I've been reading through this one and there are some intriguing observations in there:
Observations on the Epidemic of Polio-Encephalitis in Los Angeles, 1934:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751857/pdf/calwestmed00415-0071.pdf
One of the first things that strikes me about these 1930s papers is the difference in their style from modern scientific work. I find them qute refreshing: the style seems more literary and human-readable, to me, but also there seems to be more space for somewhat more personal observations: historical detail and interesting observations that may prove to be significant. The science is still there as well of course, but I can't help wondering whether researchers back in the day received a more rounded, balanced, less specialised education.
Some of the things that seemed interesting to me:
The observations place a great deal of evidence on the "pleomorphic streptococci" found consistently in nasopharyngeal swabs, findings "obtained in Rochester and reproduced and greatly extended in Los Angeles". Intriguingly, the paper states:
It appeared certain that these strains of streptococci must have etiological significance, and that they belonged in a group between those isolated by one of us during studies of typical epidemics of poliomyelitis and those isolated during a study of the epidemic of peculiar encephalitis in St. Louis.
I had to look up "pleomorphism" and the wiki entry is also intriguing:
In the first decades of the 20th century, the term was used to refer to the supposed ability of bacteria to change shape dramatically or to exist in a number of extreme morphological (changing) forms. This claim sparked a controversy among the
microbiologists and split them into two schools: the monomorphists, who opposed the claim, and the pleomorphists (such as
Antoine Bchamp or even
Albert Calmette[1]).
Monomorphic theory, supported by
Louis Pasteur,
Rudolf Virchow,
Ferdinand Cohn, and
Robert Koch, emerged to become the dominant
paradigm in modern medical science:
it is now almost universally accepted that each bacterial cell is derived from a previously existing cell of practically the same size and shape. However it has recently been shown that certain bacteria are capable of dramatically changing shape, for example
Helicobacter pylori exists as both a helix-shaped form (classified as a curved rod) and a coccoid form.
The modern-day definition of pleomorphism in the context of bacteria is now a
variation of size or shape of the cell, rather than a
change of shape as previously believed.
http://en.wikipedia.org/wiki/Pleomorphism
This seems to me to be suggesting that the idea that certain bacteria can change shape dramatically during their lifecycle was popular when this paper was written, fell completely out of fashion, but now turns out to have some truth in it after all.
What seems suggestive about this to me is the analogy to the proposed recombinant properties of the X/P MLV family: the idea that the X/P XMRV family may overlap and recombine with each other and may modify each other during their lifecycle. With retroviruses having the ability to alter DNA, it seems to make some sense that this sort of thing will be going on. RNA transcription by a retrovirus, perhaps, might not just be able to alter the structure of host DNA, but perhaps also to alter the structure of other retroviruses from its own family!
I'm perhaps expressing this poorly and by analogy, and maybe it is already well-known: the HIV viruses are so complex because they change in a dynamic fashion too. I'm coming at all this more from a computer science perspective, and there is a highly suggestive analogy there for me.
Normal computer code runs by modifying data that is external to it, in some separate area of memory. The logic and the data on which it operates are kept very separate. However, some really wild and extreme programming code - extremely bad practice and traditionally the stuff of fun and challenging competitions for geeks rather than conventional software engineering - is actually written in such a way as to act upon itself: manipulating its own code as if it were data. I remember seeing some C code many years ago that did exactly this, and it boggled my mind. Incredibly short C functions were able to produce far more in terms of output, relative to the actual length of the code, than would be possible in conventional computer programming. My memory is a little hazy, but I seem to remember one very short sequence of code that won a competition for the shortest sequence of code able to write out the Lord's Prayer. The textual content of the prayer was not present in the original code at all - it was way, way shorter - but the way that the program itself evolved as it changed itself caused the correct sequence of letters to be written out.
Such self-modifying computer code strikes me as an analogy that should inevitably hold good in the biological realm as well, and since XMRV is a very short sequence of genetic code with apparently powerful effects, that too seems suggestive. Finally, it also makes me wonder about all those empty and unused bits of DNA within genetic code: long stretches of genetic code that seems to do nothing. We assume that those blank and unused sections of the genome are merely background noise, the legacy of the randomness of the evolutionary process. But could it be that all that space is used during the lifecycle as a kind of 'data store'? Such processes might create interim states of the genetic sequences that perhaps exist only for an instant, as one genome acts upon itself and transforms itself into another. Just like a computer program, this could all happen so fast that it's over in the blink of an eye, and we might never have seen this happening. And perhaps this sort of behaviour - maximally efficient code - could explain puzzles like why the number of genes in the human genome turned out to be so small, yet capable of producing the extraordinary complexity of human life.
Self-modifying genetic code. Maybe this is all well known and nothing new here, but anyway these are the thoughts sparked in me by this comment about pleomorphism.
I was also very interested by these observations: again, appearing to be general observations and impressions of the kind one might not expect to see in a modern paper...but which I find refreshing...and also highly suggestive because there is something unusual about the epidemiology of ME/CFS and these observations seem like they might speak to those peculiarities - here are the extracts that struck me most:
(1) that the outbreak ocurred rather suddenly during unusually early, hot weather in May;
(3) that the disease was not diffusely distributed throughout the county and city,but that it was extremely high in some places...and low in other areas."
(5) that there was an unusually high incidence of multiple cases in family and other groups, often occurring almost simultaneously
(6) that there were relatively more cases among the middle class than among the poor, especially among those residing in the city
We were especially impressed by the unusually large number of cases that occurred without a history of contact, by the high incidence of cases in the upper stories of apartments or nurses cottages, on high levels or hills, and on the high sides of streets along hillsides.
Again, fascinating!
The whole "yuppie flu" business and the claim that CFS affects the middle class more than the poor, is of course part of the history of ME/CFS, and is generally disputed as a prejudice, a myth, and explained by psychologists with ideas such as "they read it in the papers and convinced themselves they had it". But these observations of a disproportionate distribution of ME/CFS amongst the middle classes are surely subject to none of these factors and can't be explained away by any of the theories from either side. What on earth could be going on here? Genetic susceptibility is an obvious idea that comes to mind, but again, this seems to me to be a hypothesis driven more by our assumptions than anything else. I suspect that the answer lies in some environmental factor, and in the means of transmission. The observation about upper stories and high sides of hillsides looks like a massive and overlooked clue. All these observations, both in this paper and historically, seem to be pointing at some environmental factor that is present in what we might think of as clean, sanitary, desirable environments, where the air is, theoretically, somewhat cleaner - or perhaps the heat, or some other aspect of environment - were the middle classes more likely to have something like central heating for example?
There is much more in the paper that is intriguing. The section on clinical observations emphasises muscle weakness, gastro-enteritis, sore throat and respiratory tract infection during the early stages, involvement of the nervous system, recurrence of fever and other symptoms during convalescence, malaise, headache, tingling sensations in the extremities, lower back pain, photophobia, lethargy, and extreme variations in type of disease and severity...anything here sound familiar?
So I'll try to pull all this together and summarise what it suggests to me:
- there is something unusual about the lifecycle of the pathogen
- the pathogen may have various states and may have self-modifying genetic behaviour and thus be hidden or latent except when in an infectious state and causing outbreaks
- the agent mediating the infections may only be infectious or pathogenic under certain very specific conditions
- the unusual heat may be significant; maybe a set of conditions including a precise temperature is required for the 'pleomorphic' transformation
- greater rates of infection by those with apparently clean air, and unusual environmental conditions (early May heat) might suggest that the
absence of some other bacteria or insanitory condition, which might normally restrict the pathogen, enables the pathogen to thrive.
- there is
something which is proportionately more likely in middle class environments which is necessary for the pathogen to thrive - heating? clean air? pets? absence of mice or infestation?
- those observations about high-up living environments: could the pathogen change state when moving from a high-temperature environment into a much cooler upper room?
And finally, I'll indicate the hypothesis I appear to be reasoning towards (and I'll admit that maybe my pre-existing hypothesis may be biasing my reasoning):
X/P XMRV can infect mold. It becomes active and infectious, perhaps modifying itself by acting upon its own genetic structure, under certain conditions perhaps related to changes of temperature and other environmental factors. Inhalation of mold is one of the primary means of infection, particularly during outbreaks, through infection of the respiratory tract.
(As an alternative, it may be that the above factors point instead towards tick-born infection; perhaps ticks fly into cool upper rooms under certain conditions. But there's no mention of tick bites in the impressions of the researchers, which I might have expected to see given the nature of their other quite careful and open-minded observations.)
Please bear in mind that all the above speculation is a vague and approximate sketch: it's more of a "discussion document" intended to spark ideas in those more specialised in the relevant disciplines than myself. I look forward to the thoughts of George and others on the above...may be it's time to call in the mold warriors...
