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Here Be There Dragons

Blog entry posted by anciendaze, Oct 12, 2011.

This post is not tagged as humor, however dark. It is intended to be a serious discussion of how people deal with ignorance and uncertainty. The title is taken from inscriptions added to make blank areas of old maps somewhat less naked.

Those dragons would naturally explain an absence of information from the region. Obviously, explorers who ventured there failed to return. This might also discourage future explorers, extending the market life of the map in question. Overall, one could characterize this kind of warning as a mental firewall -- "Thus far you may think, but no farther." Such warnings abound in the history of science.

The dragons of virology are numerous, but I think endogenous retroviruses fill up the bulk of the blank spaces on current maps of the field. These sequences are numerous, scattered all over existing genomes, and generally defective. The assumption that these may be safely ignored was good career advice early in the study of exogenous viruses. People who plunged into that jungle seldom came out with reputations intact.

These ERVs are mostly present as fragments or corrupted full sequences. In humans roughly 100,000 fragments can be fitted together into fewer than 100 complete and reliable HERV sequences. By examining alternate nucleotide sequences in different fragments it is possible to guess the original, actively-infectious sequence in some cases. One such was synthesized and demonstrated to infect human cells. It was given the name Phoenix.

While it would infect human cells in vitro, it does not appear to be the Godzilla virus some had feared would escape from the laboratory. Human immune systems seem to have evolved while it was out of circulation.

The above gives us some feel for HERVs and ERVs in general. One full sequence corresponding to 1,000 fragments is nothing exceptional. Many are homologous to hundreds of fragments. When you find a complete sequence that appears to be unique it may well be new. Finding a virus represented only by two overlapping fragments suggests it is very new, particularly if one of those fragments is not competent to replicate.

This is true of the putative ERV source of the virus contaminating the 22Rv1 cell line. Going in the opposite direction, with a complete, functional viral genome being broken into two fragments is easier. You may ask why the full sequence itself is not an ERV. This would happen if the complete sequence were a handicap to differential reproductive success of the host, especially if active replication during gestation killed offspring. In that case the only sequences which would make the transition to ERVs passed via germ line cells would be those which were non-pathogenic fragments.

Other clues to date of origin may be found via closely parallel sequences in other strains or species. The isolated sequences in NIH Swiss mice strongly suggest the virus which inserted them existed after breeding populations of that species and strain of mice separated from others. We are no longer talking about millions or thousands of years. We are talking about decades.

Having traced a virus contaminating cell lines to this source our intrepid researchers then stopped not only researching, but thinking. The search had achieved its polemical purpose. To keep going was to enter dragon country. You are not supposed to ask how such a ferocious virus came to be in two fragments in a peculiar strain of mice with defective immune systems. I use the term ferocious deliberately, because this one was more than a random assemblage of spare parts. It has a robust appetite for human cell lines, with nine easily susceptible by my latest count. (Expect more to turn up.) It does not like most rodents, including its putative erstwhile host.

Laboratory research has shown that the androgen receptors in the LTR are functional, increasing viral replication by a factor of three. In vivo experiments using chimeric mice with approximately human immune systems have shown the identified immunosuppressive domain in the envelope is also functional. Experiments on rhesus macaques have shown a tropism for sex organs and lymphatic organs. Other experiments have found the virus replicates better on mucous membranes. All such functional characteristics are relevant to its suggested role as a human pathogen. Some were unknown at the outset of research.

One striking anomaly is the way the virus can enter human cells with an XPR1 receptor. The mice in which it is claimed to originate lack these, while 80% of cells in human bodies have them. The specific strain of mice have defective immune systems without CD4 or CD8 T-cells, to allow them to accept xenografts. The host in which the virus evolved likely had CD4 T-cells, which it readily infects.

The inconsistency in all published reasoning I've seen, (and I could easily have missed some,) is that none of this is explained by its proposed origin.

Let me make an analogy. Suppose an earthquake strikes a junkyard. After the shaking stops and the dust settles you enter the place, and find an automobile with keys in the ignition. You turn the key, and it starts up. You put it in gear, and it moves. At this point, you discover the brakes don't work, crashing into a wall.

Should you conclude the shaking formed an automobile from assorted parts? Does the presence of similar fragments in the junkyard prove your case? Do the malfunctioning brakes demonstrate this? Why should you reject the hypothesis that the earthquake damaged a working automobile, causing brake fluid to drain out?
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. alex3619
    Hi Anciendaze, and interesting reworking of the idea "the map is not the territory". Sailors used to worry about sea monsters and falling off the edge of the world as well.
    Bye, Alex