Further notes about the morphostasis concept

A letter sent, 1st January 1997
You may find this of interest. You certainly ought to be aware that biology could be heading for a "Richter scale 8" earthquake iconclasm. 

This concept is either rubbish - "dung heap tripe" - or it is an earthquake iconoclasm that is set to radically alter the whole of biological/medical thinking. Once refined, it could do for biology what general relativity did for physics. It is a realisation that immediately unleashes the bounds of a constrictive conventional perspective into a vastly better paradigm of metazoan life. You cannot possibly understand the body's response to any disease (auto-immune, infective, cancer) until you have understood these principles. You certainly cannot understand immunology until you have.  

I think that I have been remarkably patient waiting for peer review to realise the importance of this concept. After all, I don't want to repeat an event like the premature claims made about "cold fusion". So, I have stayed away from the media. BUT....... it seems as though peer review is being "an ass" (see David Horrobin's article in the Lancet, 9/11/96 p 1293 et seq - I quote "History suggests a near universal rule - that innovation comes from an unexpected direction, and it is usually opposed by leading authorities in the field" - he sent me the paper partly in reply to receiving a copy of article (c) below). I am ignored by just about everyone in the field. I have a few letters that may help to highlight the responses that I have received. The general trend is, now, the cold shoulder. To me it seems like a conspiracy of silence. 

What is different about this concept? Well, it is not crippled by a radically incorrect assumption. Read any textbook of immunology and you will soon discover that immunologists are convinced that the immune system is dominantly interested in combating infection in the body. In fact, the body troubles itself little, in its primary response, about the presence or absence of infection per se. What it troubles itself about is "sick cells". The vast majority of these are identified "in house", within and by the affected cell itself. Apoptosis is its elected response and this deals effectively with the vast majority of sick cells. This single (missing) factor is the critical, core point that current immunology fails to raise to a position of dominance. The aggressive immune system is only brought into action when cells fall sick and fail to "shut themselves down in a controlled fashion" (ie, elective apoptosis). These cells are dangerous and the immune system recognises them as such. For future reference, the immune system makes sure it remembers something characteristic about these cells - and it is engineered to favour latching onto the most unusual looking peptide junk that is being cleared away from inside the sick cell. The fact that the immune system is good at identifying and preventing infection is a consequence of sick cells dying in an uncontrolled way. Because infection is a frequent cause of this, it gives the illusion that aggressive immune activity is particularly interested in infection per se. It is not! It is interested only in cells that die in an uncontrolled fashion. All the rest is "consequence": we have misinterpreted it because we are looking at it from the wrong direction.  

Where did this radically incorrect assumption (the wrong direction) come from? - the way circulating antibodies bind to bacteria and viruses and immobilise them! Antibodies are latecomers in the evolution of immune systems. So, it is a gross error to have crystallised all subsequent opinion around this early observation. It was a presumption to have assumed that "attacking infective agents" was the immune system's primary "raison d'être". But the idea sticks - like a limpet! 

I have attached abstracts of three articles.
a) The first is the (currently) published article.
b) The second is due to be published shortly and copyright is held by Pearson Professional.
c) The third is an adaptation of a commentary I recently sent to the Journal of Immunology.

 Please remember that the contents of the last two (b and c) are not yet in the public domain and, should you wish to see them, they should not be reproduced.

There are three more articles in my possession 
d) One is an earlier (1992) version of Morphostasis and Immunity - rejected unceremoniously by a number of journals but it is now looking as though this was essentially right.
e) Clinical Morphostasis which expands the "Whistle stop tour" of the published paper.
f) The Neurology of Behcet's Syndrome which is an extensive review that triggered my interest in immunology. Its conclusions are seminal.

 I think it is time that the establishment is stirred up. They may not like my style. They may find it cavalier or far too speculative in its approach. They might not like the general concept of "theoretical immunology". But.... they cannot forever continue to deny that this hypothetical approach is finding answers that conventional research methods will take an age to uncover.

There is a lot of potential glory in these ideas. It would be fun to have them attributed to me but that is a self centred rather than a social response. However, it is a social crime that the fundamental understanding of cancer, infection and auto-immune diseases is being held in limbo now the fast track to a radically improved understanding has been laid out - yet still no-one appears to be taking it.

I have attached a series of quotes which set the scene. Do not underestimate that this is a potentially shattering realisation.

This is big, big, big!

 I suspect, like the rest of the establishment, you will end up filing this in the cranks bin.

General email letter to various immunologists, 18th May 1997
I am not sure why no one wishes to speak to me on this subject. All communication so far has been one way. As far as I can tell I must live on a different planet to you. Nevertheless, I am not so daft that I am missing the importance of these concepts and I'm certain some of you know this too. Peer review seems to be being a total "ass" as far as I can see. My approach might be unconventional; it might be cavalier; it might offend those who think of themselves as professional scientists. But science has got itself into the rut of believing that speculation is an inadmissible act - only to be done in private, behind closed doors and amongst consenting adults in case someone finds you out. I heartily agree that Scientists should, and must, accept nothing (as gospel truth) that has not been rigorously proven. However, the problem with broad paradigms is that they are, at best, only guesses. They are a necessary evil and they should only be held so long as a better one doesn't turn up. Show me a major conceptual advance in science that was easily testable when it first appeared! These three quotes are from Thomas Kuhn. 

"In science, ....... , novelty emerges only with difficulty, manifested by resistance, against a background provided by expectation."

"Philosophers of science have repeatedly demonstrated that more than one theoretical construction can always be placed upon a given collection of data."

"Probably, the single most prevalent claim advanced by the proponents of a new paradigm is that they can solve the problems that led the old one to a crisis."

Let me point out that any statement saying that the morphostasis hypothesis (or paradigm) is untestable (like the current criticisms of the "danger" hypothesis) apply with equal force to the currently accepted paradigm that self/non-self discrimination is learned in utero. Perspective depends on the position from which you view an object. While the current paradigm does have appeal and has been a useful framework to date, it is now creating more problems than it resolves. A change is overdue. Like Newton's Principia, it was great in its day, still works for many situations but it is now holding up the advance of the subject.

Two journals have now rejected "From terra firma to terra plana (I must add it has matured since the first submission but not since the last (rejected 15th May).

I will accept that rejection is justifiable on grounds other than:
(a) it is not a thoroughly more predictive paradigm -- and
(b) it is not the most important thing to happen to biology and medicine for years.

I am sick of peddling this round and being told it is worthless when it clearly is not. You could now line up a million professional immunologists to tell me my amateur contributions are worthless and I would know they are deluded.

I have attached the article as a file. If you cannot read this, I will send it as a plain text e-mail should you request this.

E-mail to someone, 3rd July 1997
This is opinion but, again, I will use an authorative style for good flow!

S/NS discrimination is the same as it has always been since metazoans first evolved. It is based on cadherins, selectins and IgSF CAMs plus others. It is the process that leads to one cell docking with another. It varies according to necessity (see the points I made about sorting in embryos, sperm-egg interactions and the general principal of identity recognition). All the clues go to point out that cells in junctional communication can be ignored - they'll be OK - Karre's "don't call us if you see one of these variety". I don't know which version of "From terra firma to terra plana ... etc" I sent you but it is mentioned in the latest version.

You say something in paragraph 2 that makes me wonder if you have completely thrown off the yolk of a redundant perception - it was probably just a slip of the tongue. Doug Green kicked off Day1 of the "Models of Immunological Tolerance" debate by saying that "the immune system (non-existent for me) evolved to maximally damage parasites while minimally damaging us." Wrong, wrong, wrong if he is talking (as I'm sure he is) about adaptive immunity. Forget antibodies - their role comes late in evolution. The innner shells of the adaptive immune system are the NK (Tnk said but NK meant) like cells, Tc cells and Th1 cells - appearing in that order. Individual cells have to stand up for themselves - they are expected to keep themselves healthy and deal with their own interlopers. If they don't succeed in this they are then expected to do the decent thing (apoptosis) and mulch their dangerous contents in the process. If they fail in this, then they can't expect any mercy from the phagocytic system. Any cell exhuding cytoplasmic contents is in for the rapid chop. Now this is what the Tc cell system evolved to enhance. By remembering the strangest caricature of cells that made a mess last time, similarly caricatured cells can be encouraged into an early suicide on any future encounter. What follows is tidy, enhanced, early apoptosis followed by neighbour replication to fill the gap. And, apart from pathogens (or grafts for that matter) that sport alloantigens in their ruse for mimicry, the only cells attacked by the Tc system are self cells sporting self class I + nonapeptide (the addition of various nonapeptides probably makes many of the self-class-I-molecules+nonapeptides look like allo-class I antigens). So Tc cells are specifically interest in attacking suspect self-cells!! So where is horror autotoxicus? Again, it is there but it is nothing like the lymphocyte brigade's perception. It is the protection of healthy, self cells, in quiet communication with their neighbours. (This is where the cancer story becomes so strong). Various bits of evidence suggest that NK and Tc cells are selectively aggressive to cells that have detached themselves (worked out that they are sick). The aggressive Tc cell pays hardly any attention to foreign organisms per se. It simply looks for (self) cells sporting internally generated (nonapeptide) debris like the debris that the terminally sick cell (that primed the respective Tc cell) sported as it died catastrophically.

Th1 cells evolved as an extension of Tc cells to enhance and focus inflammation. They gave it a memory. But any induced response simply delivers lots of angry phagocytes that then search round for "other than healthy self" cells. The angrier the induced inflammatory response, the more difficult it is to masquerade as a healthy self cell. And the ultimate can happen (aggression to all local self cells however healthy) which is why a focal cut off is so necessary.

The whole of the morphostasis hypothesis was built on the structure of recurrent aphthous ulceration, Behcet's syndrome, multiple sclerosis, adjuvant arthritis and their relationship to tuberculosis. Tuberculosis, in particular, shows how the bacterium deliberately flouts the system by getting the adaptive immune process to concentrate on class-I+self-nonapeptide rather than strange class-I+tubercular-nonapeptide. In so doing it creates its own field of macrophage paralysis and a caseous soup that acts as a culture medium. The adaptive immune system, far from observing a horror autotoxicus to self cells, is designed to turn on them when they make a mess. And if they present no clearly strange class-I-nonapeptide specifities then a combination typical of the stressed tissue cell will be chosen (eg, adjuvant arthritis).

In short, Tc cells are designed to attack suspect, detached self cells.

So, yes, I agree with what you said about about lymphocyte receptors provided you are pointing out that this is part of their docking mechanism that brings them into the "communicating fold". But you say that it makes it more likely to leave self alone while dealing with the pathogen. I say that, in morphostasis, aggression is focussed on the potentially sick cell (one like this died catastophically last time), not the pathogen that makes it sick. The closest it gets to that is recognising some of the debris that the (potentially) sick cell is hanging off its cell surface as an advertisement of what is going on inside. The prime purpose is to enhance the apoptotic intracellular destruction of potentially mess making pathogens - just like the hypersensitivity response in plants. But plants are (evolutionarily) stuck with rigid cell walls.

Was that close to what you think?

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.

Notes, 6th January 2000
I suspect that many or the executives of normal science (particularly in immunology) are incensed that I have not done (and have no plans to do) any personal (conventional) research. The dominant paradigm of "normal science" is that it works hard towards exploring a current paradigm by a process of conventional exploration by laboratory or observational research. In contrast, my pre-occupation is probably seen as parasitic - feeding off the hard work and perceptual efforts of the most notorious extant workers in the field. From the start, my belief has been that the conventional view is absurd - it's not a front runner. It has also been my view that we are probably awash with basic, reductive research. We have no absolute need for new research to restructure the paradigm. New research has undoubtedly been helpful in pointing the way more clearly; but why do it (particularly if you can't because of your circumstances and commitments) when there is enough to find already to shore up a new perception?

Thomas Kuhn had this one sussed out too. He realised that paradigm shifts don't occur on the back of new research - the need to shift paradigms is already evident in extant work (nb the evolutionary analogy). If it wasn't there would be no justification for shifting paradigms in the first place.

Reply to Melvin Cohn (dated August 2003)

(Added here because it exemplifies and clarifies some of the arguments.)

First! 

I came to a need to understand the immune system from an unusual point. It is probably helpful to understand the sequence so you can see where I feel the extant perception is flawed. There is a file that describes this in more detail but here is a short synopsis. (C=comment,Q=question, A=answer).

C: I became interested in the encephalomyelitis seen in Behcet's syndrome (1976).

Q. What is different between this encephalomyelitis and the CNS inflammation of multiple sclerosis?

C: The early literature on the pathogenesis of BS recognised similarities with adjuvant arthritis.

C: Adjuvant arthritis mimics many of the features seen in the sero-negative arthritides (SNAs).

Q: Where does this adjuvant come from?  A: From the tubercle bacillus.

Q: So what does the tubercle bacillus use its adjuvant for?

C: I read a bit about immune-surveillance for cancer.

Q: What can age incidence profiles of the SNAs, TB and cancer tell us?

Q: What is the significance of the very common component disorders seen in the SNAs?

Well, at this point, and knowing little (molecular) immunology, I decided that the IS was not observing a rigid horror autotoxicus to self tissues.  The pathophysiology of TB and common diseases like acne, mouth ulcers, psoriasis and a host of other component disorders (seen in syndrome form in the SNAs) was - to my mind - "all due to immune auto-aggression" directed at self tissues.

So! That is the starting block. Even if "self" is recognised as such by the immune system it is still a long way from avoiding immune auto-aggression to it. So, there is no substantial horror autotoxicus to self antigens. Indeed, as with acne, the major attack seems to be on self and there is, simultaneously, little (and certainly ineffectual) clearance of the pathogen.

Several articles at my web site expand on Behcet's syndrome, clinical morphostasis and the evolving perception of morphostasis.

Second!

Here are some general points about successive "paradigms" of explanation. Let's call them models for simplicity. All previously popular models probably have some parochial value - parochial in both temporal and focused qualities. Thus, Aristotelian explanations seem totally off beam to us today whereas they had value in their own eras in beginning to focus our reasoning into better and better models. To call them "wrong" is as absurd as saying Newton was wrong and that Einstein will prove to be wrong (string theory seems, already, to be highlighting the parochial limits of his theories - it certainly loses definition at Planck distances and with quantum effects). They were appropriate for their era.

When you look back on earlier models, you can begin to see that, within their own bubble of applicability, the details of many theories have continuing value. New models, to be successful, rarely annihilate earlier models. However, they do highlight the presumptions that were made in extrapolating from these parochial observations to implications of a more universal significance. The true facts do not change with models. However, many of these "facts" have been burdened with interpretations that have stretched them into fables. The interpretation of the facts may be radically altered.

One salient point - that is perfectly obvious from both the "Sense of self" debate and the recent Seminars debate on self/non-self - is that there are many models of how the Immune System (IS) works and there are virtual science wars in progress between the competing conceptual camps. Now, history would dictate that they are all, to varying degrees, right. What is missing is a conceptual glue that will weld them all together into a whole. In doing so, such a perception will highlight the presumptions that have stopped their protagonists from moving forward and together. It will also highlight the parochial virtues of the older views. The older models will be subsumed as special cases of the emergent successor. A more universal perception will have been achieved.

That is history. And it will repeat itself. Perhaps not yet - but it will sometime.

Now let's get started on the specifics.

Let me start with some simple questions. Is it likely that the body uses a homeostatic system to maintain the order and form of its tissues? Even the most hardened antagonist of my view of the IS should find it hard to avoid a "yes".  Is the IS likely to play a role in tissue homeostasis? If you are tempted to say "no", then step back one. Is it likely that inflammation and its retinue of inflammatory cells have a role to play in tissue homeostasis? To answer "no" to this one would, I submit, fly in the face of a tautology.

Another question. Do simple multicellular organisms, as well as mammals, have a tissue homeostatic mechanism? Do invertebrates, as well as mammals, have inflammatory cells? Do invertebrates, as well as mammals, have an anamnestic immune system?

A last set of questions.  Do lymphocytes originate from a stem cell population that is closer to heart (or muscle or skin or what-you-like) than monocytes (macrophage precursors)? Do the surface markers of myeloid-lymphoid cells show a progression from phagocytes to lymphocytes? Could lymphocytes be regarded as amplifiers of the inflammatory response?

Your specific questions.

How does the IS assay "maintenance" and "health"? Essentially, it doesn't. "Assay" is a teleology that may come from a conviction that lymphocytes patrol the body "looking" for invaders. As David Lo's team have pointed out (1), a block of tissue cells form a network that effectively monitors the health of its own cells and tissue in general. Inflammation does not start until this network has cried "foul" and released chemicals that invite an inflammatory ingress. Individual cells monitor their own health and respond accordingly. Should you doubt these views - and the parallels in various multicellulates that range from plants to mammals - then it is worth getting a copy of a synoptic article by Trisha Gura in the New Scientist (2).

I think the preceding paragraphs have put up a good case to answer "how was it selected for?"

It might be well to recall that your assumption has a long history ….. I will answer this with a quotation: "Originality is nothing but judicious imitation." [Voltaire.] I am not staking a claim to intellectual property - I do have well defined views of what constitutes a better perception.

These have gone nowhere because they have not been mapped out onto a reasonable mechanism. I guess that you may not have read or, at least, properly assimilated the "Phlogiston" article at my web site. I do not think that the mechanism is unclear there.

All that we can do is argue about the semantics of the terms self and non-self. Well, that's not a bad place to start.  Now, one thing I think is worth considering (ignoring the teleology of "discrimination" for the moment) is what logical pairs we can consider. The body may discriminate on the basis of one or many of the following opposites.

self-epitope/non-self-epitope discrimination

self-organism/non-self-organism discrimination

healthy-self-epitope/other-than-healthy-self-epitope discrimination

healthy-self-cell/other-than-healthy-self-cell discrimination

disease/non-disease discrimination

pathogen/non-pathogen discrimination

foreign-organism/non-foreign-organism discrimination

damage/non-damage discrimination

danger/non-danger discrimination

dangerous/non-dangerous discrimination

order/disorder discrimination

homunculus/non-homunculus discrimination

psychological-self/non-psychological-self discrimination

even self/non-self discrimination (but we know this is bedevilled by multiple possible definitions of "self")

And there are probably many other possibilities.

We can look at each of these in turn and think "how much does this one contribute and when?" However, it is not - to my view - permissible to look at crossed pairs. For example, it is illogical to look at "self-animal/pathogen" discrimination or "non-foreign-organism/pathogen" discrimination or "self-peptide/pathogen-peptide" discrimination. To be logical, we must tie our parameters down as tightly as possible. Then we must consider how the system might feasibly carry out each tightly-defined discrimination.

I perceive that the way you have freely interchanged foreign-organism and pathogen is inadmissible and illogical. And I suspect it also leads to confusion.

The straightforward assumption that the IS was selected to protect against parasitism, infectious disease and the like is so obvious …. . And the world is flat, the earth is at the centre of the universe, there has to be a creator, time and distance are rigidly fixed throughout the universe - and others. No one in their right mind used to doubt these obviously obvious assumptions. Revolution is science has regularly hinged around counterintuitive proposals. The immune system may be no exception. Indeed, when agreement cannot be obtained it is very likely that there is a false assumption somewhere in the prior conceptualisations. I think this would fall under the general description "Bacon's idols".

Now that does NOT dictate that the IS does NOT tend to produce the effect of protecting against parasitism, infectious disease and the like. It hinges around the danger of the teleology "selected to protect". We cannot help talking and explaining with teleologies - the closest we can get to avoiding them is to use a mathematical rather than a social language for description. Since we can't avoid them we must be extremely sensitive of their dangers. My point is that the IS is quite mindless of the need to protect against parasitism etc. The effect occurs because it is tidying up the mess that these agents cause.

…. tied into the regulation of the biodestruction function.  So what is happening? Agreed, and without question, is the principle that the IS is capable of biodestruction. But most of this biodestruction is focused around subsets of self cells. Why? - for the following reasons.

Let's start with complement. First, C3 is secreted by phagocytes and actively concentrated in the plasma (by liver phagocytes). It is designed to constantly "condense" onto biological surfaces. Once there a cascade begins that results in the formation of C3b. If you are a healthy self cell then you secrete a C3-inhibitor that averts the C3b from triggering a pro-inflammatory cascade by moving it along to an inactive form of C3. This also applies to C4 when a cell gets coated with Ig. Two things might lead to self-cell lysis or fatal opsonisation; reduced C3-Inhibitors (do these downregulate just like Mhc Class I in sick cells?) or excessive Ig attachment. Either way, it is clear to see that there will still be a differentially greater opsonisation of other-than-healthy-self cells compared with healthy-self cells.  And this can only start in the presence of plasma and/or phagocytes (ie, after an inflammatory ingress).  Coating with Ig results only in bypassing the early stages of the alternative cascade. It attaches a marker to say "get on with complement assessment".

Now let's look at the biodestructive functions of cytotoxic and helper T-cells. Cytotoxic T-cells (Tnk and Tc) are designed to encourage self cells into early apoptosis. Unless some foreign organism could manage to incorporate self-class-I/peptide into its membrane, Tc cells will have no part to play in their disposal. So, cytotoxic T-cells are designed to encourage the melting away (by apoptosis) of self cells.

So what about T helper cells? Now, I think there may be a difference of belief here. You seem to hold that helper T cells are encouraged into aggression by primer T-cells whereas the Lafferty/Cunningham view is that APCs are the primers. Let me assume that APCs are the primers. What is it that the Th1 cell will respond to on epitope re-encounter. It will be another APC presenting a similar peptide in the jaws of its Class II Mhc antigen. It is responding to the presence of a self cell and sets off an intense inflammation in its proximity - an "inflammatory bomb". The biodestructive effect is caused by a cascade that intensifies inflammation at the location of this TCR/APC encounter; nothing more, nothing less. So where is the direct attack on the pathogen? It is, I submit, non-existent. It boils down, in effect, to a hard time for both healthy-self and other-than-healthy-self cells but it is differentially more destructive with other-than-healthy-self cells. But this is differentially cruel to organisms that are outside self cells.  For organisms that reside inside self cells, the most effective response is to differentially encourage these flawed cells to die early.  Otherwise, it must rely on a differential reduction in the infected cells healthy self signature.

There is a tendency to look on the biodestructive mechanism of the IS as something that is directed at foreign organisms. For the reasons given above, this simplistic perception is far too naïve.

You have given me no argument that Ig/TCR have a role in regulating normal physiology. Now, I think that this is your caricaturisation of what I have said. Strictly it is right but you go on, a few sentences later, to demonstrate that you equate this normal physiology with the normal physiology of chemical homeostasis (like glucose control). That is a very liberal and literal stretch of the original thesis. However, since you raise it then it is worth noting that the insulin receptor is closely related to growth factors and that islet cell physiology is intimately affected by gap-junctional communication. So you are, perhaps, not that far out in extending it to be a morphostatic mechanism: but I guess, the effect you sought was to question the perspective. 

This is to be contrasted with their roles in guiding phagocytosis, cytotoxicity, C' lysis, "transmitter and cytokine" production, etc. all biodestructive. I think that I have already shown how a different perspective can be laid out for these - and in favour of a morphostasis perspective. The facts don't change: the interpretation baggage does. (Both your view and the morphostasis view equally carry such baggage: as will any fresh, usurping view.)

What is there about that you can't buy? I buy all the facts! But I don't buy the interpretation baggage. I suspect other views more than I suspect my own but I don't even believe my own represents "the truth" or that it is secure.

Try to answer for me "what will it take to have you change your mind?" Mel, I think I see your point of view. It is not that I cannot appreciate your perspective. It is that I think another perspective is possible and, once realised, it is better because it opens up a new vista on things. I don't feel tempted to abandon my views and replace them with yours. You quote Occam's razor in support of simplicity. But, I think that we should not be seeking simple mechanisms (biology is replete with the opposite) but simple principles that follow a limited number of common themes. Find a principle or theme that is simple to state, then see that it makes sense of ideas across a whole raft of previously disparate areas of study, and you truly have found an Occam's razor.

The existence of debilitating autoimmunity shows that Ig/TCR mediated effector functions can destroy self cells and tissues. I have acceded this and even added my contention is that this is but the tip of a very large iceberg.

The Ig/TCR mediated ability to destroy cancer cells only confirms this, as the difference between cancer and non-cancer as seen by the I.S. is the presence of a "foreign" antigen. Sorry but I would say that they are not foreign (in the way we humans might conceive to be foreign). They are antigens expressed during retrodifferentiation and they are germ line encoded. The only exception might be if the mutant oncogene were a surface protein that gave rise to an entirely new peptide species. Macrophages have no trouble in recognising cancer cells in vitro. It is the anergy, necessitated by the T-cell system, that has led to their apparent in vivo invisibility as sick cells.

The destruction of virally infected cells is another illustration. I think that you are providing further arguments that come to my concept's rescue, not to its demise - see above.

…. when there is an insufficiency of eTh (delivery of Signal[2]). So, you are out on a committed limb here in persisting to believe that signal 2 is delivered by an eTh, NOT an APC (à la Lafferty/Cunningham). It might, of course, be the right limb. You claim this is simple, an Occam's razor solution: but you risk danger. Is it simplistic rather than simple? - and where is the objective evidence to support your contention? As tacit support for the perspective that I hold, it is instructive to follow the argument through carefully with both aggression or/tolerance selection and with thymic selection. By this view they end up as being the product of a repeating and much more general theme.

Let me set out, again, how I think that T-cell commitment is being made. It is important to exorcise the "tainted think" that attaches some quality to the Mhc/peptide epitope.  My impression is that it is hard for people to cast it off. Many still need to (conceptually) award the antigen a quality (a relic of self-epitope/nonself-epitope perspectives). It is JUST an epitope. All epitopes - self and non-self - are just epitopes: nothing more: nothing less: all equal: it is a truly egalitarian system. It is only their context of presentation that leads to aggressive or tolerant responses. I think this last sentence cannot be repeated often enough to ensure that it is appreciated. (Nb, "context" subsumes your "time" as a special case). Let me, for emphasis of function, create the terms Step 1 and Step 2 which represent the precursor T-cell's response to Signal 1 and Signal 2 respectively. In the thymus in step 1 (part A) the T-cell spontaneously develops a particular specificity. This is the bit that ensures the Class I or Class II molecular clasp (not the peptide) is selected for. I suspect this is promoted by a gap junctional "kiss of life" and it turns the precursor T-cell into a selectable T-cell. Effectively, it is going to restrict the recognition of peptides to those that are carried in a self Mhc clasp. Then in Step 1 (part B) the lymphocyte refines its specificity to add in specificity for the peptide groove. Both parts of Step 1 are randomly generated. From now on, selection for aggression or tolerance is the same in the thymus as it is in the periphery. Thymic presentation is almost always non--inflammatory (there may be actual or experimental exceptions). In selecting only self Mhc carriers for the "kiss of life", a lot of precursor T-cells go on to apoptosis by neglect. These apoptosing cells are presented to the carrier specific and peptide specific (but uncommitted) T-cells. The result is the demise of both CD8 +ve T-cells capable of recognising any peptide presented by a dying T-cell: or the demise of any CD4+ve T-cell capable of recognising the debris derived from an apoptosing T-cell that is ingested and then presented by a thymic APC. Effectively this step amounts to the same process as Step 2. Other thymic cells might join in this apoptosis and also be presented to encourage tolerance (thymic epithelial cells, thymic APCs, thymic macrophages). Whatever, the result is tolerance to any peptide/Mhc antigen presented after efficient apoptosis in the thymus. I don't think that we have finally excluded the possibility of suppressor T-cells that can amplify tolerance on re-encounter - so these are also possible complicators of the tolerance mechanism. Now, this process of tolerance will use the same mechanism in the periphery as it does is in the thymus - efficient apoptosis.  Inefficient apoptosis (due either to some mutant defect in its silent clearance or overwhelming apoptosis where apoptotic bodies - packed with Il-1 - spill their contents before ingestion) may invoke an aggressive response. SLE is a good example.

Aggression is induced when an APC presents (almost certainly in the lymph nodes) in an inflammatory condition (eg, rich in split Il-1, eicosanoids and interferons). Step 2 has nothing to do with any property of the antigen OTHER than in what inflammatory or non-inflammatory environment it made its debut. The lymphocytes are subsequently (or simultaneously) awarded a location address so that they are preferentially sticky to venules with a similar address code (part of Zinkernagel's localisation). So why do self cell signatures not provoke aggression? Part of the reason is that they share many peptide signatures with the apoptosing, precursor lymphocytes (and etc?) in the thymus. But the other part, and what gets left out of the reckoning, is the staggering volume of apoptotic cell 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 massive mopping up by apoptosis and you strongly augment the favouring of strange over common epitopes as fodder for aggression. The response to strange epitopes will be fast - like lighting a bonfire of thin dry timber: the response to self epitopes will be slow: like trying to start a sodden wet bonfire in a downpour.

In a way, this accords with your idea that older i-Th cells spontaneously move towards aggression. This is supported by experimental evidence (chapter and verse I would have to find). However, in denying that it is the APC that provokes Step 2, you distance yourself from my view.

Do you wish to conclude that germline selected recognition of nonself markers like Danger, Morphostasis, integrity, localization etc. can be translated into decisions made somatically at the level of recognition of epitopes (which include MHC bound peptide)? I am a little bemused about what you have in mind here. The germline "markers" of tissue mess will be analogous to the mess you and I see on our streets. First there will be the bits that get presented, nicely wrapped up in plastic bags, concentrated for quick collection. However, one or two of these gets ripped open by the foxes and the rubbish is progressively scattered all over the road. When the garbage collectors go on strike then entropy ensures that these neatly ordered packages progressively spill their contents (foxes, storms, vandals). Normally, the garbage collectors know what the bags look like and can sort them into paper waste, food waste and etc on their bag coding. It is plainly obvious for all what spilt rubbish looks like and I guess, that from time immemorial, animal cells have had a fair idea what constitutes the equivalent of connective tissue and cellular garbage. Macrophages (amoebocytes) are particularly attuned to mopping this up. Inside out membranes, spilt mitochondrial markers, spilt cytoplasmic markers will all have recognisable signatures and then there are the spilt chemicals - like Il-1 and eicosanoids - that shriek "mess ahoy".

I think that the morphostasis concept can subsume aspects of the AAR (provided you can drop your objection to APCs being the deliverers of Signal 2), stranger, integrity (order disorder discrimination), localisation and the immune homunculus. The views I find most distant from my own are yours, those of Medzitov and Janaway, Peter Bretscher and, a bit less distant, Coutinho. The main reasons for the difference with the first three is their absolute requirement that self-nonself discrimination by lymphocytes is effectively seen as a concrete reality. With Coutinho's view, the network is king and I feel this would result in a remarkably Rube Goldberg system. The network/homunculus ideas may be rewarded with an observable shift as described but they would, for me, be the passive consequence of morphostasis and not the active cause of discrimination. I think that morphostasis can subsume them all. It will show up the warts of presumption that have driven them up a blind alley and also, so far, prevented their integration.

I am sure that you will want to disagree - at least on first pass. But that is the fun of modeling. We must all accept the potential frailty of our conceptions.

(1)     Immunological Reviews, 2000, Vol. 169. Transgenic and knockout animals as models of human disease D.Lo, L.Feng, L.Li, M.J.Carson, M.Crowley, M.Pauza, A.Nguyen &C.R.Reilly   225-240**

(2)     "Roots of Immunity" by Trisha Gura in the New Scientist (Feb 18th 2000) pp24-28

Nb, David Lo's team found a lovely quote on LPS that is worth reading. It's in this article.**

Comments on "danger" vs "stranger" theories of lymphocyte activation, 1st December 2003
(adapted from a letter sent in late November 2003)

I feel sure that the immune system (IS) relies on signals generated by unwelcome tissue damage (on the one hand) and that it targets a limited “hit-list” of markers characteristic of micro-oganisms (on the other) and that it recognises them using germ-line encoded receptors . However, it is important to try and gauge how, why and (evolutionarily) when these elements arrived in the armamentarium of the IS, if we are to better understand their “purpose”.

One thing that the morphostasis hypothesis predicts (and is not specifically predicted by the other theories of IS function) is the shell like structure of IS functions. Not only are the individual components likely to have evolved in a Russian-Doll-like sequence but there is good reason to believe they might roll out  in the same ontogenetic sequence on each new challenge. Note that ontogeny tends to retrace phylogeny. (This means that the extant state of an individual's IS represents a collage of discrete maturation points along this ontogeny; and, this state depends on the various challenges met and the respective shells at which they were resolved.) This gives us important clues as to what the elements (for example, Toll-like receptors) are primarily “designed” (evolved really) to accomplish.

This shell like structure suggests that macrophage functions are likely to share many similarities to those of unicellular amoebocytes. If macrophages are recognising “pathogen” associated structures, they will probably have some counterpart and some “purpose” in unicellulates like amoebae.  

Let me digress for a moment around “pathogens”. Modern immunology uses the term "pathogen" as if this were synonymous with a foreign organism. But, the term “pathogen” signifies the capacity for harm (from, for example, a hammer through to a living organism). It is a measure of the tissue damage caused (note the past tense). A foreign organism may well have the capacity to lead to damage, but what we are describing, in calling an agent a "pathogen", is a persuant event in that it has inflicted damage. We should, by rights, call these organisms “pathogenic organisms” (forthwith POs). I suspect that shortening this term has led to much woolly headed thinking. There is a trend to consider that the IS discriminates "self from pathogens" (POs intended). But, I suggest, this pairing is illogical nonsense. The only discriminatory pairs that make logical sense are clear opposites. For example, these are admissible: 

Any or all of these could, potentially, contribute in the discriminatory function of the IS. But a crossed pair like "self vs pathogen" discrimination is almost meaningless. When the proponents of “self/nonself” discrimination use this, they are effectively scoring an own goal in favour of the proponents of the “danger” theories.

Remember that a pathogen is any agent, living or inert, that provokes tissue damage. So, that should immediately ring alarm bells about any extrapolation of “self/nonself” discrimination into a “purpose” for PAMPs, PRRs and Toll-like-receptors. What is more, it is obvious that PRRs and TLRs have functions to do with development that do not qualify as a self/nonself discrimination. There may be a common theme of recognition if it is recognising  microbacterial markers that are released from both obligate intracellular micro-organisms (mitochondrial debris spilled from the cytoplasm)) and their free living counterparts.

And so, let’s get back to the purpose of Toll-like-receptors in eukaryotic unicellulates. These organisms need to maintain their own order and structure in an environment that is inclined to promote their degradation (eg, by damage, starvation, invasion by other organisms). They do so by consuming fuel of some sort and, for them, bacteria are a major source of this. So, even in the unicellulate ancestors that eventually evolved to construct mammals, there will have been a limited set of germ line pattern recognition receptors that identified suitable organisms for ingestion. One important consequence of this is that POs that rely on their animal host for survival might do a lot worse that to provocatively display “eat me” signals to macrophages - in Trojan horse style. There is increasing evidence that POs, once inside a macrophage or cell, can set off a fresh sequence of activity designed to subvert normal intracellular physiology to their own advantage

It is worth reading what Erwin Schrodinger wrote

“A living organism . . . feeds upon negative entropy . . . Thus the device by which an organism maintains itself stationary at a fairly high level of orderliness (fairly low level of entropy) really consists in continually sucking orderliness from its environment.”

Contrast the way that certain gram negative organisms provocatively display LPS (and so heighten inflammation) with the impotence of common commensal organisms to cause any degradative effect until an animal dies Then, these organisms go into a frenzy of feeding and reproduction. So, unicellulates and multicellulates alike have little difficulty in maintaining their own integrity in a sea of non-pathogenic micro-organisms. POs, on the other hand, are highly evolved (often obliged to rely on their chosen host for continued existence; and, they use sophisticated subversion techniques to achieve this). In evolutionary terms, they are always likely to evolve a way around a new defence much faster than a new defence can evolve to counter it. Pathogenicity is always likely to end up as a balance between the successful propagation of the PO and the avoidance of the annihilation of their chosen host.

This quotation is worth heeding:

"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).

Charlie Janeways “stranger” hypothesis was firmly entrenched in the belief that attacking and killing microbes is the primary purpose of the IS. This has always meant that any observed cellular process is interpreted (square peg into round hole fashion) with the assumption that this paradigm is unchallengeable. Thomas Kuhn has a pertinent comment on that:

"Philosophers of science have repeatedly demonstrated that more than one theoretical construction can always be placed upon a given collection of data."

I would like to challenge, absolutely, the security of the 'obviously obvious' assumption that the immune system has evolved to find, kill and eliminate foreign organisms. It is beyond dispute that the system favours the survival of healthy self cells and everything else tends to be degraded. However, look at the evolutionarily old alternative complement system. All biological surfaces get C3b deposited on them. Healthy self (species) cells are protected by the inhibition of the aggressive consequences of this deposition. The system encourages the degradation of ALL biological material unless it is actively protected by complement inhibitors (HS/OTHS discrimination: mess/non-mess discrimination). Antibodies simply amplify complement deposition on those biological surfaces that have previously been associated with disorder (as judged by APCs, particularly dendritic cells). Inhibitor protection for self cells still applies but it is now harder to assert. So that sheds a different light on the specific attack on foreign organisms. The same can be said of Tc and Th1 activation. The first identifies self cells that have an MHC/peptide signature (Class I) that was previously (closely) associated with uncontrolled cell shutdown (or death). Similarly, Th1 activity just amplifies and accelerates the accumulation of phagocytes at the site of APCs displaying MHC/peptide signatures (Class II) that were previously encountered in an inflammatory context. Again, there is no direct attack on the foreign organisms by Th1 cells. However, they do encourage an inhospitable, local, inflammatory milieu.

Now, there is a naïve (to my way of thinking) belief that a mammal needs a sophisticated IS to fight infective organisms. But this flies in the face of what we know. Free living amoebae, hydra, jellyfish, sponges, insects and protean other invertebrates maintain their structural identity until they die. Then, like all other life forms, they are rapidly degraded by the plethora of organisms populating our environment. Next time you pass an aquarium, observe and wonder at the pristine structure of its resident sponges. Are these highly susceptible to infection and degradation because they don’t have a cognate (anamnestic) IS?

Whatever the “purpose” was in evolving a mammalian cognate IS it can only have led to relatively focused advantages in combating invasion rather than in the common, general principles of protection. A corollary of this is that, whatever shells of IS-function an invertebrate possesses, each shell is fulfilling its appointed task efficiently. Remember that micro-organisms can evolve advantageous mutations in days (if not a lot shorter), and certainly far faster than can a colony of amoebae; mammals are stuck with trying out a new mutation much more slowly (for full testing, 15 or so years minimum for humans where there is but one child per family; sperm and ovum can be tested at single cell rates but this probably cannot test out multicellular properties). Now, this may well be one reason why mammals have multiple, tiered defence lines. They have to be less susceptible to advantageous PO mutations. Another might be related to the relative inability of certain tissues to tolerate regeneration (eg, the brain). But multiple tiered defence lines also increase the number of potential Achilles heels that POs can learn to exploit. And, I propose, the vast majority of POs that invade mammals are focused on one or more of these Achilles heels – ie, they are highly specialised and dedicated invaders.

In looking for a “general” (common to most animals) property that enables an animal to keep itself in order (against the gradient imposed by all the potential invaders that could use it for its fuel) we should be focusing on why the defence of potential hosts against commensal organisms is so overwhelmingly efficient. Forget, for now, the POs; with these we should be looking in detail at which Achilles heels are being exploited.

There are so many observations that fit better by looking at IS function as an order/disorder discriminating system that, I contend, it at least shows up the potential frailty of the “self/nonself” perspective. Further, it may help us to focus better on the important issues that will bring better understanding and, in consequence, lead to a more precise manipulation of the system.
 

Marrow derived stem cells and cancers

Timothy Wang's group (Massachusetts Medical School) and other workers have recently reported some interesting findings that could have far reaching implications - especially for morphostasis. Bone marrow derived cells can infiltrate a wound and take on the form of local tissue cells. Cancerous cells expressing a local cell phenotype (gastric carcinoma) were shown to be descended from a bone marrow cell line rather than from a de-differentiated and malignant local cell line. The implications for tissue homeostasis (morphostasis) are, potentially, enormous. Not only would bone marrow derived cells (monocytoid cells) infiltrate areas where tissue homeostasis is disrupted but they might also, at some stage in the "resolving" process attempt local tissue regeneration. It is becoming increasingly clear that locally persistent chronic inflammation is often the prelude to the onset of cancer and that, as inflammation subsides, the immigrant inflammatory cells go on to promote resolution and regeneration. It is tempting to speculate that cancer may be, in many cases, the occasional product of a physiological repair (homeostasis restoring) mechanism that has gone wrong. This behaviour would be consistent with the idea that macrophages are closer to free amoeboid cells in their state of differentiation than tissue resident (building block) cells. Thus, free roaming amoebocytes occupy a central "shell" in the morphostatic response.
Science Daily summary
Original article in Science

One thing that has to be dealt with, should more cancers be found to be derived from immigrant myeloid cells, is the relevance of mutations and the long antecedent history of local tissue exposure. Clearly these mutations are of importance but we may have jumped to conclusions about the exact way in which they give rise to a cancerous growth.

This leads nicely into a perspective of cancer that sees it as "distorted regeneration". Inherent in the process of morphostasis is the damage -> inflammation -> debris clearance -> regeneration sequence.  To free cells of any restriction to growth (division and multiplication) it is necessary/desirable to temporarily abandon intercellular communication. To bring growth back under control and to coordinate healthy, co-ordinated differentiation amongst a group of cells, it is probably necessary/desirable to re-establish gap junctional intercellular communication. It is in the process of normal regeneration that carcinogens might facilitate this distortion. The drive to regenerate might be continuing without the system being able to "close out" (a chronic inflammatory process might be sufficient).

Once again, the morphostasis perspective opens out a view that becomes almost tautologous (inherent of the system and therefore no need to state it) whereas the old view does not inherently encapsulate it.

Grandics P. also develops a parallel concept of "The cancer stem cell: evidence for its origin as an injured autoreactive T Cell."  in Mol Cancer. 2006 Feb 14;5:6.
 

Autophagy and defence

Just as apoptosis may act as a defence mechanism to "globally" mulch (sanitize) the contents of a compromised cell, so autophagy (the intracellular destruction and re-absorption of a part of a cell without destroying the whole) is now emerging as an effective defence mechanism (see these four web pages as an example 1, 2, 3, 4 and a recent article).

This emphasises another important point about morphostasis. It is important to re-assimilate the material that is dismantled in apoptosis and autophagy. Leaving it unused invites "predatorial" species to use the material for their own gain. It would also be a serious increase in the total entropy of the host animal. It needs to be rapidly reutilised and recycled into entropy resistant self cells.

And, a last point about autophagy: there is a report that suggests that this is an important mechanism in peptide cross-presentation (Class I - endoplasmic reticulum resident peptide - to Class II - phagosome resident peptide) and it is a logical consequence of autophagy.

More to follow ......?