conferring of the fellowship of the royal college of physicians of ireland upon professor edward...

T H E I R I S H J O U R N A L M E D I C A L S C I E N C E

THE OFFICIAL JOURNAL OF THE ROYAL ACADEMY OF MEDICINE IN IRELAND.

OF

S]XTH SERIES. No. 310. OCTOBER, 1951.

CONFERRING OF THE FELLOWSHIP OF THE ROYAL COLLEGE OF PHYSICIANS OF IRELAND UPON PROFESSOR EDWARD CONWAY, F.R.S.

T H E Fellowship of the R.C.P.I. (Hon. c~usa) was conferred upon Prof. E. J. Conway, F.R.S., at a special meeting of the College, on June 14th, 1951, the President of the College, Prof. L.

Abrahamson, in the Chair. 'Dr. Conway was introduced by the General Secretary, Dr. T. P. C. Kirkpatrick, in the following terms :

MR. PRESIDENT, LADIES AND GENTLElVIEN~ I have the honour to present to you one who, in this College, needs

no formal introduction. Professor Edward Joseph Conway is an alumnus of our National University, and Professor of Biochemistry and Phar- macology in University College, Dublin.

Mindful of the words of the poet t ha t " Study is like heaven's glorious sun that will not be deep-searched with saucy looks ", in place of "saucy looks" Professor Conway has delved deeply into the chemistry of our bodies, and the drugs we use for its cure. He has made clear the almost mystic relations of those important but elusive ions of sodium and potassium. To the study of these difficult matters he has brought a wide learning, an almost infinite patience and a brilliant imagination.

By this work he has won high honour. He is a Doctor of Science of his University, a Professor in its Medical School, a Fellow of the Royal Society and a writer of high repute. We are proud to welcome him as an Honorary Fellow of our College, and I ask you to testify to that welcome with your loudest plaudits.

After the conferring, Prof. Conway delivered his Address on

SCIENCE AND THE PHYSICIAN. I. Introduction.

Medicine is not only a science in itself, combining practice and theory, but, historically speaking, it is a mother of sciences.

From its earliest associations with the University it has been linked with the development of chemistry and biology.

The University itself began in the need that was felt for schools of higher studies or Faculties of Theology, Law and Medicine. One of the earliest, that of Padua, was for centuries the leading centre in Europe of medical teaching and research. I t is noteworthy that William Harvey studied there for some years (as did Copernicus and Galileo), bringing later to a masterly synthesis the concept of the circulation of the blood. This was already advanced some distance by Italian workers, notably Colombo, Cesalpino and Fabrieius.

The discovery of the general circulation of the blood with the pumping

442 IRISH JOURNAL OF MEDICAL SCIENCE

out of blood through the arteries and the return through the veins constituting one instead of two separate systems, as visualised by Galen, and the recognition of the significance of the pulmonary system marks not only the real beginning of a scientific physiology (or at least, of the physiology of the modern period), but it is an outstanding example to all later workers how the seemingly obvious can be missed; how in science, as in other matters, there may exist a climate of opinion which characterises an age or a period.

In Harvey 's day that opinion derived from the observations and con- clusions of Galen and his Greek school, based on numerous dissections and his great authority in medical science extending over fourteen centuries.

In later ages, some, and perhaps much of what we accept today may appear, if not false, at least oddly out of focus in a world system.

It may be of interest to note here that Galen, born in Pergamum in the year A.D. 130, wrote numerous works on medicine and lectured in Rome between the years A.D. 162 and A.D. 200. Attending such lectures and demonstrations were representatives of the patrician families, rulers of consular and even Imperial rank, if one includes Severus, later to be Emperor. (One reads with some regret that Marcus Aurelius sought to conscript Galen for service in his German wars.) Thus eighteen centuries ago medical research flourished in Rome.

As to the historical relation of chemistry to medicine one may note the dictum of Paracelsus in the early 17th century, that chemistry should be directed to the preparation of medicines for the physician; for some centuries prior to this chemistry had been eoneerned with alchemy.

Robert Boyle defined it as the science of the composition of substances. It would be difficult to exaggerate the significance of Boyle in the history of chemistry, or indeed in the history of science. He was the fourteenth child of the Earl of Cork.

Such dicta of Paracelsus and Boyle may be regarded as deriving from two valuations of science in general, the utilitarian and the philosophical, though it would be a little odd to take the cloudy genius of Paracelsus as seriously utilitarian. In the one dictum science is valuable because it is useful, and in the other it is valuable in itself.

While scientists working on the highest levels in biology, physics or chemistry have been, in general, concerned with science as natural philosophy, this has by no means precluded their attention to what is useful. One may quote Pasteur: " There is no greater charm for the investigator than to make new discoveries ; but his pleasure is heightened when he sees they have a direct application to practical life." Here successful application to practical life is an agreeable by-product, but not the primary aim. Experience has shown that in science the useful tends to follow most abundantly upon an active concern with what is true. One may say that as honesty has been discovered to be the best policy as a rule, pure science is encouraged because it pays dividends.

1I. Medicine and Pure Science. a science medicine in its immediate aim is no doubt entirely prac-

tical, but is being continuously fed from the region of pure science, not only biology in a wide sense but also chemistry, physics and other

SCIENCE AND THE PHYSICIAN 443

sciences; and an intelligent appreciation of modern medicine and its advances requires some acquaintance with the progress in biochemistry and physiology.

Some of this is given to the medical student, but in the scientific pro- fessions we must now be students all our days. If one talks to a practitioner aged, say, between sixty and seventy years, he looks back at a pre-insulin period, and to a time which may seem to him one of therapeutic nihilism. While it would be difficult to overestimate the value of recent therapeutic advances, such an attitude is unconsciously un- generous to the past.

One has only to think of the anmsthetics and antiseptics then known, vaccines and sera with specific antibodies, drugs like digitalis and mercury in their various preparations, alkaloids like the quinine, mor- phine and ergot groups as well as the whole assembly of pharmacological drugs exciting or depressing various bodily functions, to realise how far in fact knowledge had advanced even then. And, even if effective therapeutic measures against pathogenic bacteria within the organism were little advanced, it is to be remembered that the position could be likened to a cemetery of dead hypotheses. In such surroundings the truth is apt to flourish and some of these hypotheses would have in- trigning headstones, ranging from alchemy (and its relations to medicine) to homoeopathy.

But while rejoicing in his greatly increased power of controlling diseases, such a practitioner may remark, referring to the new drugs-- " I wonder how these things work?"

This opens up the whole nature and value of pure scientific education in his profession.

One might answer, " Does it matter how, so long as they work?" and his expected recoil may derive from the following: firstly, a wish to maintain intelligent contact with recent advances, to understand and use them as well as possible; also to be in a position to develop ideas resulting from his own observations, which for a practitioner with wide experience are not seldom other than textbook cases; and in addition, because he is an intelligent human being (and as a professional man, aSove the average) he seeks to understand more fully what he is doing and which is so often associated with the most significant events of a patient's life. He is not content, in other words, with being a mere machinist, who neither knows nor cares how his machine really works.

What our practitioner has in mind, therefore, is a scientific culture which enables him to keep in touch, to think for himself, and to satisfy in some measure his desire for a rational understanding of the processes he sets going.

To digress a little, culture in general may be said to be the result of education, and education is usefully defined in Arnold's phrase--" some acquaintance with the best that has been thought and said in the world." For with such acquaintance, standards of value are acquired and to have such standards is to be educated.

In science, as in the arts, the mind moves through a certain geography of ideas, but culture is here one of relations rather than of values.

There is little need however to emphasise the significance of pure scientific culture or of advances in the related pure seienecs for the progress of medicine, since experience has so amply proved it. A recent


example may be instanced in the discovery of the therapeutic value of cortisone.

In the Mayo Foundation Kendall had long studied the preparation of the pure hormones of the suprarenal cortex and their physiological significance. One of those he termed Compound E. There also Hench had worked on the treatment of rheumatoid arthritis and concluded that its cause was the inadequate action of a certain hormone, of the non- sexual kind. Collaboration between these two workers and the trial of Compound E, later known as cortisone, gave rise to the therapeutic results with which we are now familiar.

III . Main Paths in Biological Science. These are not limited to studies of vitamins, antibiotics or of isolated

hormones, very important though they may be, but are directed rather to answering the following questions:

(a) How does the cell act as a system of directed energy and in relation to its environment?

(b) How does the multicellular organism act as an integrated unit? (c) How do the cell and the organism reproduce, or what are the

final operative mechanism in cell division and the nature of the genes ?

Research advances in all three, but in so far as the answers to such questions, from the material standpoint at least, are chemical answers (including physical chemistry) the first appears now, and in a logical order, as the most fundamental. I t is something that must be largely elucidated before the others can be much further advanced.

In the answering of such questions much will be added at the same time to the practice of medicine, but it would be a naive simplification to suppose that biological science exists for the sake of medical practice.

In the following, therefore, I shall consider some few points concerning the action of the cell as a system of directed energy.

IV. The Cell as a System of Directed Energy. From the biochemical standpoint the cell may be regarded as an

integrated system of enzymes, bounded by a membrane. These enzymes are catMysts and of protein nature. They direct lhe

path of the intracellular metabolism, either towards synthesis or a breakdown into waste products.

Such action requires energy and energy supplied in a certain way and directed along special channels, so that in this sense cellular action may be described as a unified process of directed energy, and the catalysts that direct this process constitute the structure of the cell. I f such enzyme systems were removed from the cell then, apart from some storage of carbohydrates, fat globules and a small proportion of breakdown products nothing would remain of material significance other than a solution of inorganic salts.

The enzyme with its protein nature may perhaps be regarded as the significant unit of material life, and it is of interest to consider very briefly how it acts.

A chemical change cannot of itself take place if free energy is thereby increased as a result. But it may still not occur even if free energy is

SCIENCE AND TItE PHYSICIAN 44.5

greatly lessened. This is due to an initial energy level or hillock that must be overtopped.

Coal in the coal-hole, fortunately, does not go on fire because of this barrier and must be heated to a certain temperature before the reaction with oxygen proceeds sufficiently rapidly to continue, automatically or progressively. Similarly all the carbon compounds observed in nature are protected as against the oxygen of the atmosphere. Without this energy barrier or hillock, we should all go up in smoke, or perhaps end with a bang, as in Chesterton's poem.

F; 9,

Encrgy level of reac rants.

)

t Encrgy of activation.

Energy level of products.

t - . * - ° - 1

Energy level of reactants.

Decrease of activation energy produced by enzyme.

Energy level " of products.

The action of the enzyme consists in diminishing or obliterating the hillock (Fig. 1), which receives the term " activation energy ". It does this apparently by providing a specific surface on which the substance fits, and is there subjected to electrical forces which lower the barrier. What exactly causes the hillock and how precisely it is removed have not yet been established.

Here the physician may ask how such ideas could lend themselves to

4~6 IRISH JOURNAL OF MEDICAL SCIENCE

Fi9.2.

nC02+ mH

t 0

I 2H ~0

t •

~ o SS

s s s s ~ J ° s ~

" t ;he electron on the H atom, , " rryJn 9 the prtmol bJologKal J cncrgy.)

~- C,~l'l(m_2p.~O(2,_p) + pH20

RH2~ --'~ R

RsH2 ~ Rj

R2H 2 ~ R 2

21V1+2~ ,.--'* 2M


the advancement of medical practice, and the Luke-Fildes hypothesis may be instanced. This gives an explanation of the therapeutic action of sulphonamides in terms of substrate competition and enzyme activity. Thus, a substance very similar in structure to an essential metabolite, but incapable itself of being changed, can block the surface of an operative enzyme, and so inhibit some essential metabolic link in a micro-organism. This, with good reason, is believed to be the manner of action of the sulpha drugs, the metabolite excluded being p-amino- benzoic acid. It is a principle of far-reaching consequence, and of much promise for a rational therapeutic advance. Such action of sulpha drugs on certain bacteria indicates very significant differences in the oriented system of enzymes. The similarity of all cells and their metabolism had been emphasiscd, and the rational hope of therapeutic progress considered to lie in sera and vaccines. This position was changed over- night by the discovery of the therapeutic value of prontosil.

Proceeding further along the view of the cell as a unit of directed energy, I shall touch upon some points connected with the origin of such energy and how the cell can utilise it.

One may say very briefly that the energy begins as the ultra-violet light of the sun, which becomes trapped through the intermediation of chlorophyll. The light energy so absorbed is held in the outer electron fields of atoms and one may in fact regard it as held by the electrons attached to H atoms. The first chemical change, as is now known, is the splitting of water into hydrogen and oxygen atoms, and in the hydrogen atoms all the energy that organisms use is concentrated. The energy is localised in the electron revolving around the comparatively large proton (Fig. 2).

The problem for the cell is how to use this electron energy to do various kinds of work, mechanical, synthetic and osmotic.

As the hydrogen atoms pass along the metabolic chain they are moving into systems of higher and higher redox potential until finally the electrons end again in oxygen; unless the electrical energy set free during this passage is trapped in some way it is dissipated as heat.

The Energy-rich Phosphate Bond. In recent years it has become established that a major process in the

utilisation of such energy is by way of energy-rich phosphate bonds. (This advance derives from the work of Harden and Young, Embden, Myerhof, Lohmann, Warburg, Lipmann and others.) The most important carrier of such bonds in the cell is adenosine triphosphate (ATP). Besides adenine and ribose this contains a chain made of three phosphate molecules, the link of the terminal phosphate being unstable and with high energy content. In the oxidative stages of metabolism such bonds are formed with a metabolite as this loses electrons. The metabolite may then transfer its high energy phosphate to adenosine diphosphate (ADP) forming the triphosphate (ATP).

The importance of this process is so great that some indication of its essential nature may be given as follows. In Fig. 3 is shown, in the upper part, a change of 3-phospho-glyceraldehyde to 3-phospho- glycerie acid. This dehydrogenation, coupled with the acceptation of the H atoms by cozymase, involves a considerable standard free

448 I R I S H JOURNAL OF M E D I C A L S C I E N C E

Fi 9. 3.

A

OH C / O H

CHOH !

CHi~OPOsH2

- - 2 H "

O C~OH i CHOH I, C H2OPO3 H2

B m

OPO3H2 0 ~OH C~OPO3H2 C.l H ~-÷2H I C HO H -2. CHOH I I CH2OPO a H2 CH~ OPO s H 2

C,,

c L o ..~o OPO3H 2 C ~ O H

I +ADP ,. " I CHOH CHOH I I

CHzOPO 3 H 2 CH2OPO3 H2 + ATP


energy change (-18,000 cals.), but what occurs in fact in the normal course of the metabolism of carbohydrate is the prior entrance of a second phosphate group (forming 1-3-diphospho-glyceraldehyde). This extra phosphate is not energy-rich, but when the compound loses two hydrogen atoms it changes to the energy-rich type. The standard free energy change in the dehydrogenation is now negligible , the electron energy of the hydrogen atoms involved being transferred to the P-bond. Finally, the 1-3-diphosphoglyceric acid transfers its high energy P-bond to ADP, forming ATP, and 3-phosphoglyceric acid appears as in the first reaction, but instead of the energy being lost as heat it is retained in ATP. (Here the dehydrogenated stage of the glycolytic process has been considered but a largely similar picture may apply to other dehydrogenations.)

When the free energy is so trapped it may, possibly, be transferred to side-chain bonds on myosin or actomyosin and impart the required energy to muscle fibrils. Also, when it accumulates from such dehydrogenations it can be used to reverse the process of dehydrogenation, by a mass action effect, and hence assist in synthesis or synthetic reactions.

A consequence of such trapping of electron energy in dehydrogenation is an increase of redox potential of the system over the non-phosphory- lated system (the potential of system B in Fig. 2 is higher than that of A). This necessarily follows since as the electrons of the H atoms are drained of their energy they must pass into systems of higher redox potential (ending finally in the oxygen system).

Thv " R e d o x P u m p " Theory.

This theory (Conway, Science, 1951) indicates another process whereby electron energy may be utilised, and transferred into osmotic. It may be illustrated by the formation of acid by the oxyntic cells of the stomach, or by yeast during fermentation. There is now much evidence to show that the process turns on the two following reactions constituting a cycle of change. In the first a catalyst such as a flavine enzyme transfers H atoms (received from a metabolite and presumably via the pyridine nucleotides) to a metal catalyst and free H ions are formed, the metal catalyst retaining the electrons. The metal catalyst acts in this manner in the cell wall or in a lining membrane, and in turn transfers the electrons centrally. These pass finally to oxygen in the oxyntic cell, but mainly to an organic acceptor in yeast.

+

In the case of the oxyntic cell, as the H ions increase a p.d. is established across the cell drawing out C1 ions (or so it may be interpreted), and when the concentration of the HC1 becomes slightly hypertonic a flow of water ensues to equalise the osmotic pressure across the membrane.

If it be now considered that steady states are in being, but by some +

arrangement the H ion concentration in the membrane or outside it is varied, further, that C1 concentrations are the same (or not appreciably different) within and without the cell then the energy requirement for the secretion of one equivalent of HC1 may be written

--AG~_F(EM--Ect)~-RT In aH . . . . . . 1


where F is the Faraday constant, and EM and Ect are the redox potentials of the systems--

CtH~--TCt -}-2H . . . . . . . . . . 2

and

2 ~ 2 ) / I ~-2e . . . . . . . . . . . . 3

+ n the membrane, and a~ is the H ion activity in the membrane or outsido the cell.

Now the potential of the flavine system increases with H ion activity in accordance with the equation--

( Red RT Ect= Eoct - - ~-F In 0x ] "~" - F In a~

With increase of a~ Ett in equation 1 would finally equal or approach +

very close to E M. Thus the electrical energy of the H ion electrons involved up to the EM limit would have been completely transferred into osmotic.

Here a process of trapping the electron energy of the H atoms as osmotic energy has occurred, and somewhat analogous to a similar happening with energy rich phosphate bonds.

Application of the redox pump theory to the active secretion or excretion of metallic cations.

The metal catalysts considered above may be considered capable of forming adsorption complexes with cations. All that need be assumed here is that the minute amount of cations adsorbed is taken out of phase. If, then, we suppose for convenience that the total metal catalyst molecule has two metallic atoms, we can wri te--

- - + ~ - - 4 - +

(I~.2B)~__M+2B+2e . . . . . . . . 5

and comparing this with

CtH ,--*Ct-l-2H+2e . . . . . . . . 6

÷

the analogy to the active secretion of H ions becomes obvious. Here an + +

inorganic cation such as Na or K is taken up in the reduced phase of the catalyst and liberated in the oxidised phase. As before the electrons would be transferred to another metal system (not forming an adsorption

÷

complex with cations like the first). I f the concentration of free B ions were increased, the potential of the first system would rise and in the


limit approach the second, all the electron energy up to the potential of the second system being transferred into osmotic.

Concerning the possible bearing of such ideas: It may be said that such advances will inevitably deepen the consideration of various medical problems. Also, one may point to the growing pharmacological usage of adenosine and related compounds. With regard to the redox pump theory and HC1 secretion in the gastric juice it is of interest to note a relation with some recent work in experimental medicine. Thus it is in agreement with FitzGerald's conclusion concerning the function of the urea-urease system in the gastric mucosa. This system is not a donor

of H ions to the HC1 of the gastric juice (a view occasionally put forward, but no longer tenable), but exerts an important neutral ising and protective function with regard to cells of the mucosa other than the oxyntic cells. This has been proved by FitzGerald et al. (1946-1951) for the human subject in a series of researches combining physiological, biochemical, histological and clinical observations leading to the introduction of a valuable urea therapy for peptic ulcers resistant to the usual forms of medical treatment (FitzGerald et al. (1946-1951), see especially the IRISH JOURN~ OF MEDICAL SCiENCe, 1950).

(This advance derives from the early work of Harden and Young, and proceeding through that of Embden, Myerhof, Lohmann, Warburg, Lundsgaard, Lipmann and others.)

In the above, only some few points have been touched upon, including such as have related particularly to my own work. To maintain a truer perspective it should be emphasised that of all the processes of directed energy in the cell, the most significant would appear to be the synthetic, whereby the oriented system of catalysts, the directing medium itself, is re-constituted or enlarged. The nature of this oriented synthesis is at present obscure.

V. Conclusion. One naturally thinks of medical practice, centred in the consulting

room and the bedside, as something very different from the medical research of a laboratory. Here it is sought rather to emphasise their mutual dependence. While it is true that the initiative in recent years has passed to the laboratories, it is equally true to say that there have been exceptions of outstanding interest. There will probably be always more than a mere chance for the observant clinician well informed in the relevant science of his day to assist in the advance of medical science.

In dealing with the relation between pure biological science and medical practice, the more spectacular advances in our knowledge of vitamins, hormones and antibiotics seemed to demand the greatest attention. It was thought preferable, however, in the very short time avail- able, to touch on some more central questions into which the pattern of such knowledge may be fitted.

To such questions others may be added at a future date and appear of special interest, including both psychical and material phenomena as we now understand such terms. These, for instance, may be the more precise nature of the psycho-physical parallelism and the possibilities of


the mobilisation from within the brain of material energy in the service of conscious ideation.

Indeed medical science may enlarge its scope beyond what we now accept if one thinks of the research spirit and drive of our times on the one hand and on the other what meaning we attach or are likely to attach to the word health, with its original derivation from "wholeness".

Also, it is perhaps worth noting that the medical school is the natural home of biological science, to which a greater future lies than to physics. The observer of the most remote events of the macrocosm has these mirrored in a microcosm within, and the material forces shaping this must appear the more important to him, even apart from any ultimate interpretation of experience. Outside consciousness quantity and number have no significance.

In conclusion, it may be said that judged from the most "practical " basis advance in the pure sciences allied to medicine is not only fruitful but necessary, and that it is short-sighted to support or confine medical research only to the immediate objective of treating disease.

I should like to pay a tribute here to the enlightened policy of our own Medical Research Council and gratefully record its generous support of the research in my own Department.

BOOKS RECEIVED.

TrD'~ and SHORT. The Medical Annual, 1951. Wright. 27/6. H.~a~xs, T. A .B. The Mode of Action of Anesthetics. Livingstone. 42/-. SHELDON, W. Diseazes of In/army and Childhood. Churchill. 6th Ed. 40/--. FRENCH, C. 1~. The Story of St. Luke's Hospital. Heinemann. 8/6. SO~SBY, A. Systemic Ophthalmology. Butterwor~h. £4 4s. 0d. HAAs and HAAS. Management of C~liac Disease. Lippincott. £2 0s. 0d. THOREK, P. Anatomy in Surgery. Lippinco~t. £9 0s. 0d. IrkeD, G. Is God in History ? Faber & Faber. 15/-. SHE~LOCX and WOLS~EN~OT.M~. Liver Disease. Churchill. 25]-. CLAYTON and ORx~. Medical Disorders in Pregnancy. Churchill. 25/-. BONNAI~, REV. A. The Catholic Doctor. Burns Oates & Washbourne. 12/6. MAY and MARUAC~r. Clinical Pathology. Churchill. 6th Ed. 30/-. PAVEY, A. E. The Growth o/ Nursing. Faber & Faber. 20/-. B~.AU~ONT, W. Diathermy. Lewis. 2ncl Ed. 21/-.

conferring of the fellowship of the royal college of physicians of ireland upon professor edward...

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