Appendix 2 - The Correspondence
This is Appendix 2 of 'A Habit of Lies.' It contains copies of much of the correspondence with individuals, institutions and journals referred to elsewhere in the site. This page is not intended as a good read, it is present merely to back up those references.
* Correspondence
* The Medical Research Council
* Dr. G. Koch
* Dr. Bretscher
* Dr. D. Bray
* Sir Aaron Klug
* Sir Dai Rees
* The University of Cambridge
* Drs. J. C. Metcalfe and T. R. Hesketh
* Sir David Williams
* Prof. Sheetz
* Nature
* Prof K. Jacobsen
* Science
* Recent
* Correspondence
This is a long document but is not intended to be read from beginning to end. It is an archive, in which you can find the stated position of particular individuals or institutions, such as they are worth. It does contain a few links and navigational aids.
This appendix contains the text of many of the items of correspondence with workers and institutions in the field. It would be inappropriate to reproduce all the letters and emphasis is given to those workers directly associated with the field or their institutions. About two thirds are included, which are fairly representative, both in substance and tone. In a few cases a section of text has been deleted, if so the deletion is marked thus .....
The correspondence normally began with a letter very similar indeed to the one given below.
Dear ,
I am writing to you as you have worked in the past, or are currently working, in the field of ligand induced capping of motile cells such as lymphocytes, or in the related field of cell surface particle movement.
As you know ten years ago I published an article (J. Theoret. Biol. (1979) 80 115-127) in which I proposed that the mechanism of capping and particle movement was that the capped patches or moving particles were induced to move by cell surface waves.
I am now writing to many workers in this field, particularly in this country. My aim is to ascertain the present status of opinion in the (field) with regard to the mechanism of capping etc.. I should say that, as far as I am aware, the scientific literature does not contain any expression of opinion concerning the validity of the wave model; I am of course principally interested in ascertaining opinions concerning this.
Accordingly, I would be obliged if you would be kind enough to answer the following questions.
1. Have you or any of your colleagues published an article which expresses an opinion of the wave model?
2. What is your present opinion concerning the various proposals for the mechanism of capping and particle movement?
3. Can you direct my reading to any article, preferably a review, written by anybody, whose opinions largely parallel your own and which does discuss the wave model?
4. Can you direct my attention to any piece of experimental evidence which in your opinion tends to disprove the wave model?
I feel I should clarify my position in asking these questions; in my opinion, the evidence in favour of the wave model would still appear to be overwhelming.
I look forward to hearing from you at your earliest convenience.
Yours sincerely John A Hewitt
8.1.91 Dear John A. Hewitt,
Thank you for your recent letter. I am not certain in what capacity you wish me to comment on your questions. I was under the impression that we were friends or at least acquaintances. I therefore find it puzzling that you choose to address me in such a formal manner. Of course you are at liberty to terminate friendships or acquaintances at will. However in such circumstances I am equally at liberty to exclude such considerations from my own response. At the very least I would like to know the purpose of the exercise upon which you are embarked. I can then judge whether it is appropriate for me to comment on the questions you raise.
I look forward to hearing from you.
Yours sincerely, Gordon L. E. Koch.
4.1.91 Dear John,
Thank you for your last letter. It was very helpful to have your "assumptions" laid out so clearly.
I wondered what your reaction to the accompanying extract was in view of your understanding that particles on cell surfaces move in a size dependent fashion.
Incidentally, I do not agree that lipid capping cannot be accommodated within the cytoskeletal attachment model. However this will require an examination of some studies on the nature of lipid capping so I hope we can defer this for the present.
Best Wishes Gordon (Koch)
(Dates are as given on letters but are apparently inconsistent.)
(Handwritten) 21.2.91 Dear John, Thank you for your letter and the clarification of the predictions of the wave model with respect to particle movement and its dependence on particle size. It did however leave me wondering how one would know that a particular observation belonged to domain 2. Do you have any predictions as to the size of particle or a particular type of cell which might be expected to behave as if it were in this domain? I also wonder whether you can direct me to the literature on the surface waves on cells as I must confess I am not too familiar with this. Best Wishes, Yours Sincerely Gordon
18-3-91 Dear John,
I think the time has come to discontinue this discussion. I now realise the reason for my original indifference towards the model you proposed. In many ways the problem from my point of view was that the surf-riding model was rather like the lipid flow model ie if there are the appropriate type of waves (lipid flows) in cell membranes they could explain the capping/particle movements observed. The test of the models is to demonstrate that the waves/flows exist and that they exist in a way which is indeed compatible with the a causal relationship between the two. In the case of the lipid flow model there was an additional assumption which I disagreed with ie that the proteins/receptors are freely diffusing in the plasma membrane.
When I read your original paper it seemed reasonable to me but the test was the demonstration of the existence of the - appropriate waves. I was not convinced by the evidence to which you referred but I assumed that with time a more convincing demonstration would emerge. That is why I asked you for your view of the current state of the subject. It seems to me that not much progress has been made so my original reservation remains. Unless one can show that the right type of wave does actually exist in cells then the model simply remains a theoretical possibility. I would contrast this with the cytoskeleton association model for which every major assumption has been confirmed, and in the prototype system for the capping phenomenon ie Ig capping on B-lymphocytes, direct evidence for stable linkage between the capping molecules and the cytoskeleton has been obtained and confirmed.
I hope you will not be offended if I do not continue this discussion on the present terms. However should a significant change take place on the issue of the existence of waves on cells please let me know.
With best wishes, Yours sincerely, Gordon (Koch)
3.1.91 Dear Dr. Koch, Some time ago I wrote to you concerning the subject of capping of motile cells. As I said in that letter I wish to ascertain opinion in the field concerning the wave model which I published some time ago (J. Theoret. Biol. (1979) 80 115-127). I wrote to you because you either work in this field or have done so. As yet I do not seem to have heard from you in response to these points. I would be most grateful if you would reply to my letter as soon as possible. The specific questions asked in my letter were as follows 1. Have you, or any of your colleagues. published an article which expresses an opinion of the wave model? 2. What is your present opinion concerning the various proposals for the mechanism of capping and particle movement? 3. Can you direct my reading to any article, preferably a review, written by anybody, whose opinions largely parallel your own annd which does discuss the wave model. 4. Can you direct my attention to any piece of experimental which, in your opinion, tends to disprove the wave model Incidentally my questions were asked and phrased with a view to elicitting both your views and the rationale behind them. ...... I do hope to hear from you shortly. Sincerely Yours John A. Hewitt
22 1 1991 Dear Gordon. Thank you for your letter of the 8th. Obviously I have hurt you by my formal manner, and I apologise for it. I was rather taken aback by your reply, I had not meant to offend you But you see, there is an issue, which I have raised before without receiving real replies. In the area of research which we are discussing, namely capping and associated phenomena, there have been three proposals put forward to account for the observations. Workers in this field, particularly in this country and including you, have chosen to acknowledge the existence of only two possibilities; not including the wave model proposed by myself. It would seem then, that these workers, including yourself, believe that my work is incorrect. I do not understand why you believe that my work is wrong. I have a clear interest in understanding the reasoning which has led the field to the view which it has arrived at, and I believe that your own position is an influential one in this area of research. Reading the literature really does not teach me anything about this, and so I am writing to you direct. The questions asked in my letter were carefully phrased to elicit responses which cited experiments which could be interpreted, in the view of the person replying, as negations of the wave model. I would be most grateful if you would reply to my letter along those lines and look forward to hearing from you soon. Yours Sincerely John A. Hewitt
30.1.1991 Dear Gordon, Thank you for your letter, yes I do want to carry on this debate until I understand the rationale being used here. Of course it is true that the cytoskeletal attachment model can account for your observations, but I do not think that it is the only, or the best, way of explaining them. More importantly, for a model to be regarded as successful, it needs to be consistent with the whole range of relevant experimental observations. The range of observations with which the cytoskeletal model is inconsistent is wide, and has been widely rehearsed. For example, I do not see how it is possible to accommodate the capping of lipids into that model. The principles of Popperian hypothesis testing require that, when a hypothesis is contradicted by experiment, it should be discarded. By contrast, the wave model has, as far as I know, no contradictions. Those workers who do not accept its correctness have not, to my knowledge, placed on the record any indications of those experiments they feel are contradictory. It is this gap which I am seeking to fill with the questions which I asked in my first letter. Incidentally, I do not understand what you mean by the "assumptions" of the wave model. My understanding is that 1. Waves on cells are an experimental fact. 2. Macroscopically, waves interact with particles in a size dependant fashion. 3. That particles on cell surfaces move in a size dependant fashion - my suggestion is that the third of these can be explained by the first two. The algebra, with which I elaborated this, does not, in itself, seem to create any additional, fundamental assumptions. In places, though, I made only rough estimates of particular physical values. I would be grateful if you would take the time to try to fill these gaps, and I hope to hear from you in due course. Sincerely Yours John A Hewitt
9.2.1991 Dear Gordon. the kind of size dependency of Particle movement on a wave which one would expect to see is. (Figure given here) Don't attach any quantitative significance to this graph but the overall shape is right. There are three regions. 1. Very small objects - molecules of protein etc. do not interact significantly with the wave, and so do not move (beyond diffusing). 3. The third region is very large objects, particles of carbon etc. These interact strongly with the wave because they are big. so they entrain onto the wave motion and move with the waves. Their rate of movement is simply that of the wave, and, within this domain, their rate of movement will be independent of size. 2. The second domain is between the two extremes. Here, the rate of movement will be slower than that of the wave itself. Also, within this region one might expect a. The overall rate of movement to depend upon the strength of interaction with the wave and thus upon the size of the object. b. The rate of motion may well not be constant, but is likely to exhibit elements of periodicity (whose frequency and regularity would be that of the wave itself). In some circumstances the object can come to a stop, or even go into reverse occasionally. (This seems so extreme a prediction that I say it with some hesitation.) Observations within domain 2, would provide some of the ways of distinguishing the cytoskeletal attachment and wave models. Iha photocopy you sent me referred. I think, to particles in domain three. Their rate of movement would measure the velocity of the wave train. Even so, if small enough objects were observed, the rate of movement should slow down - one is. though, rather limitted by the resolution of the light microscope. Sincerely Yours John Hewitt
3.3.1991 Dear Gordon, thank you for your recent letter of the 21st. I think that assigning a particular observation to a domain can be done, within the context of the wave model by: If an object is moving at a steady speed along the membrane it is in domain 3. If it is moving in an irregular manner, then one would say it was in domain two. If it is not moving (apart from diffusion) it is in domain one. In fact observations are really only available on "big" objects because these are easy to see, and on small objects because the membrane is made of them. The best thing would be to be able to look at the behaviour of particles of the same chemical type, as a function of their size. This seems very difficult to realise in practise. realise in practise. A more practical approach would be to find something which appeared to be in domain Z and then plot its position against time. This could then be analysed for periodicity. The calculations in my paper were largely concerned with determining the factors which would determine the size of particle which would entrain totally on the wave, i.e. go into domain 3. I did not discuss, in any detail, the behaviour of objects in domain 2. The conclusions I arrived at were that most of the available variables would influence the sizes at which the changes would occur. In particular, the amplitude and wavelength of the wave, the flexibility of the membrane and of the object will all, in principle, influence the size boundaries. Since these values are not known well, and some could well vary greatly, a firm figure is impossible. Basically I think you are more likely to find domain two observations in the smaller range of observable sizes of individually observable particles. For the literature on waves I suggest you read to begin with Tony Durhams review in Cell, (1974) 2 p123. This is the article that got me aware, as it were, though I would not agree with many of the figures he draws. ..... Other articles I have found with varying degrees of certainty are de Bruyn (or similar) (1946) 95 pl77. Ambrose E.J. (1961) Exptl. Cell Res. (suppl) 8 p54. Bornens, Paintrell and Celaci, (1989) 109 plO71. Keller & Cotier - Cell Biol. Int. Reps. 5 3-7. The third of these does not really mention waves, but is highly similar. I think, that the last is an article about swimming leucocytes, which I have been trying to find. Some of my papers have become mangled and I as not sure of this. If you read it, can you confirm to me that it is what I think, (I told Martin Raff I would try to find it for him). In general, I get the impression that waves become more visible when the structure of the cell cytoplasm or membrane is loosened up in some way. You will be aware I expect of the behaviour of cillia on paramecium, the periodicity of the structure of a microvillus (even after fixation) and the nature of a nerve impulse. Waves are very widespread phenomena, including in cell membranes. Yours Sincerely John Hewitt
19th July 1990 Dear John, As you know, I have never really understood the physical basis of your wave model: your replies to my questions when you gave a tea club talk in the Biochemistry Department several years ago did not clarify the situation.
As to the direction the field is taking there is, as far as I can divine, an increasing belief that particle migration is achieved by direct action of some part of the cytoskeleton. This is, of course, not a view that I share. There are two real problems in the field: (1) There exist several individuals who cherish their own models (and I am a fine example) and (2) there are relatively few experiments which shed light on the molecular mechanism of what is going on. Neither situation is surprising since any experimental evidence is very hard to come by and this allows all sorts of ideas to be tossed around. It also means that a particular view needs an active advocate to keep it alive: in the case of your wave model your absence from the fray may be leading to its being ignored. This, of course, has nothing to do with what is true or false, but more to do with personalities.
Yours Sincerely Mark Bretscher
27 7 1990 Dear Mark, Thank you for your reply to my letter. In fact I was not aware that you did not understand the physical basis of the wave model. I will attach to this letter a non-mathematical description of the kind of thing which happens when a wave and an object interact with one another. I take your point that there are several individuals who cherish their own models. There are only three basic models, with variations of each of them. I do feel however that there exists experimental evidence which allows a choice to be made between these models. It seems to me that one can apply Popperian hypothesis testing directly to this situation. By this I mean, a model once proposed, is to be challenged by comparison with experimental facts. If it is thereby contradicted it can be discounted. Conversely, if a model is not contradicted, then it may be correct. May I refer you to my paper in which I mentioned some of the experiments which contradicted the notions of both cytoskeletal and flow models. My paper also sets out positive evidence for the cofrectness of the wave model. Generally these are : 1. The phenomena to be accounted for are, broadly, are that objects which are large, by comparison with a protein molecule, move on the membrane surface, while objects which are small do not. The movement is from front to back. 2. There are several observations of wave motion, and oscillatory behaviour at the cell surface. The waves move from front to back. 3. Theory predicts. and experiments confirm, that when a wave and a particle interact the wave tends to carry the particle along with it; the wave entrains the particle. Such entrainment is seen to be more efficient for larger particles than for smaller ones, this is also predicted by theory and confirmed by experiment in macroscopic situations. Thus the wave model seems to be a model almost without assumptions. As far as I am aware there are no experimental contradictions to it. I am of course aware that you have published articles reviewing this field. You do not appear to consider the possibility that waves drive capping. On the face of it, it would seem that you consider the wave model to be unfounded. I would be very interested to know what results have led you to this conclusion. Going back to my original letter, I would be most grateful if you would answer the questions which I posed. I would of course be happy to furnish any further clarifications which you might need. Incidentally, I am in the process of moving from Rathmore Road. Please note that, for the time being, I can be contacted via 57 Stuart court Swarland Grove Bradford BD5 OSU I look forward to hearing from you in the near future. Sincerely Yours John A Hewitt
Physical Mechanism of Capping In my original paper the type of wave which I discussed was a geometric wave, such as one sees on the sea. This is because I think that such waves exist and perform a peristaltic role in aiding motility. It has been pointed out by a man in Bulgaria, by the name of Petrov, that flexing a membrane made of polar molecules would be expected to produce an electrical potential across the membrane. I might add that the corollary should also be true. Thus one would expect that the existence of geometric waves would be associated with an oscillation in transmembrane electrical potential. Thus for the purposes of this note I will consider an electrical wave, not because I think that this is likely to be the major impetus to entrainment, but because I think it is simpler to see what is happening this way. I think that the result of size dependent entrainment arises regardless of the exact mechanism of interaction between the wave and the object. We might consider then an electrical wave consisting of a pattern of alternating regions of positive and negative potential travelling along the membrane, as shown below (Figure here) If a particle approaches this membrane it will associate better with one region of the membrane, depending upon its own charge, if it is positive it will associate with a negative region of the wave and vice versa. As the wave moves along it will be dragged along by the region of the wave with which it preferentially associated. It is useful to view this situation in terms of the potential energy of the particle. If, say, the particle is positively charged it will have a high potential energy near regions of the membrane which are positive and a low potential energy near regions of the membrane which are negative. A graph of potential against position on the membrane will look like this with a series of peaks and troughs. The particle will sit in the troughs, at the bottom of the hill as it were and try to stay there as the wave moves. (Figure Here) The larger the particle, the larger, the surface area of interaction between the particle and the wave, and hence the higher the peaks in this graph. This is the reason why one would expect large particles to entrain on a wave more efficiently than small particles. The same consideration will apply whatever the mode of interaction between particle and wave. Thus the same conclusion would apply to other wave particle interactions and the same dependence on particle size would be seen It now remains only to explain the relationship between this potential energy graph, peak height and extent of entrainment on the wave. The force acting on the particle is the slope of the potential energy graph. The higher the peaks are the greater is that slope and hence the greater is the force acting on the particle. This is why on a wave tank one sees large cork objects moving faster than small ones. In the case of the cell surface however I don't think that this is the way to look at it. An object can only entrain on the wave if its random thermal energy is less than the height of the energy peak - if this is not so then random thermal fluctuations will cause it to jump from one trough to the next. The amount of thermal energy which a molecule has is independent of its size, and kT is usually taken as an estimate of this energy. Thus we have a situation where once an objects size becomes great enough for the energy of these peaks to be greater than kT it will start to travel with the wave train rather than jumping over from one wave to the next, hence size dependent entrainment. In conclusion then, a wave train on a cell surface will tend to pick up particles and carry them along with it. Small particles will tend to jump from one cycle of the wave to another, while large particles will tend to travel with the wave. I think that this describes what is seen in capping.
The following was handwritten on a reprint.
Dear John,
I don't wish to get into a long correspondence, but here's a copy of a recent paper which may interest you.
With Best Wishes Mark Bretscher
23.8.1990
Dear Mark,
Thank you for the copy of your paper, which was not only interesting in itself, but will no doubt help me in tracking the literature.
I note that you do not want to enter into a long correspondence. Of course I am writing to people in the hope of obtaining answers to my questions concerning this field. I do not feel that this should need a long correspondence, and I hope that it will not.
The questions which I posed in my original letter are, in my opinion, reasonable, and necessary, for scientific debate in this field. I do urge you to reply to them.
Yours Sincerely
John A Hewitt
Originally, no reply was received from Dr. Bray. The following arose after a letter to the then head of that MRC unit, Prof W. Gratzer.
20 June 1991 Dear Dr Hewitt
I'd like to apologise for not answering your previous letter. I have just returned from a year abroad during which I changed my address repeatedly and much of my correspondence went astray.
Your surf-riding model for capping and other cell surface movements was a highly original contribution to the literature when published but has not lasted well (like some of my own theories, alas!). It is now known that particles attach to specific receptors (usually integrins) on the surfaces of cells and that the latter are connected via proteins such as talin, vinculin, and alpha-actinin, to actin filaments on the inside of the membrane (see Burridge K. and Fath, K.R. Trends Biochem Sci 10: 104-108, 1989). The actual situation is consequently totally different to that of a surf-riding floating body.
The essence of your model, as I understand it, is that a large body is transported unidirectionally on the surface of the cell while the actin and other molecules in the cell cortex undergo small cyclic movements associated with wave motion but are not transported. There is now direct evidence, however, that during capping, cytokinesis and fibroblast crawling actin moves in conjunction with particles on the surface (see for example Cao and Wang, J Cell Biol 110: 1089-1095, 1990).
One further prediction of your model that has been shown to be incorrect is that very small particles do in fact translate on the surface of cells, evidently through an association with the cytoskeletal elements on the inner face of the plasma membrane (Sheetz et al Nature 340: 284-288, 1989).
I hope this is of some help.
Yours sincerely
Dennis Bray cc Dr W B Gratzer
July 1991
Dear Dr. Bray,
Thank you very much for your letter dated 20 June 1991, and for the references which you quoted therein, none of which cite or discuss the wave model. These references are useful in showing me, in a positive sense, what you presently believe to be correct.
However, this is not really the point I am trying to get at, which is to learn in a negative sense, your reasons for rejecting the wave model. The Burridge and Fath article (by which, I presume, you meant their article in Bioessays, rather than TIBS) deals with cell substrate adhesions. I am not aware that a relationship between this and capping and particle movement has been established, perhaps you could clarify? Since capping and particle movement seem to apply to any cell surface object, it seems unreasonable to suppose that it can be mediated by "specific" receptors.
I note your comments about the Cao and Wang article, but I have to say that it is, in my view quite wrong to talk in terms of "evidence for". I think it is evidence against which matters. The cytoskeletal model seems to predict that contact with the cytoskeleton is a necessary condition for capping. I know of no real explanation of why, if this is the case, lipids and non-transmembrane proteins can be capped.
I believe that Sheetz and his collaborators actually showed that, very small objects on the surface of the cell do not translocate, until they become larger, as assessed from their diffusion coefficient. This was the observation which they emphasised. They interpreted the intermittent increase in size as resulting from contact with the cytoskeleton. This may be so; the size dependence of particle movement is, as you say, predicted by the wave model, whether the size variation comes from within or without the cell seems unlikely to make any difference.
I have studied Sheetz's recent papers, I do not think they negate the wave model, indeed I think they are more consistent with it, than they are with Sheetz's own interpretations. For example at one point he reports intermittent forward and backward motion. He seems to feel the cytoskeleton is continuously circulating - it is hard to interpret such motion on this basis.
The view which I take in this field is, I believe, one which is a standard view of scientific method. I think Popper's paradigm of scientific reasoning applies in its entirety; as you know, this states that when a hypothesis is put forward, it is to be challenged by reference to the experimental observations. If a hypothesis fails to predict those facts, then the hypothesis should be seen as inadequate. If the hypothesis successfully predicts the observations then it may be correct, but cannot be viewed as proved.
Within this paradigm, science is seen as working by elimination; proof is not regarded as meaningful, only disproof is a strong statement. Of course, this view of science is generally accepted by the scientific community.
I am writing to you because, as you say in your letter and as is implied in your publications, you do not regard the wave model as viable.
What I would like to know is, which experimental observations, of your own or reported by anyone else, led to your view that the wave model has been negated?
As I said, the articles which you cited did not mention or discuss the wave model at all, as a result they did not deal with the issues which I am trying to get at. I do not really know to which of the experiments described in these papers you are referring me. Further, your own work goes back many years, and your rejection of the wave model seems to considerably antedate these publications.
Your letter was helpful to me, but I do not feel it has resolved the issue. Would you be kind enough to take the time to reply again, this time citing the specific experiments which led to your rejection of the wave model? Thank you for your time. Yours Sincerely John A Hewitt cc. Dr. W.B.Gratzer
29 July 1991 Dear Dr Hewitt
I'm not prepared to answer any more questions about your surf-riding hypothesis. Please ask someone else. Yours sincerely Dennis Bray cc Dr W B Gratzer
3 April 1999 Dear Dr. Bray,
Thank you for your letter dated 29th of July, in which that you state that you are not prepared to answer any more questions about my surf-riding hypothesis. You also suggest that I ask someone else.
Please do understand, I am not suggesting that, as an individual, you are under any legal compulsion to reply to my questions. As a professional scientist, however, I feel that you should. In your publications you appear, by omission, to have rejected the wave model. Surely, the accepted scientific logic as delineated by Popper, requires that it is possible to explain the rejection of a given hypothesis. Because your apparent rejection of the wave model is only by implication, I do not understand the reasoning which led to your view.
It is my research which you appear to reject - I have an obvious personal interest in knowing the reasoning which led you to that view.
I believe that I am asking you simply to fill the gap which it seems to me your papers have left. Since you were the senior author of the papers, and, I believe, the team leader of the research group, it seems to me that you are the appropriate person to make these enquiries of. If you can suggest any other individuals, I will certainly be willing to enquire of them also.
In the mean time, I hope that you will consider this matter carefully. I am enquiring of you, and I hope that you will reply to the enquiries which are being made. Yours Sincerely John A Hewitt cc Dr. W.B. Gratzer
6 January 1993 Dear Dr. Bray,
I am writing further to our correspondence concerning your position with regard to the models which have been proposed to account for the mechanism of capping and particle movement on motile eukaryotic cells. As you know, I was not satified by the replies which I received from you.
In pursuit of the clarification which I require of this issue, I have written a brief review of the status of this field as best it is known to me. A copy of "Cap That!" is enclosed herewith.
I should be grateful if you would read this review, especially those sections which refer to your own position. If "Cap That!" describes your position in way which you feel to be inaccurate or misleading, I should be grateful if you would let me know. I would be grateful also for a clarification of any points which you feel I have reported unsatisfactorily. Yours Sincerely John A Hewitt
9 June 1991 Dear Dr. Klug,
I am writing to you concerning the subject of capping and particle movement on the surface of amoeboid cells.
As you know, I worked in the Department of Biochemistry in Cambridge, as a Demonstrator, between 1978 and 1983. During that time, amongst other things, I performed some work concerning this subject. The work was published in the Journal of Theoretical Biology (1979) 115-127; it proposed that such phenomena arose as a result of wave action on the surface of the cell. I think this proposal is in fact correct.
However, a number of workers in the field appear to think that this concept is wrong. In particular, Dr. M.S. Bretscher and Dr. G.L. Koch of your Department appear to be of this view, inasmuch as they have published work in the field, in a way which omits all mention of the possibility which I raised. The result is that, although they appear to think that my work is wrong, I know nothing of the reasoning which led them to this view.
It is, of course, accepted that they are entitled to their own views. I would like to have a clear idea of the scientific considerations which led to their rejection of my work. Accordingly, I have written to them, asking them to explain, in specific terms, how they arrived at the opinions which they seem to hold. Although they were kind enough to respond to my letters, their replies did not address this issue.
I am writing to you to ask that you intercede with your colleagues on this matter and ask them to reply to my enquiries. I would be obliged also if you would confirm the receipt of this letter. Thank you for your time. Yours Sincerely John A. Hewitt ....... 27th June 1991
Dear Dr Hewitt,
I have now had a chance to follow up your letter of June 9th and have, in fact, seen the file of correspondence that Mark Bretscher has had with you. I must say that I do not think he is duty bound to mention your model when he writes about his own work. This is not a subject I have followed in detail but I have seen enough to realise that it is extremely controversial, as witness the exchanges between Bretscher and Sheetz in recent years. It seems that people feel very strongly about the models but so far I have not come across any critical experiments which really prove one model or the other, and that is what people should be doing rather than exchanging views about theoretical knowledge. In your own case, is there any direct experimental evidence for waves on the surface of the appropriate cells and if so would they actually contribute to particle motion? If one were to start discussing all the models then it seems to me that one could equally cite as an example the "rake" model which would explain why large aggregates might move (by being captured by the cytoskeleton) and small ones do not. Yours sincerely, Aaron Klug
14 July 1991 Dear Dr. Klug,
Thank you for your letter dated the 27 June 1991.
The view which I take in this field is, I believe, one which is a standard view of scientific method. I think Popper's paradigm of scientific reasoning applies in its entirety; as you know, this states that when a hypothesis is put forward, it is to be challenged by reference to the experimental observations. If a hypothesis fails to predict those facts, then the hypothesis should be seen as inadequate. If the hypothesis successfully predicts the observations then it may be correct, but cannot be viewed as proved.
Within this paradigm, science is seen as working by elimination; proof is not regarded as meaningful, only disproof is a strong statement. Of course, this view of science is generally accepted by the scientific community.
Applying this view to the situation with capping and particle movement, in my opinion
Firstly, I think there should be an exchange of theoretical views. If this does not take place, then it seems there would be an increased likelihood of the "correct" hypothesis not being included in the set of hypotheses from which elimination takes place.
Secondly, if a worker feels able to reject a hypothesis, then he can reasonably be asked, which experimental tests lead him to that view.
Thirdly, a request for proof of a hypothesis, or "evidence in its favour," before it can be considered, is of questionable validity.
As far as I am aware, neither Dr. Bretscher, nor Dr. Koch, have explained the reasoning which leads them to reject the wave model. Both these workers have omitted it from consideration in describing their own work; this seems to imply that they believe it to be false. It seems to me that they should have taken the opportunity offered by their articles, to explain why they felt that way. However, I am not suggesting that they are legally obliged to do so.
In the absence of an explanation for this rejection of the wave model being available in the literature, I wrote to them, asking their views directly. Again, I am not suggesting that, as individuals, they are under any compulsion to reply. However, in their capacity as professional scientists, matters are less clear cut. Surely, accepted scientific logic requires that they explain their rejection of the wave model!
I have read the exchanges between Bretscher and Sheetz. My feelings are that Sheetz's group have performed a very valuable series of experiments, and certainly have added further disproof to the argument against the flow models. The exchange did not change my perceptions of the field - I think both cytoskeletal and flow models have long since been disproved; in my view, these workers should have sought alternatives.
There is direct experimental evidence for the existence of waves on motile cells; ....... In macroscopic situations, waves and particles interact in the required manner - there seems no physical reason to suppose this would be different at a cellular scale.
What is more, the wave model can reasonably be linked to cellular motility - and wave mechanisms for motility have evolved frequently in the natural world.
I can think of no biological system where mechanisms of the alternative types are known to exist. For this reason, I can only regard them as being basically ad hoc, while being open to contrary evidence.
As far as I understand it, the rake model to which you refer, is essentially that which is presently championed by Sheetz. If it is not, then I do not know the model to which you refer. Could you let me have a reference in order that I can pursue this further?
Thank you for your time. Yours Sincerely John A Hewitt 17th July 1991
Dear Dr Hewitt,
Thank you for your letter of July 14th. I take your point about the ideal way in which scientific controversies might proceed but I'm afraid this is not the way things happen in practice. Moreover, in a field where there is so much conflict of opinion, it is not the duty of anyone working in the field to discuss all the possibilities whenever they write their papers. This is the sort of thing that is usually dealt with in reviews or conference proceedings. ........ Yours sincerely, Aaron Klug
8 August 1991 Dear Dr. Klug,
Thank you for your letter dated 17th of July .....
I note that you do not feel that science works in practice in the ways outlined by Popper. I think one must be cautious about the meaning of the word "works". In this field, possibly in others, it is true that workers have not always conducted their work on this basis, and I would not suggest that this is always inappropriate. The ultimate test must be whether a field works, in the sense of functions successfully. Things being what they are, I would, of course question whether that is the case in this field. I would argue that, in a "controversial" field, it is best to attempt to stay close to the ideal.
With regard to your other comments - I perhaps have not made myself clear - I am not concerned about every paper your colleagues write, nor about the medium in which they choose to record their views. I merely suggested that I thought one appropriate medium for them to explain the logic of their rejection of the wave model, would have been at least one of their various papers.
However, it is a matter of record that they have explained this point in none of their papers. Moreover, I have never been invited to a conference to discuss this topic, neither, to my knowledge, has the matter been recorded in any conference proceedings. Further, to the best of my knowledge, no review article has ever been published which explains these points. I have made use of the scientific abstracting media to search for such things, and I believe I would have found them, had they existed.
In my original letter to Drs. Bretscher and Koch, I asked them to point out to me any articles, "particularly reviews," which dealt with the wave model in a way which agreed with their own opinions. They have not pointed out any such article to me.
As I said, my concern is not with the medium your colleagues have used, but with the apparent choice not to record any explanation at all, of the reasoning which underlies their rejection of the wave model.
I do not see how scientific debate can proceed on this basis, whether or not the subject is controversial.
Further, it is my work which they have chosen to reject - I have an obvious, personal interest in knowing how they arrived at this conclusion. Besides myself and Dr. Durham, as you may know, Profs. Oliver and Berlin in the U.S. have expressed similar views to my own. They may also be interested to know the reasoning which has led your associates to reject it.
I would, therefore, be very grateful if you could approach your colleagues, and ask them to explain their reasoning on this matter by writing directly to me. Yours Sincerely John A Hewitt
12th August 1991 Dear Dr Hewitt,
Thank you for your letter of August 8th. I have stated my opinions and I am not prepared to intervene any further with my colleagues. ........ Yours sincerely. Aaron Klug
Copy of "Cap That!" sent 6 Jan 1993
22 September 1991 Dear Dr. Rees, I am writing to you concerning the subject of capping and particle movement on the surface of amoeboid cells.
I worked in the Department of Biochemistry in Cambridge, as a Demonstrator, between 1978 and 1983. During that time, amongst other things, I published a paper concerning this subject. The work appeared in the Journal of Theoretical Biology (1979) 115- 127; it proposed that these phenomena arise as a result of wave action on the surface of the cell. I think this proposal is in fact correct.
However, a number of workers in the field appear to think that this concept is wrong. However a number of workers in the field appear to think that this concept is wrong. I am referring here in particular, Dr. M.S. Bretscher and Dr. G.L. Koch who work at the MRC Centre in Cambridge who seem to be of this view, inasmuch as they have published work in the field, in a way which omits all mention of the possibility which I raised. Dr. Bretscher, in particular has several times reviewed the various mechanisms which have been proposed. Their actions seem to imply that they think the wave model is wrong, however, because this is an implication, I have never known anything of the reasoning which led them to this view.
Dr. D. Bray of the MRC Cell Motility Unit at Kings College London, likewise appears to be of this view. Because of its relationship with axonal transport, he has published work containing reviews of the proposed mechanisms in this field, in a way which omits all mention of the possibility which I raised. The result is that, again, although he appears to think that my work is wrong, I know nothing of the reasoning which led him to this view.
It is, of course, accepted that they are entitled to their own views. I would, though, like to have a clear idea of the scientific considerations which led to their rejection of my work. Accordingly, I have written to them, asking them to explain, in specific terms, how they arrived at the opinions which they seem to hold. Although they were kind enough to respond to my letters, their replies did not address this issue.
I have also written to these workers via their respective Heads of Institutions, Drs. Klug and Gratzer. Dr. Klug has declined to intervene; as far as I understand them, the reasons which he has given me are that, because the field as a whole is controversial, it is not necessary for scientists to record their reasoning. Dr. Bray has stated that he is not prepared to answer "further questions" concerning the wave model. He has not explained why he feels the wave model to be wrong.
I am writing to you to ask that you look into this matter, and intercede with your colleagues, asking them to reply to my enquiries, in particular explaining why they feel the wave model, my work, to be incorrect. Could you please, also, acknowledge the receipt of this letter. Thank you for your time. Yours Sincerely John A. Hewitt
1st November 1991
Dear Dr. Hewitt,
I write in reply to your letter of the 22nd of September concerning wave models.
I have now had the opportunity to look into the matters raised in your letter and have seen the relevant correspondence. Dr. Mark Bretscher's letter to you of the 19th. of July seems to me to crystallise very well the essence of the problem, namely that yours is but one of a number of models proposed about capping and particle movement on amoeboid cells and that the field is therefore in a state of flux. The difficulties in securing hard evidence for any of the theories mean that conflicting views are inevitable. As Dr. Bretscher points out, it is not so much a case of your work being rejected by others, simply that you are no longer in the field to fight your corner actively.
Biology is by definition a fast moving science and all researchers, no matter how talented, have to accept that what is fact today is likely to be superseded by tomorrow's breakthrough. I am sorry that I cannot be of more help. Yours Sincerely D A Rees
17 November 1991 Dear Dr. Rees, Thank you for your letter dated 1st. November 1991 and for looking through the correspondence following my enquiries to Drs. Bretscher, Bray and Koch.
You state in your letter that you feel that Dr. Bretscher's letter "crystallized very well the essence of the problem." I have to say that I did not feel his letter did this at all, rather my reaction was that it exemplified the problem. As I said in my letter to him, the nature of scientific investigation, where deciding between alternative models is concerned, is not a question of looking for evidence for a model, but of looking for evidence against it. This view has been promulgated at some length by Popper, and is generally accepted. Popper argues that it is never possible to prove a model.
As you say the wave model is "but one of a number of models proposed about capping and particle movement on amoeboid cells." Let us briefly examine what those models are; as far as I know there are three - the cytoskeletal model, the flow model, and the wave model. Within each of these themes there are a number of variations, these though are the three fundamentally distinct proposals which have been made.
In the field we are discussing, the evidence against Dr. Bretscher's own ideas has been reviewed at some length on many occasions, as has the evidence against the rival cytoskeletal hypothesis. The problem is that these discussions almost always review the field as if these were the only possible mechanisms. In fact, as far as I know, Drs. Bretscher, Bray and Koch have always reviewed the field in this way. This is, in my view, not the expression of an opinion which differs from mine. Rather, it seems to me, to be the publication of a description of the field, which is at best misleading and, arguably, simply a falsehood.
You suggest that the problem is "not a case of (my) work being rejected by others, simply that (I) am no longer in the field to fight (my) corner actively." Actually I can discern no change in the way these workers have reviewed the field during and following my presence in it. Neither has the fact that other workers advocated similar views to my own altered the basis of review. Dr. Bretscher has continued to review the field the same way regardless. In any case, I think it unfortunate that scientific debate should be seen as an arena of conflict.
I think this is a rejection of the wave model. If it is not a rejection of it, as you suggest, then, surely, the question of what position they do take in this regard is a fair one. Surely, it should be answered!
As you say, many areas of biology are fast moving fields. The question is whether this is one of them. When I learned about this field, it consisted largely of a "debate" between advocates of the cytoskeletal and flow models. Each side was able to cite what seemed to me, clear disproofs of the others ideas. From my reading of the literature recently it seems the field today consists largely of a "debate" between advocates of the cytoskeletal and flow models. Each side still seems able to cite clear disproofs of the others ideas.
Is this a fast moving, healthy science in a state of flux? The emergent picture is more a stagnant one. It could be seen as a field in which debate is locked into a sterile loop. It could be argued that the reason behind the apparent lack of meaningful progress in this field, is the reluctance of its workers to move away from their initial, unsuccessful, premises.
I do accept that "what is fact today can be superseded by tomorrow's breakthrough." Nonetheless, tomorrow's science is still built upon today's, and breakthroughs do not go unreported in the scientific literature. If there has been a breakthrough, which has superseded the wave model and of which I as yet know nothing, then I ask only that these workers tell me about it or give me the reference to it.
What seems to me to be completely absent from this field so far, has been an explanation from these workers of what evidence or argument they feel able to muster to contradict the wave model. In Dr. Bretscher's case, his letter to me stated clearly that he did not understand the wave model. What is more, he is unwilling to discuss the subject. In the circumstances I am obliged to question whether he has any reasoned grounds at all for his rejection of the it.
As I said before, the fact that the field has been reviewed in the way it has, seems to me at best misleading and, arguably, simply a falsehood. This seems to raise serious ethical issues. I would be grateful if you would let me know whether or not the MRC has a written code of conduct for its staff regarding such ethical matters. If so, I would like to know how I can obtain a copy of it.
Mostly though, I would ask that you do approach the workers in the field, and ask that they deal with the scientific issues, which my letters to them have been raising. Yours Sincerely John A Hewitt
10 December 1991
Dear Dr. Hewitt,
Thank you for your letter of 17 November. Having read the points you raise I am not persuaded to change the views I set out in my letter to you of 1 November, nor indeed, do I think it would be fruitful for me to pursue the matter further.
Yours Sincerely
D A Rees
18 December 1991
Dear Dr. Rees, Thank you for your letter dated the 10th. of December. I note that my letter to you has failed to persuaded you to alter the views which you have already expressed.
As I already said, there have, to the best of my knowledge, been three completely distinct models put forward to explain the phenomena of capping and particle movement. Dr. Bretscher in particular, but Drs. Bray and Koch also, have consistently reviewed this field on the basis that only two models have been put forward.
It seems from your letter that you do not think this to be false or even misleading.
I do not agree with you. I do think such review to be at best misleading and arguably simply false.
For this reason, and because I do not feel I have had meaningful responses to my enquiries, I am concerned by the propriety of such actions. As a body of professionals, I expect MRC scientific staff work under a code of professional conduct. I would like to know whether or not this code is written down as a formal document, and if so how I can consult it.
Would you be kind enough, as I requested in my last letter, to furnish me with this information? Also, I would be grateful if you could tell me what mechanisms the MRC normally uses to deal with ethical matters, such as the publication of false or misleading statements in the scientific literature, by members of its own staff? Yours Sincerely John A Hewitt
12 January 1992 Dear Dr. Rees,
I write following my letter of the 18th. of December, a copy of which I enclose. My letter concerned work on the subject of capping and particle movement on the surface of motile eukaryotic cells.
In that letter (and also in my previous letter of the 17th of November) I made enquiries concerning the MRC's code of professional conduct. I also enquired about the mechanisms which the MRC normally uses to deal with ethical matters, such as the publication, in the scientific literature, of false or misleading statements by members of the its staff.
I would be grateful if you would let me have a reply to those queries as soon as possible. Yours Sincerely John A Hewitt 22 January 1992
Dear Dr Hewitt,
Dr Rees has passed to me your letters of 18 December and 12 January, and asked that I reply in my capacity as Executive Secretary of the Cell Biology and Disorders Board. The delay in reply reflects my own need to familiarise myself with the correspondence and background to the matters you raise. I have also contacted the management and staff at LMB.
You enquire about the MRC's code of professional conduct in the context of false or misleading statements made by members of the Council's staff. In such cases, the first point of investigation would be with the Director of the scientist concerned. If the complainant was still dissatisfied then the Secretary of Council would be consulted, or his nominated Council Officer.
I would draw your attention to the fact that neither Sir Aaron Klug nor Dr Rees have been sufficiently persuaded that you have grounds for complaint. We all regret that you have felt slighted by lack of citation of your research but it is the normal process of the development of scientific concepts to allow full and free debate in which all participants risk their own reputations and careers if they get this wrong. We trust to the expertise of the scientific community that this eventually leads to a consensus about the truth. Under these circumstances, MRC cannot pursue this matter further. Yours Sincerely Diane J. McLaren DSc PhD FIBiol. Executive Secretary - Cell Biology and Disorders Board.
27 January 1992 Dear Dr. Rees, I have received from Dr. Diane McLaren a letter dated 22nd January in response to my letters to you of the 18th of December and the 12th of January. My letters made enquiries concerning the MRC's code of professional conduct. Whilst I am grateful for the replies which Dr. McLaren has given to some of aspects of my enquiries, there are still several points which call for further clarification.
Three possible models have been put forward to account for the phenomena of capping and particle movement. These are the cytoskeletal model, the flow model and the wave model. Drs. Bretscher, Bray and Koch have consistently reviewed this field on the basis that only two possibilities exist, omitting all reference to the wave model. This, it seems to me, is likely to mislead anyone who should read their papers.
I would be grateful then, if you would clarify the following points.
- Does the MRC have a written code of professional conduct?
- Does the MRC have formal procedures for the investigation of complaints?
- Do you agree that the omission of all reference to the wave model in the work of Drs. Bretscher, Bray and Koch is likely to be misleading?
- Do you accept that scientists have a duty to review all reasonable interpretations in relation to their work?
I look forward to receiving clarification on these points. Yours Sincerely John A Hewitt cc Dr. D. McLaren February l992
Dear Dr Hewitt,
I am responding to your letter to Dr Rees of 27 January.
In answer to your queries
1) The MRC procedures relating to professional conduct were set out clearly in my previous letter to you of 22 January;
2) Formal procedures for the investigation of complaints were also explained in my previous letter; MRC has invoked those procedures in the context of the case you mention and has not been persuaded that you have grounds for complaint.
3) & 4)The answers to both these questions was also covered in my previous letter; see sentences 2 and 3 of last para. Yours Sincerely Diane J. McLaren DSc PhD FIBiol. Executive Secretary - Cell Biology and Disorders Board.
27 April 1992 Dear Dr. Rees, I have received from Dr. McLaren a letter, dated 25 March, in response to my earlier letters to yourself and to her. This letter makes it clear that the MRC has no code of conduct nor procedures for the investigation of complaints. Dr. McLaren also points out that the responsibility for the ethical conduct of the MRC's affairs is ultimately yours.
Dr. McLaren gives the impression that she feels this is not a matter which requires attention because it would be expected to be dealt with "through normal scientific debate". I entirely agree that it should have been dealt with this way, but the fact is that Drs. Bretscher, Bray and Koch have not done so. Moreover, they have declined to fill the gaps in the debate even when asked to do so. This is why I have contacted you.
Both yourself, and Sir Aaron are employees of the MRC. Moreover, you have both had an interest in this or related areas. Neither of you could be described as detached observers; that being so I cannot accept simply any "judgement" from you. I feel a proper, reasoned explanation of how you come to your views is called for. I wish to know where you believe the arguments I put fall down.
Your letters are rather brief and I simply do not understand your rationale. Explanation has largely been limited to approving reference to Dr. Bretscher's letter.
His letter is quoted in full here:-
Dear John,
As you know I have never really understood the physical basis of your wave model: your replies to my questions when you gave a tea club talk in the Biochemistry Department several years ago did not clarify the situation.
As to the direction the field is taking there, is as far as I can divine, an increasing belief that particle migration is achieved by direct action of some part of the cytoskeleton. This is, of course, not a view that I share. There are two real problems in the field: (1) There exist several individuals who cherish their own models (and I am a fine example) and (2) there are relatively few experiments which shed light on the molecular mechanism of what is going on. Neither situation is surprising since any experimental evidence is very hard to come by and this allows all sorts of ideas to be tossed around. It also means that a particular view needs an active advocate to keep it alive: in the case of your wave model your absence from the fray may be leading to its being ignored. This, of course, has nothing to do with what is true or false, but more to do with personalities.
Yours Sincerely Mark Bretscher
Notwithstanding this letters use of such phrases as "this allows all sorts of ideas to be tossed about", as far as I know, three models have been proposed. Dr. Bretscher has consistently reviewed this field over 13 years as if only two have been. This is a rejection of the third, the wave model. My presence or absence from the "fray" made no discernible difference to his practices, neither did the support of other workers for the wave model.
I cannot comprehend how it is possible for Dr. Bretscher to reject a model which he does not understand. His last comment suggests that personality can change three to two. I reject his letter as a reply to my enquiries.
Because I do not understand your position on this matter, I previously (27 January 1992) asked you to reply to four specific questions. The answers to the first two (concerning the existence of an MRC code of practice and procedure for the investigation of complaints), are now clearly "no". Questions three and four remain unanswered. Since they are central to the issue, I would be obliged if you would furnish me with a reply.
Do you agree that the omission of all reference to the wave model in the work of Drs. Bretscher, Bray and Koch is likely to be misleading? Do you accept that scientists have a duty to review all reasonable interpretations in relation to their work? I look forward to hearing from you in due course. Yours Sincerely John A Hewitt cc Dr. D. McLaren
25 March 1992 Dear Dr Hewitt,
I write to acknowledge your letters of 18 February and 6 March.
As I have explained previously, the Director of an MRC establishment is responsible for dealing with matters of professional conduct by his staff, and is in turn responsible to the Secretary of Council. Your complaints have accordingly been considered by Sir Aaron Klug, the Director of LMB and by Dr Dai Rees the First Secretary of the MRC, both of whom have provided you with written judgements.
The Council has no specific mechanisms for dealing with this type of issue beyond those I have already described, because no two cases will be the same and each must be considered on an individual basis. In any event, one would normally expect such differences of opinion as you describe to be dealt with through normal scientific debate.
Notwithstanding the fact that you disagree with the judgements you have received from the MRC, the case has been fully considered by the Council and we can enter into no further correspondence with you.
Yours Sincerely Diane J. McLaren DSc PhD FIBiol. Executive Secretary - Cell Biology and Disorders Board.
17 July 1994
Dear Sir Dai,
I am writing further to our correspondence concerning the subject of capping and particle movement on the surface of motile eukaryotic cells.
I have now received, via my MP, Sir David Madel, and the Cabinet Office, a copy of the MRC's procedure for the investigation of complaints. I gather this was not available at the time I wrote to you asking for it.
I still do not have a copy of the code of practice under which the investigations referred to in this procedure are carried out. I am particularly concerned to establish whether or not the MRC's scientific staff are permitted to publish false or misleading statements in the scientific literature. More particularly, I note the opinion expressed by Dr. D. E. Chubin, of the US National Science Foundation (Bioscience (1985) 35 80-89 "Research Malpractice") that the omission of relevant citation is a form of misrepresentation. It would be helpful to know whether or not MRC policy reflects this view.
Could you please let me have this code or advise me how I can obtain a copy of it? Yours sincerely John A Hewitt cc Sir David Madel MP (for information) Mr. David Davis and Mr. Michael J. Talbot, Office of Public Service & Science (for information)
1 August 1994 Dear Dr Hewitt, In reply to your letter of 17 July 1994, I can confirm that the alleged misrepresentation to which you have referred in previous correspondence has been fully investigated. The conclusion drawn by the Council's Secretary is that the non-citation of your findings by MRC research scientists did not comprise misrepresentation.
Your allegation is therefore refuted and this statement serves to conclude our consideration of this matter.
(Miss.) Patricia M Cross
Below is a copy of the MRC's procedure for investigating complaints. The MRC itself substantially did not deal with my request for copies of its procedures for investigating complaints and for its code of practice with regard to false or misleading publication. The documented copied here was received following my contacts with my MP Sir David Madel, via the then Minister of State, William Waldegrave. I still do not have any code of practice. The MRC has still not explained whether its staff are permitted to falsify the scientific literature or given any indication of what types of behaviour are permitted or prohibited.
The procedure below appears to be an annex to some other document but I do not know what this might be.
Annex 1
Detailed procedures for the receipt, consideration and investigation of allegations of scientific misconduct ----------------------------------------------------------
The procedures comprise three main stages:
1. Receipt
1.1 Allegations must be in writing. They will be acknowledged in writing by the investigator, who will give the complainant a guarantee of anonymity until such time as it is decided to proceed with an investigation.
1.2 The investigator will consider the allegation and may take one of three steps:
- if the allegation is frivolous or without substance, it will be dismissed and the complainant informed in writing of the reasons for so doing;
- if, on the face of it, the allegation appears to have some substance, but the investigator has insufficient information to make a decision whether or not there should be an investigation, the complainant will be informed that he or she will proceed to an inquiry;
- if the allegation has substance, the investigator will inform the complainant that he or she will proceed to an investigation.
1.3 The Council will be informed, through the Secretary, that a complaint has been received and what action has been taken, (although the name of the complainant and the nature of the complaint will not be revealed by the investigator at this stage).
2. Inquiry
2.1 The investigator will invite a panel of not more than three scientists of distinction - of at least professorial status - to advise on the allegation under the conditions of the strictest confidentiality. These must be independent of the interests of the complainant and the person against whom the complaint has been made (the "respondent"), and at least one must be fully familiar with the area of research concerned. If these conditions can be met, one member should be a senior member of staff in the establishment involved, another a senior member of another MRC establishment, and the third a member outside the Council's service.
2.2 At this stage, it may be necessary to involve the respondent in order that they may be consulted by the Panel and/or the investigator. This will take the form, only, of confidential written communication between the investigator and the respondent, in the course of which the identity of the complainant will not be disclosed.
2.3 Similarly, clarification of statements made by the complainant may be sought at this stage.
2.4 The Panel will advise the investigator on the allegation in the light of all the evidence available at this stage, and the investigator will accordingly decide either:
- to proceed to an investigation; or
- to dismiss the allegation.
2.5 The complainant will be informed in writing of the decision, as will the respondent (but only if they are already aware of the fact).
2.6 The Council will also be informed of the decision, through the Secretary, but without details of the allegation or the names of complainant or respondent.
3. Investigation
3.1 The investigator will invite a Panel constituted as above to conduct the investigation, and will inform the parties accordingly. If a Panel was already set up under the inquiry procedure, this will normally be asked to continue with the case, but the investigator may - if this is necessary for the purposes of natural justice - instead establish a new Panel. The investigator will arrange for the provision of a confidential secretariat service to the Panel.
3.2 It is the responsibility of the Panel, and the purpose of the investigation, to establish as far as reasonably possible the truth about the allegation in a way which accords with natural justice. This will be undertaken, inter alia, by:
- seeking evidence and explanations from the parties involved, and independently. Both parties will be expected to produce such evidence as they have, in whatever form it may consist;
- extending the scope of inquiries as seems necessary or desirable. In this context, they should not hesitate to undertake or commission any necessary experimental work;
- interviewing any witnesses considered necessary;
forming a view on the veracity of each piece of evidence; and
- forming conclusions on the validity of the allegation, putting these to the complainant or respondent with supporting evidence, and considering such further evidence or explanations as may be offered;
continuing the investigation in this way until the Panel is satisfied that natural justice has been served, that further investigations are not warranted, and that it has reached a final conclusion on the allegation.
3.3 Throughout the investigation, the Panel will conduct its affairs with a degree of confidentiality such as to provide the necessary protection for the complainant and the respondent.
3.4 The investigation may be conducted through both written or oral enquiries: when interviews take place, the records will (as far as possible) be agreed with the interviewee.
3.5 on completion of the investigation, the Panel will report to the investigator in writing with its findings and any recommendations for action.
3.6 The investigator will inform the complainant and the respondent in writing of the findings, and of the action which the investigator proposes to take. If the decision is to uphold the allegations, the respondent will have the opportunity to make representations in person to the investigator before any further action is taken. Conversely, if the decision is to dismiss the allegation, the complainant will have similar opportunity.
3.7 The Council will be informed of the outcome of any investigations, together (in confidence) with details of the allegation and the names of the complainant and respondent.
The letter with which I initiated this correspondence was extremely similar to (and written at the same time as) that to the MRC staff.
19th. July, 1990 Dear John, Very many thanks for your letter of 17th. July. It was nice to hear that you are O.K. and still maintaining your interest in cell surfaces and the movement of particles therein.
In response to your specific questions I can only say that, although I have published one or two papers containing some data on lymphocyte capping, none are more recent than about 5 or 6 years ago and none expressed any views on the question of the mechanism of capping. My feeling, although I certainly wouldn't claim to be up to date with the literature in this area, is that not very much new has happened for some years - really since people like John Condeelis and Gordon Koch produced their data showing association between some ligand activated receptors and microfilaments. If I wanted an up to date view I think I would go to Mark Bretscher who, I presume, still has a strong interest in this question even though I haven't seen a paper by him for a year or so.
I'm sorry I can't be of more help but I would be interested in being kept informed of any developments. With very best wishes, Yours sincerely, Robin Hesketh.
(Reply sent on 10 August but this is lost.)
(The following letter was sent separately to both Drs. Hesketh and Metcalfe)
3.1.91 Dear Dr. Hesketh, Some time ago I wrote to you concerning the subject of capping of motile cells. As I said in that letter I wish to ascertain opinion in the field concerning the wave model which I published some time ago (J. Theoret. Biol. (1979) 80 115-127). I wrote to you because you either work in this field or have done so.
As yet I do not seem to have heard from you in response to these points. I would be most grateful if you would reply to my letter as soon as possible.
The specific questions asked in my letter were as follows
1. Have you, or any of your colleagues, published an article which expresses an opinion of the wave model?
2. What is your present opinion concerning the various proposals for the mechanism of capping and particle movement?
3. Can you direct my reading to any article, preferably a review, written by anybody, whose opinions largely parallel your own annd which does discuss the wave model.
4. Can you direct my attention to any piece of experimental which, in your opinion, tends to disprove the wave model
Incidentally my questions were asked and phrased with a view to elicitting both your views and the rationale behind them. ........ I do hope to hear from you shortly. Sincerely Yours
8th. January, 1991
Dear John,
In response to your letter of 3rd. January, I would point out that I did reply to your first letter, as your acknowledgement of 10th. August indicates. My reply covered all your questions although I did not itemise each point. I simply pointed out that I have never published a paper in which models for capping were compared and that the best advice I can give for obtaining detailed comments would be to contact someone who has worked specifically on this topic, such as Mark Bretscher or Gordon Koch.
Yours sincerely,
T.R.Hesketh.
(Note added; a paper on which Dr. Hesketh is an author, reviewing the field as indicated is referred to in the list of references, Pozzan et al. (1980))
7 January, 1991
Dear Dr. Hewitt,
In response to your letter of 3 January '91 I am sorry I am unable to be of much help to you in your enquiries and can only reiterate what I understand Dr. Hesketh has already told you. We have not worked on cap formation for about nine years and I do not have any subsequent references on this topic in my index (it was never of major interest to us). I think the easiest way for you to find any literature there may be on this would be through a Medline (or similar) computer based search although I don't think it has been an active area. If you have not contacted Mark Bretscher at LMB I think he would be the most suitable person to consult in the U.K. since he was doing the best experimental work on cells in this area at the time we were involved. It may also be worth looking at the standard undergraduate textbooks, particularly the 'Molecular Biology of the Cell' (Second Edition) by Alberts et al., which may well discuss the phenomenon of cap formation and current views on mechanism. I hope this helps you to find the information you want.
Yours sincerely,
J. C. Metcalfe
21.2.1991 Dear Robin. thank you for your letter dated the 8th of January in response to my own. As my "acknowledgement" of the 10th of August to you indicated, I am in receipt of your earlier letter. As it also indicated, I did not feel your earlier letter addressed the issues here. I do accept that my own list of references does not include one, authored by you, which discusses mechanisms of capping. Nonetheless, it seems to me that you did take a view on this matter. which was clearly indicated in the approach which you adopted to teaching it. The view you appeared to take was that my own work was wrong and misguided. You indicated this by discussing only two possibiliites, omitting any mention my own work. In the circumstances I felt it appropriate to invite vou. again, to explain the reasoninq which led you to this view. Could I ask you, please, in retrospect, to explain the reasoning which led you to the view which you have given the appearance of holding My original questions were phrased to elicit such an explanation, but, of course, if you feel another approach is appropriate, then I would be very glad to hear that. I do hope to hear from you, on these issues, in due course. Yours sincerely John A. Hewitt
21.2.1991 Dear Dr. Metcalfe, thank you for your letter dated 8 Jan. In fact I have already carried out the suggestions which you made. I was most surprised to learn that cap formation was never a major interest of yours. While I worked in the Dept. of Biochemsitry, both your teaching and your published research discussed this field and the models which had besn suggested to account for the phenomena observed. In doing so you mentioned only two of the models which had been suggested, omitting any mention of my own work The implication of these actions was very clear - that you felt my work was wrong and misguided. I do not know what reasoning led you to that conclusion. I do feel that it is unfortunate that you did not state your view in so many words, and did not explain the reasoning which led you to your view. Since the field was not a major interest of yours, I am surprised that you felt able to hold the views which you did. Even so, and in the circumstances, I can only ask you again : Will you please state that you did in fact consider the wave model to be wrong? Will you please explain, by answering my original questions, or otherwise, the reasoning processes which led you to that opinion? Yours Sincerely John A Hewitt
There followed a letter from me to Prof. Richard Perham, then head of the Department of Biochemistry which produced the following joint reply.
2nd. July, 1991
Dear Dr. Hewitt,
Professor Perham has passed us your letter of 9th. June, 1991. In response we would make the following points:
1. We invited you to give a formal Departmental Tea Club lecture on your model of cap formation (24th. November, 1982) which was attended by both students and experts (eg., Dr. M. Bretscher).
2. In previous correspondence we have referred you to Molecular Biology of the Cell by Alberts et al., 2nd. edition, pp. 333/4 for a current, independent view of cap formation. Your theoretical model is not mentioned.
3. We have no comment to make on your theoretical model (Journal of Theoretical Biology, 1979, pp. 115-127).
We now regard our correspondence with you as closed.
Yours sincerely,
J.C.Metcalfe T.R.Hesketh.
14 July 1991 Dear Drs. Metcalfe and Hesketh, Thank you for your letter dated 2 July, in response to my letter to Prof. Perham. I note the three points which you make and would reply to them as follows
I thank you for the invitation to give a seminar at the departmental tea club. You will recall that during that meeting I raised essentially the same issues as I am raising now. I had previously raised the same issues with you, for example by providing you with a preprint of the paper. I did not feel that I received any meaningful reply, although you have consistently given the impression that you feel the wave model to be unfounded. As I said previously, I have communicated with Dr. Bretscher on this subject.
I have read the comments made in the book "Molecular Biology of the Cell" concerning the mechanism of capping. As you say, the wave model is not mentioned. Dr. Raff, an author on this work, observed to me that, as an undergraduate textbook, he did not feel that this work could be expected to deal with detailed scientific arguments. I have to say, that I am disposed to accept his observation as fair - although it does not answer the scientific point. I do not know why you attach significance to this book, perhaps you would care to explain. Your own position is fundamentally different. In the first place, you work in the institution in which my work was performed. This gives your position a certain force. In your teaching, and, in the case of Dr. Metcalfe, your publication, you seem to have implied, by omission, that my work was somehow invalid or misguided. You did so before the publication of Alberts et al. I would like to know what the scientific reasoning was, which led you to feel able to do that. I should also like to know your present opinion.
I am not suggesting that, as individuals you are under any legal obligation to reply to my letters, neither are you obliged to answer my questions in any reply which you send. In your role as professional scientists however, things are less clear cut; I do feel that you should reply to legitimate questions concerning your scientific positions. I think that these are legitimate questions. That is why I feel very put out by the lack of real replies.
I do not understand what you found so unbelievable about the wave model, and I also do not understand why you seem so reluctant to tell me.
One final point concerning your letter, my work was, as you say, theoretical; I think the flow model, and the cytoskeletal model, are also theoretical - the issue is, which is least negated when set against the experimental evidence. As far as I know, no negations of the wave model have been published. Perhaps you do, if so, would you please let me know.
The view which I take in this field is, I believe, one which is a standard view of scientific method. I think Popper's paradigm of scientific reasoning applies in its entirety; as you know, this states that when a hypothesis is put forward, it is to be challenged by reference to the experimental observations. If a hypothesis fails to predict those facts, then the hypothesis should be seen as inadequate. If the hypothesis successfully predicts the observations then it may be correct, but cannot be viewed as proved.
Within this paradigm, science is seen as working by elimination; proof is not regarded as meaningful, only disproof is a strong statement. Of course, this view of science is generally accepted by the scientific community.
Applying this view to the situation with capping and particle movement, in my opinion
Firstly, I think there should be an exchange of theoretical views. If this does not take place, then it seems there would be an increased likelihood of the "correct" hypothesis not being included in the set of hypotheses from which elimination takes place.
Secondly, if a worker feels able to reject a hypothesis, then he can reasonably be asked, which experimental tests lead him to that view.
Thirdly, a request for proof of a hypothesis, or evidence in its favour, before it can be considered, is of questionable validity.
As I said before, you are not legally obliged to deal with these questions, but you have, by omission and implication, given the impression that you believe the wave model is wrong. This is especially the case as you did so from the institution in which my work was done. Surely, accepted scientific logic requires that you explain your rejection of the wave model!
For these reasons, I hope that you will correspond further on these matters, and that you will address the issues being raised here. Yours Sincerely John A Hewitt cc Prof. R.N.Perham; both Dr. J.C.Metcalfe & Dr. T.R.Hesketh
28 July, l991 Dear Dr Hewitt, We find it difficult to understand why you are unable to accept that we have answered your question as best we can more than once in response to your letters. We can only reiterate and paraphrase what we have said previously:
In our own limited studies on receptor cross-linking (3 or 4 papers from 1980-82) we never attempted in any way to test experimentally your theoretical wave model of cap formation and in our view our data had no bearing on the validity or otherwise of your model to justify discussion of it in those papers. Indeed, it would not have been appropriate to work independently on your model when you were in the Department, even if it been of more than peripheral relevance to our research.
We were and remain unwilling to express any view on the validity of your model because as far as we are aware no attempt has been made by you or other workers to test the model experimentally. It may be that there is recent experimental evidence that is relevant but it is about 9 years since we have published work on the cross-linking of mitogen receptors and we have not followed the field at all closely. We referred you to Mark Bretscher who may well be able to inform you of any recent work which bears on your model. His opinion is valuable because he has an excellent insight into molecular cell biology and because in our view he was doing the best work on the mechanism of cap formation at the time we were interested in receptor crosslinking, through his extensive efforts to test experimentally his lipid flow hypothesis. For an independent view we referred you to the 'Molecular Biology of the Cell' in which Marty Raff concludes that definitive evidence to distinguish between the two mechanisms of cap formation for which experimental evidence has been sought (lipid flow and cytoskeletal attachment) is lacking and is difficult to obtain. We can certainly appreciate that it is disappointing and frustrating for you that your model has not had sufficient impact to prompt experimental work to try to test it, but however put out you may feel about this, that is your problem and not our fault. It does not justify your unacceptable stratagem of implying that, because we refuse to guess the outcome of experimental work still to be done, we must therefore believe your model to be invalid. Nor are you are justified in attempting to harrass us into defending an opinion we have not expressed on a subject that is of little interest us.
For these reasons, as we have indicated previously, we see no point in continuing this correspondence and we formally ask you to stop harrassing us when we have made every reasonable effort to be helpful to your enquiries. Yours sincerely, J C Metcalfe T R Hesketh
22 September 1991 Dear Sir, This letter is concerned with the time when I was a Demonstrator at the Dept. of Biochemistry, in Cambridge; I held this post from 1978-83.
During that time, amongst other things, I published a paper concerning the subject of capping and particle movement on the surface of motile amoeboid cells. This appeared in the Journal of Theoretical Biology (1979) 115-127; it proposed that these phenomena arise as a result of wave action on the surface of the cell. I think this proposal is in fact correct.
However, a number of workers in the field appear to think that this concept is wrong. For the purposes of this letter, I am referring here in particular to Dr. J.C. Metcalfe and Dr. T.R. Hesketh of the Dept. of Biochemistry. Dr. Metcalfe published work in the field, which included review of the proposed mechanisms the field, in a way which omitted all mention of the possibility which I had raised. Both workers taught the subject, to final year students in a similar way, while I was in the Dept.. Their actions seem to imply that they think my work is wrong. However, because this is an only implication, I have never known anything of the reasoning which led them to this view.
It is, of course, accepted that they are entitled to their own position. However, I would like their disagreement with me to be on some kind of record, and for me to have a clear idea of the scientific considerations which led to that disagreement. I have recently been taking up this matter. Accordingly, I have written to Drs. Metcalfe & Hesketh asking them to explain, in specific terms, how they arrived at the opinions which they seem to hold. Although they were kind enough to respond to my letters, their replies have not been meaningful.
I have also written to them via Prof. Perham, their Head of Dept.. Drs. Metcalfe and Hesketh seems to be taking the line that, because they have not actually stated that they believe the wave model to be wrong, there is no need for them to defend such a proposition.
I feel this to be disingenuous. The implications of their actions seem plain. I feel they should explain their views, and in particular, why they believe the wave model, my work to be incorrect. However, they no longer reply to my letters.
I am writing to you to ask that you look into this matter, and intercede with your colleagues, asking them to answer my enquiries, in particular explaining why they believe the wave model to be wrong.
I would be obliged, also, if you would acknowledge receipt of this letter. Thank you for your time. Yours Faithfully John A. Hewitt
27 September 1991 Dear Mr Hewitt, I write simply to acknowledge receipt of your letter of 22 September about which I shall make inquiries. Yours sincerely, David Williams Vice-Chancellor.
10 October 1991 Dear Dr Hewitt, Thank you for your letter of 22 September. As I understand the nature of your concern, it involves a disagreement about scientific matters arising out of the research work of yourself and other members of the Biochemistry Department. The practice in Cambridge is to regard such work as the business of the researchers themselves and not one where institutional intervention in a dispute is appropriate unless there is prima facie evidence of serious scientific misconduct or impropriety. That does not appear to be the case in this instance and so I do not think it would be appropriate for me to raise the matter with the officers concerned, particularly since you have yourself been in touch with them direct. Yours sincerely, Vice-Chancellor.
18 October 1991 Dear Prof. Williams, Thank you for your letter dated 10 October 1991. I note that you do not fully understand the nature of my concerns.
My concern is not exactly that I disagree with my ex-colleagues, although I certainly do, it is that their actions imply that they disagree with me. The word imply is the point here. They have never stated on any record that they believe my work to be wrong, or explained how they came to that view.
When capping was first discovered its mechanism was a great mystery. Two possibilities were initially put forward by various workers; without going into details they were the cytoskeletal model and the flow model. Even at the time I did my work, I thought it was clear that both these suggestions were wrong, and so I set myself the task of devising a better one, which I did, the wave model. Again, without going into details, I think there were and are strong arguments for thinking that the wave model is substantially right. Drs. Metcalfe and Hesketh had an interest in this field and I made a point of familiarising them with my work as I was doing it.
There are then, three models which have been proposed as the mechanism for capping. Drs. Metcalfe and Hesketh taught this field in the department, while I worked there, on the basis that there were two possible models, the cytoskeletal and the flow models; amongst others, this was to Part II students doing literature projects on current research. Dr. Metcalfe published at least one paper in which he reviewed the available models, again discussing only two. These actions seem to imply that they think the wave model is wrong.
Because their actions only imply this opinion I do not know what arguments they would marshal to support it and, crucially, neither can I reply to them. It is fair to say that this situation is widespread in the field, but I view the actions of Drs. Metcalfe and Hesketh as being particularly significant, because they work in the laboratory in which my own studies were performed; the implications of their actions seem therefore very clear and are likely to be influential.
As far as I know Drs. Metcalfe and Hesketh do not contest the actual facts I state above; in any case the facts seem unequivocal. It think, therefore, that it is not really a matter of whether there is a prima facie case for misconduct or impropriety, but of whether one interprets their actions in that way. I do take the view that their actions are an impropriety, what is more, at least in their impact upon me, those actions are serious.
In any event, these problems could obviously be largely resolved by Drs. Metcalfe and Hesketh firstly, stating that indeed they do regard the wave model as wrong and secondly, explaining what reasoning led them to this view. As you say, I have been in contact with Drs. Metcalfe and Hesketh; I had precisely that objective in mind.
They have stated that they make no comment upon the wave model, instead they have referred me to a book, which does not address these issues. They also refer me to another worker; plainly, I cannot approach another worker for an explanation of their own reasoning.
In my view the replies I have received from Drs. Metcalfe and Hesketh are not meaningful; accordingly, I have written to you. I have to say that I am disappointed by your reply.
I feel that it would be unfortunate if the conduct of these workers were to receive the imprimatur of the university. You will, of course, decide for yourself how or whether to deal with this matter. In any case, I assert that the present position is manifestly unsatisfactory. I feel that matters can no longer rest where they are.
You refer in your letter to the "practice in Cambridge". Could I ask whether there is a written code of conduct concerning such matters in the University, and, if so, where I could obtain a copy?
Also, I believe that there is, in Cambridge, an institution known as the University visitor. I would be grateful if you would let me know who that is, and the procedure for making contact with them.
Mostly though I would ask you to consider this matter carefully and that you do approach these workers concerning this issue. In any event, I hope to hear from you shortly. Yours Sincerely John A Hewitt
21 October 1991 Dear Dr Hewitt, I am replying to your further letter dated 18 October. I can add nothing to what I have already told you.
There is no office of University 'Visitor' at Cambridge. Yours sincerely Vice-Chancellor.
23 October 1991 Dear Sir David, Thank you for your letter dated 21 October 1991. I am sorry that you feel unable to add anything further in this matter.
I feel, despite your letter, that there is an issue here. The reason I take this view is the absence of any meaningful replies to the question "why do you think the wave model is wrong?"
The scientific method, as outlined by Popper, has it that we arrive at truth by answering questions of this type. Within this picture science is a process of negation. If a scientist sees the wave model as wrong, I would like to know the arguments which lead them to their conclusion. This seems to me the best way of resolving the matter.
I cannot imagine where I got the idea of the "University Visitor". Even so I would be grateful if you would let me know
Whether or not a written code of conduct exists concerning such matters, which it would be possible for me to consult. The name and address of the Chancellor. Thank you in advance, Yours Sincerely John A Hewitt
28 October 1991
Dear Dr Hewitt,
The Vice-Chancellor is away from the office on business at present, and So I write on his behalf in reply to your letter of 23 October.
I understand that no written code of conduct exists covering the matters referred to.
The name and address of The Chancellor are as follows: H.R.H. 'Ihe Duke of Edinburgh, Buckingham Palace, London S.W.1. Yours sincerely, Geoffrey Skelsey Assistant to the Vice-Chancellor:
17 November 1991 Dear Sir David, Thank you very much for the letter dated 28 October 1991, from your assistant, Mr. Skelsey, in response to my letter to yourself.
I am not clear, from this reply, whether a code of conduct exists within the University, but that you feel that it is not relevant to this issue, or whether there is simply no code of conduct within the University. If one does exist, I would wish to know whether it deals with the subject of making false or misleading statements within the scientific literature or within teaching. This, I would regard as relevant to the matters referred to.
Could you please clarify the question of whether or not a code of conduct does exist within the University?
If indeed no code of conduct exists, I would be grateful if you would let me know what mechanisms the University does have available to deal with ethical matters. Yours Sincerely John A Hewitt
27 November 1991 Dear Dr Hewitt, Thank you for your further letter.
As Mr Skelsey stated in his letter to you of 28 October, no code of conduct exists in the University covering the matters referred to. There are no formal mechanisms to deal with ethical matters, which would be handled on an ad hoc basis by the authority relevant to the particular question.
As I said in reply to your first letter, the point at issue involves a disagreement about scientific matters between you and your former colleaques. I have no power to intervene in a matter of this kind. Yours sincerely, Vice-Chancellor. David Williams
14 December 1991 Dear Sir David, Thank you very much for your letter dated the 27th. of November (DGTW/MS).
As I explained before, I do not think the central point at issue here is a disagreement about scientific matters. It does appear to stem from such a disagreement.
This debate exists because the phenomena of capping and particle movement need a mechanistic explanation. Three proposals have been put forward to offer that explanation. When Drs. Metcalfe and Hesketh teach this subject, they seem to do so as if two proposals have been made. Dr. Metcalfe has reviewed this field in the scientific literature on a similar basis. These actions certainly appear to imply that these workers think the wave model to be wrong. However, neither they nor their actions say so in so many words. To the best of my knowledge, neither worker has ever said, on any record that they believe the wave model to be incorrect.
It does seem to me that, since these workers have been prepared to act as if they think the wave model is wrong, they have a professional responsibility to state this opinion, and explain the reasoning which leads them to it. In particular, I should like to know which experimental results they believe to be in conflict with my work.
They have told me that they are not willing to make any comment on the wave model. In the circumstances, I have to question whether they have any reasoned grounds at all for their rejection of it.
If, indeed, they have never had grounds to reject the wave model, then it seems to me their actions have certainly been misleading and are, arguably, falsehoods. This, I think, is the central point at issue.
Your letters do not give any indication of how you came to the view that the above facts amount merely to a "disagreement about scientific matters between (me) and (my) former colleagues". I am afraid I do not accept this to be so. I think it cannot be merely a difference of opinion, because I do not know their opinions, other than by inference from their actions.
For this reason, I am concerned to establish, in general, the University's policy on false or misleading statements in publication or teaching. I would like to know whether or not the University has a written code of conduct.
I would like to know how I can consult any such document for myself, to determine if it addresses this subject.
If, as your letters suggest, there is no code of conduct within the University, or any formal mechanism for dealing with ethical matters, then it seems that ad hoc investigation by the "relevant authority" is the only recourse. Your letter does not indicate who the relevant authority is; I would be grateful if you would let me know this, in order that I can contact him.
In the event of and ad hoc investigation being necessary, I will wish to know the arguments which have been put to the relevant authority and who is putting them. I am likely to wish to exercise an opportunity to reply to them. I will wish to know his "summing up" as well as his findings. I may well wish to be represented.
I hope this letter clarifies my position. I would be grateful if you would tell me whether or not any written code of conduct exists and how it can be consulted by myself. Also I would be grateful if you would advise me who the relevant authority is, concerning false or misleading teaching or publication. Yours Sincerely John A Hewitt
(The following is a postcard size acknowledgement slip)
From THE VICE-CHANCELLOR'S OFFICE, OLD SCHOOLS, CAMBRIDGE CB2 ITN ENGLAND (Tel. 0223-332292)
Date 18 December Reference 1603/2
THE VICE-CHANCELLOR acknowledges with thanks the receipt of your letter dated 14 December which is receiving attention.
G. B. Skelsey Assistant to the Vice-Chancellor
11 January 1992 Dear Sir David, I am writing further to my letter of the 14th of December; I thank you for the acknowledgement of that letter from Mr. Skelsey which was dated dated the 18th of December. I note, with gratitude, that it is receiving attention.
I look forward to a fuller response in the near future. Yours Sincerely John A Hewitt
16 February 1992 Dear Sir David, I am writing further to my letters of the 14th of December and 11th of January; you will recall that the acknowledgement of the first of these, from Mr. Skelsey, dated the 18th of December, indicated that this matter is receiving attention.
I would be grateful if you would let me know when you feel it likely that I shall receive a fuller reply. Yours Sincerely John A Hewitt
19 February 1992 Dear Dr Hewitt,
I am afraid that it has taken longer than I intended for me to reply to your further letter, dated 14 December. I wished to review the whole of the correspondence, and - with other pressing matters to deal with - this has taken me some time.
I am sorry to have to disappoint you, but my decision is that I can take your complaint no further. I continue to believe, as I said in my first letter to you, that this is in essence a scientific disagreement in which I am not prepared to intervene. Yours sincerely, Vice-Chancellor.
25 February 1992 Dear Sir David, Thank you for your letter of the 19th of February. I note that you have now reviewed the correspondence on this matter and come to the view that it is, in essence, purely a difference of opinion on a scientific matter between myself and my former colleagues.
As I have previously pointed out to you, other than by drawing inferences from their actions, I do not know the opinions of my former colleagues. Moreover, since they decline to give a statement or explanation of their views when I ask them to do so, there seems to be no way for me to determine their opinions.
In these circumstances, I do not understand how this matter can be seen as a difference of opinion on a scientific matter.
I would be grateful if you would explain to me how you came to your decision in this respect. Yours Sincerely John A Hewitt
2 March 1992 Dear Dr Hewitt, I am replying on the Vice-Chancellor's behalf to your letter of 25 February 1992.
I am very sorry to have to tell you that the Vice-Chancellor is not willing to add anything to what he has already said in his earlier correspondence with you. Yours sincerely, G. B. Skelsey
11 April 1992 Dear Sir David, Thank you for the letter from Mr. Skelsey (2 March 1992) in which he states that you are "not willing to add anything to what (you have) already said in (your) earlier correspondence" concerning the matters which I have raised with you.
I am anxious, for future reference, to ensure that there can be no question of your failing to grasp the nature of my complaint concerning this matter, by my not making the issues perfectly clear. Accordingly I would beg your indulgence while I explain, in detail, a particular instance of the type of conduct we are discussing.
One of the articles published by Dr. Metcalfe was the paper Corps A.N., Metcalfe J.C., and Pozzan T. (1982) Biochem. J. 204 229-237 "Kinetic Evidence for a Common Mechanism of Capping on Lymphocytes".
It should be noted that this article is about the mechanism of capping. It was published from the Department of Biochemistry in Cambridge, the very institution from which I published the wave model and in which I worked at the time of its publication. The senior author on this paper was Dr. Metcalfe.
In reviewing the possible mechanisms for capping, these authors observe that "two main types of model for cap formation have been proposed". They then review the flow model and the cytoskeletal model.
What is meant by this word "main" is far from clear. What procedures do they use to classify models into main and not main? How do they apply those procedures in this case? Do they then reject the wave model? It seems obvious to me that these questions need a clear reply. In fact Dr. Metcalfe has simply refused to enter into any form of debate on such matters.
I consider that the acceptability of this way of reviewing the field hinges on the meaning and acceptability of this word "main". Without it in the sentence, which I quoted in context from the paper above, this mode of review would have been quite simply false.
I feel the phraseology Dr. Metcalfe has used here is merely a word game with no scientific meaning whatever. The impact which this mode of review would have upon a reader would have been no different if "main" had not been included in the sentence. In other words this mode of review is no different, in its impact, from simply falsifying the field.
It seems, as you say, that Dr. Metcalfe disagrees with my view of this field. That, however, is not the point at issue. His actions seem to show not just disagreement with the wave model but disregard of it, as for similar reasons do the actions of Dr. Hesketh. It is this disregard I see as unacceptable.
The disregard these workers have for the wave model has been articulated by them quite well - "we have no comment to make on your theoretical model" - the wave model.
It seems to me, in an academic milieu, a disagreement might very well lead to an informative debate. Patent disregard, I suggest, is an altogether negative approach whose effect is likely to be the denial of debate.
There is another point about this matter which concerns me. You have told me that the University has no formal means for the investigation of complaints about academic impropriety. It can only institute ad hoc proceedings in "serious" matters. How do you decide what is a serious matter? These apparent deficiencies in the University's procedures seems to leave the burden of responsibility entirely on your own shoulders.
It would appear that this situation imposes upon you a responsibility to explain your judgements, in much the same way as a judge in court is expected to explain his findings, not merely give them. I would suggest that you do have a duty to explain why you choose to take no action, if indeed that is your choice.
In the circumstances, I would here repeat my request that you explain to me how you arrived at the view that the actions of Dr. Metcalfe, described above, can be seen as simply "a disagreement about scientific matters". Yours Sincerely John A Hewitt
14 April 1992 Dear Dr Hewitt, I am sorry, but I can say nothing in reply to your letter dated 11 April other than to repeat that Sir David Williams is not willing to add anything to his previous remarks. Yours sincerely, Geoffrey Skelsey
6 January 1993
Dear Sir David,
I am writing further to our correspondence concerning the models which have been proposed to account for the mechanism of capping and particle movement on eukaryotic cells. You will recall that I contacted you following an unsatisfying exchange of letters on this subject with Drs. Metcalfe and Hesketh of the Dept. of Biochemistry. As you know, I did not feel the replies which I received from you were satisfactory.
In pursuit of the clarification which I require of this issue I have written a brief review of the status of this field as best it is known to me. A copy of "Cap That!" is enclosed herewith.
I should be grateful if you would read this review, with particular regard to those sections which refer to your own position and that of your institution. Also with regard to the recommendations which were made by the National Academy of Sciences as regards codes of practice for scientific institutions. If "Cap That!" describes your position in way which you feel to be inaccurate or misleading, I should be grateful if you would let me know. I would also be grateful if you would clarify any points which you feel I have reported unsatisfactorily. Yours Sincerely John A Hewitt
March 20, 1991 Dear Dr. Hewit,
As regard to your hypothesis in J. Theoret. Biol. (1979) 80 115-127 on the movement by surface waves, we feel there is ample evidence in many cells that the rearward migration (ie. capping of membrane glycoproteins) does not necessarily involve a wave and I've included recent paper by Kucik et al. which discusses the issue and shows that there is no flow of membrane. It also discusses membrane attachment to the cytoskeleton and it is the cytoskeleton which is moving rearward that really describes the motile phenomenon.
In terms of expressing specific answers to questions, when I was at Connecticut there was a similar model of surfrider published by Oliver and Berlin and to my knowledge both models have not been taken all that seriously.
As an answer to question two, it is indeed a matter of attachment to the cytoskeleton and movement rearward with the rearward moving cytoskeleton that is responsible for capping.
No, I do not know of anyone who has included the wave model in their discussions of rearward capping.
In answer to question four, the disproof of the wave model is really that particle movement rearward results from skeletal attachment and not hitting the right point on a wave. In the karatocytes that we're dealing with, capping of the beads that we see is not due to a wave that we can observe on the surface of those cells (we can indeed see other undulations in that surface and we could clearly see a wave moving rearward).
One additional point is that capping is blocked by deletion of myosin in dictyostelium d. and those cells still have normal "wave" behavior. Sincerely Michael P. Sheetz
The last paragraph being hand written. No further correspondence has been received from Prof. Sheetz.
12 June 1991 Dear Prof. Sheetz, Thank you very much for your letter dated March 20, 1991. I am sorry that my reply has taken so long, but I am afraid I get very busy at this time of year. I am writing further because I think that there are a lot of points which need to be made here.
This letter will be a long one, and in it I shall raise my objections to your interpretations. It is appropriate, then, to begin by saying how much I admire your work; I do think that, more than any other laboratory, yours has consistently devised and carried through critical experiments in this field. I do admire and respect that.
I take as a starting point for discussions in this field the principals of scientific hypothesis testing, as promulgated by Popper. These have it that a hypothesis, once proposed, should be tested against the known facts; if a hypothesis fails to predict the facts, it should be discarded. It is fair to say that, in cell biology, facts are often somewhat unclear. Even so, those principals stand. Your work has disproved the flow model, but has not proved the cytoskeletal model.
Whilst the flow model is wrong, the criticisms which Bretscher levelled at the cytoskeletal model remain entirely valid, in my opinion. I will shortly list my objections to the cytoskeletal model, but first I will review the history of this field, as I understand it.
Cytoskeletal Model It is not too easy to pin down the actual origins of these ideas, but they seem to have begun 15 or 20 years ago. Originally the idea was that the interior of a cell would recognise the presence of a patch or particle on its surface. The interior, in the form of the cytoskeleton, would then catch the object and move it as seen in experiments. I would describe this as a responsive model, in that it requires a response from the cell to the presence of the patch or particle. The alternative type of model being an entrainment model, in which the object entrains on some ongoing cellular process. A responsive model implies that :-
That there are mechanisms in the cell whose role is to effect the capping or particle movement. That these mechanisms must have evolved over time. Hence that capping, or particle movement, are themselves cellular functions. Predictions made by this model are that :-
Transmembrane interactions between patch, or particle, are a necessary condition of capping or particle movement. One might expect to see some kind of chemical specificity in capping or particle movement. The model does not obviously predict any size dependency in capping. (It is not clear why a membrane protein should cap only after being patched.) In fact none of the predictions above are experimentally satisfied.
It is in fact rather difficult to identify concrete predictions of this model, because the model itself does not seem to have been precisely described anywhere. Even so the cytoskeletal model has been largely accepted. This is because of the work of Koch, Bourguignon and others, who showed associations between some patches and caps and the cytoskeleton, both chemically and microscopically. These associations appeared to take some time to develop. This has been widely regarded as decisive proof of the cytoskeletal model. For my part, I think that those observations can be accounted for in other ways. I think that this model should have been rejected, because it fails in even those few predictions which it does make.
I also think that this model should have been rejected because it is a responsive model. I think that capping and particle movement are not cellular functions, and that, therefore, any model which proposes mechanisms whose only role is to drive them specifically, must be wrong. Your own views seem to have moved away from the original cytoskeletal model; I think that your proposal, in your recent J. Cell Biol. article (which, incidentally, was not included in your letter) was an entrainment model, and, as such, quite different from the original cytoskeletal model. For that reason I would give it a different name, I would call it the actin flow model.
The Actin Flow Model The broad idea which you are putting forward as I see it, is that the cytoskeleton beneath the membrane which is composed, presumably, of actin is in a state of continuous cycling. The actin layer makes contact with various transmembrane proteins, and these drag, through the membrane, on any object which comes into contact with them. They are regarded as "scouring" the membrane surface of any large object, whilst smaller ones filter through.
I choose to give this idea a different name from the original cytoskeletal model, because it seems to be fundamentally different in character. There is no longer any supposition that the external object is recognised by the interior of the cell, or that the cell needs to respond to the recognition of the object by moving it. Instead the model is an entrainment onto an ongoing cellular process, it is an entrainment model.
The movement towards an entrainment type of model is, I think, an advance, but in other respects I think that this is an unrealistic model.
There is no direct evidence in any cell type of the existence of submembrane cycling of the type required. It has been looked for in the nerve axon, and been found to be absent (Okabe & Hirokawa, (1990) Nature 343 479-482); I think that axonal transport certainly has parallels with capping and particle movement. I think that one should look for a model which can be applied across the board here. There is no indication of what cellular function such flow might serve; such a flow would be very energy consuming, it is unlikely to exist unless it performs an important cellular function. It seems to predict that transmembrane proteins will cap without being polymerised, which is not found to be generally the case. No mechanism for the transport of depolymerised actin through the cell cytoplasm at the rates necessary is apparent. It predicts that cell surface lipids and non-transmembrane proteins can only cap by co-capping with transmembrane proteins. No report supporting this exists to my knowledge. The role of the actin accumulations beneath patches is far from clear in this model. This is ironic, since most workers in the field seem to think that the actin flow model is the cytoskeletal model. On the basis of this model, I find it surprising that you do not find evidence for membrane flow. The lipids of the membrane are a rather viscous liquid crystal; if transmembrane proteins are being continuously dragged through the membrane, would they not act like oars in water and drag the membrane along too? This would provide a motor for bulk membrane flow. I am not aware of any biological system in which a mechanism remotely analogous to this one has evolved. If it is to be believed, it is very much in need of direct supportive evidence. By and large, I find this model to be ad hoc. There is no direct evidence to support any of its contentions, except for the circumstantial evidence of capping and particle movement themselves. The most severe criticism which I would level at the actin flow model is that it fails to relate capping and particle movement to any cellular function. If motility is the function to which capping and particle movement are to be related (which everyone seems to agree) then the actin flow model seems to suggest that the cell will ride on its transmembrane proteins. But the cell moves much more slowly than the particles do, so that does not appear to work.
It might be that much of the willingness to accept this model, may come, not from the merits of the model itself, but from the feeling that it can be passed of as the cytoskeletal model. In fact I do not think that it can be; I think that, in any case, the actin flow model is no more right than was the original cytoskeletal model.
Overall, and bearing in mind my remarks about my admiration for your experimental work, could I urge you not to become too committed to this idea. I think that your work is more consistent with the wave model, and that your superb technology could go a long way to delineating an important and neglected area of cell surface dynamics.
The Flow Model We neither of us believe this to be correct, and thus further discussion at this point is unnecessary.
The Wave Model I wish to consider the topic of capping and particle movement, in terms of the function which they reflect. As I said earlier, it is generally agreed, I believe, that capping and particle movement are not, in themselves, functions, but that they relate to motility.
If we look through the natural world, we can find many places where, when evolution has wanted to achieve motility, it has done so through a wave type mechanism. Fish swimming, snakes moving, intestinal function, paramecia swimming via their cilia etc. It is not hard to construct a very long list. What is more waves have been variously reported on the surface of amoeboid cells. Indeed, I cited some of them in my paper.
In terms of their chemical kinetics, waves and oscillations have the same origins; systems which give rise to oscillations should also be capable of giving rise to wave motions. Oscillations are very widely documented in cells, one article (Rapp P.E., (1979) in Cellular Oscillators, M.J.Berridge, P.E.Rapp and J.E.Treherne Eds; J. Exp. Biology 31 pp281-306) lists several hundred such examples, but many more have been reported since. Waves are more difficult to observe, but are likely to be similarly widespread.
I therefore take it to be a fact that waves do exist on cell surfaces. The failure to observe them in any one experiment may reflect their absence, but it is just as likely (in my view more likely) to reflect the shortcomings of a particular observational set up.
I think that the cellular function of those waves is to provide a peristaltic aid to cell motility. This implies (and is supported by observation, as referenced in my paper) that the waves must travel from the leading edge of the cell to the trailing edge.
We know from macroscopic studies, that waves interact with objects by entraining them; we know that large objects entrain better than do small ones.
It seems to me that the basic facts of capping and particle movement are that large objects (patches and particles) on the cell surface move, and that small ones (protein and lipid molecules) do not move. On the basis of a wave train existing on the cell, and the waves entraining particles as they do in macroscopic situations, these basic facts are, quite simply, exactly what you would expect.
It seemed to me when I described it, that the wave model offered the big advantage of clearly relating capping and particle movement to motility, and of bringing this subject into line with the rest of biology. It is an independently testable proposition, which has no obvious negations. As such I believed I had made a valuable contribution. I also believed I was right, and I get more sure of that every time I read the literature.
The Response to the Wave Model Most workers have taken the view that the wave model is wrong because there is no "proof" of it. It has been cited a little, but not discussed. Nobody has, to my knowledge, ever put forward a single negation of it, beyond saying they cannot "see" any waves; I am inclined to reply that they cannot "see" flow either, but this does not stop them discussing it.
Scientific hypothesis testing has it that, basically, science is a negative philosophy; you can prove things to be wrong but you cannot prove them to be right.
I agree with you that the wave model has not been taken all that seriously by many workers. The implication of this, is that those who work in the field must believe the wave model to be wrong. I think it is unsatisfactory that this is merely an implication. If a worker has come to this conclusion he should support his opinion. The reasoning which has led him to that conclusion should be made available to me, and to other interested parties (I assume Oliver & Berlin, amongst others, would be interested); in short, it should be published.
In fact reading the literature does not teach me why the wave model is considered wrong, and neither, so far, has asking workers in the field. Unfortunately, your letter to me was similarly unclear. Though you were kind enough to tell me what you believe to be right, I have to say that this is not what I am asking you to do. What I would like you to do is tell me why you think that the wave model is wrong.
Your Recent Work I am referring here to your work published in Nature (1989) 340 pp315-317, Nature (1989) 340 pp284-288 and J. Cell Biol. (1990) 111 pp1618-1622.
Like others, you make no mention of the possibility of waves as the driving force behind capping and particle movement, although you have mentioned that possibility in the past, in previous articles.
It seems to me that there are a few experimental points from these papers which drew my attention.
You observe forwards as well as backwards migration in some instances, particularly when the object is intermediate in size between a protein molecule and a conventional particle. That the particles, can move intermittently backwards from their predominant course (Fig 1a of the first Nature article for example). For intermediate sized particles you observe an apparent correlation between size (as assessed from diffusion coefficient) and rate of movement. You do see diffusion in migrating particles. Fig. 3c of the second Nature article above, showing movement parallel to the direction of cell migration, seems to show some periodicity. A period of about six seconds may be present. I would be interested to know how you accommodate any of these observations into the actin flow model. It seems to me that they can all be accommodated naturally by the wave model, would you not agree?
In respect of point 4, I think you definitely have enough data points, to subject this information to a Fourier analysis. This would establish objectively whether or not a periodicity was present in it. I wonder if you might also consider looking at others of your experiments, and seeing if they display more evident periodicity.
There are a number of other experimental approaches to distinguishing actin flow from waves. One is that someone will perform a photobleaching study on the cytoskeletal components of the cell, there is no doubt in my mind that they will demonstrate, directly, that the cytoskeleton does not circulate at the rates implied by the actin flow model.
Others are to look for evidence of waves. In that regard I note from your letter that you can see "other undulations". I do not know of the distinction you draw between an undulation and a wave, so I think this calls for further clarification.
I suggest that you consider looking for evidence of peristalsis in the region of medium near the surface of the cell.
I suggest that you might consider looking for oscillations in electrical potential in the cell membrane (they do exist, and are predicted by the wave model, but it would be satisfying to correlate them with observations of the cell surface).
I would suggest, to you in particular, that you might consider constructing plots of migration rate versus particle size. It seems to me that the wave model, and the actin flow model are different in this regard. The actin flow model seems to predict an "all or nothing situation," a particle will migrate with the cytoskeleton, or not migrate at all. The wave model, on the other hand, would predict a progressive change from small objects (proteins molecules) which would not migrate, through intermediate sized objects, which would migrate at intermediate rates (and possibly display oscillatory behaviour in their migration) to large objects which would be completely entrained on the wave motion, and move at a constant, size independent, rate with no oscillations.
One final point from your letter, (before I end this interminable missive) I do not actually have the reference on the deletion of the myosin gene from dictyostelium. The results do seem interesting. I doubt whether motility is wholly unimpaired by the deletion of the myosin gene, but it may be that there is more than one mechanism of motility, only one of which is correlated with capping. Furthermore, I do not know what normal wave behaviour is in dictyostelium.
I hope that you have managed to bear with me so far, and that you will respond to, what I have said here by recording the experimental evidence for your objections to the wave model, in order that it can be subject to real debate. I look forward to hearing from you in the near future; I would also be grateful for the reference on the dictyostelium work, to which you refer.
Finally, you should know, that it is my intention to submit an article along these lines, so you might in fact treat this letter as a preprint. With best wishes Yours Sincerely John A Hewitt
23 January 1993 Dear Prof. Sheetz, I am writing further to our correspondence concerning your position with regard to the models which have been proposed to account for the mechanism of capping and particle movement on motile eukaryotic cells. As you know, I was not satified by the replies which I received from you.
In pursuit of the clarification which I require of this issue, I have written a brief review of the status of this field as best it is known to me. A copy of "Cap That!" is enclosed herewith.
I should be grateful if you would read this review, especially those sections which refer to your own position. If "Cap That!" describes your position in way which you feel to be inaccurate or misleading, I should be grateful if you would let me know. I would be grateful also for a clarification of any points which you feel I have reported unsatisfactorily. Yours Sincerely John A. Hewitt
Prof. Ralph Snyderman, The Dean of the Medical School Duke University, Durham N. Carolina 27708, USA 10 May 1994 Dear Prof. Snyderman, I am writing concerning a correspondence I have had, or more accurately tried to have, with Prof. M. P. Sheetz of the Dept. of Cell Biology & Division of Physiology at the University Medical Centre.
The problem concerns some articles and letters published in Nature in 1989 and 1990 by Prof. Sheetz and his co-workers (340 284-288, 340 315-317), and the subsequent correspondence between them and Bretscher (341 491-492, and 345 28). These articles discuss the mechanism of capping and particle movement on motile eukaryotic cells. I think the experiments they report are very elegant and well executed.
However, in reporting their work, they discuss two possible mechanisms for capping, namely lipid flow and the cytoskeletal model. My reason for writing to you, is that I do not understand why the field is reviewed in this way. In fact there is a third possibility, the surf-riding model, that was proposed by myself (J. Theoret. Biol. (1979) 80 115-127) and others. Apparently, Prof. Sheetz feels the wave model to be incorrect.
Prof. Sheetz has previously acknowledged the wave model, so he is aware of its existence, although, so far as I know, he has not recorded anywhere the reasoning which has led him to reject it. In fact I know of no worker in the field who has recorded, on the scientific record, the arguments or evidence they believe to contradict the wave model. His letter to me did not meaningfuly address the point.
I have been writing a booklet ("Cap That!") which reviews this whole matter at some length. A copy is enclosed which, I hope, will provide you with any additional information you may require. I sent Prof. Sheetz an earlier draft, although I do not know whether he received it.
Could you please approach Prof. Sheetz and ask that he write to me explaining the reasoning leading to his rejection of the wave model. I would also be obliged if you, yourself, would acknowledge receipt of this letter which is being sent by recorded delivery. Yours sincerely John A Hewitt
May 20, 1994 Dear Mr. Hewitt: I am in receipt of your letter of May 10, 1994 and a copy of "Cap That". It is a most remarkable document with figures that I shall not soon forget. Per your request, I will send a copy of your letter and booklet to Dr. Sheetz. With best wishes. Sincerely yours, Ralph Snyderman, M.D. James B. Duke Professor of Medicine
A series of letters were sent to the scientific journal Nature before any reply was received.
31 August 1991 Dear Mr. Maddox, I am writing to you about some articles and letters published in Nature in 1989 and 1990; these are the articles from Sheetz and his co-workers (340 284-288, 340 315- 317), and the subsequent correspondence between Bretscher and these workers (341 491-492, and 345 28). These contributions to your Journal discuss the mechanism of capping and particle movement on motile cells.
In doing so they discuss the two possible mechanisms for capping which it is to usual discuss namely lipid flow and the cytoskeletal model. My reason for writing to you, is that I do not understand why the field is reviewed in this way. In fact there is a third possibility, that is the surf-riding model, was proposed by myself (J. Theoret. Biol. (1979) 80 115-127). It would seem, apparently. that these workers feel the wave model to be incorrect.
To the best of my knowledge, Dr. Bretscher has never, in any article, acknowledged the existence of the wave model as a possibility. Prof. Sheetz has done so, although, so far as I know, he has not recorded anywhere the reasoning which has now led him to reject it. I know of no worker in this field who has ever explained, on the scientific record, what argument or evidence there is to contradict the wave model.
I thought at the time when I wrote my article, that the arguments and evidence in its favour were very strong; if anything, I think they have become stronger since. You will appreciate then, that I find it surprising that authors and journals still feel able to review the field in the way these papers have.
I have recently been writing to workers in this field. I am asking those workers, who feel able to review the field in this way, to explain to me the reasoning which has led to their apparent rejection of the wave model. Neither Prof. Sheetz nor Dr. Bretscher have replied in a way which I feel explains their reasoning, and neither seems willing to correspond further.
I am writing to you, asking you, as editor of the Journal which published their work, to intervene with them. Could you please ask them to record the views which they take of the wave model, and the reasoning from which they derive their views.
It may help you to know that Prof. Sheetz has moved from his address at the time of those papers, and is now at the Dept. of Cell Biology, Duke Univ. Medical Center, DUMC Box 3709, Durham, N.C. 27710. Dr. Bretscher remains at the MRC.
I hope to hear from you in due course, and would be grateful if you would acknowledge receipt of this letter. Yours Sincerely John A Hewitt
15 September 1991 Dear Mr. Maddox, Some time ago I wrote to you concerning the subject of capping and particle movement on the surface of motile eukaryotic cells. The letter was concerned in particular with the publications about this field, which had appeared recently in Nature. A copy of my original letter is enclosed.
I would be grateful if you would acknowledge receipt of that letter, and advise me of any course of action which you are taking regarding it. I also enclose a stamped addressed envelope for this purpose. Thank you in advance. Yours Sincerely John A Hewitt
11 October 1991 Dear Mr. Maddox, Some time ago I wrote to you concerning the subject of capping and particle movement on the surface of motile eukaryotic cells. The letter was concerned in particular with the publications about this field, which had appeared recently in Nature. A copy of my original letter is enclosed. I have received no reply or acknowledgement of that letter.
I have also written a reminder to you on this subject, enclosing a stamped addressed envelope for your reply - again I have received neither reply nor acknowledgement.
This letter is a further reminder to you that this matter remains outstanding. I would be grateful to you if you would acknowledge the receipt of my original letter, and advise me of any action which you are taking with respect to it. Thank you in advance. Yours Sincerely John A Hewitt By recorded delivery.
16 October l991
Dear Dr Hewitt,
I am writing in the absence of John Maddox to thank you for drawing our attention to your 1979 paper and to say that we shall be happy to pass on a copy of your letter of October 11 to Michael Sheetz and Mark Bretscher, although you will appreciate that we cannot oblige them to enter into correspondence with you. Yours sincerely, Miranda Robertson Biology Editor
3 December 1991
Dear Dr Hewitt:
I gather from your letters to Nicholas Byam Shaw and Ray Barker that you did not receive Miranda Robertson's letter of 16 October and I am therefore sending you another copy.
Yours sincerely,
Mary Sheehan Office Manager
14 December 1991 Dear Ms. Robertson, I have received from Mary Sheehan, your office manager, a copy of the letter which you apparently sent to me on the 14 October 1991 (your ref. MR/jc). I confirm that indeed I did not receive this letter.
I do feel it would be helpful if you were to pass a copy of my letter to Prof. Sheetz and Dr. Bretscher. I am aware that they cannot be obliged to correspond with me; I have merely asked them to do so. At the same time, you will appreciate, their actions seem to imply that they believe my work to be incorrect.
In a matter such as this, the view of scientific logic promulgated by Popper seems to apply; if a scientific hypothesis is put forward it should be challenged by reference to the experimental facts. If a hypothesis fails this test it should be discarded. If it successfully predicts the experimental results, it may be correct. There is no proof within this system, only disproof.
These workers are professional scientists, who seem to be acting upon the belief that the wave model is wrong. I do feel that this system of logic places upon them a responsibility to state this opinion and to explain the reasoning which has led them to it. In particular, in this matter, I would like to know which experimental results Prof. Sheetz and Dr. Bretscher believe to be in conflict with the wave model. I would like to see this opinion and the reasoning behind it placed upon the scientific record.
"Nature" has provided these workers with access to its columns to express their views. I should say I felt it right that Prof. Sheetz's elegant experiments were aired in this way. My concern lies with the manner in which these workers have chosen (and been permitted) to review the possible mechanisms. It seems they are implying their views about the wave model. In the circumstances, I suggest you should, in addition to forwarding my letter, yourself ask them to clarify this matter.
Accordingly I would be grateful if you would send me a full copy of any letter which you send to them, and of any reply which you receive from them. Yours Sincerely John A Hewitt
20 December 1991 Dear Dr Hewitt, Thank you for your letter of December 14. We have sent your original letter, with a copy of my letter to you of October 14, to Michael Sheetz and Mark Bretscher. Yours sincerely, Miranda Robertson Biology Editor
16 February 1992 Dear Ms. Robertson, I am writing to you further to my letter of the 14th of December. I acknowledge the receipt of your letter of the 18th of December and I thank you for forwarding copies of my letter, and of your own reply to me, to Dr. Bretscher and Prof. Sheetz.
At he time of writing this letter I have received no reply from either of these workers. It seems most likely that they do not intend to reply to me.
Could you let me know whether or not you have received any communication on this matter from these workers? If you have, I would be grateful if you would send me copies of their letters. Thank you. Yours Sincerely John A Hewitt
18 February 1992 Dear Professor Hewitt, Thank you for your letter of February 16. We have not heard from either Bretscher or Sheetz but shall forward any letters that may reach us. Yours sincerely, Miranda Robertson Biology Editor
24 March 1992 Dear Ms. Robertson, Thank you for your letter dated 18 February, MR/jc. I note that you also have not received replies from Prof. Sheetz and Dr. Bretscher.
This does create something of a difficulty. On the one hand, as you say, they cannot be forced into corresponding with me; on the other hand, they are professional scientists working in this field, who plainly take the view that my own published work is incorrect. More specifically, they seem to be acting on that basis.
As I have said before, as far as I know, neither of these groups have recorded either the fact of this opinion, or any explanation of how they came to it.
It does seem likely that if these workers had reasoned grounds for their rejection of the wave model, they would have pointed them out to me when they were asked to do so. I feel it likely that, in fact, they have no real grounds for their rejection of it.
This situation seems to give rise to ethical difficulties. Any person, unfamiliar with the history of this field, could be expected, on reading these papers, to draw the inference that only two possible mechanisms to describe capping and particle movement phenomena had been put forward. Such a reader would, I suggest, be mislead.
At the same time, a reader with sufficient background to be aware of the wave model, could be expected to conclude that these leaders in the field had been able to exclude it. It seems that this reader also would be mislead.
In other words, this is a misleading, arguably false, way of reviewing the field.
As the journal which published this work, perhaps you should also consider airing the counter-argument. Are you willing to publish a correction, by me, of the assertions made by these workers that there are only two models which could account for the phenomena of capping and particle movement?
I enclose herewith a copy of a letter which I received from Prof. Sheetz, along with a copy of my rather lengthy reply to him. I have received no further communication from him. The content of my letter to him would form a basis for the article I have in mind. Yours Sincerely John A Hewitt Enclosures
(Letter from J. Maddox, to which the following is a reply has been lost) 11 April 1992 Dear Dr. Maddox, Thank you for your letter dated 7 April 1992 (JM/MS). My original letters to Nature were directed to yourself, so it does seem appropriate that you write to me.
This matter has not been dealt with in the exchange of letters between myself and Prof. Sheetz, or Dr . Bretscher, to whom I have also written. They seem reluctant to correspond with me on this issue. It is for this reason that I wrote to you.
This papers which are at the centre of my concern were published, indeed given considerable prominence, by Nature. These articles purport to have decided a long standing scientific controversy concerning the mechanism of capping. They, supposedly, review the possible mechanisms and describe the experimental data produced by Prof. Sheetz as deciding the matter in favour of the cytoskeletal model. However, the original articles by Prof. Sheetz, the response by Dr. Bretscher and also the News and Views commentary by Prof. Edidin, all review the field as if only two possibilities had been put forward - which is not the case. I would like to know the reasoning which has led these groups to believe that they can reject the wave model - my work. I would also like to know why they feel able to review the field in this way without ever recording in the literature the reasoning which led them to reject the wave model.
As I said in my last letter to Ms. Robertson, to which you have replied:-
This situation seems to give rise to ethical difficulties. Any person, unfamiliar with the history of this field, could be expected, on reading these papers, to draw the inference that only two possible mechanisms to describe capping and particle movement phenomena had been put forward. Such a reader would, I suggest, be mislead.
At the same time, a reader with sufficient background to be aware of the wave model, could be expected to conclude that these leaders in the field had been able to exclude it. It seems that this reader also would be mislead.
In other words, this is a misleading, arguably false, way of reviewing the field.
It is the misleading, arguably false, character of these papers, to which I am drawing your attention. Your letter does not acknowledge these concerns.
These workers, through your journal, have plainly implied that my work is in some way deficient or incorrect. They seem to feel that it is merely theory, but that won't wash. It is no more or less theory than the cytoskeletal or flow models - and, I think, has the merit of not being demonstrably wrong!
There is another aspect of this matter which concerns me somewhat. It seems to me that I am the injured party in a this matter. There is thus some possibility that I will wish to take action in law against Nature. However these papers were published in 1989 which is nearly three years ago. I believe, though I may be wrong, that a time limit does exist on such actions and that it is three years. Accordingly, I feel I should appraise you of the possibility that I may go down this route.
However, please don't get the feeling that I am anxious test these matters in court, just the reverse. My purpose in making this statement is to protect rights under law, which I might otherwise lose due to this time factor. I would mostly like to see proper reviews of this field and corrections of those reviews which are incomplete.
I was unable to obtain prompt or satisfactory replies from the authors and so I wrote to you. I am inviting you, as the Journal which published and gave prominence to these papers, to correct this aspect of the work. What I have in mind is either a letter, or a matters arising article. It will draw attention to the points made above. Inasmuch as it will be a correction of work you have already published, it will contain no new experimental work. Considering its purpose, I think anonymous refereeing would be inappropriate.
With this wish in mind, I would invite you to reconsider your position on this matter. I would invite you to recognise the need to publish a correction of these papers.
I would be grateful also if you would respond specifically to the following points:-
Would you please acknowledge the ethical questions which are being raised with you. Do you regard the manner in which these correspondents to Nature reviewed this field as acceptable or unacceptable? Do you agree that readers are likely to be mislead by it? What actions, if any, are you prepared to take to correct the misapprehensions which readers of these papers are likely to be under? Yours Sincerely John A Hewitt 31 May 1992 Dear Dr. Maddox, Thank you for your letter of the 13 of May and for using your time to review these matters.
I note that you "guess" these workers "may not be as aware of the wave model as they might be". In this context I am not sure that awareness can be quantitated. Both groups have been aware of the wave model for many years. It is possible that they do not fully understand the wave model. Their understanding might be enhanced if they were willing to take part in debate which includes it.
I feel the essential point is that one should not have to guess their position, they should be making it clear.
Published data has been inconsistent with existing theories for many years. Bretscher's criticisms of the cytoskeletal model are known and are in no way invalidated by the disproofs of his flow model. I listed many reasons for rejecting the idea of cytoskeletal flow in my letter to Prof. Sheetz, of which you have a copy. I also suggested several ways of seeking direct evidence for the wave model.
My enquiries concerning this matter have and do include direct correspondence with the workers concerned; as you say this is one normal way of proceeding. In the main the few replies which I have received from workers are cursory. They seem to me not to address the issues being raised. As I point out in my original letters to yourself, they seem to be unwilling to correspond with me on this matter.
Prof. Sheetz's letter of which you have a copy is a case in point. This is the only letter which I have received from him. It is possible that he feels the reasons he gives there for rejecting the wave model are adequate; however, I do not think they are. In the first place he does not provide references to all the experiments concerned; I need these if I am to form my own view of his arguments. What is more, I certainly do not think his arguments are so obviously correct that they do not need to be stated! I cannot even begin to imagine the reasons for his reluctance to go on record with them. Moreover, I received no further reply to my subsequent letter. I see little point in writing letters to which I can expect no response. It is for this reason that I wrote to you.
You may recall that Ms. Robertson was kind enough to forward my letter, requesting further explanation, to these workers. However, neither myself nor Nature, received a reply.
Nature is an organ of the press. When, for whatever reason, such a body publishes articles which seem to be misleading or false, it seems to me normal to ask that same organ to publish a correction. This is what I am asking you to do.
The purpose of the questions, which I asked at the end of my letter of the 3rd of May, was to elicit a clear picture of your view on this point. Your letter did not seem to reply to them. They are repeated below.
I should be grateful if you would acknowledge the ethical questions which are being raised with you. Do you regard the manner in which these papers in Nature reviewed this field to be acceptable or unacceptable? Do you agree that readers are likely to be mislead by it? What actions, if any, are you prepared to take to correct the misapprehensions which readers of these papers are likely to be under? Could I ask that you reply to these questions? Yours Sincerely John A Hewitt
22 June 1992 Dear Dr. Maddox, Thank you for your letter of the 9th. of June. I note that you are not prepared to add to what you have already said.
I enclose herewith a further copy of my letter of 31 May. Your letters do not appear to have addressed the enquiries which I made in this and my earlier letters.
In the circumstances I would be grateful if you would let me have a copy of Nature's general code of practice, with particular regard to the publication of misleading or incorrect papers; also with regard to the reporting of dissenting views.
I would also be grateful if you would give a clear statement concerning the enquiries which I have made. In the event that I receive no satisfactory reply, I shall, inter alia, seek the assistance of the Press Council. Yours Sincerely John A Hewitt cc Mr. N. G. Byam Shaw Mr. R. Barker
6 January 1993 Dear Dr. Maddox, I am writing further to our correspondence concerning the models which have been proposed to account for the mechanism of capping and particle movement on eukaryotic cells. You will recall that I contacted you following an unsatisfying exchange of letters on this subject with Drs. Bretscher of the MRC laboratory in Cambridge and Prof. Sheetz of Duke University, N.C.. As you know, I did not feel the replies which I received from you were satisfactory. I am particularly concerned about the apparently misleading manner in which Nature is prepared to permit this field to be reviewed within its pages.
In pursuit of the clarification which I require of this issue I have written a brief review of the status of this field as best it is known to me. A copy of "Cap That!" is enclosed herewith.
I should be grateful if you would read this review, with particular regard to those sections which refer to your own position and that of Nature. I have quoted at some length from Nature's publicly stated standpoint as regards scientific ethics. If "Cap That!" describes your position, or that of Nature, in way which you feel to be inaccurate or misleading, I should be grateful if you would let me know. I would also be grateful if you would clarify any points which you feel I have reported unsatisfactorily. Yours Sincerely John A Hewitt cc Mr. N. G. Byam Shaw Mr. R. Barker
WITHOUT PREJUDICE
28 January 1993
Dear Dr. Hewitt,
I have read the document you sent and also (again) your 1979 paper in the Journal of Theoretical Biology. Reading your text, I wonder whether I and others have been over-polite in our correspondence with you.
That you have formulated a hypothesis is not gainsaid. Briefly it is that if there are travelling waves on the surfaces of the cells forming caps, if the direction of the waves is from front to back and if the position of a patch is determined by the potential energy occasioned by its enforced curvature, then that could account for capping. I agree it is distinct from Bretscher's and the cytoskeletal hypotheses.
That said, in my opinion you totally misinterpret Popper on hypotheses. What you say about falsification supposes that all hypotheses are equally interesting, but that is the opposite of the truth. For any problem at any time, the most interesting hypotheses will be those that have been most often tested and not falsified. But it also matters that a hypothesis should be grounded on previous understanding or observation: even before the Apollo project, the hypothesis that the moon is made of green cheese had few followers because it flew in the face of what was even then known about the Solar System.
The weakness of your hypothesis, which you appear to acknowledge, is that there is nothing to suggest that the travelling waves on cell surfaces are as common as they would have to be to account, on your view for capping. But it should not be beyond the wit of you and others to set out to look for them; I guess that your 1979 paper would allow some estimate of the frequency of the waves, suggesting that even a stroboscope might help you find them.
By contrast, Bretscher's hypothesis is a kind of kinetic theory of the constituents of the membrane (with the intracellular recycling an optional inference). It is not surprising that the cytoskeletal hypothesis appeared on the heels of the discovery of the cytoskeleton.
Your text implies that the scientific community has a responsibility promptly to test all hypotheses put into circulation, and to give all hypotheses what might be called equal time in what they write. That is emphatically not the case. People do the experiments that interest them and refer to the ideas they believe to be interesting. Naturally, if they judge wrongly in either role, their reputations will wilt.
I believe you also seriously underestimate the extent to which problems that seem interesting at one epoch are often made less so at another by the pace of discovery. Capping was an interesting issue in the 1970s because the migration of patches showed the malleability of the membrane surface. Now it is less interesting. So much more is now known of membranes and their constituents that it can only be a short time before there is a much fuller understanding of the constituents and dynamics of cell membranes (capping included) than people would have dreamed of 20 years ago. So if you do nothing but let a little time pass, you should be able to tell by inspection whether you are right or wrong.
My impression of your text is that it is likely to give serious scientists into whose hands it falls an impression of a querulous person unreasonably demanding that the scientific community should pay urgent attention to a theoretical speculation about a phenomenon quickly being subsumed into a broader and more interesting field of science.
I should also say that I have not taken legal advice on your document and that, while I do not believe it to be libellous of Nature (but others mentioned might think differently) I would have no hesitation in doing so if I believed it were being distributed widely.
I have written at this great length because it is clear from your text that you do not appreciate how your claims are regarded. But I do not wish to correspond with you again on the substance of your text. If by chance you do find evidence of travelling waves on the surface of cap forming cells, by all means think of Nature as an outlet. Yours Sincerely John Maddox Editor 14 March 1993 Dear Dr. Maddox, Thank you for your letter dated the 28th of January 1993.
I note the points which you make and would observe that they were largely addressed at some length in "Cap That!". I do not think I misunderstand the principles of scientific elimination. Perhaps you would be kind enough to tell me where in Popper's writings he extends the ideas of elimination in the way you describe? This letter is not the place for me to elaborate my own views on intrinsically probable or improbable models.
I agree with you that "Cap That!" is not libellous of Nature; I do not believe it to be libellous of anybody mentioned. "Cap That!" is intended to be a fair and accurate record of the development of debate and thought in this field, albeit that it describes this development from a standpoint those mentioned might prefer to see left unsaid. I believe it is indeed fair and accurate and as such is not libellous.
I am sure you realise that I did not write "Cap That!" in order to leave it on a shelf. The next version will be distributed widely. I suggest, therefore, that you take your legal advice. If "Cap That!" contains statements which are unfair or inaccurate this was unintentional. If you raise specific points with me I will endeavour to make sure that any unfairness to you is corrected, subject always to the constraint that what I finally write must indeed be fair, accurate and reflect all views. As things are, I believe and hope that a Court of Justice would be unsympathetic to your present position.
In order that your position is as clear to readers of "Cap That!" as possible, I shall incorporate the whole text of your recent letter into the next version. I shall, of course, mentioned that it was written without prejudice to the position you may subsequently take in Court.
I am sorry that you do not wish to deal with me on this matter; however, as I see things, the question is not whether you wish to do this but whether you have a responsibility so to do.
I take it that you are not prepared to correct these misleading papers. I have previously asked for a copy of your code of practice. Would you please send me a copy of your general policy or code of practice as regards the publication in Nature of papers which turn out to be false or misleading? Yours Sincerely John A Hewitt
cc Mr. N. G. Byam Shaw Mr. R. Barker
23 September 1994 Dear Dr. Maddox, I am writing further to our correspondence concerning the papers published in Nature in 1989 and 1990 by Sheetz and his co-workers (340 284-288, 340 315-317), and the subsequent correspondence between Bretscher and these workers (341 491-492, and 345 28).
You will recall that these papers review the capping field as if only two possible mechanisms exist when in fact three have been proposed. You declined to correct these papers as I requested. In explaining your position you said of my work (the wave model)
"That you have formulated a hypothesis is not gainsaid. Briefly it is that if there are travelling waves on the surfaces of the cells forming caps, if the direction of the waves is from front to back and if the position of a patch is determined by the potential energy occasioned by its enforced curvature, then that could account for capping."
And also
"The weakness of your hypothesis, which you appear to acknowledge, is that there is nothing to suggest that the travelling waves on cell surfaces are as common as they would have to be to account, on your view for capping."
I enclose with this letter an incomplete draft copy of the section of the next version of "Cap That!" that reviews the experimental case for the wave model. I would draw your attention to two sections in particular, the first being the quotations from Sheetz's own paper in The Journal of Cell Biology, Kucik et al. (1994).
"The lack of systematic drift of the diffusing particles in the frame of reference of the cell was particularly striking in the light of the dramatic centripetal cytoplasmic waves visible within the lamellipodium. We observed centripetal transport of some surface bound particles in concert with these waves on all parts of the lamellipodium, particularly with large (0.3 æm) latex beads and with large aggregates of gold particles but only rarely with individual gold particles. This centripetal transport was easily distinguished from diffusion by the steady rearward migration and relative lack of Brownian motion as compared to diffusing particles in the same region of the lamella (Fig. 3, also Sheetz et al. 1989). The diffusing particles (that is, those not moving in a directed fashion) were not influenced by the underlying cytoplasmic waves even in the lateral regions of the cell, where the motion of the waves is at right angles to the direction of cell migration".
The italicised phrase was added by myself. They remark later on (page 1621) that
"the centripetally moving waves ... seem to be correlated with the systematic transport of surface particles."
This description is particularly striking coming as it does from the same group who published these papers in Nature in the first place and being descriptions of the same cell system. As is usual, this paper did not mention the possibility that the particles were being driven by the waves!
I would further draw your attention to the quotes from Jaffe's (1994) review of calcium waves and his comment about such waves being conserved among "all or almost all eukaryotic cells." You may also note that amongst his waves he describes "contractile waves" located in the cell membrane with about the right speed to drive capping.
I have always felt the arguments in favour of the wave model were compelling and these observations seem to add further weight. On the face of it, they directly negate your criticisms of the wave model.
In the light of this information, would you like to modify your position concerning these matters? Yours sincerely John A Hewitt Jaffe L. F. (1994) Cell Calcium 14 736-745 Classes and Mechanisms of Calcium Waves Kucik. D.F., Elson E.L. & Sheetz M.P. (1990) J. Cell Biol. 111 1617-1622 Cell migration does not produce membrane flow.
2 September 1991 Dear Prof. Jacobson, I have recently read and obtained a copy of your articles in J. Cell Science (1991) 98 191-203, and Science (1990) 247 1229-1233 along with the subsequent exchange with Bretscher. These articles studied capping and reviewed the hypotheses which have been put forward to account for its causation. As is often the case, your discussion of the possible mechanisms for capping was based on the idea that there are two possibilities, namely membrane flow and cytoskeletal attachment (of one sort or another). You interpret your results as being indicative of the latter, some form of cytoskeletal attachment being responsible for capping and particle movement.
Some years ago I suggested an alternative mechanism to account for the phenomena of capping and particle movement (J. Theoret. Biol. (1979) 80 115-127.). This was based on wave particle interactions. This possibility still seems to me to offer a better explanation of the observations than do the more widely considered alternatives. Your papers do not mention this possibility at all, and I am writing in part to ask if you are aware of it?
Like yourself, many workers in this field do not make mention of the possibility of wave driving when they review the possible mechanisms to account for capping and particle movement. To the best of my knowledge, however, no worker has yet recorded on the scientific record, any reason for rejecting it. I have been writing to a number of such authors, asking if they could explain to me their views on the wave model.
This then is the other reason why I am writing to you, if you were aware of the wave model, would you be kind enough to write and tell me, why you believe it to be incorrect.
A couple of other points occurred to me on reading your recent papers
the protein which you chose to cap was the Pgp-1 protein, which you point out is known to be a transmembrane protein. This shows associations with the submembrane cytoskeleton, but I do not understand why these have to be considered relevant to capping. Surely the cytoskeletal proteins are known to be very "sticky" and may form associations with many transmembrane proteins. Such associations however seem impossible for lipids and for non- transmembrane proteins, both of which are known to cap on patching. This being so the relevance of the membrane protein cytoskeletal associations to the mechanism of capping seems to me to be doubtful.
Have you considered performing a similar study on lipids or non-transmembrane proteins to the one you reported in J. Cell Science? I should have thought this would be a more stringent test of cytoskeletal ideas than the system upon which you chose to work.
Finally, it seems to me that, increasingly, workers in this field are beginning to assert that the phenomena arise from a continuous submembrane flow of the cytoskeleton. I would like to determine if any worker has succeeded in performing a study using photobleaching techniques on the cytoskeleton. Would you be kind enough to let me know whether or not you know of any direct demonstration of cytoskeletal cycling, by this technique, or any other?
I look forward to hearing from you. Yours Sincerely John A Hewitt
27 January 1992 Dear Prof. Jacobson, I am writing to you further to my letter of the 2nd of September 1991, to which I have, so far, received no reply. A copy of this letter is enclosed herein.
I am anxious to establish, for the record, the reasoning which has led the major workers in this field to reject the wave model. Accordingly, I would be grateful if you could let me have a reply to this letter as sson as possible.
I hope to hear from you in the near future. Yours Sincerely John A Hewitt
February 24, 1992 Dear Dr. Hewitt:
Thank you for your letter of September 9, 1991 and January 27, 1992. I apologize for being so late with my reply. Indeed, I was aware of your alternate mechanism by capping.
I suppose the reasons that many do not consider your model very carefully is that the retrograde cytoskeleton movements are well established and, if linkages to membrane components are postulated, these movements offer a simple explanation of capping. Furthermore, according to conventional wisdom, the retrograde movements of patches, driven by the cytoskeleton, provide an explanation of retraction if ventral surface patches are assumed to form a bond to the substratum: in this case, patches are anchored and thus the tail of the cell moves forward. I suppose also the casual observer sees more recent evidence for retrograde cytoskeletal movements (see below) than for generalized surface waves. For instance, how and where might such waves be propogated across the cell surface? Thus, your -2-
model is less familiar and, if taken literally, would fail to predict the capping of unpatched pgp-1 (see JCB 1991, enclosed). This is because monomers or dimers would be smaller than the 600 Aølimit required for entrainment when thermal energy of the patch is considered.
In regard to your specific points, we did look at Thy-1, a lipid-linked glycoprotein (see enclosed reprint, JCB 1991). Cytoskeletal retrograde flow has been documented by Wang (JCB, 1985), Forscher and Smith (JCB, 1988), and by Theriot and Mitchison (unpublished as far as I know). Of course, in their keratocyte Nature paper last year, the photoactivated actin bar moved rearward with respect to the leading edge but not with respect to the substratum. They subsequently performed similar experiments in fibroblasts, and their bar moved backwards with respect to both the edge and the substratum.
Once again, I apologize for my tardiness. Sincerely, Ken Jacobson Professor
1 July 1992 Dear Prof. Jacobson, Many thanks for your letter dated the 19th of February and for the enclosed reprints. It is very nice to look at real photos instead of the smeary photocopies I usually read. I am sorry for the tardiness of my reply (I plead pressure of time).
You will appreciate that these letters are somewhat difficult for me to write; this is especially true of letters to workers, such as yourself, whose work I find well conceived and executed. At the same time, I am concerned about the way this field has developed over the years and it is the nature of the debate which particularly concerns me. Three possible mechanisms (with variations in each case) have been proposed to give a mechanism for capping. During reviews of the field, however, only two of those possibilities seem to be taken seriously. This seems to me to raise serious questions about the validity of the debate which has taken place.
Popper's ideas on scientific logic have it that one must negate hypotheses; this view is generally accepted. The arguments which negate the cytoskeletal and flow models have been presented at length. What seems to be missing from debate in this field, is an explanation, on the scientific record, explaining why the wave model should be rejected.
Your letter did, to some extent at least, address these issues and I have read the papers to which you directed my attention. However, you will understand that one of my objectives is to have the arguments which lead to the rejection of the wave model placed on the scientific record; it is only there that these arguments can be subject to real examination and riposte.
In the case of the cytoskeletal model, a precise definition of the model presents some problems and there seem to be at least two separate proposals going under the same name.
I will deal firstly with the points which you make in your letter and then proceed on to more general matters.
Firstly, I am not aware that retrograde cytoskeletal movements are well established. Given the polarity which exists in actin assembly some movement does seem likely, though I would not have thought it would necessarily be retrograde - it seems too me more likely to be from the membrane to the perinuclear region; if you prefer from the membrane of the cell to the inner region. This motion would be more accurately described as centripetal (or nucleopetal would you believe).
Moreover, the rates of particle motion are, as far as I understand the matter, generally greater than the known rates of actin polymerisation. This is the opposite of the situation required by the cytoskeletal flow model.
It is undoubtedly true that some transmembrane proteins make contact with the cytoskeleton. However, as judged from the capping of lipids and non-transmembrane proteins, such contact is not a necessary condition for capping to take place. Therefore such contact cannot be an essential element in the mechanism of capping. When the capping proteins and the cytoskeleton are attached to one another, it is obviously the case that the surface patch will move in association with cytoskeletal elements. This observation is certainly made, but surely this just says that if two objects are tied together they will move together. I cannot, myself, see a mechanistic conclusion flowing from this at all. However, as you know, such observations have been cited as strong support for the cytoskeletal model.
The way round the problems of the cytoskeletal model offered by many workers has been to say that the surface of the cell is being sieved in some way by those membrane proteins which do make contact with the cytoskeleton. Well, as I said above, I do not think the cytoskeleton is moving fast enough or in the right pattern for this to be workable. But, the idea seems testable using the techniques which you have already adopted to eliminate the possibility of lipid flow.
Consider the following experiment:-
Choose the membrane protein which, in your opinion, is most likely to be sieving the surface. Get antibodies to it, and convert the antibody to monovalent fab fragments which you fluorescently label. Use those fragments to fluorescently label the protein of choice. Then use your photobleaching technique to positively demonstrate the existence of a rapid flow in this case. Similar approaches could be used to demonstrate co-capping of the sieving protein with the sieved caps.
I do not think you will find these proteins flowing in the way predicted by surface sieving, if at all.
Your letter mentions the casual observer of the field. This gentleman would, I suggest, see little in the way of real evidence for cytoskeletal flows - he would however see abundant speculation about such flows from experts in the field. That same casual observer would never learn that any alternative mechanism even existed, let alone that there was supportive evidence both for waves and the wave mechanism of capping.
A good example of this is the Forscher and Smith article to which you drew my attention in your letter. You cited this article to me as evidence for cytoskeletal flow and indeed they present evidence that if the polymerisation of actin is inhibited by the use of cytochalasin B, then when the drug is removed polymerisation restarts at the membrane. I would expect that, after a period of non-synthesis, actin assembly at the leading edge would be greater than normal. But even under these conditions the rates of assembly observed are only just up to the rates of particle movement (Wang's estimate and most others are markedly slower).
The same paper describes the existence of "wave motility". The authors do not seem to interpret this observation at all. It is not in the title of the paper, neither is the bibliography on cell waves cited. This means that, any worker (casual or otherwise) interested in cell surface waves would not find this paper, or these observations, by bibliographic review. I, for example, was unaware of these observations and I am grateful to have learned about them.
I will give another example, this is from the work of Prof. Sheetz whom I am sure you know well. In his article in Nature (1989) 340 pp315-317, they observed inter alia that the particles adherent to the surface of their cells, could move intermittently backwards from their predominant course (Fig 1a).
This observation seems very difficult indeed to explain in terms of cytoskeletal cycling but seems but seems easily interpretable in terms of a wave model. However, the article made no comment at all on this, and, like your own work, did not mention the wave model at all.
This, I think, is the crux of the problem about the casual observer to whom you refer. I suggest he would be mislead by the incomplete reviewing of the field. I am obliged to say that I think you are contributing to this state of affairs. I will come back to this point shortly.
Although the equations with which I presented the wave model give an illusion of precision, the computing principle of garbage in, garbage out applies. The estimates I used for wavelength, amplitude and flexibility coefficient for the membrane were not good. Estimated values of the size of patch which would cap, will be very sensitive to changes in these variables, which in their turn, are likely to depend upon the activity of cell. I did these calculations just as examples. The 600þ limit should not be given any significance, at the same time the general predicted trends should be.
One doesn't know too much about the molecular weight of proteins such as pgp-1 in the membrane, but since they seem to make contact with elements of the cytoskeleton they will obviously be enlarged by that contact. This enlargement could be enough for them to entrain onto a wave. I think such redistributions can be accommodated within the wave model.
Overall, I am not impressed by the evidence for cytoskeletal cycling. The rates of cycling seem insufficient to explain the rates of capping and particle movement. I feel several other arguments could justify rejection this idea. I am also unimpressed by the grounds you cite for rejecting the wave model.
You ask how and where such waves might be propagated across the cell surface. I am inclined to approach this whole thing from a discussion of motility in general. Wave driven motility is possibly the most widespread motile mechanism in nature - I think more common than are legs! So, if one is looking for the mechanism of how cells move, it is a postulate that makes some sense. Convergent evolution comes about because evolutionary problems are solved the same way in similar situations.
(Flow models, such as cytoskeletal cycling are a sort of tank tread or escalator form of motility. I am not aware of any biological system in which a mechanism remotely analogous to this one has evolved.)
Waves have been observed several times on cells, the normal observation is that they begin at the leading edge and travel to the rear, this is in accord with the motion that one normally sees in other animals as they move. Occasionally (I know of only one report - Couchman J. R., Lenn M. and Rees D. A. (1985) European Journal of Cell Biology 36 182-194) waves have been seen moving the other way on cells. This is acceptable in physical terms, one can have quite independent sets of wave trains moving in different directions. It may also reflect the occasional observation of anterograde movement of particles on cells. The role of the waves on the surface of cells is likely to be peristaltic, they will push on the local medium (or on any surface or object which comes into contact with the cell).
The question of how waves are propagated is a complex one. This was discussed, though not very fully, by Durham in his paper which my work cites. More thorough discussions are given by Winfree's books ("Biological Clocks" or "The Geometry of Biological Time"). The take home message from this work is that the necessary feedback loops to generate waves are widespread in biological systems. (The same feedback loops are necessary to generate oscillations and these are very widely known. One article (Rapp P.E., (1979) in Cellular Oscillators, M.J.Berridge, P.E.Rapp and J.E.Treherne Eds; J. Exp. Biology 31 pp281-306) is an atlas of examples, but lots more have been reported since.)
I did write in detail some time ago to Prof. Sheetz, giving more detail of my grounds both for rejecting the cytoskeletal flow model and for believing the correctness of the wave model. Here I think I have said enough, if you would like more detail of my views, I will send a copy of my letter to him.
The essential point though, is that if you feel the wave model is wrong, I think this is a view you should report on the record. Reviewing the field as if only two possible mechanisms have been put forward seems to me likely to mislead readers. I must ask you to tell me whether you intend to go on reviewing the field in this way?
I hope to hear from you, explaining your likely future position on this matter, in due course. Yours Sincerely John A Hewitt cc S. Gilbert (Science)
July 29, 1992 Dear Dr. Hewitt: Thank you for your letter of 1 July. I would like to consider it in detail, but due to the pressure of teaching and grant renewal, I will not reply to you until the end of the year. In the meantime, I would appreciate a copy of your letter to Mike Sheetz. All the best, Ken Jacobson Professor
4 August 1992 Dear Prof. Jacobson, Thank you for your brief letter of July 29, 1992. I enclose herewith a copy of my letter to Prof. Sheetz from last year, which I hope may clarify further any points I am making.
There are a few aspects of my perception of the field which have changed since that time, in particular those which arise from the work on actin filament polymerisation in vivo, in part resulting from reading the references provided by yourself. Even so, the great burden of my perception remains as stated to Prof. Sheetz last year and to yourself more recently.
I will look forward to hearing from you in due course and hope that your grant applications go well. Yours Sincerely John A Hewitt
12 August 1993 Dear Prof. Jacobson, I am writing further to our correspondence concerning your position with regard to the models which have been proposed to account for the mechanism of capping and particle movement on motile eukaryotic cells. You will recall that in your letter of the July 29th 1992, you indicated that you would be replying to me later in the year.
In pursuit of the clarification which I require of this issue, I have written a brief review of the status of this field as best it is known to me. A copy of "Cap That!" is enclosed herewith.
I should be grateful if you would read this review, especially with regard to clarifying your own position. I look forward to hearing from you in the near future. Yours Sincerely John A Hewitt
Prof. Paul Hardin, The Chancellor of the University University of N. Carolina at Chapel Hill Chapel Hill, N.C. 27599, USA 10 May 1994 Dear Prof. Hardin, I am writing concerning a correspondence I have had, or more accurately tried to have, with Prof. K. Jacobsen of the Lineberger Cancer Research Center.
The problem concerns some articles and letters published in the journal Science in 1990 and 1991; these are the articles from Prof. Jacobsen and his co-workers (247 1229- 1233) and their subsequent exchange of views with Bretscher (251 318-319). These articles discuss the mechanism of capping and particle movement on motile eukaryotic cells.
In doing so they discuss two possible mechanisms for capping namely lipid flow and the cytoskeletal model. My reason for writing to you, is that I do not understand why the field is reviewed in this way. In fact there is a third possibility, the surf-riding model, that was proposed by myself (J. Theoret. Biol. (1979) 80 115-127) and others. Apparently, Prof. Jacobsen feels the wave model to be incorrect.
Prof. Jacobsen did tell me he was aware of the existence of the wave model, although, so far as I know, he has not recorded anywhere the reasoning that led him to reject it or even acknowledged its existence. In fact, I know of no worker in the field who has recorded, on the scientific record, the arguments or evidence they believe to contradict the wave model. His brief letters to me have not meaningfully addressed the point.
I have been writing a booklet ("Cap That!") which reviews this whole matter at some length. A copy is enclosed which, I hope, will provide you with any additional information you may require. I sent an earlier draft to Prof. Jacobsen, although I do not know whether he received it.
Could you please approach Prof. Jacobsen and ask that he write to me, explaining the reasoning leading to his rejection of the wave model. I would also be obliged if you, yourself, would acknowledge receipt of this letter which is being sent by recorded delivery. Yours sincerely John A Hewitt
(No reply was received from Chapel Hill)
28 January 1992 Dear Prof. Koshland,
I am writing to you about some articles and letters published in Science in 1990 and 1991; these are the articles from Jacobsen and his co-workers (247 1229-1233) and their subsequent exchange of views with Bretscher (251 318-319). These contributions to Science discuss the mechanism of capping and particle movement on motile cells.
In doing so they discuss the two possible mechanisms for capping which it is to usual discuss, namely lipid flow and the cytoskeletal model. My reason for writing to you, is that I do not understand why the field is reviewed in this way. In fact there is a third possibility, that is the surf-riding model, which was proposed by myself (J. Theoret. Biol. (1979) 80 115-127). It would seem, apparently, that these workers feel the wave model to be incorrect.
To the best of my knowledge, neither Prof. Jacobsen nor Dr. Bretscher have ever, in any article, acknowledged the existence of the wave model as a possibility or explained on record why they believe, as they apparently do, that it is incorrect. In fact, I know of no worker in this field who has ever explained, on the scientific record, what argument or evidence there is to contradict the wave model.
I thought at the time when I wrote my article, that the arguments and evidence in its favour were very strong; if anything, I think they have become stronger since. You will appreciate then, that I find it surprising that authors and journals still feel able to review the field in the way these papers have.
I have recently been writing to workers in this field. I am asking those workers, who feel able to review the field in this way, to explain to me the reasoning which has led to their apparent rejection of the wave model. Neither Prof. Jacobsen nor Dr. Bretscher have replied in a way which I feel explains their reasoning, indeed I have received no reply to my letters from Prof. Jacobsen.
I am writing to you, asking you, as editor of the Journal which published their work, to intervene with them. Could you please ask them to record the views which they take of the wave model, and the reasoning which has led them to reject it?
It may help you to know that the addresses to which I have sent my letters to these workers was, Dr. Bretscher at the MRC Lab. for Molecular Biology, Hill's Road, Cambridge CB2 2QH, UK. and Prof. Jacobsen at Lineberger Cancer Research Center, University of N. Carolina at Chapel Hill, Chapel Hill, N.C. 27599, USA.
I would be grateful if you would acknowledge receipt of this letter and I hope to hear from you in due course. Yours Sincerely John A Hewitt
13 March 1992 Dear Prof. Koshland, I am writing further to my letter to you of the 28th of January. I have received no acknowledgement or reply to that letter, which was sent to the New York offices of Science. Accordingly, I will send copies of this letter to both the New York and Washington offices to ensure that you receive at least one of them. I enclose also a copy of my original letter.
Since my letter of the 28th January things have changed somewhat, in that I have now received a letter from Prof. Jacobsen. His letter provided reference to a number of papers, however, at the time of writing, I have not had the opportunity to read them. I am thus unable for a few weeks to evaluate his reply to me.
I have still had no further reply from Dr. Bretscher. So my request remains, asking you, as Editor of the Journal which published this work, to intervene. Could you please ask him to record the views which he takes of the wave model, and the reasoning which has led him to reject it?
In the meantime may I ask that you acknowledge the receipt of this letter? I may write again when I have had the opportunity to form an evaluation of Prof. Jacobsen's letter. Yours Sincerely John A Hewitt
To: John A. Hewitt
From: Steven Lapham, Assistant Letters Editor
Date: 20 March 1992
We have received your letter of 13 March. Your earlier letter of 28 January did not reach us because it was sent to an address in New York City that is not viable.
Please send any further correspondence to our Washington, DC address (above). We plan to send you further correspondence about your two letters in a few weeks.
Thank you for your interest in SCIENCE.
8 April 1992 Dear Mr. Hewitt:
Thank you for your letter of 13 March about a technical comment by M. S. Bretscher published on 18 January 1991. (I am sorry that your first attempt to reach us was not successful).
We will be glad to write to Dr. Bretscher about your concerns and ask him if he would reply to you, but there is no way we can insist that he respond.
We appreciate your interest in SCIENCE.
Yours Sincerely, Christine Gilbert Letters Editor CKG:ssl
1 July 1992 Dear Ms. Gilbert, Thank you for your letter of April 8. I am sorry that my reply has taking so long, at this time of year I get very busy. My letter concerned an article written by Dr. Bretscher and also the articles written by Prof. Jacobsen's group to which he was responding.
I enclose a copy of Prof. Jacobsen's letter to me along with my reply. I find it difficult to understand why he has never taken the opportunity, afforded to him by his papers, of recording his response to the wave model. In any event, I do not find his present position at all convincing, so I will be pursuing this matter further.
I do take the point that you are not in a position to insist that Dr. Bretscher reply to me. At the same time, you will realise that I find the way in which he reviews the field to be both puzzling and unsatisfactory. This mode of review does seem to raise a number of issues.
For the moment, however, I would be grateful if you would write to Dr. Bretscher, asking him to explain the reasoning which led to his rejection of the wave model. Could you please let me have a copy of the letter which you send to him.
I shall contact you again when the response of these workers to my enquiries is clearer. Yours Sincerely John A Hewitt
23 January 1993 Dear Ms. Gilbert, I am writing further to our correspondence concerning the models which have been proposed to account for the mechanism of capping and particle movement on eukaryotic cells. You will recall that I contacted you following an unsatisfying exchange of letters on this subject with Dr. Bretscher of the MRC laboratory in Cambridge and Prof. Jacobsen of the University of N. Carolina. I have not yet received replies to my enquiries from Prof. Jacobsen, although he did say that he intended to do so; I have received no further replies at all from Dr. Bretscher. I am particularly concerned about the apparently misleading manner in which this subject was reviewed in the pages of Science.
In pursuit of the clarification which I require of this issue I have written a brief review of the status of this field as best it is known to me. A copy of "Cap That!" is enclosed herewith.
I have not been able to complete this review with regard to the position taken by either Prof. Jacobsen or Science, as I have so far not received a clear statement on these matters. This, despite the fact that I first wrote to you almost a year ago.
I should be grateful if you would read this review. I have quoted at some length from Science's articles on scientific ethics. I should be grateful if you would advise me of whether they reflect Science's editorial policy on false or misleading publication.
In view of the amount of time which this matter is taking, I feel I must also ask that you indicate whether or not you are prepared to publish a correction, by me, of the manner in which these papers review the field? Yours Sincerely John A Hewitt cc. Prof. D. E. Koshland Jnr. (Letter to C. Gilbert contains copy of "Cap That!".)
14 May 1993 Dear Dr. Hewitt: Thank you for your letter of 23 January and the enclosed review. It is not clear to me how the review reflects SCIENCE policy in any way other than the extent to which it reflects the process of science in a general sense. Many scientists would like their ideas to be accepted by their peers, but that does not mean that the peers are guilty of "false or misleading publication" if they do not accept an idea.
With respect to the "correction" that you propose, we generally do not consider comments on a paper after 6 months have passed since publication.
We appreciate your taking the time to write. Sincerely, Christine Gilbert Letters Editor
4 June 1993 Dear Ms. Gilbert, Thank you for your letter of the 14 May and for reading "Cap That!". I appreciated your comments on it, although I could not agree with some of the comments you made.
Firstly, I must point out that I would never suggest that a scientist might be guilty of false or misleading publication merely because s/he does not accept my ideas. The point at issue is the failure to acknowledge the existence of the wave model. Plainly both Prof. Jacobsen and his co-workers and Dr. Bretscher do reject it - and that is, of course, their prerogative.
However, what DOES concern me is that neither group has acknowledged their rejection of this alternative to their own views or indeed its very existence, although both have been aware of it for a considerable time.
The problem with the original papers is that they claimed to support the cytoskeletal flow model by elimination of the lipid flow model. The impression given is of an elimination process as suggested by Popper's ideas on scientific logic. This process is quite right but surely needs to be performed from a full set of the available possibilities. The ethical problems arise from the likely impact of this omission on the reader.
Someone unfamiliar with the history of this field, would doubtless reach the conclusion that only two possible mechanisms have been put forward to describe capping and particle movement. Such a person would, I suggest, be misled.
At the same time, a reader possessing a sufficient background, could be expected to conclude that these leaders in the field had been able to exclude the wave model. Once again a misleading impression is given.
However you choose to look at it, this is a misleading, arguably false, way of reviewing the field and, as such, is unacceptable.
I find it hard to believe that such eminently intelligent men could possibly be unaware of the impression they were giving.
As an analogy, consider the debate about the mechanism of cooperativity in haemoglobin and other allosteric proteins. Two models were put forward, one involving R & T structures and one involving "induced fit". Suppose a review considered only one of these and asserted without explanation that it was correct. Surely that would be false.
Once again, I must stress that I am not asking these workers to accept the wave model. What I am doing is asking them to acknowledge and explain their rejection of it. This, I propose to be proper scientific method.
Clearly, a false impression has been given by papers published in Science and therefore I am notifying you so you can publish a correction. Furthermore I believe you have a responsibility to do so and I see absolutely no reason why a time limit should exist.
If you feel unable to do this, I would be grateful if you would send me a copy of your general code of practice or statement of policy, relating to the publication of false or misleading statements within the pages of Science. Yours sincerely John A Hewitt cc. Prof. D. E. Koshland Jnr.
Early in January 2005, I received the following letter from Dr. Mark Bretscher of the MRC in Cambridge. It sparked the succeeding correspondence with his and with Dr. Richard Henderson, now head of that laboratory, with Colin Blakemore, Head of MRC in London and Lord. May, now president of the Royal Society.
Jan. 6th 2005
Dear John,
I am writing to you about your book "A Habit of Lies", whose publication on the web was brought to my attention some time ago. There are two points I wish to make.First, your description of lipid flow dates back to 1976, when I first published it. Although you cite supposed proofs that it is wrong from 1989/1990, you have not been generous enough to include the modifications I made to it in a major review I wrote in Science in 1984. Had you been acquainted with this, you would know that, for a fibroblast: (1) the membrane which is endocytosed is taken in by coated pits which, although not filtering out all the proteins, do remove the majority of them so that endocytosis is effectively limited to lipids and a few other proteins (like the LDL and transferrin receptors) with the result that, for a protein which does not circulate, the net effect is one of lipid flow; (2) the sites of endocytosis are roughly randomly placed on the cells, giving a reduced lipid flow rate towards the back of the cell (and this is how Abercrombie saw particles move on fibroblasts); (3) the measured rate of endocytosis is, within a factor of two, that expected for the rate of capping or particle migration; and (4) exocytosis of membrane on a rapidly moving cell does occur at the tip of the leading edge but occurs randomly on a stationary cell. All those points strongly support a flow model.
Second, you apparently fail to mention in your account the "Tea Club" talk you gave in the Biochemistry Department, Cambridge, in 1983.1 specially attended that talk and I remember that the only senior member of the department present was HBF Dixon, although it was very well attended by students and others. At the end, you asked for questions and as none was forthcoming you asked me (sitting near the back) what I thought. The discussion, as I remember it, went roughly as follows:
MSB: My trouble is that I do not understand your model. I may be wrong, but I thought a surfboard moves with the wave because it is rigid. A cork, or other small object, just bounces up and down. And to my way of thinking, a patch of cross-linked proteins is quite flexible and so would not move with any wave.
JAH: (Some dismissive comment).
HBF Dixon: John, I think you should answer Mark's point carefully, as it's important.
JAH: Well, I think a flexible raft would move with the wave.
MSB: I think an oil slick, for example, just goes up and down, but may be blown along by the wind.
Some audience participant: That's right. Another audience participant: no, it moves with the wave. And that was about the end of the discussion.My conclusion was that you had not really understood your own model, nor had you consulted people who might be able to help you clarify your thoughts. By contrast, before I published my first paper in this area in 1976 I had consulted my boss Francis Crick, James Lighthill, Walter Gilbert and Graeme Mitchison - four physicists or mathematicians.
I am very sorry about your continuing sense of injustice, but I do feel you have attacked me unfairly and would appreciate it if you would include this letter in your public correspondence with me on the web site.
Yours sincerely Mark
From: John Hewitt
To: Dr. M. S. Bretscher FRS MRC Laboratory for Molecular Biology 16 January 2005Dear Mark, Thank you for your letter of 6 Jan 2005. I am glad to note that my book and web site "A Habit of Lies" have been "brought to your attention." I thank you for acknowledging their existence but I am sure you realize that your letter does not address the concerns I express there.
If you send me a copy of your 1984 "Science" paper I will look at it again but you should understand that the issue I have raised is that of the exclusion of the wave model from dialogue, not how you recognized and corrected some details in your flow model. In any case, the existence of the kind of cell membrane flow that you suggest was roundly excluded c1990, so the current significance of your 1984 paper is far from obvious. My site summarizes the advantages of wave driving as a mechanism and contrasts it with the alternatives, including your flow model. The wave model is manifestly superior, both to your ideas and to its other competitors, but you have always just ignored it, insistently reporting three theories as two. Your omissions are clearly systematic and deliberate and thus I perceive that you reject the wave model. Naturally, if that is your judgement, you have every right to reject the wave model but my point is that you reject it in a way that evades any explanation or debate. In these circumstances, you cannot seriously believe that I am "attacking you unfairly." Rather, my site describes your behaviour accurately and dispassionately, which was the fairest thing I could possibly have done. Nonetheless, the substantive, underlying fact is that, for more than twenty years, you have habitually falsified the scientific literature and have maintained that policy of misrepresentation into the teeth of repeated protests from me. The mere fact that you have felt able to continue such behaviour, even to the present day, reinforces the points I make in my book and which I made earlier in my tea club talk. You misremember the events of that talk but my book explores much the same issues, so no real purpose will be served by repeating its content here. I will simply point out that :- 1. The audience at that talk was composed of students, researchers and academic staff who, taken together, constituted an influential and informed scientific community. 2. Any significant absences of senior staff from the audience, such as that of the Chair of my own department, can be attributed to the prevalent atmosphere of political manipulation of scientific knowledge and suppression of original thought to which you contributed. 3. Nearly fifteen years ago, I attempted to explain the physics of surf-riding to you but your response, your last letter to me, simply informed me that you did not want a long correspondence. Rest assured, Mark, that I too do not want a long correspondence. What I do want is meaningful attention to issues that I believe are important.
Accordingly, I would be grateful if you would :- 1. Confirm in writing that you reject the wave model. 2. Confirm that your publications have never acknowledged the existence of the wave model. 3. Explain in writing why you have considered it appropriate to review the field this way. 4. Write a detailed, referenced account of the reasoning that led you to reject the wave model. 5. Seek publication of that account in "Nature" and "Science," in a form that is citationally linked to and corrects your previously published articles in those journals.
I will copy your letter and this reply to the director of the MRC Laboratory for Molecular Biology in Cambridge, to the MRC chairman at head office in London, and to the President of Royal Society. I will include herewith one such letter as an examplar of that correspondence. From them I will seek the following clarification :- 1. A clear indication of whether or not it is considered acceptable for affiliated scientists to falsify the scientific literature.
In order to inform interested parties, I will, as you request, also copy these documents to the correspondence appendix of my web site, "A Habit of Lies" and I reserve the right to copy elsewhere should that seem appropriate. My intention, in so copying this correspondence, is to shed further light onto the misuse of status in professional bodies, such as the MRC and the Royal Society, by "recognized experts" who, rather than engaging in serious debate and addressing other's viewpoints, merely manipulate that debate in the pursuit of their own vested interest. In my opinion, such behaviour is an abuse of the people with whom such "experts" deal, blackens the name of the institutions with which they are associated and, ultimately, damages the entire, global, scientific community. In the past you have refused to acknowledge the wave model for capping and particle movement and have confronted it with published lies, with a wall of silence and with elegantly phrased evasions. That will not do. To satisfy me you must address the issues. Until you do so, Dr. Mark Bretscher FRS, you offer me no alternative but to think of you as a scientific liar and as a fraud.
Yours Sincerely John Hewitt
From: John Hewitt
To: Dr. R. Henderson MRC Laboratory for Molecular Biology16 January 2005
Dear Dr. Henderson,
I am writing in relation to a letter dated 6 January 2005 I received from Dr. Mark Bretscher FRS of the MRC Molecular Biology Laboratory in Cambridge. Copies of that letter and my reply are enclosed. He refers to my book and web site "A Habit of Lies," which describes, with a strong evidential base, an instance of falsification of the scientific literature and of the suppression of a serious, alternative viewpoint. Dr. Bretscher is one of the scientists named.
I was surprised to receive his letter since he has previously, for more than two decades, refused to debate with me or acknowledge the existence of my work. In the circumstances I am now quite reluctant to engage with him and I do feel that the time is past when these matters could have been resolved by exchanges between the two of us. In my view, Dr. Bretscher's actions have suppressed dialogue with alternative views, have hindered the growth of scientific knowledge and are potentially damaging to the reputations both of British science as a whole and of the institutions with which he is affiliated. Since he is a member of staff at the MRC, I am copying this recent correspondence to you. May I ask that you use your influence to encourage Dr. Bretscher to deal with this matter in a meaningful and direct way. My letter to him lists the five points that I feel he should attend to.
In addition, I would be grateful if you would let me have a copy of the MRC's current, written policy statements on whether or not it is considered acceptable for affiliated scientists to falsify the scientific literature. Please note that I am not here seeking a statement of the MRC's investigative procedures - these are available elsewhere but are not specific on this point. I am looking for a statement of whether the MRC considers intentionally false reporting in the scientific literature to be acceptable under any circumstances and, if so, what those circumstances are. I look forward to hearing from you.
Sincerely
John A. HewittTo: Dr Mark Bretscher, Dr. Richard Henderson
MRC Laboratory for Molecular Biology
From: Dr. Richard Henderson (Director, MRC Cambridge)
To: John Hewitt
20th January, 2005.
Dear John,Thank you for your letter of 16th January enclosing your recent correspondence with Mark Bretscher. I do understand that both of you have sincerely held views concerning your individual hypotheses/theories about how cell motility works, but I don't subscribe to your interpretation that there is any conspiracy to silence anyone. Mark Bretscher himself could easily argue that his theory has been wrongly ignored, but instead he continues to carry out experiments designed to test his own theory and disprove other theories of cell motility based on cytoskeletal forces. In the end, experiments will determine what is true and what is false. As Max Perutz said "In Science, Truth always wins" - see http://www.vega.org.uk/series/facetoface/perutz/index.php. So, my view would be that you need do nothing to try to "sell" your wave model. If it is true, this will emerge as experiments are performed by others, possibly aimed at testing features of other models.
I should say that your accusations that someone is a "scientific liar" or a "fraud" implies that the person involved knows what is true and what is false and is maliciously peddling a falsehood or supressing a truth. I don't understand how you can extrapolate from a reluctance to debate a hypothesis, however dearly you hold it, to lies and fraud.
I can assure you that LMB does not tolerate even sloppy reasoning, let alone fraud or lies. Everyone writing a paper or giving a seminar here is subjected to critical and rigorous questioning designed to bring everything out into the open. In science, many people sincerely believe in explanations which most others think are wrong. In the end most issues get resolved, but it can take many years.
You are of course free to advocate the views described in "A habit of lies", but I believe you are wrong. You can indeed read about the MRC position on good research practice at http://www.mrc.ac.uk/pdf-good_research~ractice.pdf and the procedure for investigating misconduct at http://www.mrc.ac.uk/pdf-mis_con.pdf. Intentional false reporting of anything under any circumstances is unacceptable but in this case, your five points do not mention falsification - only that you believe your work has been wrongly ignored. Since you now have a letter from Mark Bretscher, albeit a response to your attack on his integrity, rather than the debate you desire, it is clear that Mark Bretscher has not ignored you.
Finally, I should say I remember your Ph.D. with Max when you worked in LMB on haemoglobin, so I was surprised to catch up with you again in such an unexpected manner.
With best wishes,
Yours sincerely,Richard Henderson
c.c. Dr. Mark Bretscher
From: Mark Bretscher
To: John HewittJanuary 18th 2005
Dear John,
Thank you for agreeing to place my letter of January 6th 2005 on your web site, alongside our other letters.I agree with you that there is little point in long correspondence, so shall be brief. I do not reject the wave model - or any other model - for how patches cap. I would like to understand the molecular basis for the process. Unfortunately, I have never understood the physics behind your model (nor do those with whom I have discussed it) and so admit I have never referred to it in any publication.
If you are genuinely interested in understanding how capping works, I do think you should read and think about the 1984 Science review I mentioned in my last letter, as well as a later review I wrote for Cell in 1996. I enclose copies of both of these publications. Furthermore, I have more recently found in amoebae that both capping and cell locomotion depend on membrane circulation (as shown by ts mutants in NSF, a protein at the centre of membrane fusion; see Development (2002) 129, 4185-4192). This greatly strengthens the case for some form of membrane flow in both these processes.
Please add this letter to your web site.
Yours sincerely
Mark Bretscher14th February 2005
Dear Mark and Richard,
Thank you for your letters of the 18th and 20th of January, 2005. In the interests of brevity I will respond to both simultaneously. First, Richard, I am sorry to catch up with you this way, but I chose neither this manner nor this timing. As you say, I was privileged to work with Max Perutz and was saddened by his recent death. He was a fine scientist and an honest man who well deserved his scientific renown but, like all men, he was fallible, and his rose-tinted comments about science that you quote were ill-judged. Sociologists do not observe in science any special institutional quality that ensures truth is more likely to "out" there than elsewhere. Truth will not out in institutions that harbour and reward lying, tolerate shoddy reasoning and respond to legitimate dissent with ad hominem attacks upon the dissenter.
I am also sorry if I seem rather brusque but I have said these things before, both when I worked in Cambridge and later in correspondence with Mark and the MRC.. I realise that you, Richard, were not party to them but those dialogues were unsatisfactory. I do not wish to play academic word games.
In this field, Mark has consistently reported the existence of only two theories, even though he knows that three have been published. It is a matter of fact, not of Mark's opinion or judgment, that there are at least "three" theories in this field. No normal, educated adult could err over the distinction between two and three. Therefore, Mark has lied about the number of theories in his field and he has maintained this practice of lying for more than two decades. He has ignored the wave model, he has ignored me and he has ignored all reasoned argument. Mark's recent letter maintains the pattern of largely ignoring the issues raised with him, though it does confirm that he has never acknowledged the existence of the wave model. Falsehood is malpractice, according to the MRC's own definition and I believe that, according to Chubin, the omission of relevant citation is, itself, a form of scientific malpractice. Am I to understand, Richard, that you propose to take no action concerning the malpractices of omission of relevant citation and of lying in the scientific literature?
Richard, thank you for the links to the MRC site. I will return shortly to the document about standards, which is new to me and drawn from Nolan's recommendations. I think the procedure for investigating complaints was first written in response to my earlier requests and seemed, at the time of writing, to be a charade, designed to fob off complainants; the present version has more polish but retains the same spirit. Nonetheless, I do not think you should fob this matter off. Even though it may be inconvenient to you, lying in the scientific literature is a serious matter that needs proper attention.Mark claims that his omission of the wave model is not a rejection of it but that claim is preposterous. He plainly rejects the wave model but seems to feel that he is entitled to act upon opinions that he will not acknowledge, state, explain, explicate, justify or debate. I regard such behaviour as abusive and, given the clear evidence tending to support the wave model, I also find it to be counterscientific and unprofessional. In any event, the third of my five requests was that he will explain why he considers it appropriate to review the field as he does. Since he claims not to reject the wave model, this query is even more plainly in need of an answer. Mark, please reply to it.
Mark seems to claim that he ignores me and the wave model because he is ignorant of the physics of surf-riding. My reply is :-
First, ignorance of physics is not a reason to deny the existence of surf-riding. Whatever the physics behind it, surf-riding is a well-established phenomenon in the macroscopic world and is increasingly well-established on cell surfaces.
Second, ignorance of physics does not justify ignoring the evidence that waves exist on cell surfaces. Even after all these years, Mark's idea of membrane flow enjoys no serious experimental support, while cell waves were already known at the time of my paper. Their existence is even more clearly established now. Cell waves exist, in Jaffe's words, on "all or virtually all eukaryotic cells." Ignoring them and their implications does not seem good logic or good science - more a display of poor scholarship and shoddy reasoning.
Third, a lack of understanding of the physics of surf-riding is not some incurable, medical condition from which Mark suffers. Rather, it is an educational and intellectual state and, in Mark's case, it is a state that seems to be his choice. He has had the option of studying the physics of surf-riding at any time over the past twenty five years but seems not to have done so. Moreover, he refused to correspond with me when I attempted to explain that physics to him. Thus, his lack of understanding of the physics of surf-riding may best be seen as a state of "elective incompetence" and, as such, seems a very shallow excuse for lying in the scientific literature.Coming back to the MRC's good research practice document and Nolan's standards of "selflessness, integrity, objectivity, accountability, openness, honesty and leadership," that the MRC claims to uphold.
Dr. Bretscher's reporting does not seem selfless. Rather, he seems to proselytize his own ideas, "sell" his own theories, in a way that appears devoid of integrity or objectivity. He refuses to account for, or be open about, his reasoning and he is untruthful in his reporting. On the face of it, he seems to breach six of Nolan's seven standards. Do his qualities of leadership make up for these failings?.Finally, Richard, I come to your suggestion that my work does not need "selling" because the truth will out in the end. My reply is, first, that I have not engaged in self-interested salesmanship – you should discuss such matters with Mark. Second, my web site was not my initial attempt to deal with this issue - I directly approached everybody involved. In other words, all the people and institutions mentioned on my web site, including Mark Bretscher and the MRC, had the opportunity to resolve this matter without fuss. They did not take that opportunity but, instead, ignored my protests, while Mark continued to "sell" his work as if I had said nothing.
Thus it is, but you must understand that such behaviour has consequences. My web site, "A Habit of Lies - How Scientists Cheat," was born from your own closure of all avenues of debate and protest. If that site is now becoming better known, well and good. For my part, I want to know the reasoning that leads to the rejection of the wave model and I will continue to describe my experiences in science and explain my work until these issues that spawned my site are addressed. I suggest, Mark, on your own behalf, and Richard, not personally but in your capacity as an MRC director, that you should abandon this habit of lies and address those issues.
SincerelyJohn Hewitt
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This is Appendix 2 to "A Habit of Lies - How Scientists Cheat" by John A. Hewitt
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