The hallmark of the antibody response to antigenic challenge is its remarkable specificity. In his Croonian Lecture in 1905, Ehrlich recognized it as a biological puzzle, but considered it inconceivable that animals could produce substances capable of specific recognition of toxins that the species had never encountered before. It took the largest part of the following 70 years to begin to understand the chemical base of the biological puzzle. Even more recently, the genetic base of the underlying events has been clarified. Unique genetic rearrangements of the DNA initiate the biological diversity of somatic cells; this provides an initial source of antigen recognition. The remarkable specificity is the result of an antigen-driven Darwinian selection of proliferating clones, operating on further diversity that is generated by a high rate of point mutations in specific genes. Although the complexity of the biological events underlying the process remain largely unknown, the knowledge gained so far provides insights into alternative approaches to the production of new antibodies. Honoured President, my Lords, Ladies and Gentlemen: it is the very greatest honour for me that I have been summoned here by your most highly esteemed Society, which for more than two centuries has represented and still represents the centre of the scientific life of England, in order that I may deliver the Croonian Lecture.
In primates the retina is connected with different targets in the brain via several parallel pathways, the largest of which is that going to the lateral geniculate nucleus of the thalamus and thence to the striate cortex, the geniculo-striate pathway. When this route is damaged in man, apparent blindness in a corresponding part of the visual field occurs, despite the integrity of the other parallel pathways. In animals, it has been demonstrated by conventional behavioural forced-choice techniques that extrastriate routes can sustain a variety of visual discriminations. Comparable discriminations are also possible in some human subjects with geniculo-striate damage when forced-choice 'guessing' techniques are used. 'Blind-sight' refers to those subjects who state that they are unaware of the visual stimuli, even when performing discriminations at high levels of proficiency. Extensions of this approach are reviewed, especially to spectral sensitivity and movement discrimination. But residual capacities can also be assessed without requiring guessing responses, thereby avoiding issues of differential response criteria and other practical difficulties. Effects of 'unseen' stimuli in the cortically blind field on the visible perception of concurrent stimuli in the intact field can be measured. Also, positive reactions of the autonomic nervous system, such as the galvanic skin response, can be recorded to visual stimuli presented in the blind field. Recent evidence demonstrates that the pupil in normal adult subjects is systematically sensitive to structural and chromatic features of visual stimuli. Pupillometry reveals specific changes and residual capacities in visual-field defects of adult patients with striate cortical damage. Thus non-verbal and sensitive methods are available that permit the comparative study of normal and residual visual capacity in human infants, adults and infra-human animals.
Eggs of the ascidian Ciona intestinalis were loaded with the calcium indicator fura-2 via whole-cell clamp electrodes and changes in cytoplasmic calcium and cell currents were monitored during fertilization either in separate eggs or simultaneously in the same egg. The first indication of egg activation was the fertilization current; which reached peak values around 1 nA after 30 s. A wave of elevated calcium was detectable between 5 s and 30 s (mean = 21 s) after the start of the fertilization current. This wave spread across the egg increasing cytoplasmic calcium levels to at least 10 microM. When the fertilization current and calcium wave were complete and cytoplasmic calcium levels were decreasing to prefertilization levels, a cortical contraction wave spread across the egg surface. In eggs showing normal fertilization current, the calcium wave and the contraction wave were in the same direction. A region of elevated calcium persisted at the animal pole. Changing cytoplasmic calcium levels locally by local application of ionophore A23187 caused a contraction wave originating at the site of ionophore application. Increasing cytoplasmic calcium uniformly by facilitating calcium entry through voltage-regulated channels did not result in a contraction wave.
Human-like running is a natural dynamic mode of a simple mechanical biped. Such a machine consists of two telescoping legs with linear springs, connected by a hip joint with a torsional spring. It will run passively; no pattern of forcing is required to generate the gait. With careful design its energy consumption can approach zero, but in any case the passive cycle can be ‘pumped' by various means to sustain running over a range of speeds and slopes. Passive running can also be realized over a wide range of mechanical design parameters. Some parameter sets produce cycles that are inherently stable; otherwise the mode can be actively stabilized by a simple control law. Thus the passive running model offers an effective foundation for design of practical running machines, and also provides an insight into the physics of human locomotion.
Flukes of cetaceans are capable of absorbing energy from ocean waves for propulsion. The extent of this energy absorption is demonstrated by considering the flukes of an immature fin whale, Balaenoptera physalus . In a fully developed seaway corresponding to a wind speed of 20 knots (around Beaufort force 5) and at a low swimming speed, of 2.5 m s -1 , this whale was able to absorb up to 25% of its required propulsive power in head seas and 33% of propulsive power in following seas. Consequences of wave-energy absorption for energetics of cetacean migrations are discussed.
A brief introduction to the brain-mind problem leads on to a survey of the neuronal structure of the cerebral cortex. It is proposed that the basic receptive units are the bundles or clusters of apical dendrites of the pyramidal cells of laminae V and III-II as described by Fleischhauer and Peters and their associates. There are up to 100 apical dendrites in these receptive units, named dendrons. Each dendron would have an input of up to 100000 spine synapses. There are about 40 million dendrons in the human cerebral cortex. A study of the influence of mental events on the brain leads to the hypothesis that all mental events, the whole of the World 2 of Popper, are composed of mental units, each carrying its own characteristic mental experience. It is further proposed that each mental unit, named psychon, is uniquely linked to a dendron. So the mind-brain problem reduces to the interaction between a dendron and its psychon for all the 40 million linked units. In my 1986 paper ( Proc. R. Soc. Lond . B 227, 411-428) on the mind-brain problem, there was developed the concept that the operation of the synaptic microsites involved displacement of particles so small that they were within range of the uncertainty principle of Heisenberg. The psychon-dendron interaction provides a much improved basis for effective selection by a process analogous to a quantal probability field. In the fully developed hypothesis psychons act on dendrons in the whole world of conscious experiences and dendrons act on psychons in all perceptions and memories. It is shown how these interactions involve no violation of the conservation laws. There are great potentialities of these unitary concepts, for example as an explanation of the global nature of a visual experience from moment to moment. It would seem that there can be psychons not linked to dendrons, but only to other psychons, creating what we may call a psychon world.
Two types of bipolar cell in the Geoclemys reevesii retina were studied quantitatively by means of specific cell labelling with an indoleamine derivative (5, 6-dihydroxytryptamine, 5, 6-DHT), a nucleic acid stain (4, 6-diamidino-2-phenylindole, DAPI) and Lucifer yellow CH. Indoleamine-accumulating (IA ) bipolar cells were selectively labelled with 5, 6-DHT applied intraocularly. After the cells accumulated 5, 6-DHT, the indoleamine fluorescence was photoconverted to diaminobenzidine products to allow observation of morphological details. Close examination of many cells (cell number; n = 120) showed that the IA bipolar cells consist of a single morphological type whose axon collaterals ramify sublaminae 1, 4 and 5 respectively. This terminal branching pattern corresponds to cells that hyperpolarize when their receptive field centres are illuminated (Weiler 1981). The density of IA bipolar cells was highest in the visual streak (4130 cells mm -2 ) and lowest at the peripheral margin (1970 cells mm -2 ). By applying a small amount of DAPI to the eye, nuclei located in the most proximal row of the outer nuclear layer were labelled selectively. By using selective intracellular dye injection into DAPI-labelled cells under fluorescence microscope (Tauchi & Masland 1984, 1985), these cells were found to have Landolt’s clubs and single descending axons. Dye injections into more than fifty DAPI-labelled somata showed that they belonged exclusively to displaced bipolar cells. These comprised at least two subtypes that differ in the ramification pattern of their axon terminals within the inner plexiform layer: one was monostratified, whereas the other was bistratified. The displaced bipolar cell density was as high as 9400 cells mm -2 in the central retina, falling to 2000 cells mm -2 in the superior margin. In vitro Lucifer labelling revealed that the overall bipolar cell density in the central retina was as high as 39300 cells mm -2 . Both the conventionally located and displaced bipolar cells were included in this population. About 11% of the total bipolar cell population consisted of IA bipolar cells. Assuming that one half of the conventionally located bipolar cells are the centre-hyperpolarizing type, IA bipolar cells represent approximately 28% of the total. As displaced bipolar cells represent almost one quarter of the total bipolar population, the dislocation of their somata stands out morphologically, inviting investigation of possible functional correlates.
A series-parallel model of the kinetics of the voltage-gated sodium channel is described. It goes some way towards reconciling the time-courses of the gating and macroscopic sodium currents in the squid giant axon with the molecular structure of the channel.
Staining for motor endplates and chemical digestion of five major muscles of the domestic chicken shows that these confirm the short-fibre strap muscle paradigm. The individual fibres are spindle-shaped, terminating in gradually tapering ends. The motor endplates of the individual fibres align in cross-bands along the length of the fascicles. These bands are spaced much more tightly than are comparable bands in mammals; unlike the condition in mammals, many fibres are longer than twice the interband spacing. The spacings between bands differ by more than a factor of five along the length of each muscle. The proportions among bands remain relatively constant. These proportions are not affected by the degree of muscular contraction, nor do they change with ontogeny, suggesting that the arrangement is established before hatching.
Perceptual segregation of visual textures has been attributed to certain features ('textons') such as (elongated) blobs of given size and orientation, line crossings, and line ends. Differences in the spatial distribution of these features were assumed to be detected pre-attentively and to provide the instantaneous impression of segregating texture areas and of borders between them. This paper questions the validity of this general view and, in particular, the role of some of these features in texture discrimination. It is demonstrated that for some textons, perceptual segregation is independent of detection and discrimination of the texton itself. In addition, segregation can be strongly affected by positional or luminance jitter of texture elements or by other modifications that change the luminance distribution in the pattern but do not affect the supposed texton differences. From the textons reported in the literature, only differences in orientation were found to be fairly robust against such modifications.
In the receptor-transducer model of pharmacological agonism, rejection of the traditional assumption that receptor molecules are in vast excess of transducer molecules permits the receptors to become distributed among unbound, bound and complexed states. Under these conditions, agonist affinities are liable to be overestimated when the method of irreversible receptor antagonism is used. Graphical tests have been developed to detect distribution, and these were applied to experimental data from the interaction between 5-HT and phenoxybenzamine on aortic tissue. Significant receptor distribution was not detected by the method. However, in the model it was assumed that there was a linear relation between the concentration of ternary complex and pharmacological effect. If this relation was replaced with a saturable one the effect of receptor distribution would be masked. The implications for pharmacologists and medicinal chemists are discussed.
Voltage-activated currents were studied in whole-cell patch-clamped rat neocortical neurons growing in culture and treated with tunicamycin (TU), an inhibitor of protein N-glycosylation. The size of the Na + current decreased progressively in the presence of TU (1–2 μM). This decrease was faster in growing 5–14 day-old neurons (to ca . 40% of control after 24 hours of treatment) than in fully grown 20–40-day-old neurons (to ca . 40% of control after 68 hours of treatment). The fast transient K + current (A-current) was abolished, and the delayed rectifier K + current was markedly reduced by a 24 hour treatment with TU (1–2 μM) in growing neurons. In contrast, in fully grown neurons these currents were unaffected by the same TU treatment. The size of the Ca 2+ current was significantly reduced following a 24 hour treatment with TU (1–2 μM) in neurons at early stages of differentiation, but remained stable in 20–40-day-old neurons. It is concluded that protein glycosylation, presumably of the channel proteins themselves, is important for the functional expression of voltage-activated channels in embryonic cortical neurons during the early stages of cell growth in culture; the channels become less dependent on glycosylation in mature neurons.
Membrane currents were recorded in voltage-clamped oocytes of Xenopus laevis in response to voltage steps. We describe results obtained in oocytes obtained from one donor frog, which showed an unusually large outward current upon depolarization. Measurements of reversal potentials of tail currents in solutions of different K + concentration indicated that this current is carried largely by K + ions. It was strongly reduced by extracellular application of tetraethylammonium, though not by Ba 2+ or 4- aminopyridine. Removal of surrounding follicular cells did not reduce the K + current, indicating that it arises across the oocyte membrane proper. Activation of the K + conductance was first detected with depolarization to about –12 mV, increased with a limiting voltage sensitivity of 3 mV for an e-fold change in current, and was half-maximally activated at about +10 mV. The current rose following a single exponential timecourse after depolarization, with a time constant that shortened from about 400 ms at –10 mV to about 15 ms at +80 mV. During prolonged depolarization the current inactivated with a time constant of about 4 s, which did not alter greatly with potential. The K + current was independent of Ca 2+ , as it was not altered by addition of 10 mM Mn 2+ to the bathing medium, or by intracellular injection of EGTA. Noise analysis of K + current fluctuations indicated that the current is carried by channels with a unitary conductance of about 20 ps and a mean open lifetime of about 300 ms (at room temperature and potential of +10 to +20 mV).
ATP-sensitive K(+)-channel currents were recorded from isolated membrane patches and voltage-clamped CRI-G1 insulin-secreting cells. Internal Mg2+ ions inhibited ATP-K+ channels by a voltage-dependent block of the channel current and decrease of open-state probability. The run-down of ATP-K+ channel activity was also shown to be [Mg2+]i dependent, being almost abolished in Mg2(+)-free conditions. Substitution of Mn2+ for Mg2+ did not prevent run-down, nor did the presence of phosphate-donating nucleotides, a protease or phosphatase inhibitor or replacement of Cl- by gluconate.
The responses to local stimulation have been recorded from neurons in the intermediate part of the medial hyperstriatum ventrale (IMHV) of the domestic chick, by using an in vitro slice preparation. When the slice is bathed in gassed Krebs’ solution, a single stimulus evokes a short-lasting diphasic response. The first phase is negative and lasts some 3 ms, whereas the second, positive phase is often of lower amplitude and usually persists for about 15 ms. The first phase is little altered by perfusion with either Ca 2+ -free Krebs’ solution or Krebs’ solution containing a high concentration of Mg 2+ . In contrast, the second phase is abolished by these procedures. The post-synaptic phase is positive when it is recorded anywhere between 0.1-1.25 mm from the stimulated point; however, in the immediate vicinity (0.0- 0.1 mm) of the stimulating electrodes, the post-synaptic response is strongly negative. A pair of stimuli has to be separated by at least 10 s to guarantee complete recovery of excitability of the post-synaptic response. The recovery curve for this response shows a refractory period of some 5 ms, a peak of excitability at an interval of about 20 ms, and then a sharp trough of relative inexcitability at about 200 ms. The post-synaptic response is considerably reduced in magnitude and duration by the addition of AP-5 to the perfusion fluid; the remaining post-synaptic response is completely abolished by kynurenic acid. The addition of bicuculline methiodide in concentrations of at least 1 x 10 -6 M increases both the magnitude and duration of the second, positive phase of the response to single stimuli. This extended positive response (which may last from 500-800 ms) is abolished by perfusion with bicuculline dissolved in Ca 2+ -free Krebs’ solution. For the entire duration of the extended post-synaptic positive response produced by bicuculline, the irregular discharge of single neurons can be recorded. Like the post-synaptic positive response in Krebs’ solution, the much larger response produced by bicuculline shows a very localized negativity beneath the stimulating electrodes and displays an almost identical timecourse for the recovery of excitability following a single stimulus. The bicuculline induced positive response is also considerably reduced by the presence of AP-5; the addition of kynurenic acid abolishes the remaining post-synaptic response completely. A post-synaptic response, similar to that produced under bicuculline, can be produced by the addition of a maximally effective dose of d-tubocurarine. This response has the same pharmacological and electrophysiological properties as that produced under bicuculline, only differing in that a maximal response evoked in the presence of curare, can be increased in amplitude and duration by the addition of bicuculline, whereas a maximal bicuculline response is unaffected by the addition of curare.
If a single ion channel record is observed in which two ion channels are never simultaneously open, then it is often of interest to know whether the observations indeed arose from the activity of only one ion channel. This question can be answered if it is possible to calculate the distribution of the duration of runs of single openings in a membrane patch that contains two active channels. If the observed run of single openings is much longer than that expected for a patch with two channels it is likely that only one channel was active. An approximate method is presented for calculating the distribution of the duration of runs of single openings in a patch with two active channels; this method has the advantage that it can be calculated from observable quantities, and requires no knowledge of the details of the ion-channel mechanism or its rate constants. The accuracy of this approximation is tested by exact calculations of the properties of runs of single openings, and of single bursts, for two specific mechanisms and a large range of rate constants. The approximation is good in all cases in which openings occur singly, or in closely spaced bursts. If, as is common in practice, openings occur in clusters that are separated by long shut periods, then overlap of clusters from two different channels may be detected, if no double opening is produced, as a period in the middle of a cluster in which the probability of being open doubles. The results derived here can be applied to such a period to test whether it results from the simultaneous activity of two channels, rather than from a change in the properties of a single channel.
We describe a computer model that stimulates a combination of stabilizing and frequency-dependent selection acting on a quantitative character determined by several loci. The results correspond to many features of natural variations at both the phenotypic and genotypic levels. The model is robust, and its results are not strongly dependent either on the nature and shape of the function describing the stabilizing selection, or on the precise form of frequency dependence, except near the extrema. It suggests a mechanism for the maintenance of large amounts of variability, and shows a relation between population size and heterozygosity roughly corresponding to that found in nature. In this respect it is unlike the purely neutral model.
The visual system can extract information about shape from the pattern of light and dark surface shading on an object. Very little is known about how this is accomplished. We have used a learning algorithm to construct a neural network model that computes the principal curvatures and orientation of elliptic paraboloids independently of the illumination direction. Our chief finding is that receptive fields developed by units of such model network are surprisingly similar to some found in the visual cortex. It appears that neurons that can make use of the continuous gradations of shading have receptive fields similar to those previously interpreted as dealing with contours (i.e. 'bar' detectors or 'edge' detectors). This study illustrates the difficulty of deducing neuronal function within a network solely from receptive fields. It is also important to consider the pattern of connections a neuron makes with subsequent stages, which we call the 'projective field'.
Adopting principles learnt from insect vision we have constructed model of a general-purpose front-end visual system for motion detection that is designed to operate in parallel along each photoreceptor axis with only local connections. The model is also designed to assist electrophysiological analysis of visual processing because it puts the response to a moving scene into sets of template responses similar to the distribution of activity among different neurons. An earlier template model divided the visual image into the fields of adjacent receptors, measured as intensity or receptor modulation at small increments of time. As soon as we used this model with natural scenes, however, we found that we had to look at changes in intensity, not intensity itself. Running the new model also generated new insights into the effects of very fast motion, of blurring the image, and the value of lateral inhibition. We also experimented with ways of measuring the angular velocity of the image moving across the eye. The camera eye is moved at a known speed and the range to objects is calculated from the angular velocity of contrasts moving across the receptor array. The original template model is modified so that contrast is saturated in a new representation of the original image data. This reduces the 8-bit grey-scale image to a log, 3 = 1.6-bit image, which becomes the input to a look-up table of templates. The output consists of groups of responding templates in specific ratios that define the input features, and these ratios lead into types of invariance at a higher level of further logic. At any stage, there can be persistent parallel inputs from all earlier stages. This design would enable groups of templates to be tuned to different expected situations, such as different velocities, different directions and different types of edges.
A critical study has been made of the characteristics of the kinetic components of the sodium gating current in the squid giant axon, of which not less than five can be resolved. In addition to the principal fast component Ig2, there are two components of appreciable size that relax at an intermediate rate, Ig3 alpha and Ig 3 beta. Ig3 alpha has a fast rise, and is present over the whole range of negative test potentials. Ig3 beta is absent below -40 mV, exhibits a delayed onset and disappears on inactivation of the sodium system. There are also two smaller components, Ig1 and Ig4, with very fast and much slower relaxation time constants, respectively.
