (JSRV/ENTV), a beta retrovirus which shows a distressing tendency to jump species. It is present in both endogenous and exogenous forms, another red flag for me, which I learned from reading about MMTV, the beta retrovirus causing most mammary tumors in mice. JSRV causes a lung adenocarcinoma in sheep or goats which serves as a surprisingly good model for the pathology of human adenocarcinomas of the lungs, the most common lung cancer among nonsmokers.

Porcine ERVs A/C (gamma retroviruses) sometimes recombine in vivo to produce an exogenous retrovirus which can infect human cells in vitro. Again, we have that endogenous/exogenous interplay.

Equine infectious anemia retrovirus (EIRV) is a lentivirus. Similar lentiviruses are also found in sheep and goats as maedi/visna virus. This jump between species may have taken place far back in evolutionary time. We should, however, be alert for signs of more recent interactions because both viruses remain active in exogenous forms.

The only major category of retrovirus I've missed here (ignoring the rather strange spuma viruses) are the alpha retroviruses. Avian sarcoma leukosis virus (ASLV) fills in this blank.

Essentially every animal humans regularly consume as food has some candidate retrovirus which crosses between species and/or has both endogenous and exogenous forms. To assume humans are not repeatedly infected requires faith in multiple miracles. The alternative must be immunological control of such infections, though the mechanisms are not entirely clear.

One problem in research is that it is damn hard to find the cells which hold particular immunological memories. This has slowed research, e.g. on precisely how a 70-year-old adult can maintain immunity to measles acquired in childhood. (Whoever said a virus which only infects one cell in a thousand can't cause significant disease must be ignorant of immunology.)

In the case of bacterial infections memory cells may hold fragments of bacteria or epitopes presented in response to infection. They are unlikely to hold intact bacteria. Shift to DNA viruses which insert plasmids inside the nuclear membrane of host cells, and you can no longer feel confident the memory is any different from the infection itself. In the case of varicella zoster virus (VZV), which causes chickenpox, we know that the virus itself does persist because it can reappear to cause the disease known as shingles much later in life. VZV is a fairly large virus which does not insert DNA in chromosomes. Smaller retroviruses which do insert provirus in chromosomes almost certainly do remain intact and potentially infectious in immunological memory cells.

The host immune system has good reasons for keeping these dangerous invaders around. If it completely cleared evidence of past infections it would forget the cause of serious illness, and become vulnerable to repeated infection. The trick is to hold the captive invader latent. (This was the trail Robert Silverman was following when he found XMRV.) In old age immune dysfunction can lead to reactivation of viruses which have been held latent, this also happens in late stages of many cancers. These "opportunistic infections" of unknown origin often cause death before cancer itself kills the patient. The parallel between illness considered normal in old age and illnesses in young patients with similar symptoms is one clue that we are looking at impaired immune activity and reactivated viral infections.

One aspect of latency which I have harped upon is that the disease with conspicuous symptoms may not be the origin of the infection which compromises immune integrity. This is certainly the case with HIV infection. Most healthy individuals are capable of holding the virus latent for periods of months to years. When it can no longer be controlled, a variety of confusing symptoms caused by other infections will send patients to doctors. Prior to a specific test for HIV-1 itself, and antibodies to it, diagnosis of AIDS was difficult. Testing for the virus behind an even slower disease will likely be even more difficult.

The furor during the last two years over contamination in research on XMRV has raised the possibility that everything on Earth, except ME/CFS patients, may be contaminated by murine leukemia virus-related viruses. Overlooked in much of the literature is the extent to which the "one drop in a swimming pool" argument over contamination producing false positives also applies to the most sensitive tests for contamination.

I have long been uneasy over the extent to which many papers show great concern for false positives in testing for virus, and little concern over false negatives. A paper by Denise O'Keefe shows that contamination between runs can cause a tremendous loss of PCR sensitivity. It seems validation of an assay for XMRV is like an old-style papal indulgence -- once you have it all later sins are forgiven in advance.

A complementary problem with highly sensitive tests for contamination concerns possible false positives. Here we find remarkably little published concern. One would have to be a very slow student not to grasp the safe answer to questions about retroviral infection.

The previous post, "Domesticated Dragons", dealt with a very plausible function of dysfunctional retroviral sequences. It helps explain the persistence of ERVs in genomes, and the fact that LTRs are the last elements of ERVs to be lost. It would also present those many causes of ERV activation in a new light. What is taking place is the normal response to a similar exogenous retrovirus which might very well have been held latent until those multifarious causes described in the literature allowed it to break free of control, provoking the final host defense.

If this is, in fact, happening, it would cause serious confusion among those who display a touching faith in the application of phylogenetic analysis to microbes which routinely thumb their noses at Mendel and the original statement of "the Central Dogma of molecular biology". Retroviruses do not necessarily "breed true", or conform to mating limitations of true species. "Unbiased" estimates of probabilities are not safe bets when someone is loading the dice in the way described.

All this is still not enough trouble for me, so I will open another can of worms. Whatever you can say about tests used to show the absence of viral contamination in experiments which established the known examples of prion diseases it seems abundantly clear they would not meet current standards for preventing contamination by unknown viruses, including retroviruses. Perhaps, Laura Manuelidis was right all along.

Why am I causing all this trouble? Maybe Behemoth made me do it.
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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. anciendaze
    It is a measure of great literature that it continues to influence you after reading ends. In my case this extends to the present. There are puzzles in the text. Some may be accidents caused by writing in secrecy and the author's untimely death. Others were definitely put there to make readers think hard.

    (As example take the contradictory explanations for what happens to the participants. Did Margarita die in her apartment? Did she really fly through the air? Was this an out of body experience? Did the Master disappear because his documents disappeared? Was their relationship ever physical? What does it mean to say someone is physically or emotionally alive? What about sanity?)

    I just tripped over a buried treasure I had neglected. For some reason I kept trying to connect the description of Fagot as a choirmaster with German or French stories like Faust, or Latin mythology. It suddenly hit me that the correct word was coryphaeus, in classical Greek the leader of the chorus for a play. This was also applied to religious figures like Saint Peter. Theologians would note use of the term to describe the person who directed debate at the first Council of Nicaea, where the Emperor Constantine was a visible presence, though not officially in charge of theology. (He was not even baptized a Christian until after he abdicated the throne.) Soviet citizens of the Stalin era would immediately connect coryphaeus with Joseph Stalin.

    If all that is not enough, we have classical precedents in pagan theogony. Hermes was not only the messenger of the gods, he was also the guide for dreams and for souls of the dead: oneiropompos and psychopompos. In the Illiad he not only conveys warnings to those favored by the gods, he also causes soldiers on guard to fall asleep at critical times, hiding actions he doesn't want them to notice. These roles fit Bulgakov's character remarkably well.
  2. anciendaze
    For others who may find "The Master and Margarita" perplexing I offer this insight: the devil in that work is less the traditional Satan than the demiurge of Plato and Plotinus, an imperfect creator of the imperfect physical world. There are multiple levels of ironic reference in which the author himself is likewise treated as a demiurge, as is his surrogate, "The Master". The Master's work ends at chapter 32 with the predicted quote. The author's work ends at chapter 33 with a variant of the same quote, though this is hard to translate into English, which lacks the many grammatical inflections of Russian. Another key is that everything the author cannot say about 20th century Moscow is likely to appear in reflected form in 1st century Jerusalem, and vice versa. This does not begin to exhaust the ambiguity and irony carefully crafted into this imposing edifice.

    This was recommended to me by a recent Russian immigrant who cut my hair. I've since been wondering how many Americans would have read the prerequisites: Goethe's Faust, Dostoevsky, Tolstoy, etc. to say nothing of 19th century textual criticism of the New Testament, Marcion, Valentinus and the Gnostic gospels. (I confess I fell short of reading Gogol or Pushkin and hearing Gounod's Faust, to say nothing of the French works on Christology Bulgakov seems to have known well.) One spooky problem in explaining this work was that the Nag Hammadi texts of those Gnostic Gospels were not discovered until 5 years after Bulgakov's death. I had not realized that fragmentary texts found late in the 19th century had rekindled debate about Gnosticism among theologians, including both Bulgakov's grandfathers. What a strange background for a Soviet playwright.
  3. Merry
    Merry, your comments are welcome. I was not responding to you. Not all interactions take place in public, or on this forum. I've circulated the idea in private messages before posting.

    Yes, of course, you have a life outside PR and the confines of the blog. Good. Thanks.

    Carry on, anciendaze. Best wishes.
  4. anciendaze
    Merry, your comments are welcome. I was not responding to you. Not all interactions take place in public, or on this forum. I've circulated the idea in private messages before posting.
  5. Merry
    anciendaze, if you read my comment on your last blog post as a complaint, I'm sorry that you have misunderstood what I intended as a compliment on the cleverness of the horror story you offered at the end. I'm not competent to evaluate your hypothesis on the purpose of ERVs. I'd best keep quiet.
  6. Enid
    I stay with science - I am a biologist and am not - ancient viruses may well form part of my ancient genome - now is the time to see and understand and work with it all. (getting out of hand these bugs ?).
  7. anciendaze
    Enid, both neurology and immunology have masses of detail in which it is easy to lose sight of overall function. Both areas deal with enormous amounts of feedback, which makes it strange that researchers are seldom people a prudent person would choose to design a control system even for something as simple as a helicopter. The warfare with viruses may be older than DNA. One hypothesis is that an "RNA world" preceded the world of DNA-based life. If this was so, retroviruses could be older than the cells they infect.

    Unfortunately, the image of "nature red in tooth and claw" (Tennyson, not Darwin) has clouded recognition of cooperation, which is as fundamental as the mitochondria in most cells. There is also a tendency to conflate cooperation with altruism. (If you think the two are inseparable, ask a cat why it provides mouse-control services to humans.)

    Marco, even leaving out HERVs there is a great deal of redundancy in the human genome. Most genes appear to have been copied from other parts of the genome. Whether this was done by retrotransposons remains an open question.

    In terms of genes transcribed as proteins the human genome is so similar to the bonobo chimpanzee genome some wits have proposed that the differences in phenotype are all due to upbringing, haircuts and cosmetics. Most of the important differences are in sequences which regulate development. Exactly where you draw the line between "junk" and honest genes is a largely matter of taste.

    On the subject of Windoze, I have long said that it evolves along biological lines more than it looks like the result of careful design. Just as death is the secret ingredient in biological evolution, planned obsolescence is the secret behind Windoze. Programs which could, in principle, work forever now have an expected useful lifetime of about three years. This has been such a tremendous financial success for vendors that the concept of software obsolescence has been extended into appliances and automobiles.

    The operating system on which I am writing these comments occupies less than 200 MB. Even after adding an office suite and a full development system for recreating the software, I am using less than 500 MB for software. Everything else on a 1 TB. disk, and in 8 GB. of RAM, is for my own work, not the system. This marks me as subversive in a different sense.
  8. Marco
    I've long thought that the 8% of the genome accounted for by HERVs was a lot of redundant information to be carrying around for no good reason if HERVs are defective and 'non-coding'.

    I doubt you would be impressed if almost 10% of your new Windows software was 'junk' (some might argue its all junk).

    Worse than that, scientists estimate that functional genes represent only 3% of the human genome.

    It appears that the other 97% of junk may actually be crucial to human evolution :

    http://www.sciencedaily.com/releases/2009/05/090528203730.htm

    Scientists used to believe that most of the DNA outside of genes, the so-called non-coding DNA, is useless trash that has sneaked into our genome and refuses to leave

    How exactly does DNA "sneak into our genome"?
  9. Enid
    Well I'm certainly learning a lot anciendaze - enjoying along the way. Always thought neurology could be difficult enough but immunolgy even more complicated and for the brighter perhaps. With a "new" virus in sheep striking us now from the Continent (deformed lambs) we seem in a permanent state of warfare with these so-and-so's. Saw a very interesting programme about researchers out in Africa trying to identify "new" viruses to be forewarned before they jump species but wondered - isn't it a different "animal" so to speak at that stage. Take your point about the subversive.