What Price Intellectual Honesty?” Asks a Neurobiologist Harold Hillman

5 “What price intellectual honesty?” asks a neurobiologist Harold Hillman

Published in Brian Martin (editor), Confronting the Experts (Albany, NY: State University of New York Press, 1996), pp. 99-130

Career the University at that time, and have been the I was born in London, although both of my senior physiologist since then. In 1970, I set parents went to Scottish Universities. I was up the Unity Laboratory of Applied Neurobi- brought up to respect academics, and to ology, which I have directed ever since. I have believe that their paramount interest in life published about 150 full-length publications in was the pursuit of truth. My intention had cytology, neurobiology and resuscitation, and always been to take up a career in a university, have written five books. in which — as long as one carried out the Throughout my career, my upbringing and teaching duties assigned by the head of training led me to entertain the following department — one was free to do research in assumptions: academics’ first priority is to any area in one’s discipline, which seemed seek the truth as they define it; they are exciting. At that time in Britain academics prepared to enter into dialogue about their were protected from those with orthodox beliefs and research; they believe that opinions in power by long established tenure. evidence and reasoning should take prece- I obtained a scholarship to University dence over belief and emotion; they behave College School, London, and took a medical fairly in argument; they do not practice degree at Middlesex Hospital Medical School casuistry; and they do not use power to defend in 1956, since when I have practiced as a part- their views. I have reluctantly come to the time physician. I proceeded to a degree in conclusion that these assumptions are not neurophysiology and biophysics at the always warranted. Department of Physiology, University College, London, and completed it in 1958. I A student of the Institute of Psychiatry, also obtained a diploma in biophysics from 1958-1962 Kings College, London. My first job in 1958 was as research assistant I then went to the Institute of Psychiatry, to Professor Henry McIlwain, at the Institute first as a research assistant and then as an of Psychiatry, London. He was the most active Honorary Lecturer in Biochemistry, and I exponent of the use of thin slivers cut from stayed there until 1962. I was working on the brain for the study of the biochemistry and electrical properties of slices of brain, and was physiology of the intact living brain. I believe invited to examine similar properties of nerve that he had learnt the technique from Professor cells dissected out by hand, in Sweden. I Sir Hans Krebs, the Nobel Laureate in returned to Britain in 1964 and took up the biochemistry, with whom he had worked in position of Biochemist and Honorary Lecturer Sheffield, England. The properties of the in Applied Neurobiology at the Institute of brains of adult animals could be studied in Neurology in London. The following year I slices for up to two hours before they degener- was appointed Senior Lecturer in Physiology ated. Professor McIlwain had built up the at Battersea College and, in 1968, I was made Department of Biochemistry with a small a personal Reader in the University of Surrey. nucleus of permanent staff, and 10-15 visiting I was in charge of all physiology teaching in What price intellectual honesty? 59

research workers and students for doctorates that it was just a different way of expressing of philosophy. the value. No, I maintained that this was not At the Institute of Psychiatry, I became true, because a similar constituent had been aware of certain fairly common practices. calculated correctly, and the result reported Some people did not quote authors they did was in impossible units. not like personally, or others who had predated This mistake, once published, became the them, or had findings that senior staff did not correct values, and later publications showed like. They would fail to do control experi- similar ones. In a book written later, different ments or would discard results which gave pages show different values for the same different results from those they expected. parameter. The book is very authoritative. I When I first heard about these practices, I was did not wish to hurt the feelings of those shocked by them, but I was even more responsible, but when I wrote a paper shocked by the tolerance and cynicism which subsequently on the same subject, I inserted some of my colleagues displayed towards the correct calculation; there was some them. difficulty in publishing it. In 1958, I was discussing a particular I learned several lessons from my time at biochemical problem with a senior Hungarian the Institute of Psychiatry. Firstly, doctoral biochemist, who came to the Institute legally students have no redress against their supervi- before the Revolution and had applied for sors, since their careers would be ruined if asylum in Britain. This was granted on they made determined criticisms, or resigned condition that he remained in the same their studentships. Furthermore, well-known position. He told me that he quite agreed with academics find it relatively easy to publish in a me, but would not say so in public, as it might journal, especially if they are on the editorial risk his appointment here. board. Thirdly, the data reported in weighty I devised a simple technique for cutting books acquire an authority and inertia, which slices quickly, so that they could be studied encourages some other people to find similar sooner than by the previous technique. One of results, and dissuades others from submitting my colleagues liked the idea, and was put on different results for publication. This was my to the task of studying the properties of slices first personal experience of misdemeanour, cut in this way. We worked harmoniously and it disturbed me greatly. together, until one day he stopped coming to my laboratory, and I noticed that he was Research Fellow in Göteborg, Sweden, avoiding me in the corridor. A senior 1962-1964 colleague had ordered my friend to work with In 1962, Professor Holger Hydén, at the him rather than to develop my technique, but I Institute of Neurobiology, Göteborg, invited was too junior to be able to protest. me to do similar studies on single nerve cells I heard along the grapevine that this senior dissected out by hand from the brains of colleague was writing up a paper based on my freshly killed rabbits.1 The technique is work, and when I asked if I would be a co- brilliant in its simplicity, and is not difficult.2 author, I was told that my help would be A large number of experiments were carried acknowledged. In the event, when the paper out on the biochemistry and anatomy of the appeared, I noticed that it ended with an cell bodies, but the same question was asked, acknowledgement for my “help” with the as had been asked about cerebral slices. How technique, but I had not been asked to be a co- many of the electrical properties of the living author. nerve cell survived its separation? I was When I read the published paper, I noticed employed with many others to find out. an important mistake in one of the calcula- I had a very interesting and fruitful time at tions. I pointed this out politely, but I was told the Institute of Neurobiology under Professor 60 Confronting the experts

Hydén, who was very kind to me personally. so I wondered if one could measure the change However, I saw there two practices of which I of this ‘high-energy’ compound in retina (part had been previously unaware. A technician of the eye), composed of thousands of cells, would produce a table of results, and the when light was shone on to it. I found a supervisor would strike out some of them, considerable change. Since the retina is an without giving any reason for so doing; the outgrowth of the brain, I sought the same technician then retyped the table, discarded the effect in slices of brain, spinal cord and the original, and the new table became the raw sciatic nerve (which runs down the back of the data. In recent times in Britain, I have seen leg), and found that all these tissues exhibited research workers simply deleting values from it. Then I asked myself, “Why should one have the computers attached to their instruments. I a light-sensitive enzyme in the nerve upon do not believe these practices are widespread which one sits?” After 3 months of intensive in Sweden or in Britain. experiments; I left out all the tissue. To my The real worry was that such selected and, astonishment, the ATP itself was sensitive to therefore, misleading data should occur in light. This was unexpected and had not been published papers, and then become part of the reported before. I repeated the experiments canon of knowledge. In the real world, the with a much less sensitive method of measur- idea that they would be corrected when other ing phosphate.6 The results were the same. people tried to reproduce the experiment is I have always been of the opinion that when just wishful thinking. As a consequence of a humble journeyman of a research worker these observations, I made the decision that I finds something exciting about such an would never myself indulge in, or put my important molecule, it is likely to be either a name on publications, in which I knew that mistake or an artifact resulting from the manipulation of results or intellectual casuistry procedure. All living tissues employ compli- had occurred. During the next few years, I cated and fragile biochemical mechanisms. identified a large number of widely practised Most experiments involve killing an animal or and tolerated misdemeanours, such as not plant, arresting change within it (fixation or discussing results which disagreed with one’s inhibition), spinning it, freezing it or adding own, avoiding doing crucial control experi- powerful reagents. Any of these stages of a ments, answering important questions with procedure can and often do change the artful circumlocutions, etc.3 biochemistry of the tissue drastically, or Adenosine triphosphate (ATP) is one of the relocate particular chemicals within it. most important chemicals in the body. It is Therefore, biochemists have to demonstrate required for many metabolic reactions and it unequivocally that any effects they find arise helps to synthesise proteins. Its energy is used from the innate properties of the tissues, rather to move water and it causes muscle to than from the procedures used to examine contract. them. Experiments to test the effects of the An American research worker visiting procedures themselves are known as ‘control’ Göteborg, Dr. Joseph Cummins, developed observations, and the fundamental validity of with Professor Hydén a method for measuring any experiment designed to find out what in single nerve cell bodies4 the activity of the happens in the intact human being, animal or enzyme ATPase which breaks down ATP; plant, is largely determined by the care with these cell bodies had diameters of a fifteenth which the controls have been carried out. to a thirtieth of a millimetre; this was a very Popper7 told us that one should try to falsify significant achievement, and we were able to one’s own hypothesis with relevant ‘control’ modify the technique and find much more experiments. enzyme activity.5 The experiment involved So I embarked on a long series of control measuring very small concentrations of ATP, experiments, testing the effects of light on What price intellectual honesty? 61

compounds allied to ATP, including ADP, talking altered the stability of the ATP. I AMP, and inorganic phosphate; I tried the sought a source of sound, rich in high frequen- effect at 22oC rather than 37oC on ATP; I cies, and used some recorded bagpipe music. washed the glassware with detergents not We started doing experiments early in the containing phosphate; I took out the oxygen. morning in the warm room, close to the None of the other substances showed the light entrance of the Institute. By coincidence, sensitivity of ATP, which required oxygen, members of staff coming to work passed the and occurred at body temperature, but not door and heard the bagpipes, which they room temperature. thought I was playing to the two young ladies. I made extensive literature searches and The bagpipe music had a considerable effect could not find previous reports of this finding. on the stability of the ATP, so we tested pure One day, my technician, Miss Anita Bäckman, notes at different intensities, and different was away, and I was making up the solution. I frequencies at the same intensity; they all took the bottle of ATP out of the refrigerator, showed that at 37oC, ATP was sensitive to and noticed that it was labelled, ‘keep cool, in sound. We subsequently showed that it was the dark.’ So I wrote to Dr. Berger, the chief also sensitive to spinning in a desk top centri- chemist of the manufacturer, Sigma, to ask if fuge at 1000 rpm for 5 minutes, electric he knew of any publication of this phenome- current induced from a loudspeaker coil, and non. He replied that his company had found it different concentrations of sodium and by accident, because it had been despatching potassium ions in the range of concentrations chromatographically pure ATP from the normally found in the body. United States, but customers in Europe had ATP provides the immediate energy for complained that they were receiving mixtures muscle contraction,11 but energy is stored in of ATP and its breakdown products, ADP and muscle as creatine phosphate,12 and the ‘high AMP. When Sigma put the ATP in dark energy phosphate’ of cold-blooded animals is bottles, it did not break down spontaneously. arginine phosphate.13 So we repeated all the The company had not published the finding. experiments we had carried out on ATP on However, I felt reassured by the knowledge creatine phosphate at 37°C, and arginine that someone else had previously and quite phosphate at 23°C. They all showed the same independently detected ATP’s sensitivity to effects. Between 1962 and 1964, we did each light. experiment at least six times, and the analyses ATP used to be regarded as a ‘high energy’ 8 9 were made at random, the technicians not phosphate, until the concept was reexamined knowing when they measured the samples and it was also shown to be completely wrong whether they were control or experimental, or by the redoubtable Dr. Barbara Banks, who when they had been extracted. We did about had great difficulty in publishing these 10 70 experiments before we were satisfied that views. the technique14 was as sensitive as we could One day, Miss Anita Bäckman, Miss Inger make it, and then carried out over 330 further Augustsson and I were sitting in the warm experiments for publication. room at 37oC with the lights turned off doing an experiment. It was necessary to study light Return to Britain: the Medical Research sensitivity in the dark. We were talking to Council Unit of Applied Neurobiology, relieve the boredom of waiting for 20 minutes. London, 1964-1965 That evening, when I analysed the results of Light, sound, centrifugation and electric the experiment, it became clear that some current and physiological concentrations of agent in addition to light was having an effect. sodium or potassium ions, all affected the Virtually the only explanation was that the stability of the three phosphates. Each of the 62 Confronting the experts

six different kinds of energy could be trans- In 1964, I presented my findings at the duced or converted into chemical energy for International Union of Biochemistry in metabolism, so in 1964 I wrote a paper Washington, the (British) Biochemical Society entitled, ‘The phosphate bond as a transducer.’ and the Physiological Society, in order to hear It was a tactical error to mention a hypothesis any new criticism, and to create a better in the title, and also to include the experiments climate for publication of a full paper. At the on bagpipes, as this enabled referees to two biochemical meetings, the audiences made trivialise them. I submitted the paper for humorous or sarcastic comments, but very publication to the Journal of Physiology, strange events occurred at the Physiological whose referees said that my reagents ATP, Society Meeting in Mill Hill, London, in creatine phosphate and arginine phosphate November 1964. were not of the highest purity obtainable; I About a fortnight before the meeting, answered that such naturally occurring Professor Max Born, of the Department of substances were not pure in living animals. Pharmacology of the Royal College of The journal Nature said it had no room. The Surgeons, asked me to come over to his Journal of Molecular Biology gave no reason laboratory to set up the ATP experiments for rejecting it. The Biochemical Journal which I was going to report. I had just done wrote to me that the idea “that physical agents the first two experiments to set up the could have biochemical effects was revolu- procedure. These were not accurate enough to tionary.” I replied that, on the contrary, it had give reliable results. He then told me that he been concluded that physical agents could had wasted enough time and he wanted to stop have chemical effects, when Count Rumford doing them. I told him that I did not think this at the time of the French Revolution showed was fair, since I had done over 70 experiments that boring canons generated a great deal of in Sweden before I was satisfied that the heat. It became fairly clear that the journals reliability was great enough to start a substan- did not wish to publish my paper. The referees tive series. did not like the findings, perhaps because they I was then the second most senior worker at felt threatened by them, but I have never found the Medical Research Council Unit of Applied out why. Neurobiology at the Institute of Neurology in Professor Hans Krebs — the Nobel London. The Director was Dr. John Cavanagh. Laureate in biochemistry — wrote to me that He heard about my proposed paper, and said he thought a journal had the right to refuse to that someone — whom he refused to name — publish a paper if the referees thought that had told him that my paper would meet much there was something wrong with it, but could opposition at the Physiological Society, and I not identify the error; I respectfully disagreed. would be wise to withdraw it. He would not Professor A.V. Hill — the Nobel Laureate in say on what grounds it was to be attacked. His physiology — agreed that the effects had concern seemed so strong that I offered three probably been demonstrated, but he could not times to withdraw it if he were to say that my recommend a journal which would publish the presentation would damage the reputation of manuscript. Sir Ernest Chain, whose method15 the newly formed unit. No, he insisted, that I I had modified, agreed that the modification had the right to present it, but still he advised was reasonable, and that I had, in fact, me strongly against doing so. demonstrated the effects we claimed. Dr. Isaac Dr. Olof Lippold, the Reader in Physiology Berenblum also agreed that we had modified at University College, had agreed to introduce his technique16 suitably, but he would not my paper, since I was not then a member of comment on the experiments, as his field of the Society. He also told me that I was going research had moved to cancer. to be attacked by Professor Born, who sent me a summary of what he was going to say. I told What price intellectual honesty? 63

Dr. Lippold that I believed that I had precise in physiology in Britain. My director, answers to any questions, including Professor Dr. Cavanagh, said that he had heard that I had Born’s, which were likely to be raised. “made a fool of myself,” and that the Medical Before the meeting, Dr. William Feldberg, Research Council did not like my research. I the chairman of my session, said that he had replied that before taking up the job in his unit, heard that my presentation would be strongly I had listed the experiments I wanted to do, attacked, and probably refused publication. including those on ‘high-energy phosphates.’ I This could happen by a simple majority of requested to discuss this opinion about my those who chose to vote, and would damage experiments with those members of the my career seriously. He even offered to say Medical Research Council who did not like that I was not present, which would defer my them, but he would not tell me their names or paper to the next meeting. Knowing that arrange a meeting. Professor Born was to lead the attack, I The Physiological Society Meeting taught offered to defer giving my paper if those who me something. Eventually I published the did not like it were prepared to try to repeat effect of light on ATP,17 but not on creatine my experiments. I received no such under- phosphate or arginine phosphate, nor the effect taking. of light, sound, centrifugation, electric current As soon as I had finished my ten-minute or sodium and potassium ions in the natural presentation, Professor Born rose and showed concentrations found in living tissues on one of the two experiments I had done in his creatine phosphate or arginine phosphate. laboratory. He asserted that since these two However, a short report appeared,18 and the experiments had not shown a significant full text was circulated by the Information effect, those from Sweden I reported were not Exchange.19 significant either. I answered that I did not see Some years earlier, the American, how only two experiments with 300% error Dr. B. Chance,20 the Russian Dr. S. E. Shnoll could be used to invalidate about 330 with and collaborators21 and a Dutchman, Dr. F. only 0.3% error. Professor G.S. Brindley said A. Hommes,22 had shown similar effects, so I that I had not shown the effect of shining light wrote to each of them privately to ask if they on inorganic phosphate, or not shining light on had ever observed the phenomena I had seen. ATP solution. I replied that these had been my None of them answered, so I asked them first two slides. I was asked if I had used through the Information Exchange,23 but none spectroscopically pure reagents. No, I of them replied. Their findings supported answered, but the ‘high-energy’ phosphates mine, but I still failed to obtain full publication were chromatographically pure. Had I tried the in a refereed journal. My experiments effect on ADP and AMP? Yes, I said, and the remained suspended in an agnostic limbo, and effect was not there, as I had said in my my career was at risk. presentation. I was satisfied that I had answered every question fully and without Subcellular fractionation equivocation. In 1964 in Göteborg, I started looking into the I counted about 200 people in the audience, theory of the effects of light, sound, electricity of whom some were visitors. About four voted and centrifugation. The latter was of particular in favour of publication, about 15 against — interest, because centrifugation was so widely the rest abstained. The abstract was not used in subcellular fractionation. Usually, published. Professor Born came up to me to when biochemists, biophysicists, cytologists, say that he was sorry that my paper had been pharmacologists or oncologists tell one what rejected. I did not answer him. Professor John happens in, say, the nucleus, the cytoplasm or Butler of the Chester Beatty Institute said that the membrane of cells, they have used the I would probably not now be able to find a job procedure of subcellular fractionation. This is 64 Confronting the experts

intended to separate a fraction believed to be examined subcellular fractionation,24 I identi- particularly rich in that part of the cell, so that fied 15 assumptions, some of them contrary to its unique biochemical properties may be the laws of physics and thermodynamics; the examined separately. The steps of the second time I looked, I found 24 assump- procedure are listed in the next paragraph. All tions.25 Other biochemists might deny that experimental procedures used in the sciences some of these assumptions were inherent, or imply necessarily the assumption either that they might add others, but, with one exception, the procedure itself does not change the they have not done so. biochemistry of the tissue being studied to a In 1972, I first raised the question of greater extent than the changes claimed control experiments to test the effects of between the control and the experimental procedures on the final results of experi- tissues, or that any changes produced are too ments.26 It seemed that no one had done these, small to affect the result of the experiments. and this meant that the experiments were Does the final material extracted reflect the incomplete, and that conclusions could not be properties of the living tissue from which it drawn from them, nor could theories be came? derived from the conclusions. My uncertainty I used the following approach. I made a list about control experiments led me to write to of the steps of the procedure: for example, the the (British) Biochemistry Society Bulletin,27 animal is killed; it cools down; a particular asking whether any biochemists knew of any tissue, such as the liver, is excised; a strong published references that control experiments reagent is added to facilitate homogenisation on the effects of the procedures on the results (mashing up); the tissue is cooled; it is of experiments had indeed been done, or they homogenised; it is cooled again; the homogen- would say that these were not necessary. There ate is centrifuged (spun round rapidly); was no answer to these questions. fractions each believed to consist largely of a particular cell constituent are separated and Other procedures widely used in cytological frequently washed; substrate mixtures are research added; the product is coloured, so that the I was so disturbed by the thought that intensity of the colour read on a spectropho- subcellular fractionation might be an unsatis- tometer tells one the rate of a reaction in a factory technique that I decided to take a particular part of the cells. Of course, there are completely different technique and subject it numerous variations of this procedure. to a similar analysis. I took electron micros- Having identified the steps, I sought in the copy, asking the question, ‘How much does a literature findings indicating the extent to picture taken with this instrument tell one which each of the steps of the procedure could about the structure of the living cell?’ Since change the properties of the part of the cell, its the early 1950s, there has been a passion for distribution or activity. I then listed the relating ‘structure’ to ‘function,’ that is, the assumptions built into the procedure, which appearance by electron microscopy of a had to be true if the properties of the cells particular identifiable part of a cell with the were to reflect those in life. Finally, I listed the biochemistry it exhibits. minimum control experiments which might The light microscope had been used to satisfy one that measurements at the end of the examine living cells, unfixed tissue and long procedures reflected the original stained sections for 100 years until the 1940s. properties of the living intact structures. At that time, the electron microscope was The assumptions inherent in a procedure introduced. It permits much higher resolution are crucially important, since, like a chain, the and magnification than the light microscope, validity of a whole experiment is dependant on but the tissue can not survive the low pressure, the strength of its weakest link. When I first the bombardment of electrons and x-radiation What price intellectual honesty? 65

in the electron microscope, so it has to be is dehydrated with increasing concentrations coated with a deposit of salts of osmium, lead of alcohol; it shrinks; the alcohol is extracted or tungsten, which is not destroyed by these with a fat solvent, propylene oxide; the latter agents, and can therefore be examined. is replaced by an epoxy resin; it hardens in a Cytologists were very anxious to use this more few days; sections one tenth of a micrometre powerful instrument to look at the fine thick, or less, are cut; they are placed in the structure of cells. electron microscope, nearly all the air of Science is so complex nowadays that which is pumped out; a beam of electrons at frequently research workers have to resort to 10,000 volts to 3,000,000 volts is directed at evidence derived by other specialists using it; some electrons strike a phosphorescent techniques those citing them do not under- screen; the electron microscopists select the stand. They assume that their colleagues field and the magnification which show the perform careful and valid experiments, whose features they wish to demonstrate; the image fundaments have been examined adequately. may be enhanced; photographs are taken; My experience is that this is not always the some are selected as evidence. One can case. I believe that a proper philosophy for immediately see how far the tissue has scientists is that they should understand all travelled from life to an illustration in a book. techniques whose results they use or quote. I sought permission to do some of the They should be prepared to examine criticisms control experiments, and was told that they of findings they use as evidence in case their would be a waste of time, ‘controversial’ and I invalidity would throw doubt on the conclu- would not be able to get the results published. sions derived from them, and their value as Neither the Science Research Council, the evidence in other fields. Since truth should be Medical Research Council, nor the University universal, all scientists have a duty to resolve of Surrey would support such a project. So I all anomalies and inconsistencies not only in wrote a book about the uncertainty of bio- their own beliefs but also in those they quote, chemical techniques.29 Well known publishers and between their findings and those of other turned down my manuscript. The University workers using the same and different of Surrey Press published it as its first book techniques. and printed 2,500 copies. It sold out in Britain Unfortunately, electron microscopy was and the United States, but the publishers even more questionable than subcellular would not allow me to write a second edition. fractionation. So was histochemistry (the study In 1975, unknown to me, the Russians of tissue sections), which I chose to analyse translated it and sold out 12,500 copies. because it was somewhere between subcellular The book was reviewed by Nature, the fractionation and electron microscopy. I then Times Higher Education Supplement, Science took three techniques nearer the measurement Progress and Acta Biologica Academica end rather than the preparation end of the Scientia Hungarica. In the latter, Dr. Sandor former techniques: these were chromatogra- Kerpel-Fronius wrote, “I feel strongly that the phy, electrophoresis and radioactive measure- uncertainty is far from being as absolute as ments. Each of these had their burden of Dr. Hillman postulates. It should be remem- assumptions, many of them evidently bered, for example, that in situ experiments unwarranted.28 with radioactive tracers and those carried out For example, most cytologists know, but in vitro on isolated organelles or enzymes are readers of elementary textbooks do not, that very often in essential harmony in spite of the when one looks at an illustration of an electron unquestionable shortcomings of the methods micrograph: an animal has been killed; it cools used. Such corroborative results should assure down; its tissue is excised; the tissue is fixed us that the present understanding of at least (killed); it is stained with a heavy metal salt; it 66 Confronting the experts

some biochemical processes is close to Hydén always took the cells out in a sugar reality.” solution,32 but we tried taking them out in At the time, I regarded this as the substan- saline, which was more natural. Immediately, tive answer to my reservations about we saw a membrane around the nucleolus,33 biochemical techniques. While each technique which had not been seen before. We tried to only gave an approximation to the whole publish this finding, even resorting to the very picture, the whole story put together produced ancient practice of sending the editor of a consistent picture. various journals not only the photographs, but The most hostile reviewer of my book was slides of cells showing our membranes. We Professor J. Lucy of the Royal Free Medical demonstrated it to the distinguished micro- School. He wrote, in Biochemical Education,30 scopist, Dr. John Baker, who agreed that he that I had overstated my case “in stating that could see it. The journals turned it down, the validity of a localisation of an enzyme firstly, because it had not been shown by activity is dependant upon all fifteen assump- electron microscopy, which distorted it34; tions listed being warranted,” then he added secondly, it had not been seen before; thirdly, “(sic).” This implied clearly that he himself we had not shown that our membrane did not believe that the conclusion of an consisted of lipids and proteins, as the experiment must depend upon all its assump- Davson-Danielli and the Singer-Nicolson tions being warranted — he was saying this to models assumed. We pointed out that any lecturers, teachers and students. He pointed lipids in the original membrane would not out a real mistake I had made about liquid have survived the extraction by alcohol and scintillation although it did not affect my propylene oxide during preparation for argument. electron microscopy — despite all textbooks of life sciences showing cell membranes they Light microscopy and the brain, University believe to be of this composition. So far, there of Surrey, 1965 to date has been a Trappist response to this rather Mr. Peter Sartory, although an amateur, was in awkward point by the many electron micro- my judgement one of the most expert British scopists with whom we have tried to discuss it. light microscopists. He was a distinguished I have never understood the reasons for natural historian, a former microscope resistance to the belief in the nucleolar manufacturer, an amateur astronomer, a membrane, even although we have published former Committee Member of the Royal many photographs of it35 and offered to send Microscopical Society, and former President microscope slides to anyone in the world who of the Quekett Microscopical Club, founded in wanted to see it. 1865. By the time I met him in 1967, he was chronically ill with lung disease, having Electron microscopy smoked heavily all his life. Although at that time we did entertain doubts I had recently returned from Sweden, and about the value of electron microscopy in asked Mr. Sartory if he was interested in biology of tissues containing much water, both looking at single fresh mammalian nerve cells of us still felt that the best source of informa- dissected out from the brain by the technique tion about the fine structure of cells was which Hydén had used to examine the proper- probably electron micrographs. We were ties of cells.31 Hydén himself had agreed that it comparing our high contrast light micrographs would be useful to look at these cells by a of unstained nerve cell bodies with the latest variety of light microscopical techniques in the electron micrographs. We suddenly noticed unfixed state, which is the nearest to the living that the endoplasmic reticulum, which is a state in which cells can be examined. network believed to be a structure in the cytoplasm (the cell sap), appeared to be cut What price intellectual honesty? 67

perpendicular to the section far too often than would not accept a small piece about our solid geometry would permit. It was as if one views. Nor would La Recherche or New threw into the air a large number of coins, and Scientist. The latter wrote to me that it did not when one photographed them, the vast accept controversial articles, in a letter I majority were to appear edge on — instead of received the same week as it featured in all possible orientations. Unfortunately, this Dr. Rupert Sheldrake on the exceedingly was also true of all the apparent membranes in controversial concept of ‘morphic resonance.’ the cell, the Golgi apparatus, the mitochondrial As for the assertion that no one then membranes, the cell membrane and the believed in the ‘unit membrane’ or that it was nuclear membrane. attached to the cell or nuclear membrane, I Whereas we did not doubt the existence of listed all the latest books on life sciences in the the cell, nuclear and mitochondrial mem- reference collection of the University of branes, their sandwich (‘trilaminar’) appear- Surrey; every single one of them indicated that ance was simply impossible in solid geometry they believed the former points. At meetings (Fig. 1). Obviously, if they were random, they of learned societies, whenever anyone alleged should be seen as flat sheets as often as they that these beliefs were no longer agreed, I are seen in almost perfect transverse section. produced photocopies of these lists, and After we had begun to doubt the existence of challenged those who had denied my assertion the cytoplasmic network (the endoplasmic to name one textbook or paper (other than our reticulum) and the Golgi body on geometrical own) which said that it did not believe in the grounds, we suddenly realised that if they ‘unit membrane’ or the attachment of the existed, they would not permit the intracellular reticulum to the cell and nuclear membrane. movements which are generally regarded as Subsequently, the cytologists replied, “You evidence of the life of the cell. These don’t want to believe what you read in text- movements can be seen by low power light books.” We were so horrified by this latter microscopy, while there is supposed to be a sentiment that we wrote a letter to Nature fine network throughout the cytoplasm asking anyone at the Physiological Society, requiring very much higher magnification to the Anatomical Society or the Royal Micro- see. Furthermore, iron filings, carbon particles scopical Society to justify this view in or pollen injected into the cytoplasm spread writing.36 No one replied. So we put this list in quite freely, quite unimpeded by any fine a book we subsequently wrote on cell network which would shackle them. structure.37 Thus we had two quite different lines of Let us be clear what was happening. Firstly, evidence — each of them powerful enough to senior research workers recommended only question the existence of all the new structures textbooks containing description of cell in the cytoplasm seen with the electron structures with which they disagreed; then microscope, plus the Golgi apparatus. When they denied that these structures were so we were satisfied that we had overwhelming described; then they could not name any books evidence, we submitted a paper for publica- or papers describing what they taught as the tion. The Editor of Nature rejected it on the correct cell structure; then they alleged that grounds that the referee believed that no one at one should not believe what one read in that time (1975) still believed in the ‘unit textbooks; then they were not prepared to membrane’ or that the reticulum was attached justify such cynicism in print. The situation to the cell membrane or nuclear membrane, has not changed. but added that he agreed with us. Science gave Most cell biologists today believe that no reason for rejection. Scientific American intracytoplasmic movements of subcellular would not consider it as it had not been organelles occur, but also that there is a fine previously published; after it had, they still dense cytoskeleton in the cytoplasm; they 68 Confronting the experts

believe that the image of the cell seen by useful?,’ ‘What do you see when you look electron microscopy is three-dimensional, but down a light microscope?,’ ‘What is the nature have to tilt the stage to show some of the of the image seen by the electron micro- orientations. Thus, the views they hold about scope?’ It is only fair to say that these cell structure are inconsistent. This is questions are not usually raised when one extremely worrying, because the use of so submits a paper on the structure of cells for many approximate techniques in biochemistry publication. Various well-meaning, but is usually justified by the assertion that perhaps naive, friends suggested that if we together they make a fully consistent story. If expanded our manuscript into a book, also they do not, the justification for using such dealing with these fundamental questions, we popular techniques becomes even weaker, and might have a greater chance of publishing it. the urgency to examine the validity of the With the Audio Visual Aids Unit of the procedures even greater. University of Surrey, we made a 35-minute We were quite unable to obtain publication film, and I showed it at the International of our paper showing that all the structures in Physiological Society Meeting in Paris, the the cell first shown by electron microscopy Biochemical Society in Cambridge, the plus the Golgi body were artifacts. Among the Society of Experimental Biology at Brighton, criticism we faced was that we were not the Quekett Microscopical Club in London, electron microscopists, although I had been the Physiological Society at University using the instrument for 17 years when this College, London, and other places. was first said. Even if it were true, we believe At University College, Dr. A. Lieberman, that we do have a right to use the currency the well-known electron microscopist, said which authoritative electron microscopists after the film had been shown that he had have put into circulation. many pictures of the endoplasmic reticulum Another tactic used against us was to label and the ‘unit membranes’ in all orientations, our ideas as ‘old hat.’ Critics said that ideas which we had denied. Since his laboratory was had been considered in the 1940s and 1950s, close at hand, I suggested that he go to get when the electron microscope was first used them immediately to show the audience. His for biological tissues, and refuted then. laboratory was untidy, he said, so I asked him Unfortunately, they could produce no refer- if he would show me these micrographs if I ences to support this assertion. Another trick called on him. I telephoned him five times was to say that all biochemists and cytologists altogether, but he would not send me any studied artifacts. This was a smart way of micrographs or references showing the images avoiding discussions of which artifacts gave I requested. He did, however, send me an useful information about cells and which did interesting reference on interpreting electron not. A social trick was to exaggerate or joke micrographs, which I did not feel was a about our views. Said one chairman, “As you relevant response. I offered to announce it in know, Dr. Hillman does not believe in public, if I were to receive a micrograph membranes — ha-ha!.” At a coffee queue at a showing a full range in the expected incidence Physiological Society Meeting at University of any of the structures whose existence we College, London, I heard two students had doubted, but the full range would have to agreeing that “Hillman’s views are rubbish.” be in the same picture. That offer still remains “Have you ever read any of his papers?” I open. asked. “Of course not, I would not waste my In 1977 I was invited to give a 40-minute time.” paper at the 1979 Leopoldina Symposium on Among the more difficult questions raised ‘Cell Structure’ in Thuringia, Germany, but by our critics were ‘What do you mean by when I arrived, I found that I was not on the truth?,’ ‘What is an artifact?,’ ‘When is it programme. The Secretariat would not accept What price intellectual honesty? 69

my paper for publication on the grounds that it the economic consequences of the enormous had not been received beforehand, although I cost of electron microscopy in medical had sent in the manuscript over six months research, and I kept trying to talk about the before. I offered the Secretary another copy, scientific points. About three months later, a but was told that it was too late. As I was short article appeared on the front page.39 waiting, I heard the Secretary telling a young Exactly a week later, the Observer published a research worker, who apologised for bringing letter from the senior elected officers of the her manuscript with her, that there was “plenty Royal Microscopical Society.40 They said that of time.” When I pointed this out, the our views had been generally rejected “in the Secretary became confused, and referred me to light of overwhelming evidence to the the organisers. Nevertheless, by dint of contrary.” They said that biologists had not diplomacy, I showed my 35-minute film, and seen our views in print. (We thought that this it was followed by a 50-minute discussion. My was somewhat cynical, since some of the paper was not included in the proceedings. signatories of the letter had resisted the We had written a paper which we could not publication of our manuscript). get published, a book that solicitous referees Two weeks later, we replied.41 “We know were sure would be published by another of no circumstances in which our views have publisher, and a film which was irritating been generally rejected… Nor do we believe audiences. One day, I was invited to show our that in scientific discussions, the correctness of film by the Bristol Fine Structures Group, an idea is measured by the number of its which was composed mainly of electron supporters.” We ended, “The protagonists of microscopists. Professor Richard Gregory, the the current view have so far been remarkably psychologist, was in the audience, and asked reticent in discussing with us these important me if we had ever tried to get our views questions. May we, Sir, through the hospitality published. Yes, I said, but without success. of your columns invite the distinguished Had we thought of Perception, the journal of signatories of the letter, or anyone else who which he was editor? I said that our geometri- agrees with them, to debate these questions in cal points were suitable for his journal, but not front of a scientific audience at any place or at the biological ones. He asked me if I would be any time.” prepared to rewrite the paper to emphasise the Two years later, although I had lectured geometrical arguments. Mr. Sartory and I were widely, no one had responded to our invita- rather reluctant to do this, and then have the tion, so we repeated it in the Observer.42 One paper rejected for publication. Eventually we debate eventually occurred, Dr. John Douglas agreed to rewrite it and submit it, on condition of Brunel University arranged it with Dr. A. that we did not have to leave out any points of Robards of York University and the Royal substance. It was eventually published,38 and Microscopical Society and Dr. K. Roberts of the editor told me that “I have had a lot of the John Innes Institute on the one hand, and stick from the electron microscopists for doing Mr. Peter Sartory and myself on the other. By so.” that time, Mr. Sartory was so ill that he only About July 1977, Mr. Sartory suggested spoke for a few minutes. Dr. Robards started that we had to open a ‘second front’ — that by saying that he was speaking in a private was, we had to tell the public about this capacity, not representing any organisation. situation. I was reluctant, and it took him three The new point he made in reply to the months to persuade me that we had properly question about why most of the membranes explored all the usual scientific channels. He appeared edge on in electron micrographs was telephoned the London Observer, and I was that, like a barn door, one would not necessar- interviewed by its then science correspondent, ily see it if it were open. I replied by asking Mr. Nigel Hawkes. He kept trying to discuss why one did not see a space corresponding to 70 Confronting the experts

the size of the door when it was closed. Mr. the others had reasons why they could not: Anthony Tucker, the science correspondent of they were writing theses, seeking lectureships, the Guardian, gave a short summary of the applying for grants, or being considered for meeting,43 and Dr. P. Evennett, a signatory of chairs. Did I blame them? Do you? What the letter attacking us,44 wrote an account in would happen to their careers if they embraced the Proceedings of the Royal Microscopical controversial views? Society.45 In 1981, not long afterwards, BBC Televi- We wrote to Sir Peter Medawar, the Nobel sion made a ‘Horizon’ programme, ‘No one Prize Laureate who has published several will listen to me.’ It took the cases of Profes- books of advice on ‘good’ science, telling him sor John Laithwaite, Dr. John Hastead and that we would like to see him, and enclosing a ours. A fair attempt was made to summarise four-page summary of our views; we pointed our views, but these were ‘answered’ out that these would be understandable to a anonymously by the programme — those student aged 15. He replied that he could not disagreeing with us not appearing. Of course, comment as he was not an electron micro- this gave the impression that our views were scopist, but he referred our letter to ‘his’ so ridiculous that the ‘Establishment’ did not electron microscopist. Five polite letters and itself want to counter them. Needless to say, ten years later, we have not heard from ‘his’ we had answered the particular points several man. A recently knighted Oxford professor times. Although the producers of the invited me to discuss the matters; I travelled programme did not intend this, the effect was all the way from Guildford (taking about four most unfair to us. Nevertheless, the hours each way), but he only had 20 minutes programme no doubt gave our views more to see me, not enough time, I suppose, to visibility than desired by our critics. comment on what I said or offer me a cup of Soon after the broadcast, I was taken off all coffee. He passed me to his electron undergraduate teaching in the University of microscopist, who, after 15 minutes, said, “I Surrey, without any reason being given. I was have to go to lunch.” an elected member of the Senate. So I asked at A famous textbook writer agreed that the a meeting attended by the Dean and the Heads Robertson model of the ‘unit membrane’46 was of the Biological Departments whether I had impossible, but said that he could not take it been removed from the teaching because of out of the next edition. When I asked him why my views on cytology. I pointed out that I was not, he smiled benignly. At about that time, the senior physiologist, that I taught relatively the publisher Mr. Michael Packard agreed to little cytology, and that I told my students the publish our book,47 in the belief, which we accepted wisdom because I wanted them to shared, that biologists in general would be pass their examinations. There was no answer. very interested in a new look at the structure The Department of Human Biology was of the living cell. closed down a couple of years later. Although As I travelled round, there was hardly a I was the second senior person in the depart- single place at which I lectured where several ment and had London University degrees in people did not come up to me when I had medicine, in physiology and in biochemistry, I finished and say that they agreed with us. I was the only member of that department not always asked them their names. Would they be placed elsewhere in the University. prepared to say in public that, for example, Our policy in the 1970s had been to refuse they did not think the cell membrane was to speak to school or undergraduate students, trilaminar (Fig. 1) or that there was a reticu- because doubts at that stage might discourage lum in the cytoplasm? (Mentioning our names them from learning biology at all. However, was not necessary.) One lecturer in Edinburgh, we changed our minds, firstly because we whose name I did not note, said he would. All realised that ten to sixteen year-olds were What price intellectual honesty? 71

being taught about the reality of structures we students think about this? I subsequently said were artifacts at a time when they published a full-length paper addressing all the believed that everything they learnt was gospel points our electron microscopic colleagues had truth. They were so conditioned. Secondly, we ever raised in discussion with us or in publi- were persuaded that motivated young people cation.53 often learned better when they were presented with opposing views. Thirdly, even the Structure of the brain briefest acquaintance with the history of Every day pathologists examine beautifully science teaches us that advances have nearly stained thin sections of brain. They see the always been made when established views nerve cells and occasional nuclei clearly but were re-examined. most of the section does not stain at all, when Mr. A. Bishop, the Editor of School Science viewed by light microscopy. In 1846, the great Review, which was widely read by school German histologist Virchow gave the name science teachers, invited us to submit a ‘neuroglia’ or ‘nerve glue’ to this unstained manuscript. We wrote an 11-page paper.48 material.54 The general consensus among Two groups of electron microscopists, Dr. R. neurobiologists today is that there are four W. Horne and Dr. J. R. Harris,49 and then kinds of cells in the brain and spinal cord, Dr. R. H. Michell, Dr. J. B. Finean and Dr. A. besides the blood vessels. The nerve cells are Coleman50 took issue with us in writing; they the excitable cells, which show up; the nuclei acknowledged the help of Professor W. belong to the other cells, the neuroglial cells, E. Coslett, Dr. A. W. Robards, Dr. J. Burgess, classified into astrocytes, oligodendrocytes Dr. S. Hunt and Professor H. W. Woolhouse. and microglia. The neuroglial material is They attacked us, inter alia, for not having believed to consist of the three latter types of dealt with the considerable volume of data cells, with very little space in between them. from biochemistry which they believed After I had been taking out nerve cells for supported their view. Although we had cited it about 17 years, by Hydén’s technique,55 I several times in our paper, they had failed to conceived of the idea that Virchow was right notice that our views had originated from a — the unstained material in the brain was not book I had written about just this subject.51 We composed of neuroglial cells.56 I did a series of wanted to reply to the points made by the experiments lasting another five years, and electron microscopists. Our original paper had they all supported the following conclusions. been 12 pages long, and theirs together added There are relatively few, widely spaced nerve up to 25 pages, but we were only accorded a cells in the brain and spinal cord. Any cell letter of five pages to reply. We therefore with processes (like wires) is a nerve cell. The decided to list the 11 questions which we had greatest proportion of the central nervous raised52 which had not been answered. We system is a ground substance consisting of a wrote to all the authors of the two papers and fine granular material with ‘naked nuclei.’ I those whom they had acknowledged, inviting published this conclusion in a monograph57 them to an informal discussion of the differ- containing much evidence from the literature ences between us. Only Dr. Michell replied, as well as my own experiments. It contained and he was not willing to discuss these matters blurred micrographs, was camera-ready, and with us. He was subsequently elected a Fellow was expensive. Dr. J. R. Parker reviewed it in of the Royal Society. a neutral fashion in the Lancet and Professor This brings up some fundamental questions Brian Leonard was laudatory in Neurochem- about the behaviour of scientists. Do they have istry International, but it sold badly. a duty to engage in serious dialogue about I was also unwise enough to find that the their published work? Is it satisfactory that evidence for the existence of the synapses — they should not answer letters? What should by which nerve cells are believed to 72 Confronting the experts

communicate — contains so many inconsis- the Council of the University on 18 December tencies, that they are likely to be staining 1987. artifacts.58 I analysed transmission, whereby I took drastic action. On 5 November, I signals are believed to pass from one part of presented a paper to the Finance and General the nervous system to another, and concluded Purposes Committee showing that my labora- that the view that transmission was chemical, tory was the cheapest in the faculty, that most formulated in detail by Professor Sir Bernard academic staff members of the University of Katz,59 contained too many unproved and Surrey did not have outside funds, and that I unprovable assumptions for the theory as a had an above average research output. At least whole to be acceptable.60 I have also spoken 12 of my senior friends, mostly from abroad, about this at many meetings, but so far no one wrote to the Vice-Chancellor supporting me, has addressed my objections to the theory. although he did not report this to Senate or However, I felt a duty to propose an alterna- Council. Articles about the proposed closure tive hypothesis.61 Of course, there is not appeared in the Times, the Guardian and the enough room here to give evidence for these Times Higher Education Supplement. Two conclusions, but they are given in detail in the resolutions opposing the closure of the Unity published references cited. Laboratory were passed unanimously at the Annual Council of the Association of Closure of the Unity Laboratory University Teachers in 1988. A question was In 1988, the Vice-Chancellor of the University asked in Parliament. of Surrey forced me to take ‘voluntary’ early The Handicapped Children’s Aid Commit- retirement, on the following grounds. tee of London, which founded the Unity • The University was short of money. (It Laboratory and financed it from 1968-1981, has since acquired enough to set up five rallied around and promised me support for research professorships, and has received one year. Dr. David Horrobin, Managing £30,000,000 from its Research Park.) Director of Scotia Pharmaceuticals, who had • The University had selected those areas himself suffered for his scientific views in which it wanted to support, but mine was not Canada, also came to my aid. With this outside among them. (I have never been able to funding, the University agreed to allow my persuade the University to tell me (1) what laboratory to remain open for a further three committee met, (2) whom else it considered to years, but without any support from University select my work for not supporting, (3) why I funds for my research. was not asked to submit my publications or an annual report of my laboratory’s work, or (4) ‘Voluntary’ retirement why my laboratory’s work was not submitted Not long afterwards, I was asked to take to the University Grant’s Committee for ‘voluntary’ early retirement. The University evaluation.) offered to buy in seven years of my pension, to • My work was of poor quality. (I had give me a lump sum, and to reengage me for published at least 80 full length papers, mostly 40% part time. The total financial settlement in refereed journals, and I had written three would leave me with almost as much income books by 1988.) as if I were still a full-time assistant professor, • I had not obtained outside funds. (Nor had but I would lose my tenure. I was given three about 70% of the academic staff.) two-day ultimata delivered by the hand of an The Senate on 30 September 1987 Assistant Secretary of the University. approved a ‘Revised Academic Plan’ for The Association of University Teachers 1987-1990,62 in which all departments were took legal advice in my support. Our Univer- cut by 5%, but my laboratory was to be cut by sity had one of the strongest tenures in the 100%, that is, closed. This was approved by country. I had thought that I was fully What price intellectual honesty? 73

protected. However, the Association advised to send in an abstract and then would not me that if the University dismissed me publish it; they said that it was only because illegally, I would have to take legal action the film could not be understood unless one against it. If I won, damages to me would only saw it, but they would not tell me how many relate to my loss of income, not my senior others had been refused publication. At a position, research facilities, prestige, etc. Such meeting in August 1992 of the European a case had not been heard before. The Society of Neurochemistry in Dublin, although certainty of my winning was not by any means I was a founder member, I was speaking on a absolute. The consequences of failure of my subject relevant to most other papers, and had plea would be financially disastrous to me, and requested an oral presentation, I was given the I had a wife and four young children to last slot at 5.15 pm, after 171 papers at the end support. The Association advised me to take of a five-day meeting. The chairperson did not the offer. turn up, the room was changed, several Reluctantly, I agreed to surrender my speakers did not arrive, and several others who tenure under a number of conditions, not all of wanted to hear my talk missed it. I received an which were met. I believe that I am the only apology, but no redress. tenured academic in Britain who has lost his tenure because of his or her scientific views. Present situation Strangely enough, a few months before, I had I have shown, to my own satisfaction that (i) at ended an article on academic freedom in the least some popular important biochemical Times Higher Education Supplement with the research techniques have never been sentence, “Would you not be thankful that you controlled, (ii) most of the new structures in had tenure, and lived in a democratic cells apparent by electron microscopy are country?” artifacts, (iii) there are only nerve cells and I have continued my full time research naked nuclei in a ground substance in the brain work with my colleague Mr. David Jarman in and spinal cord, (iv) there are no synapses, (v) the Unity Laboratory. We have produced an the transmitter hypothesis is doubtful. I have atlas of the human nervous system,63 and I published all the evidence for these state- have written a book, originally entitled Letter ments, although this has not always been easy. to Students of Biology of the Twenty First The stakes are high. If I am right a very Century, now with a new name.64 I have also large proportion of experiments in basic listed the mechanisms whereby the dissemina- research in life sciences will have to be tion of unpopular views is prevented in liberal completed, and this may result in quite societies.65 different conclusions. If I am wrong, only my In recent years, without any reason being reputation is destroyed. It would be natural for given, I have been prevented from presenting a lay person to think that it would be very my views at a joint meeting in Würzburg of unlikely that any single individual was right the German and British Physiological and nearly all other life scientists wrong. Even Societies (they told me that mine was the only if my conclusions were totally correct, it is paper they would not allow to be presented). very unlikely that they would be acted upon, The European Society of Neurochemistry because there are so many academics, doctors, would not allow me to speak at Leipzig. The teachers and publishers who have a vested British Society of Neuropathology prevented interest in current views. History tells us that me showing a film because the Society said this does not happen quickly. that it had seen it before — remarkable, Every day that goes by more people have because it had never been shown before. The carried out more experiments apparently joint meeting of the Norwegian and British compatible with the current consensus, Biochemical Societies at Eidsvoll invited me therefore more people have a career interest in 74 Confronting the experts

it being correct. At the same time, in Britain at Message for the future least — where academic tenure has been Irrespective of the truth or otherwise of my virtually abolished — it is unlikely that views in biology, I believe that it would be anyone who raised the fundamental questions generally agreed that there is an international or came to the same conclusions publicly as tendency to increases in: size of research units; Mr. Sartory and I have, would ever be complexity of research; cost of carrying it out; appointed to a lectureship, be awarded a large competition for academic positions; power of grant for research, or enjoy a successful career those who decide on the allocation of research in science. funds; influence of those who control prestig- There is a widespread belief that medical ious research journals; and censorship by the and biological research is very successful66 establishments of access to the popular media. and, therefore, more resources should be put It would also be agreed that knowledge can into it. I have differentiated between two only advance when the current consensus is aspects of medical research. Since the 1940s, challenged. This is usually a consequence of many new drugs have been discovered and thought by one or a few individuals, who by developed empirically, intensive care units for definition constitute a minority. Thus it is dying patients have been set up in most large reasonable to be concerned that current trends towns, new antibiotics have been found will increase conformity and decrease individ- empirically and modified, transplantation of ual or minority challenges, which will slow skin, kidneys and other organs has become down the advance of knowledge.67 routine, cardiac surgery has become a major In addition, the large number of mecha- speciality, and steroids have been used for skin nisms discouraging the dissemination of diseases. All these have been highly successful challenging and new ideas will discourage applications of simple technologies. However, intellectual honesty,68 which is the overwhelm- we must ask what has been discovered about ing force which advances knowledge. Thus, the genesis of cancer, multiple sclerosis, the present situation will discourage academ- Alzheimer’s disease or schizophrenia. The ics from free thought. I would like to give a answer is remarkably little which has helped historical warning to all biologists that, unless us to understand the mechanism of the they address some of the fundamental ques- diseases, so that we can design rational tions which I have raised69 they are in danger treatments for them. The same may be said of spending the whole of their research about the understanding of the molecular careers, using thermodynamically illegal mechanisms by which drugs act; a large procedures, studying artifacts, repeating amount is known about what they do, but uncontrolled experiments, indulging in remarkably little about how they act in the intellectual casuistry or becoming cynical — living person or animal. none of which is good for science. If we leave aside my hypothesis that basic medical, biological and pharmacological research has not been successful because it has not addressed the fundamental problems and assumptions inherent in most of the techniques, the current situation is dangerous because it suppresses free thought, without which the advance of knowledge can only be slow.

What price intellectual honesty? 75

5. H. Hillman and H. Hydén, “Characteris- tics of the ATPase activity of isolated neurons of rabbit,” Histochemie, vol. 4 (1965): 446-450. 6. I. Berenblum and E. Chain, “Studies on the colorimetric determination of phosphates,” Biochemical Journal, vol. 32 (1938): 286-298. 7. K. Popper, Objective Knowledge, Oxford: Clarendon Press (1972): 14-17. 8. F. Lipmann, “Metabolic generation and utilization of phosphate bond energy,” Figure 1. The structure of the cell, at the left Advances in Enzymology, vol. 1 (1941): as agreed by most modern cytologists and at 99-162. the right as believed by me. In the structure on 9. P. George and R. J. Rutman, “The ‘high- the left, u is adjacent to the double cell energy phosphate’ bond concept,” Progress in membrane, g to the Golgi apparatus, and ser Biophysics and Biophysical Chemistry, vol. 10 and rer to the endoplasmic reticulum, a (1960): 1-53. network in the cytoplasm. m is a mitochon- 10. B. Banks, “A misapplication of chemis- drion containing the ‘shelves’ of cristae. np try in biology,” School Science Review, vol. represents holes in the nucleus, the ‘nuclear 179 (1970): 286-297. pores.’ In my publications, I have shown that 11. E. W. Taylor, “Chemistry of muscle the double cell membrane should not always contraction,” Annual Review of Biochemistry, appear to be cut at right angles, and the vol. 41 (1972): 577-616. reticulum or network would prevent intracel- 12. K. Lohmann, “Uber der enzymatische lular movements which are characteristic of Aufspaltung der Kreatinphosphorsaure; living cells. In the structure on the right, the zugleich ein Beitrag zum Chemismus der mitochondria appear in the cytoplasm smaller Muskelkontraktion,” Biochemische Zeitschrift, and are oriented randomly. Further details are vol. 271 (1934): 264-277. given in references.70 13. J. F. Morrison and A. H. Ennor, “N- phosphorylated guanidines,” in P. D. Boyer, Notes H. Lardy, and K. Myrbäck (eds.), The 1. H. Hydén, “Quantitative assay of Enzymes, Vol. 2, New York: Academic Press compounds in isolated fresh nerve cells and (1960): 89-109. glial cells from control and stimulated animals,” 14. Hillman and Hydén, op. cit. Nature, vol. 184 (1959): 433-435. 15. Berenblum and Chain, op. cit. 2. H. Hillman, “Hydén’s technique of 16. Ibid. isolating mammalian cerebral neurons by hand 17. H. Hillman, “The effect of visible light dissection,” Microscopy, vol. 35 (1986): 382- on ATP in solution,” Life Sciences, vol. 5 389. (1966): 589-605. 3. H. Hillman, “Fraud versus carelessness” 18. H. Hillman, “The terminal phosphate (letter), Science, vol. 326 (1987): 736. bond as a transducer” (abstract), Sixth Interna- 4. J. T. Cummins and H. Hydén, “Adeno- tional Congress of Biochemistry, New York sine triphosphatase in neurons, glia and City (26 July–1 August 1964). neuronal membranes of the vestibular nucleus,” 19. H. Hillman, “The phosphate bond as a Biochimica et Biophysica Acta, vol. 60 (1962): transducer,” Information Exchange No 1, vol. 271-283. 190 (3 July 1964): 1-33. 76 Confronting the experts

20. B. Chance, “Spectra and reaction dimensions and appearance of isolated rabbit kinetics of respiratory pigments of homoge- medullary neurons,” Microscopy, vol. 35 nised and intact cells,” Nature, vol. 169 (1952): (1987): 652-659. 215-221. 35. Hussain et al., op. cit.; H. Hillman and 21. S. E. Shnoll, M. N. Kondrashova, and D. Jarman, Atlas of the Cellular Structure of the K. F. Sholts, “Multi-phase alterations of the Human Nervous System, London: Academic ATPase activity of actomyosin preparations Press (1991). and the effect of different features,” Voprosy 36. H. Hillman and P. Sartory, “Value of Meditsinskoi Khimii, vol. 3 (1957): 54-63. textbooks” (letter), Nature, vol. 267 (1977): 22. F. A. Hommes, “Oscillation times of 102. the oscillatory reduction of pyridine nucleo- 37. H. Hillman and P. Sartory, The Living tides during aerobic glycolysis in brewer’s Cell, Chichester: Packard (1980): 102-105. yeast,” Archives of Biochemistry and 38. H. Hillman and P. Sartory, “The ‘unit’ Biophysics, vol. 108 (1964): 500-504. membrane, the endoplasmic reticulum, and the 23. H. Hillman, “Do oscillations in biologi- nuclear pores are artifacts,” Perception, vol. 6 cal system originate in their substrates and (1977): 667-673. nucleotides?” Information Exchange No. 1, vol. 39. N. Hawkes, “Mirages from micro- 298 (14 January 1965): 1-2. scopes,” Observer (11 December 1977). 24. H. Hillman, Certainty and Uncertainty 40. A. W. Robards, P. J. Evennett, J. in Biochemical Techniques, Henley on Sikorski, J. A. Chapman, R. W. Horne, and A. Thames: Surrey University Press (1972): U. Glauert, “Whose illusions” (letter), 34-35. Observer (18 December 1977). 25. H. Hillman, “Some fundamental 41. H. Hillman and P. Sartory, “Whose theoretical and practical problems associated illusions” (letter), Observer (1 January 1978). with neurochemical techniques in mammalian 42. H. Hillman and P. Sartory, “A challenge studies,” Neurochemistry International, vol. 5 repeated” (letter), Observer (16 December (1983): 1-13. 1979). 26. Hillman (1972), op. cit. 43. A. Tucker, “A sight too powerful,” 27. H. Hillman, “Control experiments for Guardian (22 May 1980), and “Seeing is biochemical techniques,” Biochemical Society. believing,” Guardian (5 June 1980). Bulletin, vol. 1, part 3 (1979): 11. 44. Robards et al., op. cit. 28. Hillman (1972), op. cit. 45. P. J. Evennett, “Fact or artifact. Debate 29. Ibid. on the reality of the unit membrane,” 30. J. A. Lucy, “Review of Certainty and Proceedings of the Royal Microscopical Uncertainty in Biochemical Techniques,” Society, vol. 15 (1980): 334-335. Biochemical Education, vol. 1 (1973): 32. 46. J. D. Robertson, “The ultrastructure of 31. Hydén, op. cit.; H. Hydén, “The the cell membranes and their derivatives,” neuron,” in J. Brachet and A. E. Mirsky (eds.), Biochemical Society. Symposia, vol. 18 (1959): The Cell, Vol. IV, New York: Academic Press 3-43. (1961): 215-324. 47. Hillman and Sartory (1980), op. cit. 32. Hydén (1959), op. cit. 48. H. Hillman and P. Sartory, “A reexami- 33. T. S. Hussain, H. Hillman, and P. nation of the structure of the living cell and its Sartory, “A nucleolar membrane in neurons,” implications for biological education,” School Microscopy, vol. 32 (1974): 348-353. Science Review, vol. 61 (1980): 241-252. 34. I. Chughtai, H. Hillman, and D. Jarman, 49. R. W. Horne and J. R. Harris, “The “The effect of haematoxylin and eosin, electron microscope in biology,” School Palmgren’s and osmic acid procedures on the Science Review, vol. 63 (1981): 53-69. What price intellectual honesty? 77

50. R. H. Michell, J. B. Finean, and A. 65. H. Hillman, “Resistance to the spread Coleman, “Widely accepted modern views of of unpopular academic findings and views in cell structure are fundamentally correct,” liberal societies, including a personal case,” School Science Review, vol. 63 (1982): Accountability in Research, vol. 1 (1991): 434-441. 259-272. 51. Hillman (1972), op. cit. 66. H. Hillman, “How to make medical 52. H. Hillman, “Some questions not research more successful,” The Practitioner, answered by the electron microscopists” vol. 231 (1987): 998-1003; 1403-1409. (letter), School Science Review, vol. 224 67. H. Hillman, “The modern tendency to (1982): 173-177. conformity with proposals for reversing it,” 53. H. Hillman, “Some microscopic consid- New Humanist, Vol. 109 (1993): 13-15. erations about cell structure. Light versus 68. H. Hillman, “Honest research,” Science electron microscopy,” Microscopy, vol. 36 and Engineering Ethics, Vol. 1 (1995). (1991): 557-576. 69. See notes 24, 25, 38, 52, 57, 58, 60 and 54. R. Virchow, “Uber das granulierte 64. Ansehen der Wanderungen der Gehirnsven- 70. Hillman and Sartory (1977), Perception, trikel,” Allgemeine Zeitschrift für Psychiatrie, op. cit.; Hillman and Sartory (1980), The vol. 3 (1846): 242-250. Living Cell, op. cit.; Hillman (1986), The 55. Hydén (1959), op. cit. Cellular Structure of the Mammalian Nervous 56. W. J. J. Nauta and M. Feirtag, “The System, op. cit. organisation of the brain,” Scientific American (September 1979): 88-111. 57. H. Hillman, Cellular Structure of the Mammalian Nervous System, Lancaster: MTP Press (1986). 58. H. Hillman, “The anatomical synapse by light and electron microscopy,” Medical Hypotheses, vol. 17 (1985): 1-32. 59. B. Katz, The Release of Neural Trans- mitter Substances (Sherrington Lecture), Liverpool: Liverpool University Press (1969). 60. H. Hillman, “A re-examination of the vesicle hypothesis of transmission in relation to its applicability to the mammalian central nervous system,” Physiological Chemistry and Physics and Medical NMR., vol. 23 (1991): 177-198. 61. H. Hillman, “A new hypothesis for electrical transmission in the mammalian central nervous system,” Medical Hypotheses, vol. 34 (1991): 220-224. 62. Senate, University of Surrey, (8/87) (30 September 1987): 1-20. 63. Hillman and Jarman, op. cit. 64. H. Hillman, The Case for New Para- digms in Cell Biology and in Neurobiology, Lampeter: Mellen Press (1991).