Further notes about the morphostasis concept – split files

(04) Comment on a published article dismissing the danger hypothesis, 8th August 2000

Two quotations come to mind

When a thing was new people said, "It is not true." Later, when its truth became obvious, people said, "Anyway, it is not important," and when its importance could not be denied, people said, "Anyway, it is not new." (William James)

Anyone who conducts an argument by appealing to authority is not using his intelligence, he is just using his memory. (Leonardo da Vinci)

My first impressions were that there are many value comments with much opinion promoted as fact. It struck me that there was no humility in it; no sign of a possibility that "I could have this wrong but ..". I respect and admire the latter.

The first page is mainly a posturing ready for the attack at the jugular. However, two points are worth noting. He says, "the notion that the immune system has evolved to recognise (dangerous) pathogens is not new." Pardon – are we talking about the same thing? He seems to think so. I doubt that you or I do. This is, to my mind, the fuzziness that comes from an inability to exorcise the old (distorting) ideas and a good advert for saying that a polarised caricaturisation is the only way to achieve exorcism. Much later on, we can return to the old ideas and appreciate their (parochial) value afresh. It also shows that he has not assimilated the perspective.

Second, he calls the danger theory a reductionist approach. Now, the ****** Journal is the very bastion of "blind reductionism". Cutting things into smaller pieces, looking in more detail, fitting around the "known principles" is the main liking of its editorial board. I never hold out much hope of finding a conceptually rich article in this journal. I think he is implying that the danger model is simplistic (we would see it as simplifying – a way of getting our heads around the broader issues).

He writes, "It should be distinguished from PROFITABLE attempts to integrate what is known about the innate and acquired immune response." Wow! – can he now deny that what I have written so far is valid comment?

He skirts around signal 1 and signal 2. He mentions the "relative importance of signal 1 and signal 2". I think this probably comes from the idea that (in vitro) absence of signal 2 is associated with tolerance so they see signal 1 as more important. But I will, here, reword them as "step 1" and "step 2" both of which are essential for lymphocyte commitment. In step 1 the respective peptide–MHC epitope is engaged. In step 2 it is awarded a binary contextual value of either "aggression on" or "aggression off". We believe that the first leads to clonal expansion and the second leads to apoptosis and so, tolerance. We have not yet (I think) absolutely dismissed the possibility that there may be clonal expansion of tolerance–promoting–T–cells. My view, and I suspect yours, is that ALL cells die and the Tc/Th system uses the step 2 switch to classify this previous mode of death (apoptosis/tolerance and necrosis/aggression). It is possible that the system has extended so that irreversibly sick cells may also provoke an aggressive step 2 stimulation (adjuvanticity of HSPs). There may not be strong in vivo relevance to the observation that peptide binding to a T–cell in the absence of "help" may encourage tolerance. Unhealthy (detached) cells, necrotic cells and apoptotic debris are cleared from the tissues to the local lymph nodes where the precursor (step 1 committed) T–cells are finally committed to tolerance or aggression.

He says, "The truth is that no serious immunologist today really believes ... etc". In the 1980s very few serious immunologists believed that the mammalian immune system was NOT lymphocentric. Very few doubted that self–nonself discrimination occurred by thymic conditioning in utero. Very few believed that plant defence had any similarities to mammals. Very few considered that the innate immune system had much influence on the adaptive system. Very few considered that every nucleated cell of the colony (of cells that constitute and animal) have the primary responsibility for looking after their own health and notifying adjacent cells and the "immune system" if something serious goes wrong. Very few considered that gap junctions were at all relevant to the immune system. Very few doubted that the immune system avoided self attack at all costs (the horror autotoxicus). What we are seeing here is conceptual erosion and *****'s article seems, to me, to be a manifestation of the terminal convulsions of a dying perspective. The immunological community is unwillingly changing its views – it is being forced, reluctantly and slowly into "revolution".

He writes, "Why should we discard the idea of "self" when really all that is needed is to recognise – as immunologists already do – that it cannot be the whole story." Simple answer: when the extant conception of self–nonself discrimination forces us up a conceptual blind alley from which it is difficult if not impossible to escape. Then it needs exorcism and a hysterical exorcism at that. One thing that I am convinced of is that – while self/nonself discrimination may be occurring – it is NOT occurring by T–cell commitment. This, for me, is an ABSOLUTE.

He writes, "One is tempted to agree that, of course, the immune system protects against danger: so do eyes, legs, teeth, and practically every other feature of anatomy and physiology (one could even argue that the stomach protects against the danger of starvation)" ... if this isn't a description of "beating back the tide of entropy" I'll eat my hat.

He writes, "Without specifying these features, the notion of danger would lack critical depth." This, I believe, should be reworded to shed its value judgement into "Until these features are specified, the notion of danger lacks the maturity to warrant abandoning other perspectives." But you (and many others) are working hard on that and the runes are already looking good.

He then gets into this "tainted think" about dangerous–antigens. I notice this often. They do not separate signal (step) 1 from signal (step) 2. Signal 2 has nothing to do with any property of the antigen OTHER than where it was met and in what inflammatory or non–inflammatory environment it made its debut. They still (conceptually) need to award the antigen a quality (a relic of self–epitope/nonself–epitope concepts). It is JUST an epitope. All epitopes – self and non–self – are just epitopes: nothing more: nothing less: all equal: a truly egalitarian system. It is only their context of presentation that leads to aggressive or tolerant responses. How often does that need to be repeated before they DO appreciate it? And what gets left out of the reckoning is the staggering volume of apoptotic death that is the daily consequence of housekeeping. All self epitopes are far more likely to be met in a non–inflammatory (tolerance favouring and paratope "mopping up") environment than in an inflammatory environment. Chance favours the prepared. The commitment to aggression is (for self/nonself) a non discriminatory, mindless event. Simply make older precursor T–cells more susceptible to aggressive commitment than young precursor T–cells, add the mopping up by apoptosis and you strongly augment the favouring of strange over common epitopes as fodder for aggression.

He then relents a bit and starts to concede that certain aspects uncovered by the danger hypothesis may have value (but danger remains anathema). I doubt if you would deny that there is a limited hit list of things that the system has learnt to regard as harbingers of doom (like LPS). But these must be germ line encoded, consequently limited in number and, even so, the value attached to them may be better understood as agents that are "potentially dangerous (mess making)" rather than agents that are non–self. David Lo's team found a lovely quotation on this:–

"The gram negative bacteria . . . display LPS endotoxin in their walls, and these macromolecules are read by our tissues as the very worst of bad news. When we sense LPS, we are likely to turn on every defence at our disposal; we will bomb, defoliate, blockade, seal off, and destroy all the tissues in the area ... All this seems unnecessary, panic–driven . . . It is, basically, a response to propaganda . . ." (Lewis Thomas, The Lives of a Cell)

He finally stops "convulsing" with the last 2 sentences above the title "Can the danger theory be tested". Implicit in these two sentences is a reluctant acceptance that it DOES have value – even if parochial. I guess that your position is that danger (mess for me) is such a dominant driving force that all other theories will be subsumed as special cases of (potential) danger (mess for me).

He next delves into philosophical bits where I think he is off beam. Essentially, I think he has replaced the reigning paradigm with a vaccuum but leaves the reigning paradigm as the covert (vs overt) explanation.

On Kuhnian revolutions and analogies to Copernican revolutions, I know where I will be placing my bets. I suspect that he will be the loser. New paradigms tend to show that older ones can be incorporated as special cases of the new. That is looking good too. Every extant perspective probably has value (they are each built on logic) and a good theory will encompass these in a such a way that it makes better sense of them all – and shows up their warts in the process.