The Rejection Letters
When a thing was new people said, "It is not true."
Later, when its truth became obvious, people said, "Anyway, it is not important,"
and when its importance could not be denied, people said, "Anyway, it is not new."
– William James, 1842-1910
(To my mind a balanced and fair letter – excerpts shown here because they cover historical points - all my edits or comments are in italics. Whilst Neils Jerne treated it as a submission, I had intended only to have him consider the value of the ideas.) " .//. far-reaching theoretical construction from a few elementary concepts. .//. most important of these concepts is the "inversion" of T-killer cell functions .//. (which is) conferred upon phagocytic cells .//. (which are regarded as) intrinsically aggressive, but are triggered to non-aggressiveness by "recognising" self, or self/self, as you say (this speculation later transferred to Tnk cells). .//.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 .//., 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.//. 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" orchestrated 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 ****. (Neils K Jerne)
This and all subsequent submissions included this concept:
In my opinion, Part 1 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? (Edwin L Cooper)
This submission included the figure above.
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.
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. .//. The author's inversion of B cell and T cell function in evolution also ignores what is known from extant animals.
I found the above manuscript potentially interesting and sent it for review to two members of the Editorial Board. 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. (Edwin L Cooper).
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. (Edwin L Cooper).
Thank you for sending me your article 'Morphostasis and Immunity' which, as you see, I am returning to you. Although I don't want to publish it, I did find it thoughtful and entertaining – I imagine your 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 ****** 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 ***** referees without a significant amount of back-up evidence are very low. It is 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 are not well known in the field. The first point wouldn't be a problem for, for example the **** Journal, which has published some highly speculative and provocative material, but the latter may be. Sorry not to be more positive. (The letter I have is dated 7/92 but I am suspicious that this is an error and it should have been 1993. However, I may have submitted it that year to this journal – after the suggestion from Edwin Cooper.)
Thank you 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 (seven months), 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. (Referee's report follows): " 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 generalisations."
Thank you for submitting your theoretical article entitled 'Morphostasis and Immunity' to *****. 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 **** and I have no option therefore but to return all copies to you. However, I do thank you for your interest in the journal. (I sent a rider with this submission including the table below. This was acknowleged in the words "all copies".)
Submissions to other journals, following this rejection, contained this table.
We have been mulling over your paper about morphostasis and immunity. On balance, we have come to the conclusion that it is not one for us. I cannot deny that we have taken a keen interest in apoptosis and other elements that you bring into your hypothesis. However, essentially you seem to have compared and contrasted modes of cell death, with the proposal of cell's self awareness. All in all we had some difficulty in getting to grips with this aspect, and if we find such things difficult, we imagine that many of our general readers will be even more perplexed. <> I must assure you that we are not averse to alien concepts, nor do we regard the article as crackpot nonsense#. We do hope that you can achieve publication elsewhere, and I think that a more immunologically competent journal is the direction to turn. (# A riposte to my submission.) (This is the covering letter and content of the submitted article.)
Thank you for your manuscript in which you attempt an explanation for the origin and subsequent evolution of immunity. I must say that you are not one to shy away from a big issue. Like my predecessor in this chair, I must decline the chance to review your paper. The problem you have chosen to tackle is impossible to address in this format, mainly because the phylogenetic data make it clear that there is not one but many roots to the evolution of a complex immune system. Undoubtedly, maintenance of host integrity against aberrant, dying or invasive cells is one component of this evolution. However, I think you will find that many organisms (e.g. tadpoles, moths etc) exhibit tightly controlled programmed cell-death systems as developmental tools, despite having very poor (or no) specific immune systems.
I must also say that my impression is that the material divides between propositions that are true, almost by definition — we know that the body has many homeostatic and protective mechanisms — and those that are untestable. How does a cell tell whether it is 'healthy' or not? And how does the investigator. If it undergoes cell death or is phagocytosed, one concludes that it is not but if it survives, does that automatically mean that it is 'healthy'? It seems to me that there are plenty of instances of damaged cells, in particularly genetically damaged, which are not eliminated a certain fraction lead to tumours of various sorts. Altogether, I would say that there are many sub-propositions here that are either self-evident (e.g. 'gap junctions are critically important in morphogenesis') or questionable. (This reply led to the idea of "widowed tautologies" – points so obvious that there should be no need to drum them home.)
Another rejection, reads as follows:
- It is proposed that the critical function of the immune system is the discrimination of heathy self from unhealthy self, or to borrow his colorful language a little, there is a sick-nonsick translation of S and NS.
- This 'sick-nonsick' form of a S-NS discrimination is indeed just like the Matzinger danger model in concept, but Matzinger went to the next step and analyzed the classical immunological literature to show how 'danger' fits better or worse than the competing associative antigen recognition model.
- Cunliffe's point of view is not easily accommodated with the observation that healthy tissue transplanted to a syngeneic individual is not rejected whereas in an allogeneic recipient the same healthy tissue is violently rejected. What made the transplant sick? The Matzinger version also has difficulty, but this criticism is faced and a special case is introduced to explain the facts.
- To keep on referring to the anamnestic feature of the immune response as its defining feature begs the question as to how the individual survived a primary infection in order to reveal the second order anamnestic property.
- Despite the colourful descriptive language, this exposition suffers from a marked absence of the explanatory mechanisms linking this view of immunity with the body of observations that must be logically linked to the view.
- It needs to be borne in mind that the immune response is a result of evolutionary selection. If the selection for resistance to infection was based on the recognition of sick versus nonsick cells, then the specificity and consequences of this determination is what is under selection, not antigen-specific antibodies and cytotoxic T-cells.
Sadly, the somewhat discursive nature of your manuscript makes it unsuitable for publication in a journal such as ***** that aims to publish new research results of immediate interest to a wide scientific readership.
In a series of publications preceding this one, the author has developed very interesting thoughts on the evolution and present-day status of immune functions. Though all of the papers are synoptic in style, they are clearly the result of qualified interpretation of research data. Most of the publications have appeared, or will appear, in the journal "Medical Hypotheses". <> The present paper is a summary of the previous synoptic papers, essentially without the addition of new aspects. Whereas readers familiar with the previous papers might welcome this, I doubt that newcomers will appreciate this very condensed summary as a first encounter with a hypothesis challenging paradigms of immunology. The essential messages are important and deserve an appropriate presentation if they are to be introduced.
Evolutionary biologists have an expression for the kind of hypotheses developed by Dr. Cunliffe: Just So Stories. They have about the same value. There is almost an infinite number of scenarios of this kind which can be developed by selecting certain facts (especially the "fashionable' ones) and ignoring others, but there is virtually no pragmatic way to test them. So, what are such sweeping claims good for? Maybe somebody will read this particular Just So Story and will be inspired by an idea that will prove to be fruitful, and this could justify the publication of the manuscript, but I doubt very much that it will actually happen. If at all publishable, it would be better placed in the Journal of Theoretical Biology (sic), presumably read by persons of similar interests as Dr. Cunliffe.
Thank your for submitting your paper to *******. We regret to say that because your manuscript did not receive a sufficiently high priority during the initial screening by our reviewing editors, we have decided not to send it for in-depth review.
I have some sympathy with your situation, and agree wholeheartedly with the quote from Dobzhansky that "Nothing in biology makes sense except in the light of evolution". However, I have some possible insight into why your recent hypotheses on "morphostasis" may not be getting the citations that you would wish. Firstly, it is not axiomatic in the immunological community that cells with capacity for "recognition" evolved solely under pressure from the pathogenic environment to generate an "immune system". Naturally, the importance of an "immune system" in higher animals does colour the language and focus of research such that this aspect can appear to exclude other valuable evolutionary insights. However, other insights have existed for many years and are accepted within the "mainstream" immunologic community. For example, simple histocompatibility recognition systems for the purpose of colonial "morphogenesis" in marine sponges, tunicates and coelenterates have been studied since the mid 1950's (see E.F. Abel  Zoologischer Anzeiger 153, 259-268), and molecular work on the recognition function of phagocytes and their receptors has been growing steadily since the 1970's. The implications of this latter body of work have been explored in terms of immune evolution certainly, but also their import for neural development, as well as cell-cell communication and development within several organ systems. Thus, your clear ideas concerning "morphogenesis" simply do not appear revolutionary. Secondly, at the heart of a good hypothesis lie its testable predictions, around which one can base experimental design and gather data. You have met the first challenge but not the latter. I would urge you, if you can, to take the predictions that arise from your hypothetical analysis and generate some results. It is at that point that citations will start to accrue.
Thank you for your manuscript entitled Flushing Out the Phlogiston? We are sorry to say that we cannot accept it for *****. The editors could not understand why you conclude that there is no such thing as the "immune system." Perhaps it is because your hypothesis requires considerably more flushing out to make your point acceptable. We are sorry your ideas have met with so much resistance. We can only hope that as you can more fully develop them they will meet with more approval. (My submission letter was deliberately provocative.)
Thank you for submitting your manuscript to *******. We have carefully evaluated your work but came to the conclusion that the paper does not yet warrant an in-depth review. /...../Papers submitted to ******* are judged on their timeliness and novelty; significance to the field and potential impact on the course of future work in the area; and whether or not they will be of interest to most immunologists.
Your manuscript cannot be accepted for publication. The reason for this decision is:
- The quality of the manuscript is substandard and below the generally accepted standards of the community.
- The paper has been reviewed by three reviewers. All of them conclude on the confuse (sic) presentation, not in line with common practice. In addition this opinion paper does not appear to include recent understanding. (Presumably, "confused" meant)
From this time onwards . . . .
I have not bothered to submit anything but simply add comments to my website. At least I don't have to question whether my opinion really is "worthless".
I am hoping that the morphostasis lesson will trumpet a reverberating raspberry around the bastions of smug reductionism. Science comes in two parts – trail blazing/pioneering stuff and consolidation. Consolidation (which includes falsification) is essential work. By nature, it may be less glamorous and needs to be rigorous. It is the foundation of authoritative science. But when consolidation is elevated to the status of being the only valid way in science and imagination is relegated to a minor task (and labelled unscientific) then we can be assured that the discipline is in mortal danger of settling into a state of smug reductionism. Painstaking dissection of detail is no substitute for regularly deconstructing then reconstructing perceptual frameworks.
Over the years I have had copious 'good advice' on how to mould my 'research' (#) to acceptable standards. Fortunately, I was both far too interested in discovering an answer and too immune from the imperative to publish for this to have wrecked the outcome.
(#) I have put paretheses around the word research because the process that I have used is a far cry from what is normally regarded as bio-medical research. Nevertheless, it is, perhaps, worth noting that this word is derived from the French rechercher — to look for/seek again. A large proportion of 'research' should, arguably, belong in the etymological realm of chercher — to look for, seek — and this seeking is largely done in the pursuit of a greater depth of detail. Deconstruction followed by reconstruction are processes that have a tendency to be forced upon us fortuitously, when it has become glaringly obvious that there is no longer much choice, rather than being actively championed goals in bio-medical science. Contrast this to physics where there is a much more cavalier deconstruction/reconstruction of older perceptions. Even so, at the end of the 19th century, many physicists were convinced that there was little left to do in their subject other than to dot the i's and cross the t's.