Address of the President Professor A. L. Hodgkin at the Anniversary Meeting, 30 November 1971 Source: Proceedings of the Royal Society of London. Series A, Mathematical and Physical Sciences, Vol. 326, No. 1564 (Dec. 21, 1971), pp. v-xx Published by: The Royal Society Stable URL: http://www.jstor.org/stable/77901 . Accessed: 03/05/2014 10:37 Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at . http://www.jstor.org/page/info/about/policies/terms.jsp . JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact [email protected]. . The Royal Society is collaborating with JSTOR to digitize, preserve and extend access to Proceedings of the Royal Society of London. Series A, Mathematical and Physical Sciences. http://www.jstor.org This content downloaded from 130.132.123.28 on Sat, 3 May 2014 10:37:23 AM All use subject to JSTOR Terms and Conditions
Transcript
Address of the President Professor A. L. Hodgkin at the Anniversary Meeting, 30 November1971Source: Proceedings of the Royal Society of London. Series A, Mathematical and PhysicalSciences, Vol. 326, No. 1564 (Dec. 21, 1971), pp. v-xxPublished by: The Royal SocietyStable URL: http://www.jstor.org/stable/77901 .
Accessed: 03/05/2014 10:37
Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at .http://www.jstor.org/page/info/about/policies/terms.jsp
.JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range ofcontent in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new formsof scholarship. For more information about JSTOR, please contact [email protected].
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The COPLEY MEDAL is awarded to MR N. W. PIRIE, F.R.S. for his outstanding work on the nature of viruses. Pirie discovered the chemical composition of viruses and his work transformed ideas about their morphology and method of multiplica- tion. He was the first to show that nucleic acid is a necessary component of a virus and, at a time when tobacco mosaic virus was thought to be a crystalline globulin, 'he made liquid crystalline preparations of several strains which he correctly -identified as nucleoproteins containing 0.500 ribose nucleic acid. He then general- iized his discovery by isolating several other viruses, with widely different stabilities 'and other properties, in crystalline or liquid crystalline forms, and by showing that all contained nucleic acid, but in amounts and held in ways that differed charac- lteristically in different viruses. His work was the first to show that different viruses differed greatly in shape and that those with anisometric particles could change their length in vitro. X-ray crystallography applied to his preparations provided the first accurate information about the sizes of virus particles and first showed them to be composed of uniform subunits regularly arranged. Pirie also showed that nucleic acids could be much larger than generally thought, and the nethods he used to prepare them were among those used by later workers who s,howed that nucleic acid alone could be infective.
A ROYAL MEDAL is awarded to DR G. HERZBERG, F.R.S.
Dr Herzberg's work has covered a wide field but has involved primarily the application of spectroscopic methods to a great variety of problems of prime importance in physics, chemistry and astronomy. His work has been original, ingenious, versatile, and skilful in design of techniques for extending the range of application of spectroscopy. He was among the early workers in the application of maodern spectroscopic theory to the determination of the structure of simple dLiatomic and polyatomic molecules, and in the course of this work many founda- tions of the theory of molecular energy levels were tested and verified. He thus derived information not only about the molecular shapes and geometry, but also about the intricacies of molecular dynamics. His precise values for certain bond lengths were of great significance in connexion with the development of theories of valency.
a [ V ] VOI 326. A. (2I December I97I)
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He has also studied many forbidden transitions in the spectra of diatomic and polyatomic molecules. In recent years, by developing new experimental methods, he has measured spectra of free radicals. He has identified by laboratory investiga- tions several interstellar lines as being due to the species CH+ and has detected molecular hydrogen in the spectrum of Venus. He has measured the Lamb shift in the ground state of hydrogen, helium and Li+.
The five monographs which he has written on atomic and molecular spectroscopy have been, and are, of outstanding anid unique importance to all concerned with spectroscopy and its applications.
He holds a high place in Canadian science and has done much for its development.
A ROYAL MEDAL is awarded to DR M. F. PERUTZ, C.B.E., F.R.S.
The complete X-ray diffraction analysis of protein structures seemed hardly possible until, in 1953, Perutz showed how the phases of the X-ray reflexions from protein crystals could be determined by the method of multiple isomorphous replacement. The Fourier synthesis of images of protein molecules then became possible and this has led to the direct determination of a rapidly growing number of these structures and a dramatic increase in our understanding of their properties.
Perutz developed this method as part of his continuing study of haemoglobin and in 1959 he was able to determine the structure of this molecule in three dimensions. His papers in that year described the tetrameric molecule of horse haemoglobin as seen in an image at low resolution which revealed the close similarity between the individual subunits of haemoglobin and monomeric myoglobin molecules. Since 1960 Perutz has described in atomic detail the structures of horse and human haemoglobin in the oxygenated and deoxygenated states. These studies have explained many of the physiological properties of haemoglobin and they have enabled him recently to put forward a comprehensive hypothesis for its mechanism of action. This hypothesis shows how the electronic states of the iron atoms affect the conformation of the haemoglobin molecule and hence its physiological pro- perties. It is being refined in continuing structural studies of increasing precision hut its general features have gained wide acceptance and it clearly represents a major step forward in our understanding of biomolecular mechanisms, including those that are important in the control of metabolism.
A ROYAL MEDAL is awarded to DR P. E. KENT, F.R.S.
Dr Kent, who is Chief Geologist of British Petroleum Company Ltd, and whose career has been largely in the oil and gas industries, is one of the most outstanding applied geologists of our time. Successful integration of fundamental strati- graphical and structural geology with economic application has been the basis of his work. His many papers on Mesozoic stratigraphy and concealed structure in the East Midlands, and his structural contour map of the pre-Permian surface have greatly extended our knowledge of the geology of this country, and he has published substantial contributions on both detailed and broad problems on areas of East
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Anniversary Address by Professor A. L. Hodgkin vii
Africa, Iran, Papua and Canada, covering various geological topics including geo- morphology, stratigraphy, tectonics, age relationships and transport mechanism in rock falls.
Dr Kent has played a leading role in petroleum exploration in many parts of the world. He has had a large influence in the discovery of oil and gas fields in the North Sea and in making the scientific results generally available. The important part his geological insight played in the discovery of the Alaskan oil fields has recently been recognized by a major award from the MacRobert Trustees, designed to encourage scientific work leading to major economic benefit to Britain. Other awards include the Silver Star of Merit U.S.A., and the Bigsby and Murchison Medals of the Geological Society.
The DAVY MEDAL is awarded to PROFESSOR G. PORTER, F.R.S.
In the last two decades great advances have followed the development of methods of studying ultra-fast reactions. The technique of flash photolysis, in which a very brief illumination is used to perturb a chemical system and the induced changes are measured by optical spectroscopy, has been developed by George Porter so as to allow resolution of events occurring on a nanosecond time scale. He has applied it with imagination and flair to unravel some important chemical problems, prominent among which is the measurement of the spectra and reactivity of short-lived free radicals and electronically excited states of molecules. He has also deepened our knowledge of photophysical processes including the mechanism and rate of spin-forbidden intersystem crossing. In recent work he has applied this technique to biologically important molecules and there is real promise that he will make significant contributions to the understanding of vital processes such as photosynthesis, while continuing to extend our knowledge of reaction kinetics.
The HUGGHES MEDAL is awarded to PROFESSOR R. HANBURY BROWN, F.R.S.
Professor Hanbury Brown, besides his distinguished earlier work in radar and in iradioastronomy, developed a new type of interferometer for measuring the angular diameters of radio sources. In the course of applying the principles of this instru- ment to optical measurements, he demonstrated the existence of photon fluctua- tions in a beam of thermally generated light. He developed his new form of optical interferometer to measure the angular diameter of stars beyond the range of the classical work of Michelson, and in the last few years has been operating a large instrument in Australia. Of special interest are his observations on multiple stars, notably the binary stars y2 Velorum, where one of the components is a Wolf-Rayet star, and ac Virginis where one component appears to be a p-type Cepheid. By combining the interferometer observations with other data, he has shown that not only can many of the parameters of a non-eclipsing binary star be obtained, including the distance, but also that when such a binary contains an unusual com- ponent, such as a Wolf-Rayet or fl-type Cepheid star, valuable new information
a-2
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viii Anniversary Address by Professor A. L. Hodgkin
about these stars can be derived. The method offers more than a hope of checking the Cepheid distance scale.
The MULLARD MEDAL is awarded to DR F. R. BATCHELOR, MR F. P. DOYLE, DR J. H. C. NAYLER and DR G. N. ROLINSON, of Beecham Research Laboratories, Brockham Park, Betchworth, Surrey, in recognition of their contribution to the development of the semi-synthetic penicillins, one of the most significant advances in the chemotherapy of bacterial disease in the last decade. The main achievements were:
(1) The synthesis of the penicillinase-resistant penicillins, 2,6-dimethoxyphenyl- penicillin and the substituted isoxazolylpenicillins, which have brought the benzyl- penicillin-resistant, penicillinase-producing Staphylococcus aureus under control; before the existence of the penicillinase-resistant penicillins this micro-organism was the cause of many deaths.
(2) The synthesis of the broad-spectrum penicillins, a-aminobenzylpenicillin (ampicillin), and a-carboxybenzylpenicillin (carbenicillin). The former is active against the most important gram-negative pathogens, including E. coli, Salmon- ella typhi, Haermophilus influenzae, and many strains of Proteus mirabilis and vulgaris, as well as being active against the usual gram-positive bacteria. Carben- icillin, in addition to the above, is also active against many strains of Pseudomonas pyocyanea, against which no other non-toxic antibiotic is available and it is usually reserved for infections caused by this organism. These penicillins have rendered invaluable service in the clinical treatment of urinary, respiratory and gastro- intestinal infections, and Pseudomona,s septicaemias.
The development was not only of major scientific and clinical significance, but also of major economic importance. The total annual turnover of the new penicillins is well over ?120 million and the United Kingdom is at the spearhead of production and is earning many millions of pounds per annum in exports and royalties.
,8 * * * * *' * * * *
At the end of a year of office I can strongly endorse all that my predecessors have said about the admirable way in which Sir David Martin and his staff look after the interests of the Society. In passing I should mention that this is Sir David's twenty- fifth year as secretary and on this occasion I would like to record our appreciation of his long and devoted service.
The last year has been a busy one for the Society and I can mention only a few of the many things that have occupied us. Under the enthusiastic leadership of the Foreign Secretary, Sir Harold Thompson, we have continued our activities in the field of international scientific relations. The European scientific exchange pro- gramme, in which 15 other nations participate, has grown steadily since its inception in 1967. Last year nearly 300 scientists benefited from the scheme at a total cost to this country of about ?145 000. Over nearly five years more than 1100 scientists have benefited. We hope that the programme will continue to grow but that more emphasis will be placed on longer term visits and on extensions for a second year.
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In March we received a delegation from the Japan Academy and Science Council, and signed an agreement for exchanging scientists between our two countries. We have also had discussions with the Chinese Charge d'Affaires, and, with the genero-us support of the Leverhulme Trust, we hope to reopen scientific exchange with China in 1972. Our relations with Latin America are developing in a very satisfactory way and we now have exchange arrangements with Argentina, Brazil, Mexico and Venezuela. The exchange schemes with Israel continue successfully.
This is Sir Harold Thompson's last year as Foreign Secretary and I cannot let the occasion pass without paying tribute to all he has done for the Society and for international science. He must derive a good deal of satisfaction from the develop- ments which have taken place during his period of office. We thank him very much for all he has done and at the same time extend a warm welcome to his successor, Professor K. C. Dunham, the Director of the Institute of Geological Sciences. Geology is by nature international in outlook and Professor Dunham's wide experi- ence of international relations will be of great value to us.
As you can see from Council's report the Officers have spent a good deal of time in keeping in touch with academies and science councils in other countries. I have already mentioned our discussions with the Japanese. In London we have also had meetings with scientists from the Federal Republic of Germany, Sweden, Norway and Denmark, the Netherlands and Mexico, as well as with our opposite numbers in Canada, Australia and New Zealand. Away matches included a visit to the Indian National Science Academy in Delhi and to the National Academy of Sciences in Washington. During the course of these discussions we compared notes on the different methods of supporting science and of the changes that are likely to take place. I was interested to find that our system of independent research c-ouncils commanded a good deal of respect and that in some instances it had lbeen copied in a rather literal way. Of course there is a wide variation in the method of supporting civil science and one cannot argue that there is any single preferred type of organization. Nor is it right to adopt a complacent attitude to the existing organization of science in this country. Scientific research occupies an increasingly prominent place in government and it is necessary to ensure that the needs of (different ministries are met in the most effective manner. But when these qualifica- tions have been made I am left with the strong impression that any country which las a reasonably satisfactory method of supporting science should think very care- fully before dismantling it. A prolonged state of uncertainty, or a very radical change, seems to have deleterious effects on scientific activity that are not easily reversed. In my view our chartered research councils have a fine record in both pure and applied research. I would not wish to see them split up, or so hampered by contract-based research that they lose control of long-term planning. These are may personal conclusions but that they are not very different from those expressed in a memorandum which Council submitted to the Central Policy Review Staff.
Several Fellows of the Society have urged me to devote my Anniversary address to a discussion of the future of the research councils. Other have argued that this is
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too close to politics and that it would be wrong for the President to take any definite line on such a matter. The decision was taken out of my hands because until this morning I have not been able to discuss either the Rothschild or the Dainton reports with my Officers and Council; as you know these were published as a Green Paper on 24 November - and I first saw the Rothschild report on 23 November. The Secretary of State for Education and Science has invited the Royal Society to submit written comments on the Green Paper by next February. In 1963 when Sir Burke Trend conducted his inquiry into the organization of civil science the Royal Society was able to consult widely among the Fellowship before giving evidence. The situation today is rather different but we will do our best to obtain a representative selection of views. May I take the opportunity of encourag- ing Fellows to read the Green Paper (A Framework for Government Research and Development) and to send me their comments as soon as possible. Having said this much, it would be a mistake to give my own initial reactions to the new proposals and I shall say no more on the present occasion. The timing of events thus leaves me free to follow my own inclination which is to talk about some matter of scientific interest. You may feel that this is fiddling while Rome burns, but, if it does nothing else, my preference for a scientific discourse will show that I regard the improvement of natural knowledge as the central function of the Royal Society.
* * e * * * * e * *
Recent work on visual mechanisms I propose to devote the rest of my address to a brief survey of recent electro-
physiological work on visual mechanisms. I chose this field because it is the one in which I have been working lately with Dr Baylor and, on returning to it after an interval of ten years, I have been astonished at the way in which preconceived ideas about the retina have been modified by recent evidence. This quiet revolution has been brought out by extensions of existing techniques, rather than by any striking invention and this may be the reason why it has received relatively little attention.
Before attempting to discuss the electrical effects of light I must say something about the anatomical and chemical background. Figure 1 is a diagram, from Boycott & Dowling (I969) which shows the principal elements in the retina. The photosensitive pigment, rhodopsin, or its cone equivalent, is closely associated with the lipid membranes lining the densely packed sacs in the outer segment of the receptor.
Light produces electrical changes in the receptors which are conveyed by chemical transmitters to the bipolar cells and thence to the ganglion cells of the optic nerve fibres. On the way the information is modified by the horizontal cells and the amacrine cells. Nerve impulses first appear in the ganglion cells and amacrine cells but are absent elsewhere. Receptors, horizontal cells and bipolars give relatively slow, graded electrical signals which modulate the rate at which chemical transmitters are released at junctions. Horizontal cells and probably some receptors are connected laterally by electrical junctions.
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FiGuRE 1. Diagram of the principal elements in the primate retina. RI, rod; C, cone; MB, midget bipolar; FB, flat bipolar; H, horizontal cell; A, amacrine cell; MG, midget ganglion cell; DG, diffuse ganglion cell; ON, optic nerve fibres. (From Dowling & Boycott i966, with slight revision by Professor Boycott.)
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xii Anniversary Address by Professor A. L. Hodgkin
The rod pigment rhodopsin is a combination of a carotenoid, retinaldehyde, with a very insoluble protein, opsin of molecular mass 27 000. Light converts the bent 11-cis isomer of retinal into the straight all-trans form. After absorbing a photon, rhodopsin passes through a long sequence of stages distinguishable by their absorption spectra. Eventually the all-trans retinaldehyde is released, but this last reaction is slow and occurs long after the peak of the electrical change.
Cone pigments also probably contain the 1.1 -cis isomer of retinal but the protein is different from that in rhodopsin. There are three different cone pigments with absorption maxima in the red, green and blue. It has been shown by microspectro- photonmetry of single goldfish cones (Marks I965) as well as by electrical recording of cones (Tomita, Kaneko, Murakami & Pautler 1967) that these pigments are in separate cones. As table 1 shows, there is good agreemernt between the wavelength
TABLE 1. COMPARISON OF ABSORPTION MAXIMA DETERMINED ELECTROPHYSIO-
LOGICALLY BY TOMITA et al. (I967) WITH THOSE DETERMINED BY MICRO-
SPECTROPHOTOMETRY (MARKS I965) IN THE CONES OF CARP AND GOLDFISH
of peak spectral sensitivity and the absorption maximum. This provides a very satisfactory proof of the theory of trichromacy which Thomas Young advanced in his Bakerian lectures and Phil. Trans. articles in I802. In this connexion I might mention that Philosophical Transactions is still a force in the scientific world and I should like to congratulate editors and others on the superb quality of the illu- strations in two recent numbers which deal with the fine structure of the retina (Boycott & Dowling I969; Lasansky 197'). In reptiles and birds, cones contain coloured oil droplets which act as an additional filter. In the turtle these oil droplets appear red, yellow or nearly colourless as can be seen from figure 2, plate I, for which I am indebted to Dr Baylor and Dr Fuortes.
Since the late 1940s physiologists have been recording electrical changes across cell membranes with fine glass capillaries filled with a concentrated salt solution such as 3 molar potassium chloride or 4 molar potassium acetate. A typical elec- trode used for muscle has a tip diameter of about 0.3 ,m and a resistance of 10 M Q; the angle of taper near the tip is usually about 200. Such electrodes will not penetrate cells in the retina but successful recordings can be made with elec- trodes of resistance 150 to 300 M Q. These probably have a tip diameter well below 0.1 nm and a more gradual taper than the tradition:al type of microelectrode. Even so they do not penetrate receptors easily unless some kind of mechanical jolt or vibration is applied. Tomita and his colleagues in Tokyo who were the first to record systematically from cones, apply mechanical vibration to the stage on
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at the base of cones in the retina of the turtle (Pseudemys scripta elegans). (Magn. x ca. 500.)
e -.... .000.
P*s. 9*.*
FIGURE 3. Photomicrograpli of a section of the retina to shsow localization of electrode position by dye inj ection (from Baylor et al. 197 I). Procion Yellow was inj ected electrophoretically into a cell identified pliysiologically as a, cone. R, receptor layer; O, ouLter limiting membrane; D, oil droplet in inner segment of stained cone. (Magn. x 360). The outer segment of the cone is not seen; it may have broken off or been out of tlle plane of the section. The uise of tlhe Procion series of dyes was introduced by Dr Alvarez and Dr Furshpan in Dr Kuffler's laboratorzy (see Stretton & Krauvitz I968).
(Faccing p. xii)
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FiGURE 4. Bipolar cell of goldfish (Cyprio) injected with Procion Yellow. This cell had previously been identified a-s a bipolar cell of the off-centre on-surround type (called an N-bipolar on p. xix). (From Kaneko 1970.)
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Presidential Address Proc. R. Soc. Lond. Plate III
~~~~~'~~~~~~~~~*~~'
FIGURE 5. Photomicrograph of tangential section of dogfish retina showing two adjacent hiorizontal cells one of which had been injected with Procion Yellow and the other with Procion Brilliant Red. Some processes of each cell are missing becauise the section was slightly oblique. (From Kaneko 197 I-
w-_~~~~~~~~~~-
FicGURE 11. Electron mnicrograph from Lasansky (I 97 1) showing triad in a a cone pedicle of Pseudemys. (Magn. x 63000.) SL, synaptic lamella in cone pedicle; LP, lateral process from horizontal cell; CP, central process of triad - presumed part of bipolar cell by analogy with primate retina. Note that synaptic vesicles are present in the cone and in one latcral process.
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Anniversary Address by Professor A. L. Hodgkin xiii
which the retina is mounted. Baylor, Fuortes & O'Bryan (I971) achieve the same result by applying an oscillating voltage (which is probably associated with some mechanical vibration) to the electrode tip. An additional element in the technique is to use an animal with large rods or cones. Successful recordings from receptors have now been obtained in carp (Oikawa, Ogawa & Motokawa '959; Tomita I965),
nocturnal gecko (Toyoda, Nosaki & Tomita I969), Necturus (Bortoff I964; Werblin & Dowling I969; Toyoda et al. I969), turtle (Baylor & Fuortes 1970), bullfrog (Toyoda, Hashimoto, Anno & Tomita I960) and axolotl (Murakami & Pak I970).
Horizontal cells are easier to impale and records from these cells were obtained in 1953 by Svaetichin who at first took them for cones.
In a complex and condensed structure like the retina one may know that the electrode tip is in the vicinity of receptor cells but it is impossible to localize the impalement by direct observation with the microscope. However, what can be done is to inject a fluorescent dye through the electrode and identify the cell by subsequent histological examination. Figure 3, plate I, which was obtained by Baylor & Fuortes (1970) shows a t-urtle cone marked with Procion Yellow and figure 4, plate II, a goldfish bipolar cell marked with the same dye by Kaneko (1970). Figure 5, plate III, shows two adjoining horizontal cells marked by Kaneko (197I) with different dyes. This is a particularly interesting case since the author had previously established that the two cells were connected electrically. The experiment therefore proves that adjacent horizontal cells are coupled through junctions which allow ions to pass but restrict the diffusion of dyes with a molecular mass of about 500.
The procedure of dye-marking is exceedingly laborious but it need not be repeated on every occasion. The electrical response of cones, rods, horizontal cells and bipolars to flashes of light covering different areas on the retina are easily distinguished, and, once the hard work of marking has been done, one can usually tell in a few seconds which type of cell has been penetrated. The use of high resist- ance electrodes combined with the technique of dye-marking has thus transformed retinal electrophysiology into a much more precise subject than it was ten years ago.
Many invertebrates have photoreceptors which are larger and more easily impaled than those of vertebrates. By 1965 a number of different eyes had been studied and in nearly every case the general pattern was found to be the same. Light increased the conductivity of the cell membrane and depolarized the cell - -that is it made the inside of the cell less negative than in the resting condition. 'This is what one would expect since the photoreceptor is continuous with the nerve fibre. A positive-going signal (depolarization) is what is needed to activate nerve and one would expect light to set up a wave of this polarity in the receptor cell. It therefore came as a surprise to many of us when Tomita and others showed that in the receptors of vertebrates light decreased conductivity and made the inside of the cell more negative (Tomita I965; Toyoda et al. I969; Baylor & Fuortes I970). This breaks the general rule that stimulation depolarizes cells and increases conduct- ivity. You may feel that it is unreasonable of physiologists to be disturbed by a simple change of polarity or to think that the eyes of all animals should contain
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xiv Annivers3ary Address by Professor A. L. Hodgkin
the same basic mechanism. But there is rather more to it than that. Electrical changes in the nervous system are usually conveyed from one cell to the next by a mechanism which involves the release of a chemical transmitter. I know of no exceptions to the rule that transmitters are released by a positive-going change in the internal potential of the cell which contains them. It therefore seems necessary to suppose that the vertebrate rods and cones release transmitter continuously in the dark and that light suppresses this ionic release by making the inside of the cell negative (Trifonov, Chailahan & Byzov I971). The arrangement might have the advantage of spreading the total load on the metabolism of the receptors and adjacent cells. In the dark, ionic pumping and resynthesis of transmitter in receptors are maximal but there is no breakdown and hence no regeneration of
outside
1 El 1ER
inside FIGURE 6. Equivalent circuit of photoreceptor. The resistance RI increases with
light in vertebrates and decreases with light in invertebrates.
photopigment. In a bright light ionic pumping and resynthesis of transmitter are minimal and regeneration of photopigment is maximal. Load spreading of this kind might be important in a tissue in which a rich blood supply might interfere with good optical resolution. One can also argue that a dark object moving against a light background, is a more interesting stimulus than the converse. Physiologists and psychologists test the eye with flashing lights but these are not the natural stimuli which an animal encounters in its everyday life.
The electrical properties of both vertebrate and invertebrate receptors can be represented by the simple circuit diagram in figure 6. The resting potential is maintained by the battery Ep which in some cases can be identified with the e.m.f. of the potassium concentration difference. In parallel with this is the variable resistance R. which represents channels permeable to sodium and, to varying extents, to other ions. In most invertebrates light decreases RI and depolarizes the cell. In the vertebrate retina the receptors are depolarized in darkness to a level of about -25 mY because the sodium channels are all open. Light closes the channels and the cell interior goes negative to a maximum value of -60 mV. In a very elegant piece of research, fiagins, Penn & Yoshikami (1970) have provided evi- dence about the mechanism in more detail. They used external microelectrodes to map the distribution of current around rods in the rat's retina. Their experiments show that in the dark there is a continuously circulating current: positive current
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leaves the base of the cell, possibly carried outwards by potassium ions, and enters the rod outer segment where the pigment is contained; here sodium entry is probably the dominant mechanism. The cell is maintained in a steady state by metabolic pumping and runs down quickly if metabolism is inhibited with cyanide. Light reduces the standing current and hyperpolarizes the cell. When part of the outer segment is illuminated the change in current is confined to the region on which light falls.
The electrical signal produced by light has a remarkable wave form which will I think repay a detailed study. Figure 7, which is from Baylor et al. (I97I), shows the signals produced by turtle cones in response to 10 ms flashes varying in intensity over a 1000-fold range. Note that the response to strong light saturates when the potential has increased from -35 to -53 mV. This upper level corre-
light
-55t 0 0.2 s 0.4
FIGU:RE 7. Response of turtle cone to flashes of light of different intensity; the numbers on each curve give the logarithm to base 10 of the light intensity. The vertical scale gives the internal potential. (From Baylor et al. I97I.)
sponds to the potential at which the variable sodium conductance is almost completely suppressed; the potential then becomes equal to that of the battery ER.
A striking feature of all records of receptor potentials is that the response arises with a very marked delay; this is more clearly shown in figure 8 which is on a faster time scale. At low light intensities the response is directly proportional to the quantity of light and it then has a characteristic shape similar to that seen in the receptors of Limulus and other invertebrates. This raises the hope that the basic transduction mechanism may be similar throughout the animal kingdom, in spite of differences of polarity between vertebrates and invertebrates. Fuortes and I (i964) found that the linear responses of Limutlus receptors to a flash of light of intensity I and duration AXt could be fitted by
V/(IAt) = Kcntn-le-t, (1) where V is the change in internal potential, t is time, and K, ac, /? and n are con- stants. ac and , are rate constants and n is a number which may be said to deter- mine the order of the delay; it is about 10 in Limulus and 7 in turtle cones (Baylor et al. 1971).
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xvi Anniversary Address by Professor A. L. Hodgkin
A major problem confronting anyone who attempts to construct a model of a light receptor is to account for the changes in sensitivity which enable photo- receptors to deal with a wide range of light intensities. You are all familiar with the increase of sensitivity that occurs as the eye becomes adapted to darkness. From the work of Dowling (i960) and Rushton. (i96i) it is known that dark-adaptation is closely linked to the regeneration of rhodopsin from its bleached products. The opposite process, related to photolysis, which builds up under the influence of light and desensitizes the eye, may be called light-adaptation, though the word is not always used with this restricted meaning. There is another more rapid effect of light which is normally investigated by experiments of the increment-threshold type. As is well known, a flash of light is less easily seen when superposed on a
light
-10~~~~~~~~~~~-.
20
0 80 ms 160
FIGURE 8. Similar to figure 7 but on a faster time base. The vertical scale gives the displace- ment of the internal potential from its resting value. (From Baylor et al. I97I.)
steady background. This kind of desensitization which occurs almost immediately, and which disappears almost as soon as the background is switched off seems too rapid for a simple bleaching mechanism.
Some years ago Fuortes and I (I964) studied the changes in sensitivity that occur when the photoreceptors of Limulu8 are desensitized by bleaching or back- ground. We found that both acted in a similar way, the effect being to reduce amplitude and time scale. Although closely linked the two changes differed strikingly in magnitude. If the time constant of the response is halved the ampli- tude is reduced by 2n where n is between 7 and 10, so that halving the time scale is associated with a 100- to 1000-fold reduction in amplitude. This is consistent with equation (1) if bleaching or background increases /8 but has little effect on the other constants. Figure 9 illustrates one of these results.
Raising the temperature had quite a different effect to bleaching or background since it shortened the response to a flash and at the same time increased its ampli- tude (Borsellino, Fuortes & Smith I 965 ). The results are consistent with both ca and/8 having temperature coefficients (Q1o) of about 3 and would seem to eliminate aqueous diffusion as a likely cause of the long delay in the generator potential.
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Anniversary Address by Professor A. L. Hodgkin xvii
Baylor and I have recently been studying the behaviour of turtle cones and have found that here again bleaching and background act in rather similar ways, the effect in both cases being a decrease in the amplitude and time scale of the response. This helps to explain the familiar observation that time resolution improves as the light intensity increases. The result is also interesting because there has been a long debate as to whether changes in sensitivity occur in receptors or at some later stage in the retinal pathway. Our results show that there is a large effect at the receptor level but do not exclude neuronal changes later on.
In the final section of this review I should like to refer briefly to the part played by the horizontal cells and bipolar cells in the analysis of visual signals. To begin with I should mention some general points. A physicist or engineer might suppose
6 -
4-I
I ~~~~~~b .5~~~~~~~~~~~t
2 4
0 0.5 1.0 1.5 time after flash (s)
FIGURE 9. Effect of bleaching on response of Limulus ommatidium to flashes of duration 20ms (from Fuortes & Hodgkin I964). o, response of dark-adapted eye to 20 ms flash of intensity 0.008; ., response of light-adapted eye to flash of intensity 0.126 obtained 40s after 10 s exposure to light of intensity 1. Temperature, 6 'C. Curves a and b were calculated from equation (1) with / = 13 and 17.9 s- respectively; n was 11 and a and K were the same in both cases. Curve c is for a modified hypothesis in which the time scale of one stage of exponential delay did not alter.
that the function of the retina and optic nerve is to project a television picture on lto the brain. There are two objections to this notion. In the first place it does not r-eally solve anything because one needs to postulate a homunculus who observes the picture and issues appropriate orders to the motor side of the animal. The second drawback is that the idea corresponds very poorly to the facts. During the past twenty years it has become increasingly clear that the retina does a great deal of analysis on its own. In all retinas there are optic nerve fibres which act as con- trast detectors (Barlow I953; Kuffler I953) and in some animals there are fibres which respond specifically to objects moving in certain directions, others which are orientation specific, as well as edge detectors and uniformity detectors (Barlow, Hill & Levick i964; Levick, I965, I967). Of course the more elaborate analysis is
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xviii Anniversary Address by Professor A. L. Hodgkin
carried out in the cortex but one is at first surprised to find how nmuch goes on in the retina itself.
I do not propose to talk about anything as comnplicated as a movenment detector but I should like to refer to two relatively si'mple circuits which enable the eye to pick out white or black spots on a grey background. It is now clear that the initial part of the analysis is carried out at an early stage irn the passage of informatioln through the retina, and that it occurs in a efrcuit involving only cones, horizontal
o 0000 0 0 0 0 00 00 0 0 0
0 000 cone o
> X
bipolar
ThounE 10. Diagram of the junction in a conle pediele between conle, horizontal cell and biolar cell8 based onl the drawing biy Dowling &; Boycott (1966) representi:ng the connexions of a midget bipoar cell in primate fovea. Int most eases the situation is more complicated in t;hat5 bipola:r dendrites go toe several re eptors but the organization of the triad is similar. iFlatl bipolars make simple oo tact with the 00 e pedi le. The circles represent vesieles which probably contain transmitter.
cells and bipolar cells. Processes from these cells mzeet; in a triad t1 the base of the- cone (figure 10 and figure 11, plate III). Horizontal cells are electrically coupled together and :receive an inlp t from a large number of cones. Their intze nal potential at anly poinlt is determined by the light intensity avera ged ovrer a large area round that point. In the ease of a white spot on a grey surround the potential of a central horizontal cell is determined by the light; intensity of the surround and that of a cenztral cone by the light intensity of the c ntral spot. In tsh turtle eye the experi- ments of Baylor et at. (1971) suggest that trausmitters released by cones and horizontial cells couple these cells in the negat;ive-feedback loop? shown in figure 12. Here the cone signal is conveyed with the same polarity t-o the horizontal cell and is then fed back, in opposite polarity, to the cone. The bipolar process is strategically
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Anniversary Address by Professor A. L. Hodgkin xix
placed to respond to both cone and horizontal cell transmitters and Werblin & Dowling (I969) have shown that central and peripheral light acts in opposite direc- tions on the bipolar cell potential. They also established that there were two classes of bipolar cells which may be called N (negative-going) and P (positive-going). N-bipolars follow the cone potential and are made negative by central light; P-bipolars reverse the cone potential and are made positive by central light. In both cases the surround, working through the horizontal cells, has the opposite
cone
+
reduction in reduction ii _ horizontal cell in cone + .' transmitter transmitter
horizontal I x cell
N-bipolar
'FIGURE 12. Diagram showing possible mode of action of cone, horizontal cells and bipolar cell in turtle retina. For a circuit containing a P-bipolar the signs in the bipolar process should be reversed.
effect to that of central light. Thus the P-bipolar gives a positive signal to a white spot on a grey background and the N-bipolar a positive signal to a black spot on a grey background. A uniform field does relatively little to either class of cells. We do not know how the information in the bipolars is used later on in the retina] inetwork but there is little doubt that it provides the basis for the surround effects described many years ago by Dr H. Barlow (I953) and our new Foreign Member, Dr S. W. Kuffler (I953).
I am indebted to Dr D. A. Baylor for much helpful discussion.
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