VIEWPOINT
Viewpoint
The idea is more important impor tant than the experiment
John Martin
Some would say that the proposition the idea is more important than the experiment is so obvious it is not worth discussing, others have vehemently disagreed with it. I think it is useful in several ways to analyse the relative value of the two most important events of research. I believe the weight put on an idea or experiment will affect the way science is managed, particularly, the way in which an atmosphere of creativity is generated. An experiment without an idea has little value—it lacks direction. Science has an ability to perform an almost indefinite number of experiments; time, money, and energy can be invested to little purpose. An idea is universal and transcending; an experiment, although reproducible, is limited to those conditions which make it reproducible. The purpose of science, and especially medical science, is to change the world. Let us therefore take the concept to extremes to test its validity. It is clear that an idea alone without experiment can change the world in a way that has practical consequences, resulting from the idea itself without any experimental science intervening. If I look at a stirrup, I can see that this is a product of a single idea. A horseman somewhere in central Asia thought that to put a ring on the end of a rope would help him stay on the horse. No experimentation was necessary. Observe the outriggers on a canoe, again these were not the result of painstaking experiments, but they were a single intellectual leap, the product of an internal vision which gave the solution to capsizing a canoe with a sail. The most obvious manifestation of this concept in medical science is Jenner’s idea of vaccination. This was arguably the greatest medical advance ever, which has prevented more human suffering than any other medical advance. Jenner applied his idea directly by vaccinating his neighbour’s child. Is what I am saying obvious? There has been much serious and even violent discussion about the relation between idea and experiment, in decisions about Nobel prizes. However, the Nobel prize committee in medicine and physiology itself practises the concept the idea is more important than experiment. For example, Salk did the experiments that showed vaccination against poliomyelitis to be efficacious. He was also involved in its worldwide development, and is now a household name. However, the Nobel prize for vaccination against poliomyelitis was given to the biologist who had the idea that poliomyelitis virus could be grown in tissue culture. His name is forgotten, but his novel idea was the sine qua non for Salk’s later more practical work.
Lancet
2000; 356: 934–37
British Heart Foundation Laboratories, Department of Medicine, (Prof J F Martin Martin FMedSci) University College London WC1E 6JJ, UK (Prof
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An idea comes from the mind, it is the essence of man. Even though the difference in DNA between a chimpanzee and a human being is negligible, the qualitative difference is the human ability to create abstract concepts, an ability which is central to humanity and of which there is no evidence in other primates. Thomas Aquinas summed it up: “the essence of the human being is to take two concepts which are themselves abstract, then to put them together to form a new abstract concept which is unlike the two original concepts”. He maintains that if this is done within the human being there must be an abstract machine to do it. Is this ability to abstract, a product of a highly developed neural network, or the product of a machine that is not physical, and that does not require atoms to fulfil its role (but clearly would need a biochemical connection to manifest itself)? If an abstract machine exists, I do not think that it was necessarily produced from a source outside man himself. Could it not have been a product of evolution? The best explanation for the origin of the universe is that it came from a singularity of infinite density and no volume. This concept is utterly incomprehensible if not understood as the product of a mathematical deriviation. However, if that concept is credible then it is no less credible to say that a non-physical priniciple within the human being arose as a product of evolution in order to explain Aquinas’ philosophical explanation for our ability to abstract, just as Stephen Hawking’s mathematical extrapolation helps understand the origin of the universe. Perhaps the great problem of the next 100 years in biology will be to understand what makes a human being a human being. Most of my colleagues in neurobiology would not agree with what has just been said, but would maintain that man’s ability to have ideas comes from his highly complex neural network. The consquences of either believing one proposition or the other are profound, legally, socially, politically, and morally. The solution to the problem of “what is a human being” can only come from an interaction between science, philosophy, and sociology. Surely we need to understand what is the nature of man before we can plan his appropriate society. The way man changes the world and creates society is based upon his ability to abstract. This was the subject of a poem I wrote about New York (panel). If fantasy is a play of ideas, then I find the expression of fantasy in abstract painting and music superior to science for two reasons. First, art is a tool for the self analysis of the individual, both the producer and the consumer. An understanding of self is a higher pursuit than the remit of science which is to measure the universe and predict its behaviour. Second, art is unique. If a poem is not written or a painting not
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VIEWPOINT
New York is one great minimalist abstraction An Immense beauty created by Either horizontal or perpendicular lines. But how could man Who is round and soft Create such rigid linearity Unless within himself there is A minimalist abstraction?
painted, no other human being in the future will ever write the same poem or paint the same picture. However if the scientist were to die the day before his great discovery it would only be a transient loss; the discovery is sure to be made within the next few years. Scientific concepts are put together often most fruitfully in a non-linear fantasy, which is both spontaneous and intuitive. Such fantasy will often give rise to experiments which are risky, and certainly are not likely to attract funding. However, I believe that such experiments are to be encouraged. The environment in which a play of ideas can occur, that leads to this nonlinear fantasy, can be aided by having a multidisciplinary team in a relaxed environment, where intellectual creativity is valued at least as much as the discipline of experimentation. I would like to give a few examples of how fantasy has helped experimentation. In the late 1980s and early 1990s, I was associated with the translation of basic discoveries of the role of nitric oxide in biology into the clinical field. Nitric oxide is known to be an important signalling system throughout biology. We showed that the inducible form of nitric oxide synthase was found in the myocardium of patients suffering from dilated cardiomyopathy. This result published in The Lancet lent support to the hypothesis that overproduction of nitric oxide might hold the heart in dilatation, inhibiting cardiac contraction. This finding was an important advance in the understanding of the disease, which I reported at a meeting of the European Society of Cardiology in Barcelona. Before my presentation, I spent time wandering through the gothic quarter of the city. One of my favourite secluded squares contains the church of St Philip Neri. His statue, which stands above the door, shows the saint performing an auto-thoracotomy, his hands holding his ribs apart to show flames of love leaping from his dilated heart. Above is a quotation in Latin from the Pslams: “Oh Lord dilate my heart with love for thee”. A problem in Catholic theology has been the nature of grace. Grace is that which God gives to man to help him live a worthy life. It is the essence of the love of God. At the meeting the following day in Barcelona, I was able to report not only that nitric oxide might be involved in dilated cardiomyopathy, but that if St Philip Neri was asking God to dilate his heart with love for him, then perhaps grace is nitric oxide. A multidisciplinary team is more likely to give rise to non-linear fantasy than a monovalent team. My young colleagues and I were relaxing one evening and discussing our findings on dilated cardiomyopathy. One gynaecologist among us suggested that the uterus was very much like the heart; their function was to contract, the uterus rarely and the heart 72 times a minute. We wondered whether nitric oxide delivered to the uterus might not inhibit its contraction just as it inhibits the contraction of the myocardium. We discussed that
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premature labour was a common cause of infant mortality and disability, and there was no convincing treatment that might inhibit the unwanted contraction of the uterus in early pregnancy. We wondered whether nitrate patches used in the treatment of angina could inhibit premature labour. The young gynaecologist pleaded to be allowed to use nitrate patches, with the permission of his consultant in obstetrics, in extreme circumstances. I told him that he must be focused and disciplined and that he should finish his present project on the uterine pharmacology of nitric oxide before going into clinical studes. I went home and to bed. I was woken in the early hours by the young gynaecologist telephoning to exclaim “I’ve done it and it works!”. After our discussion he had returned to the labour ward where he was on duty for the night, where a young Ethiopian woman was in labour with twins at 22 weeks of pregnancy. He discussed the matter with his consultant, who agreed it was reasonable to try the nitrate patches in these extreme circumstances because of their low risk and the potential benefit. The young gynaecologist sprinted to the coronary care unit, returning to the obstetric ward with the necessary patches. Just as patients with angina have those patches over their heart (although the delivery is of course via the bloodstream) the patches were placed over the pregnant abdomen. Within half an hour the contractions had ceased. The efficacy of nitrates in inhibiting premature labour has been shown by a controlled clinical trial undertaken by the young gynaecologist. Admiral Fisher at the battle of Jutland said “Any fool can obey orders, in war the important thing is not to obey them”. Perhaps the same applies in science. The flow of ideas to give a non-linear fantasy may be something that arises out of European culture. Might not the US culture support a more linear direction of ideas? Vascular endothelial growth factor (VEGF) is important in the fetus for the growth of blood vessels. This finding has led to its potential use in inducing new blood vessel growth in ischaemic tissue, or in inhibiting angiogenesis in tumours. Our group looked at the problem differently. We had originally suggested that atherosclerosis might have its origin at the adventitial side of the blood vessel, not only at the luminal side as thought previously. We had therefore approached vascular biology from an obtuse angle, which led us to suggest that ischaemia of the outer media of an artery, caused by occlusion of the vasa vasorum, might be responsible for changes leading to intimal hyperplasia. Thus, we suggested that the gene for VEGF which causes angiogenesis in the fetus might have a quite different second role in the adult artery. Again thinking from the outside in, we were able to transfect the gene for VEGF to rabbit arteries, showing that acting via its receptors uniquely found on the endothelium, presence of the gene product caused production of nitric oxide and prostacyclin from the endothelium lining the artery, which in turn inhibited intimal hyperplasia occurring in response to a variety of damaging agents. These ideas and experiments led to the concept that the delivery of the gene for VEGF from the outside of vessels might be used clinically, to inhibit intimal hyperplasia which occurs at anastomoses after vascular surgery. This new treatment is at the moment in phase one clinical trials. Our US colleagues are exploiting VEGF gene treatment to encourage angiogenesis in ischaemic tissue.
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VIEWPOINT
To make clinical advances for such discoveries, it was necessary to establish a biotechnology company. Large pharmaceutical companies would not take the risk, and there was no mechanism within the grant-giving agencies to supply the large amount of money needed. Should a professor found a biotechnology company? This notion has been the subject of much debate in UCL (University College London). However, I believe that professors should not only be allowed to form biotechnology companies, but they should also be encouraged to do so. Universities own a large amount of intellectual property, which is very valuable. Up to now, intellectual property has been given to the world in the form of publications or ideas given freely to industry. The formation of biotechnology companies that are in part owned by the university will allow the possibility of income to the university from those companies in the future. Such income could not only fund scientific research within the university, but also fund departments in humanities. Perhaps science departments have a duty to fund poorer dep artments, in which fundraising is difficult. This model is being tested here at UCL, and has every chance of being successful. This system might not only bring funding to departments that are in difficulty, but it might also give the university the possibility of being relatively independent from government. If the academic who founds the biotechnological company is not involved in its early development, then no development will occur. However, the following rules might help: the objective of the academic must be science and not profit; there must be a defined benefit to the university; and there must be transparency about the involvement of the academic’s time and resources. During the process of setting up our company (Eurogene), I have learnt much about the commercial world. I have also learned how academia is seen by that world. I have seen the enormous weakness of the banking industry in understanding science and its potential. I am sure that they also see the weaknesses of academia. What is needed is a meeting of academia and investors so that each side can know the other on equal terms, and each side can attain its objective without losing its integrity. The possibility of financial independence for the university and the support of the arts in university by science depends upon that relation. One of my greatest passions in life has been the study of platelets. They are biologically unique in that they have no nucleus and are produced from megakaryocytes by an unknown process which is not mitosis. Each megakaryocyte produces between 2000–3000 platelets. The understanding of this process is difficult since there is no biological precedent. Platelet changes may be one cause of acute coronary syndromes (myocardial infarction and unstable angina). I have no clear fantasy about what happens in the coronary artery in the minute before chest pain, but only a blurred conjunction of possibilities. Acute coronary syndromes are simply syndromes made up of a specific clinical description, electrical changes on the electrocardiogram, and enzyme changes in the blood. At the moment, we treat the syndrome in exactly the same way irrespective of what might be the pathophysiological cause of occlusion of the coronary artery. We are in fact at the same stage of therapeutic development as medicine was, when anaemia was treated only by transfusion of blood, without the understanding that
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there were several diseases which lead to the endpoint drop in haemoglobin, each one having to be treated individually. We now have specific treatments for iron deficiency, vitamin B12 deficiency, and bone marrow failure. If we can define pathophysiologically all the diseases that lead to the syndromes of unstable angina and myocardial infarction, then we will be able to design specific treatments as we have done for anaemia. What is lacking in this quest is not our technical ability to do biological experiments on the cells involved in the blood in the coronary artery, but it is a lack of ideas that holds us back. One of the biggest leaps in non-linear fantasy that I have been involved in is platelet production. The original observation that platelets are produced from bone marrow megakaryocytes arose from a single study by Wright in 1908. That study has been handed down in the folklore of medicine as definitive. However, there is now good evidence that megakaryocytes mature in the bone marrow and then circulate in the venous circulation. The idea arose that perhaps all platelet production occurred in the lungs. Circulating megakaryocytes would be ejected from the right ventricle with great kinetic energy because of their large size, and they would impact into the capillaries of the lungs. Because of their enormous size they could not pass through the pulmonary circulation. The megakaryocytes would be changed by a physical process of fragmentation to produce platelets, which would leave the lungs via the pulmonary vein in a process driven by the kinetic energy of the right ventricle. Since the hypothesis was first proposed, there has been much circumstantial evidence supporting it, however, it proved impossible to design a definitive experiment. With these thoughts in my mind, I was sitting in a bar in Elsenor in Denmark with among others, John Dickinson, Professor of Medicine from Barts (St Bartholomew’s, University of London). He had a fascination with digital clubbing. When he asked me what the cause of clubbing might be, I immediately saw the possibility that if there were abnormal circulation between the pulmonary artery and the pulmonary vein, or from the right heart to the left heart, then megakaryocytes might bypass the lungs without being fragmented. Such abnormal circulation might happen around tumours, during the inflammatory process of septic-lung disease or in a right to left cardic shunt. Megakaryocytes being extremely large cells would then travel in the axial flow at the centre of the artery, being carried along the brachial artery to the final capillary bed in the fingers, where they would fragment as though they were in the lungs. The lungs have high levels of nitric oxide and prostacyclin that would prevent secretion of megakaryocyte contents. However, in the fingers large amounts of platelet derived growth factor (PDGF) might be released from the megakaryocytes granules. The action of PDGF could produce all the signs of clubbing. Delighted with our new idea, there and then we started writing our hypothesis article which later appeared in The Lancet . There was both applause and criticism from my colleagues, applause because of the intellectual advance of fantasy and criticism because of no experimental evidence. The article provoked much correspondence, but little more. However, 2 years later pathologists from Oxford did an observational study, whereby they examined the capillaries in the ends of the
THE LANCET • Vol 356 • September 9, 2000
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VIEWPOINT
fingers of patients with lung disease with clubbing and lung disease without clubbing. They showed that digital capillaries or arterioles from patients with clubbing contained megakaryocyte material, whereas the controls did not. Is it possible to create a favourable atmosphere in which fantasy might flourish? I believe that the role of the professor as a leader is not only to give intellectual direction to a group, but also to create such an environment. The atmosphere should be one in which even the most junior members of an academic team can express themselves without fear. It should be open, democratic, and relaxed. If the professor supports work financially and to some extent intellectually, and encourages his more junior colleagues to publish without his name on the paper, then this gives them
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confidence to express themselves as they wish, hopefully in exciting new directions. It is difficult to achieve the degree of personal honesty to understand why academics put so much of their lives into research. It is certainly not for money, and fame is ignoble motivation. While reading Churchill’s History of the English Speaking People, I was struck by his description of Richard the Lionheart. “He loved war not for political gain or glory but as other men love either science or poetry: for the excitement of the struggle and the glow of victory”. I think that sums it up for me, I do research for the excitement of the struggle and the glow of victory. I am a British Heart Foundation Professor of Cardiovascular Science. The analogy comparing acute coronary syndromes to anaemia arose in conversation with Prof Attilo Masari.
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