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Various letters that I have sent and received

 

It should be noted that, from the earliest to the lastest versions, the quality improved and the speculation became less wild. My "method" has been to speculate wildly, overshoot, then search for supporting evidence to make corrective adjustments. My earliest versions are now so embarrassing I hate reading them. I have only included one of the acceptance letters (Southampton Health Journal). I may add the rest later. Grammar and spelling were pretty much as written – scanned documents.

1982_12_16_lttr_from

Dear Jamie,
I have at last managed to read both papers and I have gone over them quite carefully. I hope you do not mind that I have made some alterations in penci1, to the text, which I hope will improve the flow. You have obviously put a great deal of work into preparing these two articles, but I am afraid that if they are to be accepted for publication you are going to have to do even more. The decision is obviously yours, but I think that you would manage to get your article on "Neuro-Behcet's" published much more readily than the one on "Immune Surveillance". I think for somebody in your position, in General Practice, to publish such a challenging article as the latter would be an achievement indeed, without the previous reference to the work that you have done in the field, contained in your other article.
I think it would be easier to deal with the article "Immune Surveillance and Morphostasis" first of all. I accept that this article is a little bit outside my field and I have great difficulty in following some of your arguments, but you would sell your case much better if you simplified the vocabulary. On several occasions, you are simply too verbose and use too many adjectives qualifying a single noun. The second criticism is that you have tended to use words which have a new meaning, for example "auto-aggression, mono-component and tissue-tract-epicentres, and even perhaps horror autotoxicus". I certainly accept that somebody writing a new hypothesis article for the Lancet could get away with some, if not all of these, but this simply makes your task more difficult. By the term mono-component, I take it you mean a disease affecting a single system. Perhaps that would be more acceptable than the former term. I take it you have replaced the term auto-immune by the one auto-aggression and this obviously occurs in the other paper as well. I really feel that it would be in your best interest to stick to the one that has been traditionally accepted. In both papers you make frequent reference to the fact that "multiple sclerosis is now generally considered to be a cell-mediated auto-aggressive disorder". I am afraid you really must modify this. I agree that there is evidence that cell-mediated immune mechanisms are involved in M.S. for a number of reasons, but obviously you should quote references with respect to this. There is doubt, however, on the active role in M.S. People are uncertain if these features of cell-mediated immunity in M.S. are the consequence of the disease or in fact they play a part in the aetiology. I am afraid to describe the disease as a cell-mediated auto-immune disorder moves the definition along a little too far at this stage. On pages 10 and 11, you quote a number of features of cell-mediated immune disorders and, at a later stage, claim that multiple sclerosis conforms with features numbers 1 to 6. I would challenge several of these. For example number 3, the familial aggregation with sibling predominance - although some papers would support this others would suggest that the occurrence of M.S. in parents of sufferers is just as great as amongst siblings. I agree that there is an excess during the puerperium. There is undoubtedlv an excess during pregnancy as well rather than a reduction in a number of relapses during pregnancy. The other feature you quote as being characteristic of MS - a therapeutic response to immunosuppression - is, I am afraid, untrue on the basis of the clinical trials that I have seen. Therefore, when you are quoting M.S. as a possible auto-immune disorder you cannot really quote conformity with all these six features. On page 11, you mention an inverse relationship between the severity and degree of overlap on the one hand, the disease incidence on the other. I think your quote for the incidence of M.S. is a little low. You are obviously suggesting the incidence is one per 100,000, presumably per annum, when the real figure is nearer five per 100,000 per annum. The inverse relationship holds true for Neurosarcoid and Neuro-Behcet's, but surely rheumatoid arthritis is often a severe disease and is by no means rare. I do not think the argument is absolutely water-tight. 0n page 12, you also use the term "Encephalitis of M.S.". By this, do you mean that M.S. has almost wholly a neuraxial involvement. I honestly do not think any of us think in terms of M.S. giving rise to either meningitic or encephalitic features. I certainly have examined over 1,000 patients and cannot recall firm clinical evidence of either, although I quite accept that there may be meningitic involvement at post-mortem. These are most of the criticisms I have concerning this particular paper and obviously some refer to your paper on Neuro-Behcets as well.
Neuro-Behcet's Paper: I obviously had considerable difficulty in following all the references which you had not written out fully, but I managed to find out which ones you were referring to in most instances. I would be interested to know what reference you are quoting in number 160. I cannot remember any reference to benign multiple sclerosis from people who are concerned with primary care study. With regard to the abstract I agree that the encephalitis of B.S. follows a clinical course similar to M.S. but I would not think one could argue that the lesion distribution was exactly the same, as the predominant feature in M.S. is spinal cord involvement which is not a feature of B.S. You did not include Table 1 but I presume that you have it somewhere. On page 3, you mention constitutional disturbances and I think obviously you should exclude laboratory investigations as they cannot be included in that term. If you are hoping to publish the paper in America, you must not use the term "fortnight" which means nothing to an average American uncertain what you mean by the first two lines on Page4.
You use the term uveo-meningo-encephalo-myelitic. I know that you do define what constitutes the disorders elsewhere, but I wondered if this was a generally used term. It, is incredibly cumbersome, but if others have used it then I am sure it is reasonable. On Page 5, you detail a number of the neurological features occurring in the encephalitis of BS and I think it would have been useful if you had annotated these as a) b) c) etc in the text. Your case review study is comprehensive, but I am afraid the references only go up to 1973 and 1974 and there have been several recent reviews which you must include if you are now about to publish. I think you should devote more space to giving a breakdown of the 96 cases that you located in the literature so that one can see what proportion of this total had had involvement of each of the different types of neurological disease. In updating your review, I am sure the must be some CT Scan reports of the appearance which would be helpful. You use the term proteinosis. I presume this is another Americanism and may be acceptable over there but is obviously not acceptable in the U.K. I also could not find figure 10, but presumably you have got it at home. I am not a Pathologist, but I would have thought that the main feature of MS is perivascular infiltration, whereas the main feature of B.S. is necrotising encephalitis. I have difficulty seeing how this can be part of the same disease process although I accept that there has been a claim that some areas of involvement in patients with BS look very like MS plaques. You give a reference Adams 1977 - I wonder if you could quote me what the whole reference is because I would be delighted to read it. You argue that the meningitic component gives rise to pleocytosis. This may be so but obviously the cells could have originated from the ependymal lining. You make reference to the rarity of disease in pre-menopausal women, but I am not sure to which disease you refer and you should obviously have a reference for this. On page 25 you use the term pseudorheumatic. This undoubtedly has appeared in previous papers but it is a very woolly term. On Page 26 you mention the thorny question of saprophytic treponemes in plaques. I think the consensus of opinion is that these findings were purely artefactual and nobody is willing to accept that treponemes have anything to do with M. S. If you want to mention this then you must mention references which discount the theory. As I mentioned earlier, I feel you should certainly publish the paper on Neuro-Behcet's first. You should not have too much difficulty publishing an overall review of this disease. It is perfectly justifiable to raise the similarities to multiple sclerosis but I do not think you should carry conjecture as far as you have. The paper is really too long and the total volume must be reduced. You must remove the weak points and try and stick more definitely to a smaller number of salient features.
I know this must seem like harsh criticism dear Jamie, but I have tried to look at this paper through the eyes of a reader. Papers should not, therefore, be too long, too complex or too involved. Otherwise the poor reader loses interest rapidly. You certainly have a number of excellent points to make on Neuro-Behcet's and I have certainly learnt a lot about the disease from your paper. I do not feel fully qualified to constructively criticise your paper on Immune Surveillance and Morphostasis from the immunological point of view and perhaps you should ask somebody else to read that at a later stage. I know you were thinking of the American market and I think it is easier to get a longer paper published there. I do not think that any of the current U.K. neurological journals would take a paper of this length. I would like to hear further from you on a number of points that I have raised and if I can be of any help in the future please do not hesitate to contact me again. By the way, I am on the move again since I did manage to obtain a Consultant post at the XXX Hospital, which in these days of reorganisation has been renamed XXX Hospital. I start approximately in April. Best wishes for the festive season.
Yours sincerely,

1983_05_17_from

Dear Dr Cunliffe,
I have read your ideas on the Primacy of Macrophages and my feeling is much the same as at the end of your lecture: there is some truth in your concepts but they lack precision.
My approach to immunology has always been molecular, and I look forward to the day when the functions of histocompatibility antigens, the T-cell receptor and lymphokines can be understood with the same clarity as now applies to immunoglobulins and complement. The functions of macrophages and the various dendritic cells in antigen presentation will then be much clearer. Until that day many conflicting notions about cellular functions will persist.
The possibility of la on macrophages acting as antigen receptor of broad specificity was mooted in 1977 (Feldmann, 267:10 ; Rosenthal et al, Nature 267:156) but is no longer popular. These class II histocompatibility antigens are now thought to control the specificity of cellular interactions during antigen presentation.
There is no chance of my laboratory beng diverted to look at macrophage function except where it applies to macrophage interaction with tumour cells. The terms of our grant s are stringently confinedto neoplasms of the lymphoid system.
I return your papers with this letter. I am afraid lack of time prevented me opening envelope 2.
Yours sincerely, ***

1983_07_04_journal_from

Dear Dr Cunliffe
Thank you for submitting your article for possible publication in XXXX. I am afraid, however, that we feel it is too speculative to be of interest to our broad readership while the T cell recognition mechanisms remain unresolved.
Although it appears that these questions may very soon be answered, at this stage we feel your manuscript would be more suitable for publication in an immunology journal.
With regret, I am therefore returning it to you so that you may submit it elsewhere without further delay.
Yours sincerely

1983_07_14_journal_from

Dear Dr Cunliffe
I acknowledge the receipt of yur manuscript “An essay on immunity” which you submitted for publication in XXX. According to the procedures of this journal, I have sent it to the editor-in-Chief for reveiwing. The other material (parts B, C and D) has been sent on to XXX who is at present in his house in France.
With kind regards,

1983_08_22_journal_from

Dear Dr. Cunliffe,
Earlier this month I received your letter of 9th July with inclusions A,B,C, and D, which was forwarded to my address here in Castillon. A copy of manuscript A was sent to XXX.
I am impressed by your encompassing and erudite description of the immune system, and by the perseverance with which you derive a far-reaching theoretical construction from a few elementary concepts. As you point out, the most important of these concepts is the "inversion" of T-killer cell functions. This inverted function is conferred upon phagocytic cells, as explained on page 2, and in Table 1. The phagocyte, according to this thesis, is intrinsically aggressive, but is triggered to non- aggressiveness by "recognising" self, or self/self, as you say.
Lymphocytes, on the other hand, are triggered to aggressiveness (and B-cells to antibody production) by recognising non-self. This property requires a large repertoire of receptors, a repertoire that may be called "complete", in the sense that virtually any "foreign" macromolecule can be recognised by receptor-ligand binding. I am missing, in your theory, a consideration of the fact that antibody molecules and antibody-like B-cell receptors display, in their variable regions, molecular surface profiles (idiotypes) which present "foreign" antigenic determinants (idiotopes) against which the system is capable of making antibodies. Considering the huge receptor repertoire which can recognise all idiotopes, we may postulate that the idiotypic repertoire is likewise complete, in the sense that the system itself possesses a set of idiotopes similar to virtually the entire universe of foreign antigens. I have exploited this concept in proposing a "Network Theory" (Annales Immunol. Inst. Pasteur, 1974, 125 C, p. 373). An enormous experimental idiotype literature has since arisen.
This is only to emphasize that lymphocytes (the role of which you relegate to a slave function orchestrated by phagocytes) can be triggered when recognising non-self. You now introduce a "phagocyte receptor repertoire" which recognises self/self. You specify that "recognition" involves complementary molecules (LIGANDs - RECEPTORs) which bind together rather like substrates to enzymes.
I now repeat the argument I already made in 1960 (Annual Review of Microbiology, vol.14, p.348), namely: why should a "healthy self cell" be recognised, if the only action upon "recognition" must be to leave that cell in peace? I trust that you realise the cogency of this argument. "Recognition" requires LIGAND-RECEPTOR binding. Though this binding is reversible, we would have to accept that in a healthy animal, phagocytes are continuously engaged in binding and unbinding to and from healthy cells. A phagocyte that has just unbound from a healthy cell is quite likely to bind again to that same cell a moment later or, if it drifts away, to bind to another healthy cell, unbind, etc. I find this an unattractive concept, as specified in the middle block of your Table 6, and I prefer to regard as the true elementary property of the immune system its ability to recognise non-self by members of its huge repertoires of molecular receptors. Thus I relegate the role of phagocytes to a "slave function" orchestated by this enormous capacity of lymphocytes to recognise "foreign".
I do not expect to convince you. Considering the large amount of synthetic thought that you have brought to bear on these problems, I would suggest that you submit your essay to another journal, such as the "Journal of Theoretical Biology".
I am sending a copy of this letter to XXX, and to you I send my kindest regards.
Yours sincerely,

1983_10_19_letter_from

Dr. Cunliffe,
Rumor is now fact and XXX can be contacted in Paris at the following address: XXX
You may wish to write to him there directly rather than wait till early 1984 when XXX will return to the XXX.
Sincerely

1983_10_26_journal_from

Dear Dr. Cunliffe,
Thank you for your letter and enclosures. Please do not worry about the manuscript not being in the appropriate format at this stage. We will send it out for refereeing in the normal manner, and will let you know what our referees' comments are. I will,in the meantime, keep all the other material, including the manuscript entitled. 'The Morphostatic System'.
Yours sincerely

1984_01_21_journal_from

Dear Dr. Cunliffe,
Our referees have now considered your manuscript, which, we regret, we cannot accept for publication. The referees have commented that the manuscript presents purely speculative notions without any scientific basis and much of what it presents does not concur with known immunological fact. They feel also that it falls in to a category not acceptable to this journal.
I am returning your manuscript herewith.
Yours sincerely

1984_03_29_lttr_from

Dear Dr. Cunliffe,
I did not open the envelopes (Pandora's Box?) but only because I am momentarily under considerable time pressure (more than usual). However, what I have read, convinces me that we are very far apart in our way of thinking. I do not believe that macrophages play any degree of specificity — even a broad kind (and I do not know of any evidence suggesting that they do); I do not think that Mhc molecules have receptor functions; I am convinced that the complement system has nothing to do with Mhc; I hope, eventually, to disprove the notion that the T complex is in anyway related to the Mhc, etc., etc. It would take a very long time to explain why I believe all this; perhaps we shall meet some day at a meeting and then we could argue about the points. I was not sure whether I was supposed to return the material you sent to me. If not, I would like to go back to it some day and spend more time thinking about it — which is the least your ideas deserve.
Sincerely yours,

1984_07_05_journal_from

Dear Dr Cunliffe,
Thank you for your engaging letter of June 10, which took a fortnight to reach me. I do not think you are a crank, but I am not, I fear, going to encourage you to contemplate this journal as the place for your Hypothesis. I can undertake only a tiny fraction of I am offered, and I do not think your proposition can win my support.
Yours sincerely,

1991_01_01_lttr_to

Dear Dr XXX,
I wonder if you would be prepared to look at this article entitled "Morphostasis and Immunity" and see if you feel there is any value in the concept?
You know me better as a local GP than as a writer of hypotheses on immunity. I have had a fascination for this subject over the last 14 years. It began with an interest in the neurological complications of Behcet's syndrome. I wanted to get a feel for what what causing this disease. It soon became obvious to me that I was going to have to learn some immunology and also look at a variety of other diseases to see how each was structured and responded to age and immune status. The immunological interest has, to a very large degree, taken over. I've touted these ideas around in less mature form for some time. In particular, the article on Behcet's syndrome has been seen by several people who consider it to be too hypothetical. I've included a copy simply to demonstrate that my allegation that MS and neurological-BS are potentially "linked" is not an idea presented without considerable thought and reading. Please do not waste time looking through this. Since the assumptions eventually feed back to enhance the morphostasis hypothesis, it reinforces my own conviction that there is some value in these ruminations.
I recently saw your two articles, in which you suggest that auto-immunity might be the unfortunate result of a physiological response rather than a totally inappropriate immune phenomenon. I felt that you might, therefore, not be too hostile to my presumptive intrusion into an expert field: particularly as the hypothesis fulfils the premise that immune auto-aggression (auto-rejection) is a normal process.
My increasingly busy life (and committment!) as a GP mean that I am able to spend less and less time on a subject that demands reading and knowledge over an exceptionally wide and expanding stage. I have grown resigned to the idea that my efforts may have no other reward or recognition than that they were good fun. But!!......... I still have this feeling that it's a pity other people might not get round, at the very least, to considering seeing things from my point of view.
I'm still trying to tidy up the references and get up to date sources BUT I cannot do this rapidly with only occasional days in the library, so my apologies that the reference lists may seem incomplete or inappropriately old at times.
If asked for a short paragraph to justify WHY you should spend any of your valuable time reading this, this would be my reply: This concept welds morphogenesis, morphostasis, inflammation, phagocytosis and amnestic immunity into a well integrated continuum. It offers a pretty clear explanation for the prevalence and pathophysiology of three broad groups of disease (auto-rejective, cancer and infections). It offers a neat explanation for the precipitate evolutionary emergence of the amnestic immune system around the era that protochordates and vertebrates originated.
Yours

1991_04_01_lttr_to

My apologies for hounding you. Have you managed to spare some time to look at the hypothesis I sent you? I was considering sending it off to the Journal of Theoretical Biology though I would rather wait for some criticism first. Don't worry if you cannot afford time to look at it but I'd be grateful if you would let me know.
Once again, I have been through it searching out the flowery language and the non-sequiturs so there is a more readable version should you prefer it.

1991_05_01_lttr_to

Thank you for your reply. I wondered about invading your privacy with yet another version but have decided, since the English in this has been made deliberately plainer, you may as well have access to it when you do find the time. The content is little changed.

1991_05_19_lttr_to

Dear XXX,
Many thanks for taking the time and trouble to come along and talk to me last Wednesday night. I hope you didn't get too annoyed with my undisciplined mind.
I know you are busy and may well not find time for a while to think on this but I have enclosed an article on invertebrate immunity that discusses at length the idea of specific recognition by phagocytes. It fails to address the problem of the "generation of phagocyte specifity" in a ZDC and to conceive that the affected cell itself, or its immediate neighbours, might identify its own "sickness" rather than leave this identification to the immune cells. The authors look on the loss of (healthy) self identity as entirely passive.
One thing that may well not have come across clearly to you is the analogy I made on the development of the vertebrate eye. Superficially it looks far too complex to have evolved gradually but its evolution can be traced back in graduated developments from some very rudimentary light receptors. There is an analogous problem in the immune system. How do you develop, in the space of a very short evolutionary time, a complicated and sophisticated anamnestic immune system (I have spelt it right ONCE in the article!) at the moment of the evolution of the branchiates. This conundrum has taxed many people. The system would seem to be next to useless until an extensive repertoire is possible. IF, however, the genes encoding diversity of receptors began their evolutionary life in order to select a single ZDC specific receptor (generation of specificity to allow specific phagocyte recognition) then this can develop right from a two receptor choice through to a million, and more, receptor choice in gentle graduations. Flip it around into the generation of diversity about the time the branchiates emerged (and a thymus) and you have the rudiments of a highly versatile anamnestic immune system.
The idea that intense immuno-inflammatory activity "saturates" and hence leads to local surveillance depression in intensely inflammatory lesions, came from clinical features and particularly the behaviour of pathogens like TB and syphilis. Syphilis is a far greater mimic of the BS syndrome complex than is TB, which you would soon realise if you looked hard at it. So the need for a focal switch off (focal anergy) arrived, in concept, as a clinical necessity. You seemed surprised at what I said about staph boils – the attached extract from a book reinforces the concept that bacteria DO use this "saturation" effect as a cloak for unbridled activity.
The section on "WHERE DO LYMPHOCYTES AND ANTIBODIES FIT IN" is, recently written, badly explained and needs further reading and revamping. I will do this. The principle that it is a simply permittive rather than a highly directive system is what needs to be emphasised. Similarly, "MORPHOSTATIC EVOLUTION" could be better presented.
STUDY LEAVE
I've enclosed the note about DoH sponsered study leave, though a sticky problem with this is that it leaves me somewhat out of pocket. You could help to support me, if you felt able, by emphasising the value of the study I have already done and the probability that it will be of benefit to myself and, possibly, others if I had further leave to pursue these ideas. A word with Bob Thomas in the postgraduate centre would secure the support needed.
Yours sincerely,

1991_10_15_to

Dear XXX,
I really don't know what to do with this article. I’m probably deluding myself that there is either basis or value in the ideas presented. Those people who have seen earlier versions don't seem to see significant value in it. I'm more or less totally isolated from academic immunology. My interest in the subject stemmed from trying to understand what was causing Behcet's syndrome (the essential reason for playing with these ideas). There is a long article on this which I have only alluded to in this article - it's not published. It struck me that you would be in a position to see value in the concept if it is there. I can no longer find time out of my busy professional life as a general medical practitioner to pursue these ideas in anything more than a superficial way (much as I'd like to do nothing but that). I'm beginning to believe that I have no ideas that the world of immunology wants or needs. But! I can't help feeling this is too "round" and predictive to be total rubbish. I'm hoping that you might see just a glimmer of benefit in this way of conceiving the immunological process.
I hope you don't mind me imposing on you.
Yours sincerely,

1991_11_15_journal_from

Dear Dr. Cunliffe:
On October 26 I received your manuscript entitled: "Morphostasis and Immunity." Before making any comments, I would like to know why you chose to send the paper to me.
In my opinion, Part I is more interesting and has some potential, but this is difficult to decipher in such a lengthy presentation. For further consideration, I would need to review a greatly shortened version. Once this is done, what are your plans and how do I fit in?
Yours sincerely,

1991_11_26_to

Dear ***
Thank you for your reply.
I chose you because of your interest and influence in immune phylogeny. Also you are in position to broadcast this locally or generally if you considered it had value.
The enclosed article is a synopsis of Part 1 of the article I sent in October. Referencing will be more difficult here and may simply evolve into a reading list based on the numbered sections. I have tried to be more direct. I hope that I have stripped it down to the bare bones. I consider that its content must belong either in the trash can or it is important. I don't believe that there can be much intermediate ground. If it's the second, it NEEDS broadcasting. I am not unduly concerned how this might be done nor is my main goal to grab the credit. I have found myself academically isolated and, consequently, impotent at interesting anyone in this idea. I simply hope that the concept rather than I will be taken seriously.
What are my plans? To persuade someone in one of the main fields of immunology (and the best is probably immune phylogeny) to find some very good reasons why this is undoubted rubbish or to take it seriously.
Where do you fit in? I'm not sure that I am sure. I have no mentor. I have no resources beyond a local medical library and my office at home. I would appreciate help and I thought that you, as the editor of a journal on immune phylogeny, might be willing or able to point me in the right direction.
By the way, Part 2 was largely complete before Part 1 was conceived. It was from this direction that I approached the subject.
Yours sincerely,

1991_12_16_to

Dear ***
When you suggested I rewrite the article it gave me the opportunity to do some more reading and thinking and it seems I have been slow to appreciate that Tnk cells probably ARE the inverted Tc cell. The reasoning is outlined in this addendum. Many of the assumptions are too speculative for anything more than rumination. No references are given here but I'll provide them if you wish.
Either this enormous jig-saw puzzle is coming together very quickly or I'm just a crank! I hope you can figure out which statement is correct.
Yours sincerely,

1991_12_21_journal_to

Dear Professor C,
I hope that you are not losing patience with me BUT this hypothesis CONTINUES to evolve. A number of points have become clearer. I have corrected some errors and improved the explanations given in the last letter I sent you.
The main reason for writing today is to send you this explanation of how I now think SELF/NON-SELF discrimination is ultimately organised. This was finally synthesised this morning.
I have also made some improvements to the main article I sent you that I will send but only if you request it.
Yours sincerely,

1992_01_28_journal_from

Dear Doctor Cunliffe,
RE: 1358 Morphostasis and Immunity
I found the above manuscript potentially interesting and sent it for review to two members of the Editorial Board. The version dated 12/4/91 was the one which the editors read.
Prior to that version at least three others were sent: the first, a cumbersome one was sent on October 15, 1991 with the suggestion that it be shortened, which was done in the November 25 version and another November 29. After them, I received three additional letters, on 12/30/91, 1/2 and 6, 92 with more text and figures. In my career, I have never experienced this manner of submitting a paper unless you assumed that I was piecing it all together here! If this is the case, by now a final version should be in my office. As you mentioned in your letter of November 26 "you were not sure where I fit in" (prompted by my earlier inquiry). I must confess that neither then nor now do I know where I fit.
As you can see from the enclosed comments, the recommendation is that the paper be rejected. Given this information and the episodic and impetuous writing, I strongly urge two options: 1) accept the rejection; 2) revise the paper according to the referees' suggestions and with the new material resubmit a revised, well thought out manuscript for another round of reviews.
I trust that you will make a wise decision.
Yours sincerely,
Ref 1
Date Received by Editor 12-11-91
J. CUNLIFFE Author:
Title: MORPHOSTASIS AND IMMUNITY
This article, though readable, contains very little of value. The idea that the vertebrates' immune system originated from “morphostasis”, as the author describes, has been proposed in various versions in the past. A hypothesis on a theory would have value if it were focussed on a problem(s) more clearly formulated and had a certain prediction to be tested experimentally. The present paper has none of these elements but discussed several aspects in a rather unfocussed and uncritical manner
Advice to Editor: Reject
Date: 15th January 1992
Ref 2
Date Received by Editor 12-11-91
Author: J Cunliffe
Title: MORPHOSTASIS AND IMMUNITY
If there are any useful original ideas being presented here, they are so deeply buried in verbiage and unprofessional style that it would be impossible for anyone used to reading Immunology to discern what they might be. It is simply not necessary to invent new, stylistic language to describe new thoughts about a subject. The entire "discussion" has the cast of an undergraduate term paper which needs a good deal more work and much more careful documentation. Our responsibility, as scientists, is to communicate information and ideas in such a way, that all can understand.
Here, fundamental aspects of the subject are completely ignored. Just what is the evidence that macrophages were, at some time in the past, undergoing gene recombination so as to be epitope specific? When one looks at their function in extant animals, it is clear that they gain, not lose, the capacity to incorporate the variety of antigens, especially when one is considering proteins that are soluble. Certainly, they were originally able to discern foreign from self, but they could only do so when the material was in particulate form, as pinocytosis was not yet available to them. The author's inversion of B cell and T cell function in evolution also ignores what is known from extant animals. It is clear that a, perhaps the, principal step in the evolution of immune reactivity in the vertebrates was the development of a molecule for recognition and response, antibody. Even the most primitive extant vertebrates produce Ig, but as far as can be discerned, they do not have the various T cell subsets postulated by the author. In this regard, too little attention is paid to the fact that epitope-specific T cells do not bind peptide ligands directly, but must have them presented by MHC-antigen bearing cells, a mixed population that includes B cells. I could go on, but I will restrain myself to just noting that the newest suggestions from network theory about anamnesis are that cells may not even be involved directly and that anti-idiotypic antibodies and their counterparts, which oscillate in their production over time, might be responsible. Finally, it would have been useful for the author to have incorporated some of the latest results on the functioning of the peptide-binding pocket of MHC Class II antigens, with respect to differential binding affinities of self/non-self peptides, in any discussion of the mechanisms of self-tolerance. Similarly, recent cytokine work with regard to anergy in tolerance,... but I promised that I would not go on.

1992_03_02_journal_to

Dear Professor C,
Thank yου for your reply and the referees' comments. These comments have not altered my convictions. Ι believe Ι can counter each criticism. Ι am sure you are extremely busy and do not want to be caught up wasting your time on what you may consider a dead end. So Ι will be brief in this letter. Perhaps you have ΝΟ reservations about the referees' responses. In this case you should file the enclosed envelope into your litter bin together with this letter and read no further unless Ι get round to resubmitting the article officially. If you do have reservations, then the envelope explains how Ι consider the referees have SUBSTANTIALLY missed my point.
These are the points:

1. This idea is either a major conceptual shift or hopelessly wrong. Ι recognise the probability lies with the latter. Ι am unreservedly convinced that there is no middle ground. It is too committed.
2. If it could be a major conceptual advance then the momentum of conventionalism is clearly far greater than Ι anticipated and accounts for what Ι regard as unreservedly damning criticisms. When Ι cannot understand why the referees have failed to appreciate the merits of this shift Ι remain unsure how to progress it.
3. Ι cannot find enough time to dedicate to progressing this idea: Ι am unable to escape from my work. Nor do Ι have significant influence to infect others with this idea: Ι am an isolated general practitioner who has no connection with any department of academic immunology.
4. If this idea is a major conceptual advance then it is far too important to allow personal aspirations and the desire to see my name in print interfere with its dissemination. Ι am content to forfeit “ownership" of what is, anyway, a synthesis of other peoples' ideas and endeavours. Please do not feel there should be any secrecy or confidentiality in how you respond to this letter. Publication is not my prime concern: infecting others with the concept is. You would see, should you read my letters again that I did not explicitly ask you to submit this article for publication. I merely asked if you thought there were ideas here worth "broadcasting". It seems to me you must have considered they were at least worth exploring.

What Ι really want and need are informed ears to bend. And a general plea for "HELP!" in anyway you see fit even if that meant passing the idea over to other people to progress. It struck me you were a person who has thought long on self/non-self discrimination in non-vertebrates and would be in a position to understand the implications of this concept if anyone could.
The main criticism which clearly stands is that a communication should be understandable to the reader. However, it would need a book to outline the reasons for every opinion. With very few changes Ι am convinced the article is still essentially correct. Ι have highlighted these minor changes in the fresh copy.
Yoυrs sincerely
(the envelope referred to was the reply to the criticisms)

1992_03_24_journal_to

MY RESPONSE TO THE CRITIQUES: The shorter critique states that the concept of morphostasis has been proposed before. This is a strange comment when I quote the source of the idea. I have just carried out a Medline search over the last 5 years. It quotes three instances of the use of this term. Two did not concern immunology. There was one on lymphoid directed morphostasis in the liver. I don't claim to have invented "morphostasis". I do propose that it is a fundamentally crucial process. It is the PRIME function of inflammatory and other immune cells. There should have been thousands of references to it, not just one. Langman was, in the past, one of the main protagonists of specific phagocytic recognition. The quoted article from Coombe, Ey and Jenkin gives an extensive review of the literature on this idea. Katz and Skidmore (Self recognition and cell communication – I have the photocopy but no reference) got close to what I'm suggesting but they failed to drive the concept home. None of these authors have made the final step to say that self(cell)/non-self(cell) recognition is made by virtually every cell in the body and that immunological self(Ag)/non-self(Ag) reactivity is the consequence, not the source, of self/non-self discrimination. Here is a quote from Edelman (1991) p177 (1b). "The origin of the entire Ig superfamily from an early N-CAM-like gene precursor has deep implications for the understanding of the role of adhesion in processes that are not concerned with morphogenesis but rather with immune defense, inflammation and repair" (ie, morphostasis!!). (See below also).
The second referee's longer critique is more provocative. He has clearly been ruffled by my presumption. However, I regard this response as evidence that he has failed to grasp the implications of what I am suggesting. It seems to me that he is caught in the straight jacket of conventional perception. He is clearly convinced that the final explanation will come only in detailed dissection of intricate mechanisms. To me this is analogous to being given the bits of a smashed watch and then studying the intricacies of each individual part to work out the whole. It will probably get there in the end. However, an alternative is to stand back and, from every possible viewpoint, hypothesise wildly, piece together the broad principles then refine these until the details begin to fit. In particular, this referee seems to be caught in the quagmire conviction that lymphocytes and antibodies are ultimately responsible for distinguishing self from non-self. The fact that they TEND to be aggressive to non-self antigens and TEND to be tolerant of self antigens is consequence rather than source of self(cell)/non-self(cell) discrimination. I will take his points in order:

1. "Verbiage and unprofessional" style: indubitably NOT the style of most articles on immunology: and I intend that as a criticism. I love to read Jan Klein (hope he wasn't the referee!): plain anglo-saxon and a minimum of jargon where it will suffice! I have consciously and laboriously toiled over this goal. I have introduced no greater technical complexity than is absolutely necessary. Where I have used "jargon" I have listed it in a table. I have invented FOUR new terms, ZDC (zygote derived colony), US (unhealthy self), OTHS (other than healthy self) and the "generator of specificity". I think these are self explanatory: in my view they were vital concepts. My presumption here has clearly annoyed him again. Wild hypothesiser I certainly am. I know this is unfashionable in medicine and biology. BUT, is it a bad thing?
2. "Macrophages rearranging their genome:" This has been a major conundrum. Nowhere is there anything but the merest soupcon of evidence that phagocytes can specifically recognise self Mhc. The need for a cell that does or did this came from the clinical realisation that auto-rejection is a NORMAL, regularly employed process (based on the work I have done leading up to an analysis of neuro-Behçet's syndrome, other sero-negative arthritides and multiple sclerosis). There is no automatic horror autotoxicus to self epitopes where T cells are concerned. When auto-rejection is so general, it must have physiological significance: it must be part of the morphostatic mechanism. Unless it's a Heath Robinson (or in American, Rube Goldberg) system, self/non-self discrimination can't be left to cells that are regularly able to mount an aggressive response to self epitopes. This realisation led directly to the OTHS concept. I have been slow to appreciate that Tnk cells might offer a way out of this conundrum and could be the cells that (originally?) recognise(d) self Mhc (this only occurred to me just before Christmas). Phagocytes, lymphocytes, fibroblasts and platelets are all derived from the same lineage. They are almost certainly all descended from a primitive scavenger. They have simply caricaturised and refined specific properties of this general scavenger to make the mature mammal more versatile.
3. To my mind, this referee now demonstrates that he has not grasped the concept that I have proposed. All the IgSF (Immunoglobulin superfamily) molecules employed right up to and including natural killer cells are acting exclusively as CAMS and CAM receptors. N-CAM and the Cadherin family trigger the immediate construction of membrane holes to form communicating gap junctions. In so doing the adjoined cells become a cooperative synctium. A similar process PROBABLY occurs in phagocytes and Tnk cells (though some other adaptation may bypass the need for gap junctional communication). Cells that fail to make contact by appropriate CAM recognition are given larger, leaky holes but in the receptor membrane alone. This increases their intracellular Ca++ levels and reduces their membrane potential. I half suspect this leads to a capacitive triggering of a membrane action potential in the lamellipodia of the phagocyte or the Tnk membrane. It is of interest that cells that MUST uncouple before they perform their differentiated function (eg, nerve cells and muscle) display large amounts of negatively charged sialic acid on their surfaces. Similarly, macrophages have one of the highest membrane potentials of all cells (I can't at the moment find the source but I'm sure I have read this). It was only with the advent of Tc cells that receptor/ligand interaction was detached from the CAM function. (It may prove to be that it was even detached in Tnk but, logically, this is neither likely nor necessary.)
   Free IgSF molecules are NOT intentionally released at any of these stages. Phagocytes are NOT required to pinocytose various molecules. I doubt that a ubiquitous principle like gap junctional communication is ignored by phagocytes or natural killers and I strongly suspect that, at the phagocyte's podium, it attaches and electrically couples with underlying self tissue. I strongly suspect that this accounts for a major part of self/non-self discrimination by these cells.
   I risk being lynched now. Antibodies are icing on the cake. Extremely useful, evidently important but dominantly aimed at preempting the proliferation of blood borne pathogens and pathogens that colonise epi/endothelial surfaces. It's quite clear that the role of antibodies in tissue rejection (and hence auto-rejection) is minor if not minimal. The vast mass of animal life copes well without them. " Cell-mediated immunity clearly precedes humeral antibody production in phylogeny" (Manning and Turner 1976). We can safely put antibodies to one side until towards the end – which is more or less where they evolved. Looking for the explanation of self/non-self discrimination amongst antibodies is, to me, manifestly Heath Robinson (Rube Goldberg). Saying that "the first step in immune reactivity was the development of a molecule for recognition and response, antibody" seems, to me, an empty comment when Cadherins, N-CAM and other CAMs are already regarded by many as the origin of this recognition and response (01). Lymphocytic cells that bear resemblance to Tnk cells are even seen in invertebrates. Beta-2-microglobulin was around long before antibodies and specific immunity. No! Antibodies are a "recent" adaptation of ancient mechanisms. (They are all the more necessary when you consider that blood is a broth held at 37 deg C with the capacity to disseminate microorganisms all over the body: morphostasis in the blood cannot happen as it does in tissues: special arrangements – the spleen – have to be made.) To me, immune network theories of self/non-self discrimination smack of the need for an "immaculate conception" – the repertoire needs to be complete before it can adequately work or so many stipulations have to be put upon it that it becomes Heath Robinson (Rube Goldberg).
4. "Even the most primitive extant vertebrates produce Ig, but as far as can be discerned, they do not have the various T-cell subsets postulated by the author." I quote above from one of the earliest books on immune phylogeny (Manning and Turner) and I'm not aware that opinions have altered on this. If these cells have not been identified then the question is rather "Why?" than evidence that they never existed.
5. I have not microscopically dissected this spring in the watch because it is detail not principle. The principle predicts the detail. Start with a simple CAM/CAM interaction like N-CAM. This is recognised in a straight like/like interaction and leads on to immediate GJ communication (the insertion mechanism is, I suspect, akin to the complement cascade with C3 like amplification leading to large patches of apposing membrane holes). Tnk cells probably evolved to recognise a deliberately individualised CAM (Mhc class I precursor). This population of pleomorphic CAMs in the "herd" were developed to ensure a greater individual specificity and acted as a "backstop" check of self identity. They brought with them the "generator of specificity". So, when the generator of diversity arose its SOLE preoccupation was in the recognition of Mhc ligands: NOT a diverse set of non-Mhc epitopes. The evolution of membrane recycling and peptide (pocket) presentation of antigen simply acted to make peptide/self Mhc combinants appear like a set of pleomorphic Mhc antigens that the inverted Tnk like cell (now a Tc like cell) was ready primed to recognise. With the evolution of antibodies the restriction of this specificity to a limited set of Mhc allotypes was bypassed by introducing complex gene rearrangements and somatic hypermutation. [In the beginning (the primitive Tnk like cell), germ line V genes would probably have been sufficient without the necessity for even D-J rearrangement].
6. So too, he seems to have misunderstood the proposed principle of the prime function of T cells and antibodies. The principle is simple – there's no need to dissect detail here: no need to delve into the complexities of peptide pockets, cytokines, suppressor mechanisms and immune networks. T-helper cells and antibodies are largely concerned with heightening inflammation and of bringing cells possessing particular epitopes to the attention of phagocytes (and Tnk cells). Direct killing is NOT the prime function. They are not remembering epitopes just to "kill" them. The precursor lymphocyte logs the context in which it first set eyes on its epitope. If it was inflammatory then at the next encounter it will recreate a rapid and potent inflammatory response rather than wait for the "cell damage-cytokine-inflammation" cascade to build up. "Tipped off" inflammatory cells can then settle down much more quickly and aggressively to their phylogenetically ancient task of sorting HS from OTHS. The main difference is that they're doing it much more quickly and with better targeting. But they are also doing it more hamhandedly – they'll "bash"
   anything that looks remotely suspicious (hence the focalisation of this response). Tc cells are relatively more independent but even these are only allowed to become aggressive if they have been primed by IL-1 from APCs in an inflammatory encounter. And these, too, encourage a rapid inflammatory response once they start attacking cells.
   On the other hand, if the first presentation of the epitope was non-inflammatory, suppression is favoured. Most paratopes specifying self epitopes are confined to the suppressor pool unless they are infrequently exposed or nearly always exposed in inflammatory situations (eg, heat shock proteins). This certainly accords with clinical and experimental experience. This is the broad principle: we can leave the detail to the watch dissectors. It need not concern the principle that suppressor T cells tend to choose slightly different parts of a molecule than helpers. Anyway, this may be a result of cooperative presentation rather than of "self" selection (like Th/B-cells).
7. The author's inversion of B-cell and T-cell function: First I didn't suggest the inversion of B-cell function. ONLY of Tc cell function. The purpose of this inversion is for a Tnk like cell to specifically recognise self Mhc alone (at least 2 possible epitopes in a diploid animal). The term pure self is used to distinguish self from self+x (this formal term obscures the principle). These paratopes were originally used as CAM receptors to establish communication with self cells. Cells that could not make such communication were attacked by Tnk like cells.

This all sounds arrogant but I'm becoming increasingly confident that this hypothesis can take whatever knocks are thrown at it. Those that do hit hard reveal a misunderstanding that, once corrected, leads to an enhancement of the whole.
Let me tabulate the advantages of this way of perceiving the process:

1. Seamless integration from embryonic development to anamnestic immunity.
2. The innate and the acquired immune system are no longer seen as fundamentally disparate entities. They are fused into a seamless whole.
3. Automatic explanation of preferential alloreactivity by T cells.
4. A clear evolutionary progression from organisms with no cellular differentiation, through simple organisms with phagocytes, then the evolution of a retinue of specialised cells all derived from the primitive scavenger starting with Tnk like cells, going to Tc like cells, Td like
   cells, Th like cells and finally B cells. (This progression is logical.)
5. A far clearer perception of the cancerous process (not detailed here but there is good evidence that gap-junctional communication is involved (02)).
6. The potential to explain the process of ageing (03).
7. It all makes excellent biological sense. Indeed, it integrates so many biological, developmental and immunological mechanisms into a continuous whole that it has the rumblings of biology's equivalent of the "grand unification theory" of physics.

There is a strange double-think that pervades immunology when it comes to the subject of the phagocytic recognition of non-self and unhealthy self. Every MEDICAL STUDENT knows that phagocytes recognise dead, damaged, sick and effete cells. Every medical student knows they can recognise foreign organisms [particularly non-(dedicated)-pathogens] and eliminate them. Every text book devotes its statutory (short) introductory opening to the importance of phagocytes and innate immunity: then, almost without fail, each author is seduced, with indecent haste, into an intense dissection of the principles of anamnesis and lymphocyte function. What makes this worse is that the anamnestic immune system is not essential to prepare cells for phagocyte attention. The phagocytic system works well in invertebrates. Self/non-self discrimination works well in invertebrates. Hardly any of the specific points that I have written in the main article could be said to be in any way radically new BUT, the emphases on what's important IS. I am even more convinced now that the conventional perception is flawed.
There can be no doubt that the reason for this tendency to ignore the fundamental importance of phagocytes is a lack of understanding of the mechanisms of self/non-self discrimination by these cells. There is, at the very least, a strong possibility that this may be because no significant research has been carried out on the junctional communication between these cells and underlying somatic cells.
Am I deluding myself? Is all my assumption JUST the mad rambling of a crank? I don't pretend that I am specifically right in all that I have proposed but I KNOW that I'm not wrong in the general "flavour": and this "flavour" is a long way detached from conventional perception and wisdom.

THE MOLECULAR MECHANISMS UNDERLYING HS/OTHS DISCRIMINATION
"Morphogenesis is an integral part of a morphostatic system. It is, therefore, reasonable to expect that the component elements of morphostasis will use molecular machinery that is genetically related for they have (presumably) been closely associated through every epoch of metazoan evolution."
"Horror Autotoxicus must be built upon the possession of specific and recognisable whole cell properties (very probably expressed at the cell surface): these probably aid the co-operative "docking" of one cell with another."
These quotes come from the original article that you suggested I shorten. Since December I have taken some annual leave to get much needed time in the library and I believe I now understand the process better. The following is a synopsis of this. As you will see, it largely obviates the need for the mental gymnastic of inventing HS and OTHS. No one I have read has suggested an explanation in these terms. It is necessary to be familiar with aspects of gap-junctional communication in development to understand it fully. The following statement is a now a central tenet:
"SELF is established by making holes in the membranes of apposing cells and lining them up to create gap junctions. This allows cells to become electrically coupled and so to act as an electrical and, probably, a cytoplasmic continuum. This ability to couple membranes dates back to the very earliest multicellulates. It relies on the controlled, ordered, simultaneous adjacent membrane insertion of membrane holes. Cells learned, from the start, to allow the uncoordinated, bigger, higgledy piggledy insertion of leaky holes into organisms that fail to demonstrate the membrane LIGANDs used as a focus for the tidy construction of gap junctions: electrical discontinuity and a lower membrane potential encourage phagocytes to attack. Unhealthy self cells can elect to be rejected by uncoupling from adjacent cells then dropping their membrane potential: they can also abandon the membrane LIGANDs that specify self."
The easiest way to proceed is to list the salient points and give a list of supportive references. In all of this I'm treating the whole thing as a jig-saw puzzle. The jig-saw pieces are individual research reports. I contend that there are enough of these already existing to piece together a very nearly complete overall picture. Missing pieces need to be guessed then searched for. Guesses need to be matched against facts and then the dross thrown out. At any point there WILL always be an element of dross though, I suggest, this is mostly concentrated, now, in the more specific assumptions. To clarify this I have written the following notes with:

1. reported fact left unhighlighted
2. probably correct highlighted green
3. guesswork highlighted yellow and
4. wild assumptions highlighted pink.

1. Gap junctional communication is not particularly specific but it appears to be highly selective (a concept well recognised in Ab/Ag interactions)(04).
   
2. Gap junctional communication is critical in development. Development fails if GJ communication is disrupted (05).
   
3. When CAMs (cell adhesion molecules) interact with each other or their receptors, this interaction appears to lead directly to gap-junctional communication. CAMs precede GJ insertion and both are necessary for normal development to occur (06a) (06b).
   
4. Embryos are made up of a number of compartments that have clearly defined boundaries of communication through gap junctions. These correspond with important developmental fields (07). These boundaries also correspond to specific CAM expression (07).
   
5. The compartments are of two sorts. First, high permeability junctional complexes allowing the free passage of lucifer yellow. I suspect that these enable a large block of cells to be organised by homoeotic genes as if they were one complex cell (eg, look at the complex structure of paramecium). Second, other junctions that allow the free passage of ions or rectifying junctions that occur at communication boundaries (08) (possibly of significance in the way embryonic cells sort, with endoderm to centre and ectoderm to the outside) but are insufficiently large or extensive to allow easy passage
   of lucifer yellow.
6. N-CAM is not confined to neural tissues. It is expressed strongly and for long periods in neural development. It is expressed more transiently in many other sites. It is a recognised IgSF (Immunoglobulin Super Family) molecule. A number of authors have considered these molecules to be the the probable ancestors of immune IgSF molecules (Edelman is one (01)).
7. The hypothesis is that the scavenger cell developed a CAM receptor molecule to specifically recognise the respective CAM on other self cells (perhaps a beta-2-microglobulin like molecule). It used this as a means of communicating electrically with the underlying self cells (at its podium). A cytoplasmic finger from the scavenger could trigger the phagocyte into aggression if it encountered a cell not in direct electrical communication (via gap junctions through the membrane where it sits on underlying tissues). This may be done by the induction of a capacitative current that then triggers an action potential. Other recognition strategies are used. Changing surface sugars in sick cells is one (loss of the sialic acid residues may increase the capacitive current – sialic acid being negatively charged). The phagocyte probably also has a limited set of receptors for epitopes that are indubitable markers of their non-eucaryotic origin and never occur as part of self. Dedicated pathogens will deliberately avoid displaying these.
8. Now, the beta-2-microglobulin like molecule (see (7)) is gradually found to be inadequate as a backup identity check because various pathogens discover ways of mimicking or interfering with its machinery. This is when a new cell was required (perhaps like the natural killer cell) to recognise a more pleomorphic set of CAMs that are deliberately pleomorphic in a population and more or less unique to each individual. An appropriate set of specific receptors needs to be selected, in embryo, to recognise this unique ligand. These, I contend, are the origin of T cell receptors and they led, by inversion of function, to the cytotoxic T cell. In this vein, note that TNF and lymphotoxin are selectively toxic to cells NOT in gap junctional communication (09).

That leads us on to self/non-self discrimination. It is occurring as part of cell-cell "docking" based on CAM expression. CAM interaction leads to junctional communication, just as it does in embryos and in tissue regeneration (CAMs are reexpressed during periods of regeneration). The proposition here is that phagocytic and Tnk recognition is also achieved through a similar process.

When cells fail to establish communication, membrane reactions begin that lead to the release of a variety of prostaglandins and other cytokines. Similarly, when cells become unhealthy they break junctional communication and become prey to attack by both adjacent cells and inflammatory cells that are (in consequence) called into the area (10). When I first started thinking in these terms, I had found very little literature describing elective suicide and I even looked at plants for evidence of this (the hypersensitivity reaction). However, interest and literature on this have become abundant recently and there are several recent articles, one in Adv Immunology (11), one in the Annual Review of Biology (1991) and the enclosed (very readable) article from the New Scientist. Individual cells DO decide that they are sick and/or redundant. They DO have the the capacity to invite attack by adjacent cells and also to invite phagocytes along to effect their elimination. There is no need to presume that antibodies and lymphocytes are the sole or even the major assessors of healthy self status.
Calcium changes within the cell are all important in this election for "disposal by consensus". Ca++ ions act as second messengers for a variety of cell processes including apoptosis, nuclear division, growth factor stimulation and they are closely tied into the inositol-PO4/DAG/protein-kinase-C network of intracellular second messengers. In this respect, cellular identity and cell health is all tied into proto-oncogene activity and this in turn into gap junctions and communication competence (02). A much clearer understanding of cancer thus seems an imminent prospect.
When cells are attacked by C9 or perforin, they are made leaky, their cytoplasmic membrane potential falls and Ca++ ions are allowed into the cell. These molecules carry LDL receptor and epidermal growth factor receptor motifs. Any deeper significance of this escapes me at the moment but one important feature is that the receptors they mimic are both endocytosed in clathrin coated pits (like the Mhc molecules themselves).
By now I hope that you will be aware that this suggests a clear path in self/non-self discrimination beginning in sponges, that show differential aggregation (for they, too, have gap junctions), through to the complex mammalian immune system. In this respect, it is interesting to read that differential sorting is, in embryos, a direct consequence of CAM expression (12). The reasons why embryonic cells sort according to tissues rather than according to species is that their CAMs have remained highly conserved across widely separated species (13).

REFERENCES
01a CAMs and Igs: Cell Adhesion and the Evolutionary Origins of Immunity Edelman GM Immunological Reviews 1987 100:11 23+
01b Cell Adhesion Molecules: Implications for a Molecular Histology Edelman GM and Crossin KL Annu Rev Biochem 1991 60:155-190
02 Role of intercellular communication in the control of critical gene expression during multistage carcinogenesis. Yamasaki H, Enomoto K, Fitzgerald DJ, Mesnil M, Katoh F & Hollstein M CELL DIFFERENTIATION, GENES & CANCER Ed Kakunaga T et al IARC Scientific Pubs No 92, ISBN 92 832 11928 Pubs, International Agency for Research on Cancer
03a Development of the aging cell surface Kelley RO, Vogel KG, Crissman HA, Lujan CJ & Skipper BE Exp Cell REsearch 1979 119:127-143
03b Cellular senescence: A Reflection of Normal Growth Control, Differentiation or Aging? Peacocke M and Campisi J J Cellular Biochem 1991 45:147-155
04 Garrod DR, Nicol A "Cell behaviour and molecular mechanisms of cell-cell adhesion." Biol Rev 1981 56:199-244
05 Evidence mounts for the role of gap junctions during development. Green CR BioEssays 1988 8:7-10 (General introduction to GJs and development)
06a Neural Differentiation, NCAM-mediated Adhesion and Gap Junctional Communication in Neuroectoderm. A Study In Vitro. Keane RW, Mehta PP, Rose B, Honig LS, Loewenstein WR and Rutishauser U. Journal Cell Biology 1988 1307-1319 (Linking NCAM expression + gj communication)
06b Regulation of Connexin 43-Mediated Gap Junctional Intercellular Communication by Ca++ in Mouse Epidermal Cells Is Controlled by E-Cadherin Jongen WM, Fitzgerald DJ, Asamoto M, Piccoli C, Slaga TJ, Gros DG, T akeichi M & Yamasaki H J Cell Biol 1991 114:545-555
07 Gap Junctional Communication in the Extraembryonic Tissues of the Gastrulating Mouse Embryo. Kalima GH and Lo CW J Cell Biol 1989 109:3015-3026 (Lucifer yellow compartments and ionic coupling compartments)
08 Formation of hybrid cell-cell channels Werner R, Levine E, Rabadan-Diehl C & Dahl G Proc Nat Acad Sci 1989 86:5380-5384
09a Resistance to the cytolytic action of lymphotoxin and TNF coincides with the presence of gap junctions uniting target cells.
Fletcher WH, Shiu WW, Ishida TA, Haviland DL & Ware CF
09b Relationship between tumour cell morphology, gap junctions and susceptibility to cytolysis by tumour necrosis factor. Matthews N & Neale ML Br J Cancer 1989 59:189-193
10a Intercellular communication and tissue growth. II Loewenstein WR and Penn RD J Cell Biol 1967 33:235-242 (Description of communication changes in wounding etc)
10b Gap junctional structure and cell-to-cell coupling regulation: Is there a calmodulin involvement? Peracchia C & Bernardini G Fed Proc 1984 43:2681-2690?+
11 Programmed Cell Death in the Immune System Cohen JJ Advances in immunology 1991 50:55-77+ (General discussion
apoptosis etc)
12 & 13 CAMs and cell sorting CAMs and embryonic sorting across species barriers (I have been searching for this reference but can't locate it amongst my photocopies: this discusses the relationship of specific CAMs to cell sorting in disaggregated embryos and also to the fact that cross species similarities in CAMs accounts for selective organ rather than species reaggregation.) This is alluded to in other articles (01 and 16).
14 Growth Factors Modulate Junctional Cell-to-Cell Communication Maldonado PE, Rose B, Loewenstein WR J of Membrane
TBiology 1988 106:203-210
Behçet Mophoregulatory molecules Edelman GM Biochemistry 1988 27:3533-3542+

1992_05_26Vjournal_from

May 26, 1992 – why discrepancy?

RE: 1358BR Morphostasis and Immunity
Dear Doctor Cunliffe,
Your manuscript has been read through several rounds of peer review. Unfortunately, the advice that I have received from the Associate Editor is to reject it.
Why not consider sending it to Immunology Today where, if accepted, you will receive a much wider readership.
I express my appreciation for your interest in XXX.
Yours sincerely,

1992_07_13_journal_from

Dear Dr Cunliffe
Thank you for sending me your article ‘Morphostasis and Immunity’ which, as you can see, I am returning to you. Although I don’t want to publish it, I did find it thoughtful and entertaining – I imagine you surgeries are very interesting!
In approach your article is completely the opposite to the type we publish: it is long, leisurely and wanders across a wide range of subjects, while we tend to go for short, tightly focused pieces. Your paper is four times longer than the recommended length of our Viewpoint articles. You could certainly write a more focused article, for instance your ideas on electrical coupling and self assertion. However, its chances of getting through IT referees without a significant amount of back-up evidence are very low.
It’s difficult to think of other journals that might be interested. You’re posing the dual problems of a long, speculative article and the fact that you’re not well known in the field. The first point wouldn’t be a problem for, for example, the XXXX, which has published some highly speculative and provocative material, but he latter would be.
Sorry not to be more positive. Yours sincerely

1993_02_06_journal_to

Dear Professor XXX,
Re: "Morphostasis & Immunity" Your ref: ####
I spoke with "your secretary" this week who explained that it is taking longer than expected to receive a reply from your referee. In the six months since I first sent the manuscript I have continued to explore these ideas. I hope you don't mind if I take this opportunity to send this newer version with better language and more refined ideas. Whilst the basic concept is unchanged I have done some fine tuning and added references that add to the overall understanding. I have also added a few sketches that help to see how things might have evolved. Whilst these are too speculative to include in the article they do add some "colour" to the concept of MAC/GJ relationships.
Of particular interest are the references listed below.
Yours
HOMEOTIC GENES AND COMMUNICATION COMPARTMENTS.
Coelho, C.N.D. and Kosher, R.A., (1991). "A gradient of gap junctional communication along the anterior-posterior axis of the developing chick limb bud." Developmental Biology
148:529-535.
Martinez, S., Geijo, E., Sanchez-Vives, M.V. & Gallego, R. "Reduced junctional permeability at interrhomberic boundaries." Development 116:1069-1076 1992
Risek, B., Klier, F.G. and Gilula, N.B. (1992). "Multiple gap junction genes are utilised during rat skin and hair development." Development 116:639-651.
CANCER
Yamasaki, H., Carcinogenesis. "Gap junctional intercellular communication and carcinogenesis." 11:1051-1058 1990
HEAT SHOCK PROTEIN and CLASS I MOLECULES
Flajnik, M.F., Canel, C., Kramer, J. & Kasahara, M. (1991). "Which came first, MHC class I or class II?" Immumogenetics 33:295-300

1993_02_06_to

Dear XXX
Re: "Morphostasis and Immunity" Your ref: ***
I am concerned that I have still not received any communication from you regarding this manuscript. It is now 32 weeks since I sent it and the only feedback I have had was as a result of my telephone call 4 weeks ago to ***. I am particulary concerned that a rejection now will have resulted in a very substantial delay before I have a chance to submit it elsewhere. I would be very grateful if you could indicate how seriously you are taking this; do you regard it as cranky nonsense or potentially important - it can't, by its nature, sit in the middle. In view of the delay, I would appreciate some indication of the probability of rejection or acceptance and the progress towards a decision: I would not want to wait much longer before I withdraw it and submit it elsewhere unless I am reassured it's being taken seriously.
Yours sincerely,

1993_03_04_journal_from

Dear Dr. Cunliffe,
Thank you very much for the new version of your paper. We will not be sending this on to the referees. We are very embarrassed by the length of time our referees have taken with your paper, but have finally obtained a referee's report. I regret to say that it is very negative. I am enclosing part of the report. In general, our referees feel that the paper is far too discursive. I would not advise you to revise the paper in anything like its present form. I return both versions of your paper herewith.
Yours sincerely
Referees report Ms 3983: Cunliffe: Morphostasis and Immunity
"lg supergene like LIGANDs develop to act as a focus on which to grow highly specific gap junctional plates and create developmental compartments. The genes specifying these molecules can now be copied then altered by a 'mix and match' process to generate a set of LIGANDs which have a great variability within a herd. These pleomorphic LIGANDs will now act as the final arbiters of healthy self in each individual. Over many meiotic generations, they have eventually evolved into Mhc class I LIGANDS. Newly developed scavenger cells may now be able, when required, to electrically couple with any somatic cell that displays self specific LIGANDs and observe a horror autotoxicus to it. These scavengers need a mechanism to produce and/or select self specific RECEPTORs unique to each ZDC (zygote derived colony). This must be done post-meiotically over a number of mitotic generations - the 'generation of specificity'. (This possibly coincides with the evolution of amniotic embryos.) These scavengers resemble natural killer cells'.
As this passage from pages 26 and 27 of the manuscript shows, the author sets great store by 'seamlessness', the integration of large areas of biological thinking into what he himself is not ashamed to propose has the promise of a 'grand unification theory'. I am reminded of the aspirations of Herbert Spencer, who was also not ashamed to attempt the integration of everything in his System of Philosophy. And I am tempted to recall what George Eliot said about Herbert Spencer as well, after a visit with him to Kew Gardens for a “scientific expedition” to test some notions or other, that “if the flowers didn't agree with his theories, why, tant pis pour les fleurs!” The author feels that immunologists are barking up the wrong tree, with all their emphasis on lymphocytes, receptors, major histocompatibility antigens and so on. Or so he says, in no uncertain terms at the beginning of his essay. Surely, he argues, we should concentrate on other criteria by which health and disease are recorded in animal tissues. For reasons which are not absolutely clear to me, he focuses his attention on epithelia, where electrical connectivity is a sign of health, and disconnection evidence of disorder. There is something appealing to him about the fact that gap junctions have holes in them, evidence that cytotoxic mechanisms and normal healthy interactions between cells are seamlessly related to each other (see the Figure appended to the manuscript). Although the manuscript is very long, I do not in fact see any argument as to why the author has selected this attribute as the key marker of health and disease. It just seems to be his idea, that's all. To substantiate his notion that immunologists are missing the point (his phrase), he urges that signals involved in the formation and failure of epithelial connectivity are older in phylogeny than components of the immune system. So what? The immune system is what it is; its evolution is a matter of interest, a lot of conjecture, and increasingly pertinent evidence from lower vertebrates and invertebrates. Lets get on with something small and discriminating and leave the author to his fervid generalizations.

1993_03_09_journal_to

Dear Professor X,
Re: "Morphostasis & Immunity" Your ref: #### Thank you for your reply and the return of my paper.
Please don't be offended if I play devil's advocate and put this point: I do it tongue in cheek. Seven months is an unaccepta bly long delay to come up with a reflex dismissal of my concept, pronouncing it (as I see it) wrong and worthless. In view of this delay you owe me a favour! I'm going to request two. Please feel free, now, to file this letter to your waste paper basket at any stage you feel fit. I will not anticipate a reply.
" .. tant pis pour les fleurs!" implies that I have swept aside large chunks of known fact to suit my own ideas. Not so! And to suggest otherwise is a clear indication that the referee's emotional rejection of it has exceeded his comprehension of what I have said. He has misinterpretated the presentation. I have only called into question the perception of the facts not their validity. I point out that two important points are missing from current perception that, once appreciated, put everything else in context. The first that every individual cell has the ability to decide and communicate that it is sick (surely a safe bet) and the second that phagocytes are designed to recognise this sickness and do so by noting the absence of healthy self identity (again a pretty safe bet). Current immunological philosophy does not incorporate either of these as "raisons d'etre" in the immune system.
I know that this concept belongs either on the dung heap or it is a critically important perceptual shift. Its very nature di ctates that there is no middle ground. I think you all need to be sure I'm a crank before the concept is finally dismissed.
What's wrong with "fervid generalisations" if they are coming up with answers that the current dissective plod will take mont hs or even years to stumble across. The biological and medical community are renouned for disliking broad hypothesis. Nature ran a whole viewpoint article to point out this lack of adventure. Can you be absolutely certain that this is not another instance where conventional perception has been "stick in the mud"? Furthermore, the history of important conceptual shifts suggests they often come from unexpected sources and have often been dismissed at the beginning. I'm sorry that the referee has been offended by its inflammatory style but the points remain. We are missing the point and realising this carries the promise of very important advances in the understanding of immunology, metazoan evolution and embryology. No point in being annoyed if it turns out to be true.
Alright! I accept that the probability is that this will prove to be junk. But it is getting very predictive and I quote two recent instances of this later. The second of these predictions concerns embryology and I have highlighted it so that you can, if yo u wish, go straight to that section before reading anything else. Please note that I'm a lone "researcher" with no access to experts other than through submission to journals: I don't expect that I have written a "publication ready" article but I have no doubt tha t I am sitting on an idea of critical importance to all biologists and doctors.
Yours

1993_03_09_journal_to

MY RESPONSE TO THE REFEREE's COMMENTS (I am not sure which response was posted – this or the next 1993_03_15_journal_to)
It seems to me that this referee has been offended by the essay from the opening paragraphs. I cannot, though, see the evidence that he has properly understood what I am saying and he has certainly misinterpreted it when he implies that I am am throwing aside vast tracts of accepted knowledge to suit my own theory. He is far and away more guilty of prejudice in his reading than I am of the alleged disregard for accepted knowledge. There are a number of assumptions that I see as misinterpretations.
"The author feels that immunologists are barking up the wrong tree, with all their emphasis on lymphocytes, receptors, major histocompatibility antigens and so on. Or so he says in no uncertain terms at the beginning of his essay." First, I have not said this. My words were chosen very carefully. It is self(cell)/non-self(cell) discrimination that is not carried out by lymphocytes. I agree that this is hard to swallow when we have been brought up on the assumption that self(epitope)/non-self(epitope) discrimination is the basis of self/non-self discrimination and that convention dictates that this is carried out either by lymphocytes or antibodies. Here is a critical point! Unless you have fully understood the premise that zygote derived cells choose to communicate only with healthy self cells, you will not comprehend the rest. The result of this principle is that there is a tendency for lymphocytes to observe tolerance to self antigens (epitopes) and to encourage aggression (inflammation in fact) at the site of non-self epitopes. This was fully explained in the section "ANAMNESTIC IMMUNITY". The referee has not, apparently, grasped this point or the significance that it is fully compatible with current knowledge.
I do not dismiss any of the known facts about " lymphocyte function, receptors, major histocompatibility antigens and so on". I have simply said that the lymphocyte's principal role is to remember the inflammatory or non-inflammatory context in which it first encountered its respective epitope and became committed. On any subsequent encounter, phagocytic (inflammatory) cells are encouraged to accumulate in a pre-activated state to assess cells on the basis of their healthy self status. It's subtle but VERY important. Tc cells are in a half way house, able to kill directly but passively dependant on phagocytic cell signals to tell them what cells have unhealthy self status before an aggressive activation can take place. Prior encounters with epitopes met in a healthy self context ensure that (in general) Tc and Th cells with receptors for self epitopes are disabled and so unavailable for use to accelerate the inflammatory process.
"Surely, he argues, we should concentrate on other criteria by which health and disease are recorded in animal tissues." With a sarcastic air, this sentence dismisses a very important point. I could point you to a large number of articles that emphasise the ability of individual cells to monitor their internal function. Once we credit individual cells with the ability to monitor their own health status, the subsequent recruitment of appropriate T-cell receptors to aggression or tolerance will follow on the basis of this cell's assessment of its own healthy-self status (a combination of health and correct location). I'm sorry! But to dismiss this point as not being common sense is a foolhardy step: particularly as embryology is replete with examples of cells that decide they are unwanted and proceed to self destruct.
"Epithelia". The referee has managed to mention "epithelia" twice in a paragraph. I have written "epithelial" once and then not even within the general text or in remotely the same context (table 8). I can't even guess where this presumption has its origin. However, he is right that I have made very sparse explanation of where I have conjured up the concept of junctional communication as an indication of health and disease. This was clearly an oversight, brought about because I have had no one before to point out the omission. I have appended some reprint excerpts that qualify this.
".. he urges that signals involved in the formation and failure of (epithelial again!) connectivity are older in phylogeny than components of the immune system." Well! He's certainly showing he's missed a critical concept here. What could be older than CAMs and cell communication? Cell sorting in both sponges (frequently quoted as a primordial representative of self/non-self discrimination) and mammalian embryos is led by CAMs and there is mounting evidence that they lead on to GJ formation. Surely, he is out on a limb here if he doesn't acknowledge that the immune system evolved from an N-CAM like gene? And as CAMS lead on directly to GJ insertion, doesn't that make you pause and wonder if IgSF CAMs have Ig regions that also lead on to membrane hole formation? (See below).
Perhaps the way to progress these ideas is to lay down a challenge. I can set out the bare bones of the hypothesis and, if anyone can prove it to be mortally flawed, then I will capitulate and apologise for my amateur intrusion. However, I contend that the evolutionary gradualism that this hypothesis suggests far supercedes anything that has been previously suggested. And it points clearly to an overall appreciation of the process that is otherwise lacking at the moment. I shall not include that here but would, of course, willingly supply it.
PREDICTION
You are an embryologist (a factor is choosing your journal). You should appreciate the importance of its predictive value in one of the next points. There are two important predictions that literature searches have subsequently supported.
The first was the the idea that Tc function evolved as an inversion of Tnk function. This arose out of the necessity (in the hypothesis) for a cell that recognised self on the basis of specific Mhc Class I identity. This prediction was made in January 1992. Veersteeg's and other articles to support it appeared from July 1992.
The second is embryological. This has only recently (2-3 weeks) fully formed in my mind. There are two major CAMs in development

1. The cadherins that seem to have great importance in cell sorting.
2. The immunoglobulin superfamily CAMs (like N-CAM). These don't appear to have the same importance in sorting.

There are also two sorts of junction in embryos. First, junctions at compartment borders that display electrical communication but don't allow the free passage of Lucifer yellow (a molecule a little larger than retinoic acid). The second are the junctions within a compartment that allow the "transparent" passage of Lucifer yellow.
I have proposed that the construction mechanism for gap junctions and for complement membrane attack complexes have originated from the same primordial genes (and I'm becoming convinced GJs were first). You need to appreciate that the C9 molecule that forms MACs does not need the complement cascade to construct MACs. However, without it they form much more slowly and are smaller than the complement MACs. More critical, though, is the purpose of the C4/C3 cascade mechanism. It is designed to start MAC construction at the site of 3 or 4 closely situated and activated immunoglobulin constant region genes and then spawn hundreds of closely packed MAC constuction sites. Extrapolating this to the Ig (constant region) like motifs of IgSF CAMs leads to the prediction that high density, Lucifer yellow "transparent" junctions are formed only where N-CAM (or another IgSF CAM) is present.
Armed with this prediction, last night I pulled out all my articles on CAMs and carefully read through them again. Although I have quoted Keane et al's paper in my manuscript, I had not previously appreciated the importance or implications of their study beyond the fact that CAMs lead on to GJs. The findings reported in this paper are fully consistent with this prediction.
It leads on to another predictiion. Note that homoeo-domains are found and probably have a function in unicellular organisms. In the fertilised egg and particularly the multinucleated drosophila egg they define form and function within the cytoplasm so that when compartments form, their fates are already defined. The nature of embryonic compartments and their borders are such that this suggests that (a) electrical continuity through the embryo gives it a sense of "self" (not shared by the trophoblast) and (b) blocks of cells within a compartment are deliberately joined by morphogen "transparent" junctions to permit homoeo genes to map out the morphology of each compartment as if it were a single "super cell".

1993_03_15_journal_to

TWO FAVOURS!
The first favour I request is this. May I see the full transcript of the criticism(s)? You implied that you might have more than one. At least I can then address the points were I to submit a revision elsewhere.
The second, I suspect, you may have a strict policy to refuse. Can you consider my views on the criticism? Let me state now that authorship is not my prime goal though I would be dishonest if I didn't admit it appeals. I can forego it if that what it takes to make someone listen. I am a solitary worker who has been constantly interested in this subject for 19 years. I have no one to discuss this with. To reach those who might understand it, my only recourse is to submit it to a journal.
MY RESPONSE TO THE REFEREE's COMMENTS
This referee appears to have been offended by the essay from the opening paragraphs. I cannot, though, see the evidence that he has properly comprehended what I am saying and he has certainly misinterpreted it when he implies that I am am throwing aside vast tracts of accepted knowledge to suit my own theory. He is more guilty of prejudice in his reading than I am of the alleged disregard for accepted knowledge. There are a number of assumptions that I see as misinterpretations.
"The author feels that immunologists are barking up the wrong tree, with all their emphasis on lymphocytes, receptors, major histocompatibility antigens and so on. Or so he says in no uncertain terms at the beginning of his essay." First, I have not said this. My words were chosen very carefully. It is self(cell)/non-self(cell) discrimination that is not carried out by lymphocytes. I agree that this is hard to swallow when we have been brought up on the assumption that self(epitope)/non-self(epitope) discrimination is the basis of self/non-self discrimination and that convention dictates that this is carried out either by lymphocytes or antibodies. Here is a critical point! Unless you have fully understood the premise that zygote derived cells choose to communicate only with healthy self cells, you will not comprehend the rest. In practice, this principle leads to a tendency for lymphocytes to observe tolerance to self antigens (epitopes) and to encourage aggressive inflammation at the site of non-self epitopes. This amplification of the inflammatory response can so extreme that we had, for a long time, come to regard lymphocytes as the prime executors.
This was explained in the section "ANAMNESTIC IMMUNITY". The referee has not, apparently, grasped the significance that this is fully compatible with current knowledge.
I do not dismiss any of the known facts about " lymphocyte function, receptors, major histocompatibility antigens and so on". I have simply said that the lymphocyte's principal role is to remember the inflammatory or non-inflammatory context in which it first encountered its respective epitope and became committed. On any subsequent encounter, phagocytic/inflammatory cells are encouraged to accumulate in a pre-activated state to assess cells on the basis of their healthy self status. It's subtle but VERY important. Tc cells are in a half way house, able to kill cells directly but passively dependant on phagocytic cell signals and the sick cell itself to tell them what is an unhealthy self cell before an aggressive activation can take place. Prior encounters with epitopes met in a healthy self context ensure, in general, that Tc and Th cells with receptors for self epitopes are disabled and so unavailable for use to accelerate the inflammatory process.
"Surely, he argues, we should concentrate on other criteria by which health and disease are recorded in animal tissues." To me this sentence has a sarcastic air and flippantly dismisses a critical concept. It is easy to find large numbers of articles that emphasise
the ability of individual cells to monitor their internal function. Once we credit them with the ability to monitor their own health, the subsequent recruitment of appropriate T-cell receptors to aggression or tolerance will follow on the basis of this cell's assessment of its own healthy-self status (a combination of health and correct location). I'm sorry! But to dismiss this point as not being common sense I see as a foolhardy step: particularly as embryology is replete with examples of cells that decide they are unwanted and proceed to self destruct.
"Epithelia". The referee has managed to mention "epithelia" twice in a paragraph. I have written "epithelial" once and then not even within the general text or in remotely the same context (table 8). I'm not sure where this presumption has its origin. However, he is right that I have made very sparse explanation of where I have conjured up the concept of junctional communication as an indication of health and disease. This was clearly an oversight and the ommission reflects the fact that it has not been through peer review. I have appended some reprint excerpts that qualify this and it also needs pointing out that the sequence of events in apoptosis (separation and rounding up) are entirely compatible with this.
".. he urges that signals involved in the formation and failure of (epithelial again!) connectivity are older in phylogeny than components of the immune system." Well! I think this shows that he's missed a critical concept here. What could be older than CAMs and cell communication? Cell sorting in both sponges (frequently quoted as a primordial representative of self/non-self discrimination) and mammalian embryos is led by CAMs and there is mounting evidence that they lead on to GJ formation. Surely, he is out on a limb here if he doesn't acknowledge that the immune system evolved from an N-CAM like gene? And as CAMS lead on directly to GJ insertion, doesn't that make you pause and wonder if the Ig like regions of IgSF CAMs are also designed to amplify membrane hole formation? (See below).
A CHALLENGE
Perhaps the way to progress these ideas is to lay down a challenge. I can set out the bare bones of the hypothesis and, if anyone can prove it to be mortally flawed, then I will capitulate and apologise for my amateur intrusion. However, I contend that the evolutionary gradualism that this hypothesis suggests far supercedes anything that has been previously suggested. And it points clearly to an overall appreciation of the process that is otherwise lacking at the moment. I shall not include that here but would, of course, willingly supply it.
PREDICTION
You are an embryologist (a factor is choosing your journal). You should appreciate the importance of its predictive value in one of the next points. There are two important predictions that literature searches have subsequently supported.
The first was the the idea that Tc function evolved as an inversion of Tnk function. This arose out of the necessity (in the hypothesis) for a cell that recognised self on the basis of specific Mhc Class I identity. This prediction was made in January 1992. Veersteeg's and other articles lending support to this appeared from July 1992.
The second is embryological. This has only recently fully matured in my mind.
There are two major CAMs in development:-(1) The cadherins that seem to have great importance in cell sorting. (2) The immunoglobulin superfamily CAMs (like N-CAM) that don't appear to have the same importance in sorting.
There are also two sorts of junction in embryos:-(1) Junctions at compartment borders that display electrical communication but don't allow the free passage of Lucifer yellow (a molecule a little larger than retinoic acid). (2) Junctions within a compartment that allow the "transparent" passage of Lucifer yellow.
I have proposed that the construction mechanism for gap junctions and for complement membrane attack complexes have originated from the same primordial genes (and I'm becoming convinced GJs were first). You need to appreciate that the C9 molecule that forms MACs does not need the complement cascade to construct them. However, without it they form much more slowly and are smaller than C3 dependant MACs. Most critical is the purpose of the C4/C3 cascade mechanism. It is designed to start MAC construction at the site of 3 or 4 closely situated and activated immunoglobulin constant region genes and then spawn hundreds of closely packed MAC constuction sites. Extrapolating this to the Ig (constant region) like motifs of IgSF CAMs leads to the prediction that high density, Lucifer yellow "transparent" junctions are formed only where N-CAM (or another IgSF CAM) is present.
Armed with this prediction, I pulled out all my articles on CAMs and carefully read through them again. Although I have quoted Keane et al's paper in my manuscript, I had not previously appreciated the importance or implications of their study beyond the fact that CAMs lead on to GJs. The findings reported in this paper are fully consistent with this prediction.
This leads on to another predictiion. Note that homoeo-domains are found and probably have a function in unicellular organisms. In the fertilised egg and particularly the multinucleated drosophila egg they define form and function within the cytoplasm so that when compartments form, their fates are already partly defined. The nature of embryonic compartments and their borders suggests that:-(a) electrical continuity through the embryo gives it a sense of "self" (not shared by the trophoblast) and (b) blocks of cells within a compartment are deliberately joined by morphogen "transparent" junctions to permit homoeo genes to map out the morphology of each compartment as if it were a single "super cell".

1993_07_22_journal_from

Dear Dr Cunliffe,
Thank you for submitting your theoretical article entitled "Morphostasis and Immunity" to Immunology and Cell Biology. I have examined the manuscript closely and feel that, in its current form, the ideas have not been fully developed.
I am very sorry to tell you that your paper is unsuitable for publication in Immunology and Cell Biology, and I have no option therefore but to return all copies to you. However, I do thank you for your interest in the journal
Yours sincerely,

1993_07_11_journal_to

Either this or the following letter was sent.
Dear Dr XXX,
I wonder if there are concepts in this hypothesis that are worth sharing. Will you consider it for possible publication in this or an amended form? This version is much shrunken and therefore skips across a lot of detail. I have enclosed drafts of two (earlier) articles simply to emphasise that the ideas introduced briefly in Morphostasis and Immunity has been thought through in some detail. This is particularly pertinent to Clinical Morphostasis which contains an appropriate bibliography. It was the clinical hypothesis which led on to Molecular Morphostasis. This followed as it then seemed the logical conclusion.

1993_07_11_journal_to

Dear ***
I wonder if there are concepts in this hypothesis that are worth sharing. Will you consider it for possible publication in this or an amended form?
This version is much shrunken and therefore skips across a lot of detail. I have enclosed drafts of two (earlier) articles simply to emphasise that the ideas introduced briefly in Morphostasis and Immunity have been thought through in some detail. This is particularly pertinent to Clinical Morphostasis which contains an appropriate bibliography. It was the clinical hypothesis which led on to Molecular Morphostasis. This followed as it then seemed the logical conclusion.
Yours sincerely,

1993_07_18_file_created

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