peter christopher caldwell, 25 january 1927 - 7 june...

1927 - 7 June 1979Peter Christopher Caldwell, 25 January

E. J. Denton, F. R.S.

1981, 153-172, published 1 November271981 Biogr. Mems Fell. R. Soc.

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PETER CHRISTOPHER CALDWELL25 January 1927 — 7 June 1979

Elected F .R .S . 1975

By E. J, D e n t o n , F .R .S .

P e t e r C h r i s t o p h e r C a l d w e l l was born on 25 January 1927 in A ppleton (Cheshire) near W arrington (Lancashire). H is father’s family had lived in W arrington and the villages around this town for m any generations. Its m em bers were well respected but, unlike m ost of their neighbours, they held firm to the Rom an Catholic faith during and after the Reform ation. Because of this steadfastness they had not only been subjected to heavy fines but, since the two universities and m any professions were closed to tjiem,*they had made their careers in business. Peter, and this Christian nam e appears tim e and tim e again in the history of the Caldwells, was proud of his family’s industrial achievem ents and, for example, the fact that ‘Caldwells’ had m anufactured m any of the shovels used to dig the canals and construct the railways of Britain. P eter’s great-great- grandfather, another Peter and the founder of the firm, lost an arm in an industrial accident and, in 1780, used the com pensation paid to him to set up a forge. A remarkably resourceful m an he continued, w ith an artificial arm, to play the violin in a local string quartet.

T h e family of P eter’s m other, D r M argaret Joyce W arburton, also came from the north-w est of England. H er grandfather, Thom as Hall, was the co-founder of M onks Hall & Co. L td of W arrington (later part of the British Steel Corporation), and, through one branch of his m other’s family, he was related to D. J. Finney, F .R .S . She was an early woman medical student in M anchester and am used Peter by saying how unim pressed she had been by the privilege of seeing the apparatus used by R utherford for studying artificially produced nuclear disintegrations.

W hen a child Peter Caldwell’s individual character was a focus of his fam ily’s affectionate pride and, sometimes, am usem ent. H is interests w ere num erous and ardently pursued and some enthusiasm s of his childhood were m aintained through his life. One, for steamships, was formed when he was very young by the sight of vessels steam ing through the fields near home— along the M anchester Ship Canal. He then jum ped

153



154 Biographical Memoirs

with such uncontrolled excitem ent that his N anny smacked him hard and fastened him firmly into his pram . U ndiscouraged he followed through his life the movem ents of the great ships of the w orld across the oceans and made detailed models of the ones that m ost attracted him.

W hen he was seven years old his family moved to N orth Wales and it was am ong the Clwyd Hills that he developed a passion for natural history. A country walk w ith Peter Caldwell was always a very slow affair because he found som ething to investigate w ith almost every stride. H e became an expert on butterflies and when only about eleven he designed and carried out a population and m igration study by m arking cabbage whites w ith coloured spots. These, when released, perplexed some local experts. M uch later in Septem ber 1962 he was delighted to capture, w ith a hat in Plymstock (South Devon), a specim en of the N orth A m erican Com m on Eastern swallow tail butterfly Papilio asterias w hich it seems had never been seen before in the south-w est or, indeed, anywhere in Britain. It was an instructive measure of his enthusiasm and persistence to follow his efforts to see w hether or not this was a genuine m igrant.

T he religion of P eter’s family determ ined the choice of his public school. T he Caldwells had strong links w ith the Benedictines. For generations m em bers of his family had entered this order as monks, and the Roman Catholic parishes around W arrington were run by the Benedictines. So, in 1940, he was sent to A m pleforth in the N orth Riding of Yorkshire where he proved a fine general scholar. Tw o fields, in which he showed marked ability from an early age, m usic and science, held the best prom ise of a career and Peter Caldwell found the decision between them difficult. He was greatly helped in his dilem m a by a very gifted schoolmaster, Dick G oodm an, who was one of the people who m ost shaped P eter’s life. He made Peter realize that science could be great fun as well as a stern intellectual discipline and persuaded him that it was m uch easier for a scientist to have music as a hobby than for a m usician to have science as a hobby. M r G oodm an not only gave Peter Caldwell an excellent training for the Oxford Scholarship Exam ination bu t because Cyril H inshelwood was T rin ity College’s wartim e tu to r in chem istry, he made sure that this college was P eter’s first choice. T rin ity College in tu rn did m ore than ju st accept Caldwell; he was made a M illard Scholar.

Those meeting Peter Caldwell for the first time were struck by his exceptionally gentle and kindly face. T h is first im pression was streng thened by closer acquaintance. T here are people who cause, or encourage, trouble and seek always to accentuate differences. T here is a larger group whose m em bers find themselves, m ore or less unwillingly, draw n to either one side or the other in any conflict taking place around them. Peter Caldwell belonged to a group of rare people who naturally remain outside quarrels; it would irfdeed have seemed wrong to try and involve him in the kinds of personality problem s which arise in m ost com m unities. T his detachm ent did not arise from a lack of interest in the



Peter Christopher Caldwell 155

relationships of those around him bu t from other people recognizing in him a com plete absence of quarrelsom eness and a dedication to intellectual activities. In a sim ilar way he was am bitious to make im portan t scientific discoveries b u t being w ithout envy he had a ready pleasure in the successes of others. As a rule he was som ewhat absent m inded, being abstracted in thought over some scientific, m usical or oenological p ro blem , bu t he was very entertaining com pany w hen relaxed. H e had the engaging habit of posing a question or problem on one occasion and then on m eeting you, perhaps three m onths or a year later, giving the answer w ith his first words and not quite understanding that you had not been continuously engaged in finding an answer.

In his physical m ovem ents Caldwell com bined a relative clumsiness in some large m ovem ents (this m ade him rather poor at some games, e.g. football) w ith an exceptional steadiness and skill for other m ovem ents w hich enabled him to carry m anipulations through by hand for which his colleagues needed m icropositioners. T h is also m eant, to everyone’s surprise, that he was particularly good at shooting.

Caldwell’s main academic interests outside science lay in music and his colleagues in the D epartm ent of M usic at Bristol U niversity found that he possessed analytical knowledge which, in its detailed understanding, was that expected of a professional musician and a teacher of music. H e played the piano skilfully and he was the author of a num ber of com positions including 30 piano sonatas. He m uch enjoyed asking m em bers of the m usic departm ent to nam e the com poser of a M ozartian pastiche and after a series of guesses being able to reply ‘Caldwell’. P eter’s special delight lay in the music of Schubert—partly because of its tunefulness bu t also perhaps, as D r A drian Beaum ont has suggested, because he so m uch enjoyed Schubert’s ability to take a them e and then ‘work it o u t’ w ith great com pleteness. Like others before him he had the am bition to know how Schubert had m eant to finish the famous 8th sym phony and he worked hard to trace M ozart’s last clarinet concerto.

Science, music, ships and butterflies were by no means all of P eter’s interests. He enjoyed fine claret, had a very good eye for a bargain, and understood the provenance and virtues of the wines he bought. It was indeed very sad after his death to find his notes on wine saying, for example, ‘not to be opened before 1983’. He had also, at one period, an enthusiasm for stocks and shares and his room in the P lym outh L aboratory then contained innum erable back issues of The Financial Times. T here was even one copy protecting the bench under his dissecting microscope so that his friends could tease him for ‘trying to read between the lines’. H ere again, his interests were (partly) intellectual ones, he was not content to speculate bu t always searched for logical reasons behind market movements.

M usic helped to bring Peter Caldwell and Phoebe-A nn H ill together. Miss H ill was the daughter of a distinguished airm an, A ir Chief M arshal




Sir Roderic Hill, who was, at the tim e of their meeting, the Rector of Im perial College, London. One evening in 1952 while walking from the Botany D epartm ent of U niversity College L ondon past the Slade she heard someone playing the piano in such an attractive way that she decided to listen more closely to the concert tha t she im agined to be taking place. T o her surprise she found Peter Caldwell playing alone. T hey soon became friends and after a little while everyone at U niversity College, apart from Peter, knew that he would m arry Phoebe-A nn. A natural modesty prevented him thinking that he had a chance w ith this talented and very attractive girl.

Phoebe-A nn and Peter were m arried in 1955. T heirs was a very happy m arriage with five children, their twins H elen and M argaret and Philip, A nn and Thom as. T heir final home, W hite Oak House, Nailsea, a small farm with many buildings, allowed Peter to follow another hobby, that of rearing livestock and it was not unknow n for there to be goose eggs incubating in the kitchen, the newly hatched in the hall, and large goslings outside the front door. He claimed to have devised a technique that greatly increased success in hatching eggs. Like m any others who shared the Caldwells’ hospitality, I still rem em ber Peter best in the setting of the happiness of his life w ith Phoebe-A nn in a hom e of com peting and, to Peter, com pelling interests.

Oxford, 1945-50

Following graduation in the H onours School of N atural Science Peter Caldwell stayed in Oxford to work in the Physical Chem ical Laboratory with Professor C. N. (later Sir Cyril) Hinshelwood. In 1937 Professor Hinshelwood had extended his studies on chemical kinetics to bacteria. He had quickly realized that although bacterial behaviour was very m uch more complex than, for example, that of the grow th of polym er molecules, there were very striking simple facts to explain. How could bacterial cells grow in very simple m edia at well-defined rates and compensate for changes in these rates produced by changes in the media, including the addition of inhibiting substances, and how could they synthesize all the complex com ponents of their structure? At about the time that Caldwell began his studies Brachet (1944) and Caspersson (1947) suggested that there was a very intim ate connection between RN A and protein synthesis and Caldwell decided to survey the phosphorus metabolism of Bacterium lactisaerogenes and find how the am ounts of thevarious phosphorus com pounds changed with changes in the buffered media in which the bacteria were grown and with the state of the culture. His experiments, some w ith E. L. M akor and Sir Cyril H inshelwood, gave clear results. D uring the logarithm ic grow th phase of a culture the assimilation of phosphorus was autocatalytic and could be described by the simple relationship dX/d t = K % where X was the am ount of




phosphorus w hich had been assimilated and K g the grow th constant of the cells. T h e rate of grow th of the cells was not affected by lowering the phosphate concentrations even down to the lowest level at w hich it was analytically m easurable (then about 10_ 6 m ). If grow th was stopped by breakdow n of the buffer or by exhaustion of the phosphorus in the m edium , then, ju s t before grow th stopped, there was a m arked drop in the am ounts of ribose-3-phosphate and purine nucleotides containing ribose-3-phosphate, bu t the am ounts per cell of nucleic acids rem ained constant. If the bacteria were grown in the presence of m-cresol they form ed filaments of abnorm al length w hich contained sm aller cells than usual yet the content of D N A per cell had the usual value. F rom their investigations it followed tha t under varying conditions of grow th the average am ount of D N A per cell was constant and that bacteria were in this respect sim ilar to the nucleated cells of higher organism s. T hey drew the general conclusion that the duplication of the deoxyribose structure m ight be one of the principal factors controlling cell division. T h e ir studies, w hich also showed tha t there existed an approxim ately linear relation between the am ount of RN A per cell and the rate of grow th of the cells, strongly supporting the view that RN A was intim ately concerned in the synthesis of protein.

In Caldwell’s D .Phil. thesis, and a subsequent publication by Caldwell and H inshelwood, a strikingly original idea was advanced. An analogy was draw n between autosynthesis in bacteria and crystal grow th and the hypotheses advanced that ‘in the synthesis of protein, the nucleic acid by a process analogous to crystallisation, guides the order in w hich the various am ino-acids are laid down, w hilst in the form ation of nucleic acid the converse holds’. These hypotheses led to a molecular interpretation of the process of form ation of protein. F rom A stbury’s observation (1947) that the spacing between the residues in a polypeptide is approxim ately equal to that in a nucleic acid the suggestion was made that there was a correspondence between the two kinds of polym er (protein and nucleic acid). Taking the num ber of basic units in a nucleic acid as five (two pyrim idine nucleotides, two purine nucleotides and a ribose phosphate) Caldwell and Hinshelw ood (1950) suggested that, in the synthesis of a protein, the am ino-acid side chain guided into a particular place depends on the nature and relative positions of two adjacent nucleotide units. W ith five such basic units, 25 different inter-nucleotide arrangem ents were possible. T h is num ber corresponded well w ith the num ber of different possibilities in a chain. In this scheme ribose phosphate alone (i.e. w ithout a base) was considered as a possible fifth ‘le tter’ needed to make a doublet code work. At the time that it was made this assum ption was reasonable since the best nucleic acid analyses suggested that the total ribose acid was more than the total purine and pyrim idine bases.

In the account of their work, Caldwell and H inshelwood also wrote: ‘T he specificity of a protein molecule m ust involve the arrangem ent of




am ino-acids in the peptide chain [it has been ascribed by Pauling {Endeavour 1948, 7, 43) to the folding of the chain and since this is probably governed by the arrangem ent of am ino-acids in the molecule— in particular by the relative positions of polyfunctional am ino-acids capable of form ing cross-linkages—these two views are equivalent]’.

W e now know that some of these ideas were wrong. In particular that of protein molecules governing the order in w hich different nucleotide units are arranged in a nucleic acid and the use of a doublet rather than a trip let code. T he central ideas, of a coded nucleic acid w hich specified a sequence of amino acids in a protein and that the folding of the protein w ould follow from the sequence, were however brilliant ones.

An exam ination of the draft of Caldwell’s D .Phil. thesis shows that although Hinshelwood made a num ber of corrections and suggestions to the thesis those pages dealing w ith the coding hypothesis were left virtually unchanged. Caldwell had, moreover, discussed this hypothesis at a meeting of the Oxford U niversity Alembic C lub in N ovem ber 1949 at which he gave a lecture on ‘Nucleic acids and auto-synthesis’. G reat credit m ust be given to him and to H inshelw ood for the first clear discussion of the ‘coding’ problem .

Following the successful conclusion of his D .Phil. studies, Caldwell left Oxford in 1950 to spend the next five years at U niversity College London. He joined the Biophysics Research TLJnit which Professor A. V. Hill, its founder, had built up again after the war and w hich was entering a second outstanding period of scientific achievem ent. Caldwell was at first an H onorary Research Assistant, then an I.C .I. Research Fellow (1951-54) and, from 1954 to 1955, an Assistant L ecturer in the D epartm ent of Biophysics form ed under Professor (later Sir Bernard) K atz when H ill retired.

U nder A. V. H ill a great deal had been discovered about the energetics of muscle. A. V. him self had concentrated m ainly on m easurem ents of mechanical movements and of heat production. Against the high sensitivity of heat m easurem ents—the tem perature rise of about 3 x 10 _ 3 K in a single tw itch of a frog’s muscle could be m easured quite easily— certain knowledge of chemical events in contraction was meagre. A t an earlier tim e it had been thought that the im m ediate sources of chemical energy for contraction were glycogen and creatine phosphate bu t by 1950 the critical role that adenosine triphosphate (A TP) was likely to play had been recognized. I t was known, for example from the work of Engelhardt and Ljubimowa, that the main structural protein of muscle, myosin, is an enzyme able to split A TP. In 1950 H ill pointed out, however, that ‘No certain evidence exists that any of the chemical changes at present known or believed to take place as a result of m uscular activity occur otherwisethan in recovery___’ W ith H ill’s encouragem ent Caldwell was the first tomake quantitative determ inations of organic phosphate com pounds by paper chrom atography. He found that if there were any changes in A T P




and A D P (adenosine diphosphate) concentrations in muscle on contraction these m ust be very small indeed. A T P is now known to be the im m ediate energy source for m uscular contraction bu t although it does break down to A D P this com pound is rapidly reform ed into A T P at the expense of creatine phosphate. Changes in A T P were later found by R. E. Davies who poisoned muscle so that the re-synthesis to A T P from creatine phosphate was com pletely prevented.

So far Caldwell’s work had been that of a chem ist who had stopped living processes at tim es of in terest and analysed extracts of cells. H e now began to work on the pH inside living cells, an im portan t subject on a num ber of distinguished scientists had worked. By making an im portan t technical advance, using his new m ethod on im portant cells, and w riting a fine review, Caldwell was to make a m ajor contribution to this field.

Before 1950 a variety of m ethods, all w ith serious lim itations, had been adopted to estim ate intracellular pH . Caldwell successfully developed a glass pH electrode small enough to be inserted into the giant axon of the squid and the large m uscle cells of crustaceans. T he preparation of these electrodes, w hich dem anded ingenuity and great m anipulative skill, m arked an im portan t advance and his studies were the forerunners of m any others w hich depended on m icroelectrodes fashioned from various ion-selective glasses. A t first Caldwell worked on muscle preparations from specimens of Carcinus maenas (diam eters of single fibres about 600 pm), later in the course of his work he discovered that the leg muscles of M ata squinado consisted of very large fibres (1-2 m m in diam eter).

T h e theories on intracellular pH were divided into two groups. One was based on the D onnan equilibrium and pH thought to be that expected under conditions of therm odynam ic equilibrium if hydrogen ions were free to move to all parts of the cell and the surrounding m edium bu t certain o ther ions were not free. T he same answer would be given if both the undissociated form and the corresponding acid (HA) or a base (BH) were free to move. In the special case of H + , O H - and H C O J ions we would have[H + extracellular] [O H " intracellular] _ [H C O J intracellular][H + intracellular] [O H - extracellular] [HCO3 extracellular]

It was thought that the D onnan equilibrium did apply to potassium so that if it applied to hydrogen ion too a consequence would be that

[H + extracellular] _ [ K + extracellular][H + intracellular] [K + intracellular]

T h e second group of theories involved the active transport of hydrogen ions at the expense of m etabolic energy.

Some authors, notably Boyle and Conway (1941), held that both equations applied to muscle whilst others, including Fenn and Cobb



(1934), had advanced reasons against (1) being true of muscle. I t was always, of course, possible that there was an uneven distribu tion of ions w ithin regions and subcellular com ponents of cells and Caldwell discusses some consequences of heterogeneity in cells.

A lthough tungsten m icro-electrodes did not give consistent and reliable determ inations of pH , Caldwell showed that his glass micro electrodes could be trusted. W ith these electrodes he was able to give very clear answers on intracellular pH for muscle and nerve fibres. In neither of these cells was the pH determ ined by the D onnan equilibrium . O n the few occasions when the internal pH was that expected on the basis of the D onnan theory the fibres had been exposed to such severe conditions that they showed serious signs of deterioration. F rom his experim ents Caldwell concluded that in vivo the internal pH of nerve and muscle fibres is probably regulated by an internal carbon dioxide-bicarbonate buffer system responding to the external carbon dioxide tension and the active extrusion of hydrogen ions.


P l y m o u t h , 1955-60

In 1955 Caldwell became a Beit M em orial Fellow and moved to the M arine Biological A ssociation’s (M .B.A.) Laboratory on Citadel H ill, Plym outh. Later, in 1957, he was awarded a Royal Society research appointm ent and became the Alan Johnston, Lawrence and M oseley Research Fellow.

T he move to Plym outh was not a surprising one. T he relations between the biophysicists at U niversity College and the Association were close ones and A. V. H ill held very strongly that the best way to give a young physicist or chem ist an understanding of, and a feeling for, biology was for him to be exposed to the im m ense variety of biological material to be found in a m arine station.

U ntil 1933 (when J. Z. Y oung dem onstrated that the giant nerve fibres of squid were exceptionally favourable m aterial for physiological studies) the high speed of nervous reactions, the m inute quantities of material involved and the small diam eters of m ost nerve fibres had proved formidable barriers to advances in our knowledge of the processes involved in the transm ission of nerve impulses. Since that date great advances had been made particularly by work in P lym outh and in the M arine Biological Laboratory, W oods Hole, Mass., U .S.A . In Plym outh, Caldwell was naturally attracted by the work being carried out there by very distinguished visiting scientists, including A. L. H odgkin and R. D . Keynes, who spent every autum n at the M .B.A. working on the giant nerve fibre of the squid Loligo forbesi.During his five years in Plym outh, he generally divided his year between work on squid giant nerve fibres




during the ‘squid season* (Septem ber-January) and work on the very large muscle fibres of crabs during the rest of the year.

In muscle, energy for contraction is derived im m ediately from the breakdow n of high energy com pounds bu t in nerve the im m ediate energy needed for the transm ission of nerve im pulses is that stored in large concentration differences of ions between the inside of a nerve axon and its surrounding m edium . O f particular im portance is the fact that the concentration of sodium ions is very low inside an axon and high in the m edium w hilst the reverse holds for potassium ions. In a series of brilliant researches on crab and squid nerves, A. L. H odgkin, A. F. Huxley, B. K atz, R. D. Keynes and their colleagues showed that, w ith each nerve im pulse, some sodium ions enter the axon (3-4 x 10-12 m per nerve im pulse per square centim etre of nerve m em brane surface) and that this influx of sodium ions is m atched by a corresponding bu t slightly delayed efflux of potassium ions. T he m ain m ovem ents of electrical charges characterizing the nerve im pulse can be explained in term s of the movem ents of these ions. A consequence of this process is that, if acting alone, the transm ission of nerve im pulses would gradually abolish the concentration differences on w hich they depend. I t followed that another m echanism (or m echanisms) m ust exist to m aintain the concentration differences of ions between axon and m edium and, since the nerve m em brane was known to be relatively perm eable to potassium , interest centred on the active extrusion of sodium ions from the axon against a concentration gradient and in the m echanism — a sodium pum p— which this process required. Caldwell devoted m uch effort to finding the source of energy for the sodium pum p.

By the tim e Caldwell w ent to Plym outh H odgkin and Keynes had shown that certain metabolic inhibitors such as cyanide and 2,4 dinitro- phenol (D N P) reduced the active outflow of sodium ions from giant axons to a low value. T he effect was, to a substantial degree, reversible. Caldwell studied the effects of these substances on possible energy sources for the sodium pum p. He started in 1955 by making chrom atographic estimations of the A T P , arginine phosphate and orthophosphate on single squid giant axons— the first determ inations of these com pounds in single cells. He did not confine his chrom atography to these substances and, in the course of his work, he devised a new m ethod. H e showed that a num ber of substances, difficult to locate because there was no simple spraying agent, could be detected by a process of differential charring. T he chrom atogram s were held over a heated surface and m any of the regions where substances were present charred m ore rapidly than did the rest of the paper. In the absence of inhibitors the three main phosphate fractions found in the axoplasm of squid axons were orthophosphate, A T P and arginine phosphate. W hen axons were im mersed in sea w ater containing cyanide (2 x 10“ 3m) or D N P (2 x 10~4 m , pH 6.5-6.8) there were marked reductions in their content of A T P and arginine phosphate.




Since these changes ran parallel w ith the changes found earlier for sodium efflux this suggested tha t A T P and arginine phosphate m ight play some part in the active transport of sodium.

Following this Caldwell and Keynes joined in a fruitful collaborative study. Among other findings was the fact that ouabain, a cardiac glycoside of plant origin, in low concentration (10 ~ 5 m in the sea w ater in w hich the axon was bathed), had no significant effect on the levels of A T P and arginine phosphate inside axons yet it caused a sharp drop in the efflux of sodium. T hey began experim ents in w hich small quantities of likely sources of m etabolic energy and inhibitors of m etabolism were injected into giant axons w ith the m icrosyringe invented by H odgkin and Keynes. In this work, in the course of which they gave the first direct proof that A T P was the source of energy for the sodium pum p, they were later joined by A. L. H odgkin and T . I. Shaw.

It was already known from work by H odgkin and Keynes that one of the properties of the ion transport system in squid nerve fibres is that the outflow of sodium ions is reduced to about one quarter by rem oving potassium ions from the external m edium . It was necessary, therefore, to consider the sodium pum p(s) as having a K + dependent com ponent and a K + independent com ponent. T he experim ents of Caldwell, Hodgkin, Keynes and Shaw gave support to the view that m etabolism drives the sodium pum p by generating high-energy phosphate bonds carried to the axon m em brane by substances like A T P and arginine phosphate. T hey found, for example, that injection of arginine phosphate, A T P , or substances which m ight provide a supply of A T P at the m em brane, increased N a + efflux while injection of other related substances, e.g. creatine phosphate or adenosine m onophosphate (AM P), was ineffective.

Arginine phosphate and A T P did not, however, act in precisely the same way. T he N a + effluxes resulting from injection of A T P differed from the normal efflux in that they were not reduced by removing external potassium , w hilst the N a+ effluxes resulting from injections of arginine phosphate resem bled norm al effluxes in being substantially reduced when external potassium was removed. A nother difference was found by Caldwell working alone. He discovered that if axons were placed in sea water of pH 8 their content of arginine phosphate was greatly reduced whilst that of A T P was scarcely affected. D espite the low value of arginine phosphate the efflux of sodium rem ained close to its norm al value.

T he two sides of the nerve m em brane were clearly very different w ith respect to the sodium pum p. T he external application of A T P and arginine phosphate was ineffective in restoring N a efflux to poisoned axons whilst equally ineffective was the internal application of ouabain in concentrations of around 10- 3 m , i.e. one hundred times that which substantially reduced Na efflux when applied externally. T h is was the first example of a spatially orientated enzyme showing different sensitivities to inhibition on its two sides.




T h e discoveries of Caldwell and his colleagues com plem ented those of Skou (1951) who dem onstrated A TPase activity in particles derived from crab nerve and showed tha t this activity was enhanced by sodium ions and enhanced even fu rther by potassium ions and sodium ions in com bination. T hese are properties expected for a coupled sodium —potassium pum p system if the energy for the transfer of sodium and potassium across the system is provided by the hydrolysis of A TP; this hydrolysis taking place only if sodium and potassium are available to move across the system.

Caldwell, H odgkin, Keynes and Shaw (1960) made fu rther attem pts to unravel the com plicated relations between the sodium pum p, its possible sources of energy and various m etabolic inhibiting systems. T hey found an unexpected connection betw een the degree of inhibition of the m etabolism and the coupling between the sodium efflux and the potassium influx. In one experim ent after the efflux of sodium had been greatly reduced by rem oving potassium , this efflux was found to increase sharply w hen cyanide was added. T h is increase was transient reaching its peak in about half an hour. I t was not affected by potassium concentration and it corresponded to a stage at w hich A T P was still present in the axon whereas m ost of the arginine phosphate had broken down.

T h e work in Plym outh on nerve fibres was accompanied by studies by other groups on other cells, particularly on red blood cells, and a very considerable variety of inform ation on sodium pum ps appeared in the 1950s and 1960s. Caldwell gave a good deal of thought to these data. L ater in 1970 while in Bristol he gave his conclusions and speculations in a very careful and thoughtful review w hich form ed chapter 11 of a book on Membrane and ion transport (edited by E. E. Bittar). In this review he critically discusses the various models which had been advanced to explain sodium /potassium transport across m em branes, including one of his own.

Caldwell’s scheme was a modification of one suggested by T . I. Shaw. T h is was based on the hypothesis that there were in the nerve m em brane interconvertible com pounds X and Y having the properties that X could com bine specifically w ith potassium and Y w ith sodium. T o pum p sodium in exchange for potassium , X was converted to Y on the inside surface of the m em brane and Y converted to X on the outside of the m em brane and the ion carrier diffused backwards and forwards across the m em brane. Caldwell had to explain among other results: the relation (given by Caldwell and Schirm er, 1965) between the free energy available and the reduction of sodium efflux when potassium is removed from the bathing m edium; the evidence obtained by P. F. Baker and T . I. Shaw that, in squid axons, three sodium ions are transported per A T P split; and the actions of various inhibitors (some of these are described above). He suggested that.free energy from A T P is made available inside the m em brane and this is divided into three subunits of energy which were applied to the conversion of free sodium carrier to free potassium carrier on the outside of the m em brane.




T his could be brought about by the form ation of a high energy interm ediate in the m em brane that gave rise to three molecules of another interm ediate on the outside of the m em brane. T h e breakdow n of the la tter w ould then be coupled to the conversion of Y to X on the outside of the m em brane. H e recognized that one intellectual difficulty of schemes such as his own was the idea that a com paratively large ion-carrier complex could diffuse across a m em brane 5-10 nm thick . T h is difficulty did not exist in some other m odels w here the transport system was regarded as lying across the m em brane and capable of existing in different configurations w ith varying affinities for ions. T h is m eant that only the ions m oved across the m em brane and not the molecules com posing the transport system. Caldwell kept an open m ind on this problem , pointing out that some substances, e.g. valinom ycin, owed their antibiotic properties to an ability to increase the penetration of m em branes by certain ions. He noted that if the molecules involved in sodium /potassium transport were similar in structure to these antibiotics this would give a reason for the apparent linkage of the transport of certain amino acids to the sodium ion concentration gradient across cell m em branes.

B r i s t o l , 1960-79

In 1960 Caldwell moved to the U niversity of Bristol to become a lecturer in the D epartm ent of Zoology. He proved a valuable m em ber of this large and famous departm ent, finding num erous opportunities to help his students and colleagues from his wide knowledge of physical chem istry, physiology and certain aspects of natural history. At first he was only an indifferent lecturer to large classes of elem entary students, finding difficulty in simplifying argum ents and in avoiding m entioning every m ental reservation. Later, w ith m ore experience, he became a lucid speaker on general topics. F rom the very beginning of his lectureship he proved, however, to have a gift for teaching advanced and interested students, especially those who were lucky enough to be trained by him in research. In what sometimes proved a difficult period for the D epartm ent of Zoology, Peter Caldwell was always a conciliatory influence and he m aintained everyone’s affectionate respect at times when there were serious divisions among staff m em bers. For his scholarly contribution to the life of the U niversity and his scientific distinction he was prom oted to a readership in 1966 and to a personal chair in 1978.

Perhaps as a consequence of becom ing a university teacher Caldwell devoted a good deal of his tim e to w riting scientific reviews, including those on ‘the factors governing m ovem ents and distribu tion of inorganic ions in nerve and m uscle’ (1968); on ‘liquid junction potentials and their effect on potential m easurem ents in biological system s’ (1968); on ‘models for sodium /potassium transpo rt’ (1970); and (with C. C. Ashley)




on ‘calcium m ovem ents in relation to contraction’ (1974). Since these were m uch 'm ore than com pilations of references, discussed difficult and controversial problem s and also contained original ideas, they represented an enorm ous effort. T hey are widely appreciated as substantial contributions to knowledge.

T hroughou t the whole of his career in Bristol Peter Caldwell m aintained strong links w ith the M .B .A .’s laboratory in P lym outh, spending m any weeks there almost every year and serving as an elected m em ber of the A ssociation’s governing Council.

W hen not busy w ith squid nerve fibres Caldwell continued his work on muscle. W ith G. W alster he evolved the first successful techniques for the cannulation of a giant fibre from a crustacean muscle. Caldwell and W alster used M aia squinado bu t these techniques were subsequently copied by a num ber of scientists usually using the very large muscle fibres found in giant barnacles. In his experim ents on pH Caldwell had introduced his electrode into the side of a muscle fibre, a m ethod unsatisfactory for m easurem ents which lasted m ore than 15 m in since retraction and clotting started at the point of entry and spread gradually down the fibre. H is new m ethod involved cannulation of a single muscle fibre and a longitudinal insertion of m icro-electrodes and m icroinjectors. T h is procedure allowed experim ents lasting 2-3 h and a num ber of very interesting observations were made.

It was thought that the effect of a m em brane depolarization spread down the sarcoplasmic tubular system causing the release of ionized calcium which activated the contraction and the A TPase of the acto- myosin system. Relaxation was produced by the removal of ionized calcium perhaps by a special soluble relaxing factor. Consequences of these hypotheses were that contractions independent of m em brane depolarization should be given by the injection of calcium ions and that the tim e to relaxation should increase with the injection of increasing am ounts of calcium. Caldwell and W alster’s experim ent substantiated both of these predictions. W ith H. Portzehl and J. C. Ruegg, Caldwell made another im portant advance concerning the calcium in intact muscle fibres. T hey were the first to perform experim ents w ith calcium buffers based on E G T A (ethyleneglycolbis(|3 am inoethyl ether)iV,iV,Ar' -te traacetate), a substance later employed very widely. T his substance has only a small affinity for m agnesium and neither magnesium nor the levels of sodium and potassium were expected to have any marked effect on the Ca^ + concentration given by the calcium -E G T A complex. T he question to which they addressed themselves was: what is the threshold level of calcium ions needed for contraction and hence what is the upper lim it for the level of ionized calcium in resting muscle? T he values found for the threshold were between 0.3 and 1.5 jx m . T his was the first direct evidence that the ionized calcium in cells is 0.3 p.M or less. T his concentration was close to that found by Hasselbach and M akinose at about the same time




for the level of ionized calcium at w hich isolated m yofibrils split A T P . In isolated muscle systems the same authors found that particles derived from the sarcoplasm ic reticulum could reduce the concentration of calcium ions to 10~7—10~8 m . Portzehl, Caldwell and Riiegg thought it likely tha t relaxation, following the contractions produced by the in jection of calcium -containing solutions into M aia m uscle, was due to the accum ulation of this calcium in the sarcoplasm ic reticulum .

Caldwell was greatly interested in the action of caffeine on muscle. W ith W alster he had found that caffeine injected into M aia muscle caused contractions w hich were independent of changes in m em brane potential. In general he favoured F ran k ’s (1962) view tha t caffeine caused contractions by displacing bound calcium from binding sites inside the muscle. In work done w ith C. C. Ashley the effects of E G T A and E D T A injected w ith the caffeine were studied and in general they found tha t bo th substances could suppress the contractions produced by injected caffeine.

I t seemed reasonable to suppose that, if contraction involved the release of ionized calcium into the sarcoplasm of m uscle and relaxation its removal, there m ight be an increased exchange of calcium between muscle fibres and the ir surroundings during contraction. Caldw ell’s cannulated Maia m uscle fibre was an excellent preparation to test this prediction. W ith A. G. Lowe he showed tha t if 45Ca was injected as 40 m M C aC l2 the contraction of about 2 m in was accom panied by a rapid loss of 45Ca. T h e rate of 45Ca loss then fell to a low value from w hich it could be greatly increased by m aking the m uscle contract again the 2 m M caffeine.

In Bristol Caldwell gave a great deal of tim e and care to the work of a succession of Ph .D . students including C. C. Ashley, Alison Brading and C. Ellory. All made significant contributions to knowledge and all have continued to play notable roles in the fields of work to w hich Caldwell introduced them . M ost of Caldw ell’s experim ents were m ade on m arine invertebrates; exceptions were those on the somatic m uscle cells of the roundw orm Ascaris lumbricoides w hich is found in pigs. T hese cells tu rned out to be surprisingly different from m ost excitable tissues. W ith Alison Brading, Caldwell showed, in 1964, tha t the resting electrical potential between the inside of the cell and the surrounding m edium was rem arkably insensitive to changes in this m edium . T h u s in m edia w ith com positions based on Ascaris haem olym ph the resting potential of about 30 mV only decreased by 1.5 m V when the potassium concentration in the m edium was increased tenfold (in m ost excitable tissues such a change in potassium would cause a decrease of 40-50 mV). T h e resting potential was somewhat m ore sensitive to changes in chloride bu t even so is only changed by 13 mV for a tenfold change in this anion.

At first Brading and Caldwell favoured an explanation of the ir results w hich depended on changes in the perm eability of the muscle m em brane




counteracting the effects of changes in ionic concentrations. In 1964 de Castillo, de M ello and M orales gave another explanation w hich depended on the operation of a sodium ion electrical shunt. N either of these hypotheses fitted later work by Caldwell and Ellory on m em brane perm eability. In 1968 Brading and Caldwell analysed the results obtained on Ascaris in term s of the G oldm an constant field equation and decided that these could not be explained sim ply by the contributions of sodium, potassium and chloride to the resting potential and that there m ust be another factor probably representing an electrogenic ion transport m echanism. In support of this idea they noted tha t there are large carboxylic acid fluxes across the Ascaris muscle m em brane. T hey also found that GABA (y-am inobutyric acid) had m uch greater effects on the com ponents representing the unknow n factor in the G oldm an equation than on the com ponents representing potassium and chloride.

A fter taking his Ph .D . in Bristol w ith Peter Caldwell, C. C. Ashley w ent to the U .S .A . and w ith E. B. Ridgeway developed a very sensitive m ethod, using the photoprotein aequorin, extracted from the jellyfish Aequorea, to follow rapid changes in ionized calcium changes inside single crustacean muscle fibres. T hey showed, for example, that ionized calcium is released into the sarcoplasm of muscle in a tetanus and apparently removed from the sarcoplasm w ithin 1 m in of stopping stim ulation. R eturning to Bristol, to work on a grant awarded by the M .R .C . to Caldwell, Ashley carried out work which gave m uch of our basic knowledge of the detailed calcium changes during contraction and relaxation. In 1972 Caldwell, Ashley and Lowe brought th<sir various skills together to work on the efflux of calcium from single crab and barnacle muscle fibres. T hey found that contractions caused by electrical stim ulation, by injection of non-radioactive C aC l2, by caffeine and by im m ersing fibres in high potassium solution were all associated w ith m arked increases in 45Ca efflux. T he results obtained w ith E G T A were especially interesting. In the am ounts used the concentration of calcium ions should have been lowered to about one-hundredth , i.e. to about 1 nM, bu t the efflux of calcium was, cut by no m ore than to one-half. T he explanation of this small change probably lay on a com pensating release of calcium ions from the sarcoplasmic reticulum to bring the concentration back to a value of about O.ljtM. Evidence that such a release takes place was given by Ashley from work with aequorin. T he behaviour of the calcium efflux from Balanus and Maia muscle fibres injected w ith E G T A was in m arked contrast to that from squid giant axons. In such axons Blaustein and H odgkin (1969) had shown that the injection of E G T A in similar concentrations to that used by Caldwell and his colleagues lowered the rate constant some hundred times from its resting value, a result suggesting that, relative to muscle, there is little readily releasable calcium in nerves.

In 1974 Caldwell, w ith Ashley, reviewed the work to that date on




calcium movem ents in relation to contraction. T h e rapid advances m ade possible by using Caldwell’s techniques for handling single m uscle fibres together w ith those devised by Ashley and his colleagues using aequorin are very striking ones and, for example, a detailed analyses of the tim e course and m agnitude of the calcium changes in relation to isom etric tension response had become possible.

In the early 1970s, alongside his continuing work in phosphorus com pounds and calcium, Caldwell began to study the m ovem ents of amino acids into single nerve cells. A t first he used m ethods developed by others— com paring isotope uptake into paired axons w hich had been treated differently. T h is had the serious lim itation tha t it yielded only one or two m easurem ents per experim ent. In 1973, w ith T . J. Lea, he devised a new and powerful technique. He showed that if a small, 100—200 pM, glass fibre scintillator was inserted longitudinally into an axon in the same way as was com monly done w ith capillary electrodes then 14C disin tegrations in the axoplasm in the im m ediate vicinity of the scintillator could be m easured. T he technique was also applied to the uptake of calcium as 45Ca in crustacean muscle fibres.

In their experim ents on giant axons Caldwell and Lea carefully validated their new m ethod. T hey showed that there was close agreem ent between the influx rates obtained w ith their internal scintillator and those obtained by counting the activity of extruded axoplasm. T hey concluded that the d istribution of the [14C] am ino acids in the axoplasm m ust have been almost uniform and that, if appreciable am ounts had been taken up by the surrounding Schwann cells, these m ust have been beyond the range of the scintillator. T heir results on glycine and glutam ate uptake showed that this did not take place by any one m echanism . It had been strongly suspected that the uptake of am ino acids w ould be m ediated by transport systems which form ed part of the sodium pum p so special attention was given to the action of the inhibitor ouabain. Caldwell and Lea found that, in contrast to the rapid inhibition of the sodium efflux given by ouabain (discussed earlier by Caldwell and Keynes), the inhibition of glutam ate and glycine influxes only became apparent after a delay. For glutam ate the influx rem ained norm al for 40-50 m in after the application of ouabain. Sim ilar effects were found w ith glycine bu t the influx of this amino acid had a substantial ouabain-insensitive com ponent. Caldwell and Lea also found that the glycine influx was not normally sensitive to the replacem ent of extracellular sodium w ith choline. T hey concluded that at least a substantial part of the uptake of glycine and glutam ate is m ediated by transport systems w hich do not form part of the sodium pum p m echanism and do not depend on sodium gradients. T his was a useful finding since it was known that amino acid transport systems in other tissues are sodium dependent.

Tow ards the end of his life Caldwell became interested in using the large cells of invertebrates as models to study special problem s relating to




nervous disorders. One of his last published works was (with N . D. G oldstuck) on the uptake by squid axons of delta-am inolaevulinic acid w hich is produced in greatly increased am ounts during the acute phase of hepatic porphyrias. H e also paid special attention to the consequences of replacing sodium by lith ium in physiological m edia because dosing w ith lith ium was thought to be helpful in some nervous disorders.

W orking successfully in an im portan t field of physiology Peter Caldwell was increasingly asked to give invited lectures at international scientific m eetings and his authoritative and thoughtfu l lectures, like his reviews, were greatly appreciated. H is national and international repu ta tion securely based on deep knowledge and achievem ent grew steadily and in 1975 he was elected F .R .S ., a distinction w hich he valued m ore than any other.

Early in 1977 Caldwell suffered a serious heart attack and was unconscious in hospital for three days. H e m ade a good recovery and re tu rned to work bu t had another attack and died on 7 June 1979.

Peter Caldwell was a quiet b u t convinced Rom an Catholic and his strong religious sense gave him com fort in the last two years of his life w hen he was very ill. D uring this period he never ceased to plan new experim ents and had, for example, high hopes for his recently developed m ethod of using scintillators inside living cells.

I am greatly indebted to M rs Phoebe-A nn Caldwell for very helpful inform ation and to Professor R. D. Keynes, F .R .S ., and D r Q. Bone who critically read my m anuscript and gave me their com m ents.

T h e photograph is by G. A rgent.

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J . Physiol., Lond. 301, 401-413.




peter christopher caldwell, 25 january 1927 - 7 june...

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