Flushing out the phlogiston ~~~?
This article grew up around the core part of a letter I sent to the web site "HMS Beagle" (then the fortnightly journal published at the BioMedNet site) and to the various participants of the "A sense of self" debate" (see references in the "phlogiston" article). To me it seemed rather like the final pieces of a jigsaw puzzle flying together. There are undoubtedly mistakes in here but, equally, there are also many useful insights.
The phlogiston title is potentially (analogously as well as literally) inflammatory. Its use reflects my own feelings of melting exasperation (and annoyance that it had taken so long) that, at last, the veil of obscurity, that had made it hard to work out what was going on, had been removed and things had become much clearer.
It is an annoyance that I cannot cite this work. If there is anyone out there who would be prepared to let it have a place in a citable journal, I would be most grateful for this.
Note (2012/03/20): On re-reading this article, I note that I have not sufficiently emphasised the ability of phagocytes (and, indeed, all zygote derived cells) to recognise, ingest and assimilate microbes (in general). I guess that I have deliberately over-emphasised the mess/non-mess perspective without emphasising the anciently acquired ability of phagocytes (amoebocytes) and other cells to recognise and assimilate bacteria as "food". It was part of the earlier writing and I have failed to re-emphasise it here. In retrospect, this may be a confusing omission for readers who have not carefully followed the evolution of the ideas developed at this website. The important point is that the adaptive immune system is not primarily a bug hunting and killing system — even though the way it is primed may frequently appear to suggest that this is its apparent purpose. The innate immune system simply takes microbe ingestion in its stride, it needs little provocation to do so and it does so very efficiently (with the vast majority our biosphere's microbes — the non-pathogenic species). The big provocations come when microbes are recognised (by the triggering of Toll like receptors which identify PathogenAssociatedMolecularPatterns — or as I prefer MicrobeAMPs) and then they go on to provoke cellular damage. It is the addition of cellular damage that now stimulates an aggresive adaptive immune response and this then amplifies local innate immune activity on any future encounter. We "acknowledge this" in our ubiquitous experimental reliance on adjuvants.
You may ask "where does he conjure up this speculation about non-specialist phagocytes being able to ingest microbes?" However, unless they actively suppress the function, it will remain an anciently acquired part of their genetic constitution. It looks as though phagocytes certainly exaggerate this capability. But it is unlikely that other zygote derived cells completely suppress the capability and there is occasional reference to this anyway — just as adjacent static cells can manage to clear a small amount of apoptotic debris without enrolling the help of professional phagocytes. (To read more about this enter "cell-autonomous immunity " in a search engine.)
- The main article to look at is in the links above but don't forget to digest the above paragraphs first.
- The earlier versions of this paper are visible below: but, only bother if you take an interest in the timing.
Rejection notes: These were the comments given in the last of many rejection letters
January 1999: Thank you for your manuscript entitled "Flushing Out the Phlogiston . . . ?" We are sorry to say that we cannot accept it for *****. The editors could not understand why you conclude that there is no such thing as the "immune system". Perhaps it is because your hypothesis requires considerably more flushing out to make your point acceptable. We are sorry your ideas have met with so much resistance. We can only hope that as you can more fully develop them they will meet with more approval.
(My submission letter was deliberately provocative.)
- The myelopoiesis of various inflammatory and immune cells from a megakaryocyte precursor could facilitate a mechanism to produce a "layered immune cell response."
- This article, from Kogame et al seems to demonstrate such a layered progression. This is also compatible with my suggestion of a Russian doll structure in the responses to debris.