Address of the President Sir Alan Hodgkin at the Anniversary Meeting, 30 November 1972

Address of the President Sir Alan Hodgkin at the Anniversary Meeting, 30 November 1972Source: Proceedings of the Royal Society of London. Series B, Biological Sciences, Vol. 183, No.1070 (Feb. 27, 1973), pp. 1-19Published by: The Royal SocietyStable URL: http://www.jstor.org/stable/76129 .

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Proc. R. Soc. Lond. B. 183, 1-19 (1973) Printed in Great Britain

Address of the President Sir Alan Hodgkin

at the Anniversary Meeting, 30 November 1972

Award of Medals 1972

The COPLEY MEDAL is awarded to SiR NEVILL MOTT, F.R.S. At an early stage in his career Mott had already established a reputation as a

pioneer in the field of atomic collision theory based on the new wave mechanics. He was the first to show that Rutherford's scattering law remains exactly valid when this mechanics is employed, and to point out the importance of symmetry in scattering problems. He was also the first to apply Dirac's relativistic theory to these problems and showed that under certain conditions electrons may be polarized by double scattering. Even as early as 1932 he realized the importance of conservation laws in limiting reaction cross sections. All of this work was characterized by a remarkable degree of originality and physical insight combined with mathematical skill.

When, at the age of 27, he became professor of theoretical physics at Bristol, he abandoned the study of atomic collisions to work on the theory of metals and alloys, in order that he might relate his work more closely to that of a new group of experimenters. Within a few years he was recognized as one of the leading international authorities in this field, to which he contributed a number of important papers on electronic bands in metals and on the electrical conductivity of alloys and its temperature coefficient.

Later he turned to semi-conductors and insulators, throwing light on the physical processes involved in the formation of oxide films and in the electrical conductivity which can be induced by various means in polar crystals. His theory (with Gurney) of the formation of the latent image in a photographic emulsion has found general acceptance, and has stimulated fresh experimental work in research departments of the industry.

When war broke out he found that his activities as a quantum physicist had no war application, However, in 1943 he was appointed superintendent of theoretical research in armaments at Fort Halstead where he remained until the end of the war. He made an outstanding contribution to the theory of the fragmenta- tion of shell and bomb cases under the effect of the explosive charge.

After the war he returned to the Wills Laboratory at Bristol. Under his guidance a flourishing theoretical group carried out work of great importance on the mechanical properties of materials. Mott's personal contributions were mainly to the theory of plastic deformation in metals, developing the understanding of bulk behaviour in terms of microscopic derangements of the crystalline structure.

I [ 1 ] Vol. I83. B. (27 February I973)



2 Anniversary Address by Sir Alan Hodgkin, P.R.S.

Thanks largely to this work we now have a much closer understanding of the factors determining mechanical strength as well as other properties of matter.

After his election as Cavendish professor at Cambridge in 1954 he continued to work in the same general field. Despite the numerous preoccupations associated with the directorship of a large laboratory Mott continued to carry out personal research as well as contributing to the work of others. In particular he has added much to the theory of the behaviour of amorphous materials as well as to the solution of more fundamental questions such as the basic reasons why some atoms form metallic solids.

The RUMFORD MEDAL is awarded to DR B. J. MASON, F.R.S.

Mason's research has centred on the microphysical processes in clouds to which study he has brought outstanding expertise in the design and execution of experi- ment in the laboratory and the interpretation of its results in natural clouds. Among the complex processes he and his colleagues have investigated, with notable success, are the collision and coalescence of cloud droplets, the break-up (and attendant electrification) of large drops, the nature of ice-crystal nucleation and droplet freezing, the form of ice crystals, as a function of external parameters, and the separation of charge associated with the collision of cloud particles and the splintering of freezing droplets. The broad aim of these studies has been to determine the conditions under which clouds remain stable aerosols or through insta- bility lead to precipitation and, in regard to charge separation processes, to arrive at a quantitative theory of thunderstorm electrification and discharge. Although a satisfactory theory of the latter does not yet exist, Mason has shown that the pyroelectric property of ice arising from the greater mobility of the HI ion than of the OH1 ion and their separation in a temperature gradient is almost certainly of dominant concern.

More recently, as director of the Meteorological Office, Mason has encouraged research on the dynamical aspects of cloud structure and the release of precipitation in relation to the problem of atmospheric evolution. He has also strongly encouraged the development of the hydrodynamical theory of atmospheric evolution and is widening its application in weather forecasting through the use of the most advanced high-speed computers and of atmospheric models of increasing sophistication.

A ROYAL MEDAL is awarded to SIR DEREK BARTON, F.R.S.

Barton's ou'tstanding contribution to organic chemistry has been his theory of the conformation of compounds containing the cyclohexane ring and his recognition of the significance of axial and equatorial bonds. The theory provided a logical explanation of the chemical and physical behaviour of many of these compounds and it has been extended to other classes, especially the terpenes, steroids and carbohydrates. These concepts were later extended to conformational



Anniversary Address by Sir Alan Hodgkin, P.R.S. 3

transmission and the behaviour of several types of larger molecules has been clari- fied by application of these ideas.

Barton's studies of terpenes led him to examine the potentialities of photo- chemistry in synthesis, and he developed a useful intramolecular photochemical rearrangement which was used in a synthesis of aldosterone. Another contribution of great importance has been Barton's recognition of phenolic coupling as a key step in many biosyntheses, particularly of alkaloids. This has inspired much research in many laboratories, and it was used extensively by him in his syntheses and biosyntheses of the alkaloids of many varying groups exemplified by morphine and related compounds. Notable syntheses have been achieved of several compounds in the important antibiotic families of tetracycline and penicillin. He has also developed several useful novel synthetic methods, for example, the preparation of carbon-carbon double bonds. His work is characterized by elegant experimentation, and the development of important theoretical ideas.

A RoYAL MEDAL is awarded to DR F. H. C. CRICK, F.R.S. In 1953 Crick and J. D. Watson proposed the double-helical model for DNA,

in which the bases are arranged in complementary pairs so that the molecule is capable of self-replication and is thus the essential carrier of genetic information in living cells. This proposal was based on an inspired interpretation of the results of X-ray diffraction analysis of DNA carried out by Wilkins and his collaborators, and on the chemical analyses of Chargaff and others. The replication scheme inherent in the double-helical structure of DNA made it possible for the first time to discuss the mechanism of heredity in molecular terms; it has been the most fruitful concept in the whole of biology during the past 25 years, and has been the basis for the explosive development of molecular biology.

Besides his part in this dramatic discovery, Crick has continued to play a leading role in many other aspects of molecular biology. He has a profound understanding of the theoretical basis of X-ray diffraction, and has made important contributions to X-ray studies of crystalline proteins, fibrous proteins and viruses. These include the theory of diffraction from helical structures, the coiled-coil model of a-keratin and related proteins, the structure of collagen, and the theoretical basis of the construction of 'spherical' viruses.

He has played a very important part in increasing our understanding of the way in which the genetic message is carried on DNA (the 'coding' problem), and of the mechanisms by which it is translated into specific sequences of amino acids in the proteins synthesized by the cell. Crick was responsible for much of the theoretical treatment of the coding problem which led to the original hypothesis of a triplet code, and collaborated with Brenner and others in providing some experimental support for this theory. Crick was also responsible for the so-called adaptor hypothesis, which provided the conceptual basis of the mechanism for translating code triplets on the DNA into amino acids in a polypeptide chain.

I-2




A ROYAL MEDAL is awarded to DR W. B. LEWIS, C.B.E., F.R.S. Lewis was a pioneer before the war in the application of electronic techniques to

nuclear problems (counting etc.) and on radar. Throughout the war he was deputy head of T.R.E. (now R.R.E.) and was directly involved with most of the major technological developments.

Dr Lewis is senior vice-president, science, Atomic Energy of Canada Ltd and for over 25 years has been the principal force scientifically and technologically in the development of heavy water reactors both for research purposes and even more importantly for power generation. This concentration of effort in a special- ized field of nuclear technology has in the event been fully justified, the heavy water reactor using natural or slightly enriched uranium now ranking as a significant and economic technique for generating power. The major credit for this must go to Dr Lewis who has answered his critics by positive demonstration through results emerging from a long and extensive research programme allied to the construction of major power stations in Canada.

The DAvY MEDAL is awarded to PROFEssoR A. J. BIRCH, F.R.S. In this country Birch has worked at the universities of Oxford, Cambridge and

Manchester. His first important discovery was the so-called Birch reduction, the reduction of aromatic rings by sodium in liquid ammonia, a reagent which he has also exploited in other contexts. A notable application was the partial synthesis of the medicinally useful 19-nortestosterone. He has also made important contributions to our understanding of the chemical mechanism of reductions by dis- solving metals.

His second major contribution has been the structural elucidation and bio- synthesis of natural products. On the structural side his work on sesquiterpenes and phenolic compounds has been particularly noteworthy. In the course of this work he developed his well-known acetate hypothesis, which states that many natural products, particularly aromatic compounds, are derived from the head to tail linking of acetate units. The pattern of oxygenation on alternate carbon atoms implicit in the hypothesis led to the modification of the structures of a number of natural products which previously has been incorrectly formulated. The validity of the theory has been supported by numerous biosynthetic labelling experiments. He has also studied the incorporation of the terpenoid precursor, mevalonic acid, into fungal metabolites and other types of natural products.

More recently he has developed applications of organometallic reagents, especially metal carbonyls in organic syntheses. All of Birch's work is characterized by its ingenuity and the outstanding skill employed in its operation.




The DARWIN MEDAL is awarded to DR D. LACK, F.R.S. The researches of David Lack, Director of the Edward Grey Institute of Field

Ornithology, Oxford, have greatly advanced our understanding of ecological speciation in birds, and of the breeding habits and other factors that limit their numbers in natural populations and determine the separation of closely related species. His gifts for keeni field observation and original interpretation were early shown in his Darwin's finches (1947), which did much to promote the interaction of ecological and evolutionary studies, and which still provides a continuing stimulus to new generations of readers.

In The natural regulation of animal numbers (1954, reprinted 1970), he was able, by careful weighing of evidence, to set out arguments for the view that density- dependent processes are the prime regulators of animal populations. Twelve years later, in 1966, he developed his arguments further in Population studies of birds, a sequel based upon new researches by a number of workers who had been in large measure stimulated by his example. These and his other books, which include Ecological adaptations for breeding in birds (1968) and Ecological isolation in birds (1971), are models of what can be achieved in organizing complex data by a writer with a clear and logical mind, aided by a graceful and stimulating mode of presenta- tion. He has successfully achieved in them an intention well set out in his own words: to avoid intricate and nebulous theory, and also to avoid an arid enumera- tion of bare facts.

Working with such distinction in a tradition of which Charles Darwin remains the prime exemplar, David Lack is pre-eminently fitted for the award of the Dar- win Medal.

THE BUCHANAN MEDAL is awarded to SnR RICHARD DOLL, O.B.E., F.R.S. for his outstanding contributions to the prevention, diagnosis and treatment of disease, by his epidemiological studies using advanced mathematical techniques. Although his interests have ranged widely over the field of medicine, Doll has devoted much of his attention to cancer and in particular its etiology; his approach has been to choose problems that seemed capable of providing a quantitative relation between incidence and the prevalence of a suspected causative agent. With Sir Austin Bradford Hill he made the now classical study, extending over many years and still in progress, of the smoking habits of doctors, which provided overwhelming evidence that smoking is a principal cause of lung cancer and chronic bronchitis and is implicated in the production of other respiratory and digestive tract cancers and of coronary thrombosis. With the late Dr Court Brown he showed the existence of a quantitative relation between exposure to ionizing radiations and the subsequent incidence of leukaemia. Other studies have thrown light on causes of cancer of the uterine cervix, occupational hazards of gasworkers as a pointer to the effects on the population of atmospheric pollution, and differences in the geo- graphical incidence of cancer which may suggest clues to its causation. Doll has



6 Anniversary Address by Si'r Alan Hodgkin, P.R.S.

extended the principle of the controlled clinical trial into more difficult fields of application such as cancer and leukaemia, and has explored more complex experimental designs and methods of statistical analysis which enable several pairs of treatments to be compared at the same time. He has also applied computer science to problems of classification of disease, analysis of small epidemics, models of car- GinogenesiS and the estimation of man-years at risk in a population.

The HUGHES MEDAL is awarded to DP. B. D. JOSEPIISON, F.R.S.

Josephson, who is a reader in physics at Cambridge University, is a mathematical physicist of great originality and physical insight. His work has been in the field of solid state and low temperature physics and it is in the latter subject that he has made the most remarkable contributions.

In a letter published in 1962 Josephson made, from arguments based on quantum theory, what would seem to many to be absurd predictions concerning certain phenomena at a junction between two superconductors. One was that in general a current would flow across such a junction in the absence of a bias voltage. The second was that when such a voltage V is applied in excess of a certain small critical value it generates a current with an alternating component of frequency e V/h where h is Planck's constant and e the electronic charge. Both of these predictions, which are the most striking examples of quantum effects on a macroscopic scale, have been confirmed experimentally.

A little later Josephson considered the effect of a steady magnetic field applied at the junction. He found that such a field should modify the current in a manner depending on an oscillatory function of the field so that the variation of current strength with field strength is similar to the variation of light intensity across a diffraction pattern. This also has been verified experimentally.

In addition to this outstaniding work Josephson has also carried out important work on the Doppler shift in the Mossbauer effect and on critical phenomena.

The LEVERHULME MEDAL is awarded to DR J. B. ADAMS, C.M.G., F.R.S. for his

contributions to the design and construction of nuclear particle accelerators. His first experience of this kind of work was gained with a relatively modest

project, the 170 MeV frequency modulated cyclotron at A.E.R.E. liarwell. After a year or two of other work in klystron design, he was encouraged by the late Sir John Cockcroft to take an interest in the design of a proton synchrotron for C.E.R.N., Geneva. Originally this was to be a 15 GeV synchrotron of conventional design, but the principle of alternating gradient focusing was published just when serious design work was about to begin. At first very high field gradients, and very high energy and very cheap accelerators, were proposed; but then possible snags were recognized and the practical applicability of the new principle came under doubt. This was a difficult time at which to launch a major project, but Dr Adams succeeded brilliantly in leading the C.E.R.N. team's investigation of




the possibilities. A progressive but sound 28 GeV design was adopted and brought to practical realization in 1960. The project took a remarkably short time, and was finished well ahead of the comparable machine at Brookhaven in the U.S.A.

After the completion of the C.E.R.N. machine, Dr Adams was for a time the director of the whole laboratory. He then became director of A.E.A.'s fusion laboratory at Culham which quickly acquired a leading international reputation. However, after a few years he again took charge of a European team to build a very high energy accelerator, the so-called 300 GeV machine. The invitation to under- take this came from European physicists despite the fact that at the time the United Kingdom did not propose to take part in the programme. He soon found ways of improving the programme in efficiency and economics and the work is proceeding very effectively with the United Kingdom now participating.

The MIULLARD MEDAL is awarded to DR W. R. BooN of Imperial Chemical Indus- tries, Limited

Ever since Adam was expelled from the Garden of Eden (where presumably these matters were better organized), Man has had to contend with the invasion of his food crops by the unwanted growth of weeds. Until comparatively recently, this he did indeed by 'the sweat of his brow'. Now the ingenuity of chemists has provided a more subtle and far less laborious solution to the problem, in the form of the bipyridyl herbicides. Although the different technical skills of many people have been involved in the development of these compounds, the part played by Dr Boon is unqiue Almost alone in the earliest days, he appreciated the potential value of these agents whose properties were so completely different from those of the conventional weedkillers. For example, they were not translocated in soil; indeed they were inactivated by such contact. Furthermore, they only exhibited herbicidal action in the presence of light. As if these did not seem handi- cap enough, the difficulties of preparing the necessary chemical intermediates, even in the laboratory, had convinced maniy that ultimate large-scale manufacture was virtually impossible. By his scientific and management skills, Boon eventually translated these differences and difficulties into a practical method for weed control in normal agriculture, provided new ways of reclaiming waste land, for example by the simultaneous application of seed and herbicide, and in addition held out the promise for ploughless cultivation. These discoveries have provided a source of economic benefit to this country through manufacture and use, and are playing an increasingly important part in helping to feed the developing and hungry nations of the world.

* * * * * * * * * * *

I want to start by saying something about Fred Bawden, who died after a short illness on 8 February. His sudden death is a severe loss to British science and is deeply felt by all who knew him. The Royal Society owes him a great debt for the way in which he combilned the office of Treasurer with the many duties that fall



8 Anniversary Address by Sir Alan Hodgykin, P.R.S.

to the Director of a large institute. He became our Treasurer in 1968 and saw us through the difficult period when we were settling into our new home in Carlton House Terrace. Bawden's good sense and sound practical judgement were invalu- able in our meetings, and we all enjoyed the light-hearted way in which he conduc- ted business. I found myself looking forward to even the dullest of meetings if I knew Fred would be there. We all miss him very much.

After Bawden's death the Foreign Secretary, Sir Kingsley Dunham, acted as Treasurer until the election of Dr J. W. Menter in May. I wish to extend our warm thanks to Dunham for taking on this onerous task in addition to his many other duties. At the same time we congratulate him on the knighthood conferred last summer.

We were delighted that Dr Menter accepted Council's nomination for the post of Treasurer. His distinction as a scientist, as well as his experience of industry and finance will make him an exceptionally valuable officer at a time when it is important for the Society to keep in close contact with applied science. In thank- ing the Treasurer for his report I would wish to endorse his remarks about the admirable way in which the Society is served by Sir David Martin, Dr Keay, Mr Le Grand and all the permanent staff. It is a pleasure to express my gratitude to them and to the officers and Council for everything that they have done for us during the past very busy year.

As in previous years a large fraction of our parliamentary grant and a good deal of effort have been devoted to international activities of one kind or another. These are described in Council's Report and I shall not do more than pick out some of the highlights. As you know, the European Science Exchange Programme has been expanding steadily since it began in 1967. In a statement to the House of Commons, Mr Rippon announced that Her Majesty's Government would provide us with funds to permit the doubling of the European fellowship programme. It was subsequently agreed with the Department of Education and Science that the Society should aim at awarding about 150 fellowships in each direction in 1975, this being double the number awarded in 1970. The additional support was offered in the context of the balancing system of bilateral agreements with partner countries, some of whom have already indicated their willingness to expand the existing programme.

We have been active in developing our relations with China, first by corre- spondence and later by an exchange of visits between ourselves and the Academia Sinica. We hope that these visits will lead to a regular exchange of scienitists between our two countries, for which the Leverhulme Trust has generously provided us with financial assistance. Some movement has already begun and last summer Professor Dorothy Hodgkin visited China and was able to make a detailed com- parison between the very similar molecular models of insulin which had been worked out independently in Peking and Oxford. We all believe in the value of international scientific collaboration but it is particularly gratifying when it leads to a hard and clear crystallization of knowledge of this kind.




It is not customary for the President to review all the Society's activities in his Anniversary address, but I would wish to mention two events which have given me particular pleasure. In 1969 the Royal Society helped to send an expedition to the Western Indian Ocean in the hope of obtaining specimens of the coelacanth Latimeria. Careful plans were made for distributing frozen material, but in the event no Latimeria were obtained and the expedition failed in its primary objective, although it brought back much interesting material. We tried again last year and this time had better luck. A joint expedition, with France and the U.S.A., went to the Comores in January, February and March. Two specimens of Latimeria were acquired and both were kept alive for a short while after capture; a film of fin movements was made on the second occasion. Arrangements for distribution worked well, and frozen or preserved tissues were sent to some 50 scientists in Europe and America. In addition to increasing our anatomical knowledge of Latimeria, the resulting investigations are providing much new information about the animal's biochemnistry and physiology. Some preliminary publications are beginning to appear. In the 6 October number of Nature I noticed one by Chavin (1972) on the thyroid and another by Dartnall (I972) on visual pigments. From the second article it appears that Latimeria shares with a deep-sea shark (Centroscymnu,s coelolepis) the distinction of having its main visual pigment with an absorption maximum at the shortest wavelength (473 nm). The shift towards shorter wavelengths in the visual pigments of deep-sea fish is generally regarded as an adaptation to an environment in which the proportion of light of longer wavelength is greatly reduced.

The appointment of research professors and research fellows is one of the ways in which the Society does make a direct and obvious contribution to the improve- ment of natural knowledge. You will therefore be pleased that Her Majesty's Government has made funds available for two additional Royal Society research chairs, giving us a total of 12 in all. In August 1972 Council announced the appointment of Professor M. F. Atiyah, F.R.S., to a research professorship in the Univer- sity of Oxford, from 1 January 1973. I believe that this is the first time we have appointed a pure mathenmatician to a research chair and I am glad that we are able to fill this gap with such a distinguished person. It is hoped to announce the other new appointment very shortly.

At the time of our last Anniversary meeting we had just been invited by the Secretary of State for Education and Science to give our views on the Green Paper A Framework for Government Research and Development. More than 100 Fellows sent in written comments and 170 Fellows attended a meeting on 11 Janu- ary 1972. A committee appointed by Council met four times between mid-December and mid-January and its draft memorandum was discussed at a special meeting of Council. Our report was sent to the Secretary of State early in February and was published soon afterwards. Advance copies were also sent to the Select Com- mittee on Science and Technology before whom Sir Harrie Massey and I appeared on 9 February. At the time, many of us felt that the period allowed for consultation was too short and that a major reorganization of science was being pushed




through without adequate opportunity for consultation. In retrospect I am relieved that the period for consultation was not unduly prolonged as it undoubtedly in- hibited some of our normal activities, including research which is after all our central function. It also appears that the Government had largely made up its mind and the most that we could hope for was some amelioration of the rather stringent recommendations of Lord Rothschild's report. The White Paper on the same subject, which appeared in July, recommended transfers, building up to ?20 million per annum in 1975, from the D.E.S. to customer departmients. The intention is that this sum will be used to commission applied work from the Medical, Agricultural and Natural Environmental Councils and it has been left to the research councils and departments to work out mutually satisfactory arrangements. The White Paper stresses the importance of partnership and cooperation between customer departments and research councils - a point which was a central feature of our own memorandum. The Council for Scientific Policy is to be recon- stituted and the new Advisory Board of Research Councils which replaces it will clearly have an important part to play in ensuring that the reorganization does not weaken the support that research councils give to universities, or disrupt essential contributions from pure science. I do not wish to reopen the debate on the merit of the arrangements. However, it may be right to consider the likely effect of the reorganization on British science as well as its possible impact on Royal Society policy. As to the former, much will depend on the attitude of the customer departments and the scientists whom they appoint. Rather more than half the grant to the Agricultural Research Council will be transferred from the science budget to the Ministry of Agriculture, Fisheries and Food. It would be highly damaging if an attempt were made to push all the strategic work covered by this sum into short- term projects, but this danger seems less acute than it did a year ago. Ministerial statements about the importance of the research councils have been encouraging and the A.R.C. and the M.A.F.F. appear to be setting up the kind of partnership that we envisaged in our memorandum. Relations between the Medical Research Council and the health departments (D.H.S.S. and S.H.H.D.) have always been good and there is no reason to think that the Ministry will wish to kill a goose that has laid a number of golden eggs in the past.

The research council whose position worries me most is the N.E.R.C. This is partly because it is relatively new and partly because the ?4.5 million to be transferred from the science budget is to be split between several ministries, among which the Department of the Environment and the Department of Trade and Industry are the major share-holders. It is not obvious that either of these departments will feel the responsibility for keeping N.E.R.C.'s institutions financially healthy or for providing the expensive capital equipment, new ships for example, that are likely to be needed for marine biology and geophysics and oceanography. There is also the danger that useful integrated programmes will be fragmented if the departments pursue separate paths. I regard our marine laboratories and organizations like the National Institute of Oceanography as major national assets which



Anniversary Address by Sir Alan Hodgkin, P.R.S. 11 provide essential support for university science and yield practical returns within a reasonable period of time. Yet they do not fit at all easily or naturally into the customer-contractor relation and might be in serious difficulties under the new regime. My feeling is that it will eventually be necessary to provide the research councils with new fLnds to replace those transferred to customer departments.

In some ways it is paradoxical that the N.E.R.C. should be in difficulties because it is in the field covered by that Council that science has made one of the greatest contributions to the prosperity of this country. I would expect a historian of the future to single out the discovery of North Sea gas and oil as perhaps the most important technological contribution to this country's economy in the present period. These discoveries were made by geophysicists and geologists working for the oil companies and cannot be attributed directly to organizations under the control of the N.E.R.C. Yet I do not think it a coincidence that they were preceded by a period of great interest in the continental shelf and a renaissance in the sub- jects of geology and geophysics. It is the N.E.R.C.'s function to look after these sciences and one hopes that the basic support that it gives in this area will not suffer from the reorganization.

The danger that preoccupation with objectives may be self-defeating applies throughout science and was foreseen long ago by Francis Bacon. After pointing out that 'the real and legitimate Goal of the Sciences is the endowment of human life with new Inventions and Riches' he continues:

'Thus (as we have before observed) had anyone meditated on balistic machines and Battering Rams, as they were used by the Ancients, whatever application he might have exerted, and though he might have consumed a whole life in the pur- suit yet would he never have hit upon the Invention of Flaming Engines, acting by means of Gunpowder: nor would any person who had made woolen Manufactories and Cotton the subject of his observation and reflection, have ever discovered thereby the nature of the Silkworm or of Silk.'t

Francis Bacon's conclusions are as valid today as they were 350 years ago and in the new framework of science I trust that the Royal Society will continue to be a strong voice for the importance of pure science, both for national prosperity and as one of the great intellectual activities of this country.

During the last few years scientific administrators have been so busy working out new arrangements for financing research that there has been little opportunity for quiet reflection about the changing needs of fundamental science. In the past, one of the ways in which research councils or similar organizations have been able to help research is by ensuring that new techniques are made widely available to scientists. In physics this may involve setting up some very expensive piece of equipment in a laboratory like C.E.R.N. or Harwell. There are also occasions on which it may benefit the country's economy, as well as being in the interests of pure research, to encourage firms to develop new instruments, new chemicals or

t I am indebted to Professor R. V. Jones for drawing my attention to this passage from the Novum Organum.




labelled compounds of various kinds. The organization for supplying radioactive isotopes from Harwell, and later Amersham, which has been of great benefit to British science, would not have evolved in this country if it had been left to com- mercial enterprise. All this is understood by our research councils who should be well equipped to handle the developments that are likely to result from in- creased European collaboration in science. But no organization has yet made much progress with the more difficult problem of ensuring an adequate supply of what might broadly be called biological material. Under this heading I would include living animals of all kinds, special chemicals found only in certain rare plants and animals, cultures of special cells (tumour and otherwise) as well as the more obvious tools of medical research like labelled antibodies. The position with regard to the supply of living animals is better in the U.S.A. because the much larger population of scientists provides a base to support powerful and enterprising firms capable of supplying all sorts of exotic animals. This is not to say that nothing has been done in this country; the N.E.R.C. supports a culture centre for algae and protozoa at Cambridge; our marine biological laboratories are helpful in supplying living material and the universities have set up an organizationl at Millport whose function it is to supply them with some of the material they need for teaching and research. But there are more animals in the sea than those at Millport and I believe that this whole area is one which requires more thought and planning. To give the problem some reality, and also to introduce a little science into my address, I shall devote the rest of my time to describing some cases where unusual animals have made an important contribution to our knowledge of function. This is an enormous field and if I had the necessary knowledge I might tell you about Professor J. W. S. Pringle's ferocious water bug (Lethocerus), which has the slowest oscillating muscles in the animal kingdom, or I could talk about the sea hare Aplysia with its giant neurons, or about the many important advances which have resulted from the study of electric fish. But to quote Sherlock Holmes in connexion with the giant rat of Sumatra these are 'stories for which the world is not yet pre- pared'. Were I to attempt such a survey, my address would last much too long, or be too condensed to be interesting. In order to limit the field I shall confine myself to three cases in which material from unusual animals has led to significant advances in neurophysiology and related fields.

Aequorin as an indicator of ionized calcium The remarkable properties of aequorin were first described by Shimomura,

Johnson & Saiga in 1962 during their studies of Aequorea forskalii, a luminescent jellyfish which appears in vast numbers during the late summer off the northwest coast of America. In this animal, and probably in other luminescent jellyfish, the method of producing light is quite unlike anything encountered previously. It does not involve ATP or the luciferin-luciferase mechanism found for example in fireflies. The jellyfish manufactures aequorin, a protein of molecular mass about 30 000, which emits light when it comes into contact with calcium ions. It seems



Anniversary Address by Sir Alan Hodgkin, P.B.S. 13

likely that an entry of calcium into the cells containing aequorin is responsible for the natural luminescence of the jellyfish and that in the quiescent state aequorin is prevented from reacting by an exceedingly low intracellular calcium concentration. The structural change triggered by calcium ions must be substantial as a reaction yielding 60 kcal/mol (250 kJ/mol) of aequorin is required to give photons at the peak wavelength of 460 nm. In the living animal the end product of the reaction must be restored to its original state by some metabolic process, but nothing is known of this mechanism.

The first experiments in which aequorin was used as a biological indicator of ionized calcium were those of Ridgway & Ashley (I967). I shall describe them briefly because they show how important questions can be answered by judicious use of biological material. During the period 1957-67 much evidence accumulated to show that the contraction of muscle fibres was initiated by a release of calcium from compartments in the sarcoplasmic reticulum. Proof of this hypothesis came partly from J6bsis & O'Connor's (I966) work with murexide (another calcium indicator) and at about the same time from Ridgway & Ashley's experiments on giant muscle fibres injected with aequorin. You are probably all familiar with the small barnacles (Balanus balanoides) on which you scrape your feet when swimming off a rocky coast. Balanus nubilus, which is found off the American Pacific coast, is similar in shape but may be as much as 15 cm in height. As was first shown by Hoyle & Smyth (I963) this species contains large muscle fibres, about 2 mm in diameter, which are excellent objects for physiological study. After injecting aequorin into these fibres and mounting them in front of a photomultiplier Ridgway & Ashley were in a position to test the calcium hypothesis. In a quiescent muscle the rate of light production was at a level corresponding to a very low ionized calcium concentration - probably well below I ymol/l. Electrical stimula- tion caused the muscle to contract but the rise in tension was preceded by a dramatic increase in light production - as would be expected if the contraction is triggered by the release of calcium ions.

Since that time several research groups, including my own, have made use of aequorin, but, in general, progress has been restricted by the absence of any com- mercial source of the protein. At present the only way to obtain aequorin is to rely on the generosity of a colleague in America or to go to Friday Harbor in Washington and extract the substance yourself. It seems to me that this is a case where an appropriate firm should be subsidized to develop the supply of aequorin. One need not think only in terms of America or Canada. Other luminescent jellyfish contain proteins similar to aequorin and Tima batirdii which has recently been abundant in the approaches to the Baltic may provide a suitable supply for European scientists.

Tetrodotoxin and the sodium gatting mechanism in nerve The primary change which enables nerves and some other excitable tissues to

propagate an electrical impulse is a selective increase in permeability which allows




sodium ions to move inwards across the surface membrane. During the period 1947-51 when Huxley, Katz and I were analysing ionic currents in the squid giant nerve fibre we would have given a great deal for a compound which had the specific effect of blocking the sodium-gating mechanism. Local anaesthetics like cocaine do block sodium channels but they also affect potassium permeability, and in general are rather unspecific. Although we did not know it at the time, chemists and biologists in Tokyo and Stanford, U.S.A., had already investigated a substance with exactly the required properties. This is the poison tetrodotoxin

0- Hd H OH1 HO 0~~~~~~ ~NH2~C

H2N -- NA Cl O H 2 NNH2 C I HN HO ~ ~ ~ ~Hf

(a) tetrodotoxin (b) saxitoxin

FIGURE 1. Structuro of (a) totrodotoxin and (b) saxitoxin; tetrodotoxin from Goto, Kishi, Takahashi & Hirata (i965), see also Woodward (I964); saxitoxin from Wong, Oesterlin & Rapoport (I 970I).

obtained from the Japanese puffer fish or from certain species of newts, which is now known to block the sodium channels in nerve at an exceedingly low concentration. Its structure, which was determined by Woodward (I964) and others is given in figure 1. The compound was made commercially available by the Sankyo Com- pany in Tokyo in 1965 and has proved a most useful tool in electrophysiology. Saxitoxin, a shellfish poison, which is made by the dinoflagellate Gonycaulax, and subsequently concentrated in mussels or clams, has similar pharmacological effects to tetrodotoxin but a different chemical structure. As can be seen from figure 1, one feature common to both compounds is the guanidiniuim group, of which there are one in tetrodotoxin and two in saxitoxin. This is interesting because guan- idinium is one of the quaternary nitrogen compounds which can pass through the sodium channel.

I have not time to give a systematic review of the properties of tetrodotoxin but felt you might be interested in the following brief notes on its history, which is ancient, as well as in some of its recent applications. According to C. Y. Kao (I966), one of the earliest references to the subject is in the first Chinese Pharma- copea, which was once attributed to the legendary Emperor Shun Nung in the third milleniuM B.C. Shun Nung was supposed to have tasted and described 365 drugs, among which tetrodon eggs were classified with the medium drugs that had some tonic effects but were toxic in excess. The Pharmacopea was in fact probably written in the first or second century B.c. but even so it is remarkable to find such an early reference to a recondite chemical.




Li Shi Chen's Pharmacopea which was published at the end of the sixteenth century recognized that the poison was confined to the liver and eggs but recommended tetrodon fish as a tonic to 'supplant inadequacies'. According to Kao this recommendation was sometimes interpreted in China and Japan as implying effectiveness in cases of sexual impotence. In spite of the Chinese saying 'To throw away life eat blowfish', puffer fish is regarded as a delicacy in Japan and can be safely eaten in properly licensed restaurants. The Royal Society delegation to Japan suffered no ill effects from eating it in 1970, though I must confess that I was too nervous to be properly appreciative. Previous Royal Society experience was less happy since Captain Cook and his naturalists J. R. and G. Forster were severely poisoned in 1774 and were probably lucky to survive.

After these historical references, which are all taken from Kao's excellent review, I shall return to the present day and describe one very interesting application of tetrodotoxin. This is to use tetrodotoxin to determine the density of the special 'gated' channels through which sodium ions enter the nerve membrane. The method which was introduced by Moore, Narahashi & Shaw (I967) and refined by Keynes, Ritchie & Rojas (I 97I ) is basically simple. As I have already mentioned, tetrodotoxin has a very high affinity for the sodium channels. When a small volume of a weak solution of tetrodotoxin is equilibrated with a nerve containing many small nerve fibres an appreciable amount of tetrodotoxin is bound by the nerve. The quantity bound can be estimated by assaying the solution after it has been in contact with a nerve. In this way one can estimate how many molecules of tetrodotoxin are required to block all the sodium channels in a given area of membrane. This number should be equal to the number of channels because the concentration-action relation indicates that one molecule of tetrodotoxin combines with each channel. As some tetrodotoxin may also be bound in an unspecific way the figure obtained is strictly an upper limit to the number of sites. However, the affinity of the compound for the sites is so high that the error introduced by unspecific binding may not be large. The result obtained in the three nerves which have been examined by this method are rabbit cervical vagus 75, crab leg nerve 49, and lobster leg nerve 36 sites per square micrometre (Keynes et al. 197I). From this result and the known sodium entry per impulse it follows that about 500 sodium ions pass through one channel during a single action potential.

Before leaving tetrodotoxin I should mention two interesting points about its specificity. The first is that although tetrodotoxin blocks both inward and outward movements of sodium through the sodium channel it is only effective when applied externally (Moore I965). The second is that nerves from animals which contain tetrodotoxin are resistant to the poison, the blocking dose in preparations from tetrodon fish or newts of the genus Taricha being 10000 to 30000 times higher than in frog nerve. On the other hand, these tetrodotoxin resistant tissues can be blocked by saxitoxin whose action is normally very similar to that of tetrodotoxin (Kao I966).




Giant nerve fibres In analysing the mechanism of nerve conduction physiologists and biophysicists

have been greatly helped by the existence of very large nerve fibres in certain animals, of which the squid is the most important example. It is arguable that the introduction of the squid giant nerve fibre by J. Z. Young in 1936 did more for axonology than any other single advance in technique during the last forty years. Indeed a distinguished neurophysiologist remarked recently at a congress dinner (not, I thought, with the utmost tact) 'It's the squid they really ought to give the Nobel Prize to. '

The giant nerve fibres from a large specimen of Loligo forbesi, which is fairly common off the British coast, are about 0.7 mm in diameter and 10 to 20 cm in length. With such a large cell it is possible to carry out many experiments which would not be feasible with preparations from conventional laboratory animals. As an example, I might menition the methods of perfusion or dialysis which enable the experimeter to control the composition of the solution inside the surface membrane. This technique has proved extremely useful both in testing the ionic theory of nervous conduction and in finding out how cells use metabolic energy to move ions against concentration gradients. The direction which future research may take is illustrated by a recent article by Rojas & Armstrong (197I). These authors showed that perfusion with the proteolytic enzyme pronase caused a characteristic change in the time course of the sodium permeability. Under normal conditions a step-depolarization leads to a transient increase in sodium permeability but after treatment with internal pronase the inactivation mechanism disappears and the increase in permeability lasts as long as the depolarization. Methods involving perfusion or injection have also been useful in showing up asymmetries in the membrane. Thus certain quaternary ammonium compounds block the potassium- gating mechanism in a characteristic way when applied internally but not externally, whereas tetrodotoxin, as I have mentioned, acts only on the outside.

From this brief review you can see that there are a large number of interesting experiments waiting to be done with giant nerve fibres. The problem is that such experiments usually have to be carried out at marine laboratories during the few months when squid come in-shore.

Some of the difficulties which face biologists interested in working on squid are illustrated by recent experience at Vifia del Mar in Chile. Here the cold Humboldt current sweeps for two thousand miles up the west coast of South America bring- ing the phosphate and other nutrient materials which sustain a great wealth of marine life. Near the end of the food chain is Do8idicus gigas, a large squid which feeds on the anchovetta that form the basis of the important fishing industry of Chile and Peru. Apart from their large diameter, nearly 1 mm, the fibres of Dosidicus are advantageous in that they run without branching for many centi- metres. This greatly simplifies dissection and provides neurophysiologists with an almost ideal preparation. Under the leadership of Professor M. Luxoro and




Professor E. Rojas the small marine station at Vifia del Mar was built up into a first class laboratory which was visited regularly by North American scientists, who helped to equip it and keep it in touch with recent development. There were set-backs, as when in 1968 the station was flooded by a tidal wave, but in general all went well until 1971. In that year and I believe also in 1972 Dosidicus disappeared completely from the in-shore waters where it had previously been caught on hook and line from small boats. One hopes that the squid will return or that they can be caught further from the shore by larger ships.

The cause of the sudden alteration in population is not known but it may be related to a phenomenon which has this year had devastating consequences for the fishing industry in Peru (Loftas I972). As I have mentioned, the great wealth of marine fauna off the coast of Chile and Peru is sustained by the nutrient material brought north in the cold Hurmboldt current. In Peru, fishing is one of the country's major industries and normally accounts for about 30 % of its exports, besides providing food for a substantial fraction of the population. However, in certain years, of which 1972 is unfortunately one, the Humboldt current is overpowered by a current of warm water flowing south from Ecuador. The warm-water con- dition, which is known as El Nifno, disrupts the normal food chain with disastrous results for the anchovetta and for the fishing industry. When faced with a calamity affecting the livelihood of a large number of people it seems absurd to bother with the disappearance of an unusual animal like Dosidicus in which a few academic scientists happen to be interested. However, it does not seem impossible that the two phenomena have a common origin and both serve to illustrate our ignorance about the dramatic changes in marine fauna which occur from time to time in all parts of the world.

In Europe squid have been studied at Plymouth and at certain Mediterranean laboratories such as Naples or Camogli near Genoa; there is also a station at Split in Jugoslavia which is occasionally used by scientists from the U.S.S.R. In the U.S.A. most of the work on squid is done at Woods Hole on Cape Cod or at Johns Hopkins University, Baltimore, where Dr L. J. Mullins's group manage to keep Loligo pealii alive in laboratory aquaria after transporting them 150 miles from Ocean City. Loligo opalescens on the West coast of the U.S.A. has been used occasionally but its fibres are too small for the more taxing experiments. Pollution has driven squid from Tokyo Bay but Doryteuthis bleekeri and Loligo edulis are available at Misaki and other marine stations in Japan.

After Viia del Mar in Chile or Pucasana, a small laboratory in Peru, both of which are temporarily out of action so far as squid are concerned, Plymouth probably provides squid with the largest nerve fibres. A counterbalancing advan- tage of the Mediterranean stations is that the squid at Naples or Camogli survive longer in aquaria than at Plymouth. This may be partly because the common Mediterranean species L. vulgaris is more robust than L. forbesi obtained at Ply- mouth. However, a more important reason is that capture by hook and line, which is possible in the Mediterranean, is less injurious than trawling which seems

2 VOL 183. B.




to be the only reliable method in the English Channel. Although the supply of squid at Plymouth is variable and is liable to be interrupted by gales during the late autumn months when squid are abundant, some work has been done there in every year since 1947. At its present size and fishing capacity the laboratory can probably accommodate 6-10 research workers during the squid season. In recent years about half the axonologists at Plymouth have come from this country and about half from overseas, some from as far away as Chile. The laboratory has so far not had to turn away any applications from axonologists but the demand for places would certainly be higher if the squid season were at a more convenient time for university scientists.

Squid provide other preparations which may become as important as the giant nlerve fibre. Examples are the retinal photoreceptors (Hagins I965) and the synapses in the stellate ganglion studied with such interesting results by Katz & Miledi (I967). For experiments oni synapses, small squid are better than large ones because it is easier to keep the ganglion oxygenated if the preparation is small. In an attempt to meet this demand, Plymouth have recently improved the supply of the small squid Alloteuthis which is common throughout most of the year in the English Channel. From the unpublished work of A. C. Crawford it seems that the ganglia of Alloteuthis may prove just as suitable for investigating synapse as those from Loligo vulgaris. I mention this point partly in the hope that it may tempt Katz and Miledi away from the joys of Naples and partly because the Ply- mouth laboratory is for once in the happy position of having a supply which exceeds the demand.

A European marine biological station with access to deep water

The interest of marine biologists is moving from in-shore shallow waters to the deeper parts of the ocean. Since much of Europe is surrounded by a continental shelf, deep-water animals can at present only be investigated by research vessels after a cruise of several hundred miles. This severely restricts the type of experimental work that can be done with deep water animals. For the future it seems worth while thinking of the possibility of a marine laboratory with ready access to deep water. A long length of coastline needs to be considered since there is as far as I am aware no major marine biological laboratory on the Atlantic coastline of Spain or Portugal. However, I have been told by marine biologists that there are strong arguments in favour of a site on the island of Madeira (which belongs to Portugal). One can see from a map that the sea bed falls away sharply off the coast and that it reaches a depth of 4000 m at a distance of about 70 km from the island. In addition to providing information about deep-water animals a station on Madeira, on which there is a good airport, might bring European biologists into contact with the extraordinarily rich fauna which abounds in that part of the ocean. This proposal has no official status whatsoever but I mention it here in case it may interest some of our European colleagues who are present on this occasion.




REFERENCES

Chavin, W. I972 Thyroid of the coelacanth Latimeria chalumnae (Smith). Nature, Lond. 239, 340-341.

Dartnall, H. J. A. I972 Visual pigment of the coelacanth. Nature, Lond. 239, 341-342. Goto, T., Kishi, T., Takahashi, S. & Hirata, Y. 1965 Tetrodotoxin 21. Tetrahedron 21,

2059-2088. Hagins, W. A. I965 Electrical signs of information flow in photoreceptors. Cold Spring

Harb. Symp. quaint. Biol. 30, 403-418. Hoyle, G. & Smyth, T. I963 Giant muscle fibres in a barnacle Balanus nubilis Darwin.

Science, N.Y. 139, 49-50. Jobsis, J. F. & O'Connor, M. J. I966 Calcium release and reabsorption in the sartorius

muscle of the toad. Biochem. biophys. Res. Commun. 25, 246-252. Kao, C. Y. I966 Tetrodotoxin, saxitoxin and their significance in the study of excitation

phenomena. Pharmacol. Rev. 18, 997-1049. Katz, B. & Miledi, R. I967 A study of synaptic transmission in the absence of nerve impulses.

J. Physiol., Lond. 203, 459-487. Keynes, R. D., Ritchie, J. M. & Rojas, E. I97i The binding of tetrodotoxin to nerve mem-

branes. J. Physiol., Lond. 213, 235-254. Loftas, T. 1972 Where have all the anchovetta gone? New Scient. 55, 583-586. Moore, J. W. I965 Voltage clamp studies on internally perfused axons. J. gen. Physiol. 48,

part 2, 11-17. Moore, J. W., Narahashi, T. & Shaw, T. I. I967 An upper limit to the number of channels in

nerve membrane. J. Physiol., Lond. 207, 529-537. Ridgway, E. B. & Ashley, C. C. I967 Calcium transients in single muscle fibres. Biochem.

biophys. Res. Commun. 29, 229-234. Rojas, E. & Armstrong, C. 197I Sodium conductance activation without inactivation in

pronase-perfused axons. Nature New Biol. 229, 177-178. Shimomura, O., Johnson, F. H. & Saiga, Y. I962 Extraction, purification and properties

of aequorin, a bioluminescent protein from the luminous hydromedusan Aequorea. J. cell comp. Phy8iol. 59, 223-239.

Wong, J. L., Oesterlin, R. & Rapoport, H. 197I The structure of saxitoxin. J. Am. chem. Soc. 93, 7344-7345.

Woodward, R. B. I964 Structure of tetrodotoxin. Pure appl. Chem. 9, 49-74. Young, J. Z. 1936 The giant nerve fibres and epistellar bodies of cephalopods. Q. Jl micro8c.

Sci. 78, 367-386.



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Address of the President Sir Alan Hodgkin at the Anniversary Meeting, 30 November 1972

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