CHEMISTRY AND THE ART OF HEALING

Download CHEMISTRY AND THE ART OF HEALING

Post on 31-Jan-2017

213 views

Category:

Documents

1 download

TRANSCRIPT

  • CHEMISTRY AND THE ART OF HEALINGAuthor(s): FRANZ BERGELSource: Journal of the Royal Society of Arts, Vol. 112, No. 5093 (APRIL 1964), pp. 320-334Published by: Royal Society for the Encouragement of Arts, Manufactures and CommerceStable URL: http://www.jstor.org/stable/41369343 .Accessed: 28/06/2014 10:40

    Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at .http://www.jstor.org/page/info/about/policies/terms.jsp

    .JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range ofcontent in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new formsof scholarship. For more information about JSTOR, please contact support@jstor.org.

    .

    Royal Society for the Encouragement of Arts, Manufactures and Commerce is collaborating with JSTOR todigitize, preserve and extend access to Journal of the Royal Society of Arts.

    http://www.jstor.org

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/action/showPublisher?publisherCode=thersahttp://www.jstor.org/stable/41369343?origin=JSTOR-pdfhttp://www.jstor.org/page/info/about/policies/terms.jsphttp://www.jstor.org/page/info/about/policies/terms.jsp

  • CHEMISTRY AND THE ART OF HEALING

    The Sir William Jackson Pope Memorial Lecture by

    FRANZ BERGEL , Ph.D., D.Sc ., F.R.I.C. , F.R.S. ,

    Professor of Chemistry y University of London , Institute

    of Cancer Research: Royal Cancer Hospital , delivered to the Society on Wednesday 2

  • APRIL 1964 CHEMISTRY AND THE ART OF HEALING

    Technology and some resenting the fact that their colleagues at the older academic institutions are called Bachelors or Masters of Science and Doctors of Philosophy, while they are just Dip.Techs. They should look at Pope and say, 'There because of the Grace of God could go I !'

    Pope certainly combined in his thinking and doings both the applied or techno- logical aspects of chemistry and the academic, fundamental ones without apparent conflict.

    Some in the audience may ask the question, how can one honour and remember Pope by a lecture carrying the rather sweeping designation 'Chemistry and the Art of Healing'. When I received the invitation of the Society I had not read Professor Chain's Trueman Wood Lecture which I, unfortunately, had not attended. There, under the chairmanship of the late Lord Nathan, Chain dealt with the 'Academic and Industrial Contributions to Drug Research'1 and,- by implication, described the love-hate relationship between chemistry and pharmacology on the one side and medicine (the Art of Healing) on the other. This theme and related topics are also illuminated from many angles in papers read at the second British Congress on the 'History of Medicine and Pharmacy', published last year under the title Chemistry in the Service of Medicine? They contain large parts of historical and medical-scientific information3 which I could have easily rehashed for my lecture to this Society. But - and bearing also in mind that our Chairman, Sir Charles Dodds, dealt with the subject matter in 1956 during another Pope. Memorial Lecture from, so to speak, 'down-under' by emphasizing 'The Debt of Chemistry ,to Medicine'4 - I felt strongly that it would better serve the purpose and aims of this lecture if I restricted my talk to one part of the whole, namely to the Science of Stereochemistry and some of its interplay with the Art of Healing. In this way, a more appropriate tribute could be paid to the memory of Sir William Pope, who had done so much for the advance of our knowledge of molecular configuration.

    ATOMS AND MOLECULES IN SPACE

    Of course it is impossible to present the total impact of atoms and molecules in a Euclidian three-dimensional space (because this is what stereochemistry stands for) on the aetiological and therapeutic problems of medicine, starting with the last cen- tury, when the daring and imaginative concepts of Pasteur, van Hoff, Wislicenus opened up the 'space age' of chemistry to the latest results of molecular biology of proteins, isozymes, nucleic acids, genes. No, I can only give a selection of examples centred on organic compounds, ignoring unwillingly the stereochemistry of sulphur, phosphorus and metal complexes and picking out those items which will illustrate the significance of stereochemical features of molecules, large molecules, aggregates for the healthy state of cellular particles, cells, tissues, organs and whole organisms, if one or the other biological subunit or unit is out of order, for the necessary steps of healing these lesions (Table I).

    It sounds very comical to-day that about ninety years ago the idea of atoms, of which molecules and thus chemical matter is composed, existing in fixed, so to speak, solid (

  • JOURNAL OF THE ROYAL SOCIETY OF ARTS APRIL 1 964

    Table I. From atoms to whole organisms

    stalwart German chemist, ridiculed the book La Chimie dans E space* finishing his outburst with: 'The prosaic chemical world had little liking for these hallucin- ations. ' These 'hallucinations' and additional ones have proved over the years to be real and are applied daily to many problems even by the most prosaic among us. Those of us who are trained in chemistry do not need a reminder of what primary, secondary, tertiary and quaternary structures are. But as these form the baselines of further considerations of our subject matter, I shall give them to you in an over- simplified manner, as if they had been discovered only a few moments ago.

    PRIMARY, SECONDARY, TERTIARY AND QUATERNARY STRUCTURES

    In the case of primary structures what are called isomers have the same empirical formula but differ in properties, for example, in the placing of substituents on ring systems (Table II). Extending this to larger molecules, this may include the sequence of a given number of amino-acids in polypeptides or even over long stretches of nucleic acids the variation of the sequence pattern of the pyrimidine and purine bases. Secondary structures are more complicated: 'stereoisomers' can be either of a geometrical configurational nature, such as 'cis- trans' or they differ in their optical configuration (that means, due to their asymmetry, they will change to a different degree or in a different direction the plane of polarized light on passage through a solution of them). This includes mirror-image couples called enantiomers, belonging to the l (laevo) or d (dextrorotatory) or racemic dl species. Compounds with more than one optical centre are in some instances called dia- stereomers. In addition to these geometrical and optical configurations there exists, most pronounced among cylic structures, the phenomenon of conformational isomerism, all due to the relative rigidity of the carbon bonds, imagined to be inside a tetrahedral pyramid (Figure 1). The chemical example is that of cyclohexane with its chair and boat forms. Going over to larger molecules such as polyyclic

    322

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • APRIL 1964 CHEMISTRY AND THE ART OF HEALING

    Table II. Molecular organization

    compounds (i.e., steroids) or chains of amino-acids in polypeptides and proteins, configurational and conformational features become very complex but are of the utmost importance from a biological point of view. Without paying any attention to details of this vast field I should like to remind you of the facts, mainly based on the work of Astbury, Pauling and Corey, and Ambrose and Elliot,7 that polypeptides especially of a fibrous nature can arrange themselves conformationally in space either in an extended zig-zag line (-form) or, caused by hydrogen bonding between the amido groups and CO, in a folded form (a), or in corkscrew-like helices, or in a grid-like pattern. The stability of these secondary structures, apart from the hydrogen bonds, is increased by the side chains, the conformation of the C-C bonds and sometimes by metals. Similar secondary structures have been encoun- tered in the other class of proteins, called globular, which form most of the enzymes and other functional cell-constituents, such as haemoglobin, but there a second process of folding can take place, leading to what is known as tertiary structures. This brings positions in the chain nearer to each other which otherwise may be

    323

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • JOURNAL OF THE ROYAL SOCIETY OF ARTS APRIL 1 964

    Figure i . Stereochemical models constructed by Dr. J . H. Lister and Mr. A. L. Steward of the Chester Beatty Research Institute

    at relatively great distances. Of course the opposite, namely a separation of such juxtapositions, may take place from time to time and alter the degree of the biological activity. The stability of these loops, folds and hollows, is probably regulated by van der Waal's forces, ionic bonds, again hydrogen bonds, and of course conformational facilitation, built into the chain itself. Some tertiary structures depend on the formation of true chemical or covalent bonds such as S-S or disulphide bridges or, as I shall speculatively suggest further on, bonds between CO and amino- or amido-groups. In a number of biological materials, secondary, tertiary and what one ought to call quaternary structures, come together. The latter consist of aggregation or association of large molecules in the form of homomers, if composed of the same subunits or heteromers, if a number of variants join up. Representatives, to be given further attention later on, are haemoglobin, isozymes and the double helix of DNA. I mentioned before that if one goes further than such structural combinations, then one enters the field of biology, with the organization of DNA in chromosomes, RNA in ribosomes and of proteins in the latter or in mitochondria, lysosomes and the cytoplasmic fluid of the living cell; there are membranes enveloping the nuclei, the organized particles and the cell with phospholipids, sterols and carbohydrate-protein complexes, which follow again configurational and conformational rules.

    324

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • APRIL 1964 CHEMISTRY AND THE ART OF HEALING

    THE FOUR STRUCTURAL TYPES AND THE ART OF HEALING

    Having quickly laid the foundations, we are now in a better position to answer the main question : what has the Art of Healing gained from our knowledge of the four types of chemical structures accumulated over many years by many workers? I have already made the statement that all life processes in health and during illness, when brought down to molecular level, are governed by the rules of spatial arrange- ments. This refers not only, as it was pointed out, to materials of the body consti- tuents, with their most harmonious interplay under normal conditions and often with their specific irregularities under pathological ones, but also to therapeutically useful compounds isolated from natural sources or synthesized by the chemists in the laboratory.

    It is one of the great pleasures of the scientists dedicated to biological and medicinal chemistry to elucidate the primary structures of natural products which either possess valuable remedial properties or function as essential components of cells and tissues. First the scene was dominated by the investigations of plant alkaloids; then came the period of synthesis of drugs from aspirin to the more complex ones of modern times (as reviewed last year by Professor Chain1); then new challenges arose from the discovery of the hormonal steroids and antibiotics such as penicillin, actinomycin, streptomycin and many more, and now we are in the midst of the polypeptides: the top events being the establishment of the structure of insulin8 and the adrenocorticotropic hormone (ACTH), recently synthesized with all its 39 amino-acids by Schwyzer.9 Other highlights are the brilliant yet painstaking studies of the amino-acid sequences of ribonuclease, myo- and haemoglobin and cytochrome C.10 The attack on the nucleotide sequences in nucleic acids, themselves studied extensively by Todd and his school, is still mounting. However, the elucidation solely of primary structures is not sufficient, because with the exception of a relatively small number of simple drugs all these substances of medical importance carry at the same time secondary, if not tertiary structural features as well.

    SECONDARY STRUCTURES OF DRUGS AND RECEPTORS

    Let us take first the problem of action mechanism of remedies, whether they are of natural or synthetic origin. Their pharmacological or chemotherapeutic effects depend on the successful transport to and interaction with sites present in living matter, called receptors (even agents against viruses might interfere more with host cells than with the virus particles). Consequently the old puzzle of structure-activity relationships, expressed by this pseudo-mathematical expression V = f (CD+CR) (pharmacological effect is an applied function of drug and receptor constitution) can only be solved through precise assessments of the steric features of CD and CR. Beckett11 extensively reviewed these problems a few years ago. The crux of the matter is that where there exist either geometrical or optical configurational or confor- mational isomers of pharmacologically active agents, one type of isomeric form is more potent than the others. Whether one considers sympathomimetic amines of the

    325

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • JOURNAL OF THE ROYAL SOCIETY OF ARTS APRIL 1 964 adrenaline group (with differences of 45-800 between certain activities of enantiomers), or parasympathomimetics and their antagonists, the atropine-like drugs, or whether one looks at the central nervous system depressing drugs of the morphine group and analogues, one meets with the same phenomenon: the stereospecificity of pharmacodynamic action. But apart from the physico-chemical properties of the drugs themselves, these observations permit reasonable specula- tions (which in some cases amount to certainty) as to the steric arrangement of the receptor site. I do not wish to discuss the well known case of substrates and antagonists of choline esterase, where the receptor is an enzymic entity which has allowed Concise studies of the structural requirements of drugs and the mecha- nistic features of the receptor. But let us take the chapter of analgesic remedies, where insight into the steric arrangement of the as yet unknown receptor sites has been gained by conclusions drawn from the configurational and conformational characterization of the most potent agents. Earlier work on a synthetic analgesic, pethidine and its derivatives, by the research department at Roche Products12 has shown that a structural isomer, nor-isopethidine, when resolved into its optical isomers, was only active as the laevo-rotatory compound. This was, crudely speak- ing, followed by the important discovery of Beckett et al .n that the more active analgesic of each enantiomeric pair derived from the basic structure of d (- )- alanine (strangely enough the opposite to that belonging to the natural amino-acid alanine). He and Casey,13 passing muster of a great number of existing and newly synthesized analgesics, put forward a hypothetical picture of the receptor surface to which the really powerful analgesic has to fit, or the other way round: the drug has to have spatial characteristics which must join smoothly the biological locus of action to trigger off the desired effect. The authors stipulated the existence of a cavity (maybe due to tertiary structures of tissue components) which dictates the configurational and conformational properties of the active drug species.

    There are instances when the drug specificity does not depend on a lock and key mechanism with proteins (so well illustrated by enzyme-substrate interplay). May I mention briefly the situation with the antibiotic antinomycin D (Figure 2), the anti-tumour action of which seems to depend on its formation of a complex with DNA, thus producing an inhibition of the DNA-primed RNA-synthesis and consequently interfering with the usual synthetic events in living cells. While its fixation to the nucleic acid is to a large extent due to the three-ring system, the two identical peptide chains must also play a considerable part, because Burchenal et al.u have observed with biosynthetically produced analogues differ- ences in toxicity and chemotherapeutic indices. The presence of an unnatural D-aminoacid which also occurs in other antibiotics of peptide nature, is of interest. My colleagues Mauger and Wade15 have studied the possibility of replacing by synthetic means the peptide chains in actinomycin by other amino-acids to alter the toxicity and anti-tumour activity in a favourable direction. These investigations have been prompted by the successful use of actinomycin D against certain tumours of childhood by the team at the Children's Cancer Research Foundation in Boston.16 So far the combination of the three-ring system with another decapeptide, namely gramicidin S of Russian origin (obtained by courtesy of Professor F. Gause,

    326

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • APRIL 1964 CHEMISTRY AND THE ART OF HEALING

    Figure 2

    Moscow),17 has given a product, not yet quite characterized, which shows dimi- nished toxicity and also diminished uptake of orotic acid into RNA.

    Another example of the distinct influence of optical configuration on anti-tumour activities refers to a series of amino -acid and peptide derivatives studied for some years by my colleagues Stock, Johnson and Wade.18 Natural forerunners were dis- covered in form of the mould products azaserine and DON in America;19 in both cases they are only effective as carcinolytic agents when possessing the L-configura- tion. Their mechanism of action has been explained by Buchanan20 on the basis of their interfering with the biosynthesis of a purine, one of the essential bases of nucleotides and the nucleic acids. With the synthetic phenylalanine derivatives, on the other hand, the optical configuration may play its main part in the ease of transport either towards or into the target cells. When comparing the l- (melphalaii), the d (medphalan) and the racemic species (merphalan or sarcolysin), differences in toxicities, anti- Walker tumour effects, effects on chromosome breaks, circulating blood elements, mutagenic effects on Drosophila flies or inhibitory effects on amino-acid incorporation were observed. That stilboestrol is not so far the only drug really therapeutically effective in any kind of cancer,11 as Chain claimed in his Trueman Wood Lecture, is demonstrated in the case of malignant melanoma in a patient treated successfully with melphalan in regional perfusion. After several years there is no recurrence of the disease.

    An intriguing state of affairs exists within a group of peptides, derived from mel- phalan. Similar work has been carried out independently by Russian scientists, see18

    327

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • JOURNAL OF THE ROYAL SOCIETY OF ARTS APRIL 1 964

    Figure 3

    although, as far as one can judge, some of their method of synthesis has not always led to optically pure products. On the other hand, my colleagues Johnson and Wade18 have achieved such purity with a number of N-acetyl aminoacyl melphalans (Figure 3) and in association with their biological collaborators demon- strated that the optical configuration of the second amino-acids which does not carry the cytotoxic 'warhead' (the nitrogen mustard group M) has great influence on the toxicities and anti-tumour effects of the members of this series. It could be shown that the l-l dipeptides are always more potent than the d-l isomers. This is also valid for dipeptides with free amino groups. I should like to illustrate this with a recently made diastereomeric couple, l and D-a-glutamyl melphalan ester hydro- chloride, prepared by one of our visitors from Hungary, Dr. Maria Szekerke. The l-l derivative proved to be more effective against the Walker tumour and more toxic to the rats than the d-l compound. These melphalan peptides with other anti- tumour agents such as mannitol derivatives and epoxides have various degrees of configurational specificity which, as I said before, may be due to effects on their rates of transport or of cell membrane penetration. Whether their configuration plays also a part in their attachment to nuclear DNA, we do not know, although alkylating agents such as these, according to my colleagues Lawley and Brookes,21 may exert their cytotoxic effects via a cross-linked alkylation of guanine moieties belonging to the two strands of the DNA double helix, as proposed by Crick and Watson.

    TERTIARY AND QUATERNARY STRUCTURES OF MACROMOLECULES

    This brings us straight to the spatial characteristics of biologically important macromolecules which play a crucial part in inheritance, good or bad, and together with the functional proteins in health and, undesirably, in disease. DNA as target of antitumour agents has been just mentioned. Its spatial behaviour, proposed by the Cambridge scientists, cannot be a completely rigid one because the genetic information which the molecules carry, whether for the operation of protein synthesis via a complex go-between of various RNAs or for regulating functions, has to be perpetuated by replication of the exact sequence of nucleotides, three of which represent the code for one specific amino-acid. All this has been published and presented in lectures, one of the latest by Perutz in the series of the Scientific Basis of Medicine. What is of interest to us is that the double helix of DNA has to uncoil to form single strands which then can act as templates for the construction of a new strand from single nucleotides. The helix to random coil process involves the rupture of two hydrogen bonds between base pairs and may take, according to

    328

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • APRIL 1964 CHEMISTRY AND THE ART OF HEALING

    Eigen and others,22 from io-4 to several seconds, dependent on the molecular weight of the DNA. This is a relatively long interval during which surprisingly few, if any, mistakes are made. But if something interferes, chemicals or ionizing radiations, then a lot of wrong things can happen. While the control mechanism of the amino- acid sequence in proteins is at present in the process of being elucidated, one knows very little, as yet, about the control of conformational, tertiary and quaternary features. The answer may be hidden among others, in a working hypothesis by Monod and Jacob21 on allosteric proteins and cellular control systems (see also Dean and Hinshelwood24). Monod himself, on the occasion of the Sir Ernest Kennaway Memorial Lecture last Autumn, has explained the whole concept of regulating genes, repressors and inducers and the rle of small molecules bringing about conformational changes in the functional proteihs, and even alterations of tertiary and quaternary structures.

    I should like to come back now to the brilliant work by Kendrew and Perutz25 who elucidated in conjunction with American and German scientists (the latter responsible for the clarification of the aminoacid sequences) the tertiary and quaternary structures of myoglobin and haemaglobin. There is no doubt that the proper function of haemoglobin as an oxygen transferring system depends on conformational features, such as the occurrence of a-helices of the peptide chains ; on their secondary weird folding and on the combination of sub-units, i.e., two a and two chains in haemoglobin A, carrying four prosthetic groups. While diseases arising from abnormal haemoglobins, such as sickle cell anaemia, can be caused by a faulty amino-acid sequence, they also traced back, e.g. in thalassaemia, to wrong associations of chain units.

    Yet another group of functional proteins, belonging to the family of enzymes, has been discovered during recent years as possessing steric features of great biological importance. While traditional enzymes consist of proteinous apoenzymes with, on the whole, permanent chemical and physical characteristics, some bio- catalysts either consist of groups of proteins with similar qualitative but different quantitative enzymic properties or are composed of subunits which have to form aggregates to become specific and efficacious. In all cases the members of these aggregates may differ in their stereochemical and physical characteristics, such as electrophoretic mobility.

    I cannot go into the fascinating problem of association and dissociation as it happens with the enzyme glutamic acid dehydrogenase, which when dis-aggregated into subunits by agents, among them the hormones, oestrone and thyroxine, loses its activity as glutamate metabolizing biocatalyst, yet gains activity vis--vis alanine. But what should be mentioned are the so-called isoenzymes or isozymes like lactic acid dehydrogenase (LDH), which occur in various organs in different proportions of their subunits but change the pattern of these proportions in presence of disease; for instance, following a pathological incident in the heart, called a myocardial infraction. Work on the possible genetic control of the isozymal mixtures is proceeding in a number of laboratories ; we at the Institute of Cancer Research and the Royal Marsden Hospital are particularly interested in their pathological alterations in the framework of our co-ordinated studies on the

    329

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • JOURNAL OF THE ROYAL SOCIETY OF ARTS APRIL 1 964 characterization of human cancers by other means than the traditional histo- or cytological ones. Investigations by my colleagues Leese and Yasin are in progress, similar to those carried out by A. L. Latner in Newcastle and by D. M. Campbell at Hammersmith, aiming at the estimation of isozymal activities in certain human tumours by various means and in comparison with those of normal tissues. Recently French workers26 have reported on their findings with another enzyme aldolase which can utilize equally well in adult liver fructose- 1, 6-diphosphate and fructose- 1 -phosphate as substrates. It has been known before that isozymes alter their pattern during the development from foetus to the grown organism. The French scientists observed that the aldolase of human primary liver tumours (hepatomas) behaved more like that of foetuses in that the enzyme mixture was distinctly less effective with fructose- 1 -phosphate as substrate.

    If, as in our characterization programme, these enzyme studies, are extended to other isozymes, and include coenzymes and apoenzymes, applying among other techniques that developed by Lowry et al?1 for minute quantities of tissue, and are linked up with biological parameters, then we should be able to produce biological-biochemical profiles of human cancers which would, so one hopes, help greatly the clinician in the diagnosis, prognosis and selection of the correct therapeutic procedures.

    SOME THOUGHTS AND SPECULATIONS

    These remarks indicate a progression from the molecular level to cellular, tissue and organism levels (see Tables I and II). Such move is essential for the total comprehension of all events which are at the basis of the Art of Healing, because it should be built on the foundation of 'wholism'. In consequence it is imperative that chemists, when using their knowledge in the service of medicine, must never lose sight of this progression. But this on its own would be futile, unless the clinician, the biologist, pathologist and cytologist did travel at the same time the other way, from the whole man, back to organs, tissues, cells and their organization, down to the molecular level. It is no good having only a one-way traffic. Perhaps it would help if one thought sometimes in terms of the

    * Science of Healing' and the 'Art of Chemistry'.

    To finish my lecture I shall return for a short while to this 'Art' of molecular patterns. We had been discussing the possible changes from one steric form to another, particularly of secondary, and more so of tertiary and quaternary struc- tures. But what kind of mechanism does operate in vitro and in vivo to safeguard the opposite, namely the stabilization of some of these structures? (Because from an inheritance and health point of view this is just as important as their lability, allowing for adjustments during the life process.) At the beginning I indicated that the semi-rigidity of the carbon-carbon bond helped by the bulk of residues, van der Waal's forces, hydrogen and ionic bonds, metal chelates and disulphide bridges in proteins, will contribute to lessen the mobility of structures without completely preventing necessary changes by temporary rupture of these relatively low energy links. Further bonding possibilities have been considered by my

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • APRIL 1964 CHEMISTRY AND THE ART OF HEALING

    colleagues Lewis, Harrap, Peutherer, Orr and myself for some time and are those due to interaction of amino-, amido and SH groups on the one hand, and carbonyl (CO) on the other. These, so we propose, may become operative under biological conditions, when proximity and reactivity of such groups allow them to form covalent bonds, going beyond the comparable but weaker hydrogen bond. There are a number of examples among natural and synthetic products, and our obser- vation of the behaviour of amino- acids in presence of ketones under mild conditions and of cysteine with pyridoxal phosphate28 which I cannot expound here, have strengthened our belief that such interactions are less rare than hitherto thought. They include even amido-groups, as demonstrated with models by M. Peutherer,29 and although we do not completely agree with Dr. Wrinch's30 cyclol hypothesis for protein (CO.NH - COHN interactions, occurring very rarely) we are at this ment not disinclined to speculate that under certain favourable conditions such amido-carbonyl links together with or instead of hydrogen bonds occur in nature. They may form points of fixation, say, in the tertiary structure of haemo- globin or between the surface of enzymes and their small or large substrates. It is also not excluded that keto-steroids may in addition to other means attach themselves in this way to amino-acids and polypeptides, all this triggering off conformational changes. Of course, this is based on only preliminary observations brought together as a working hypothesis. But this, Mr. Chairman, has happened in other parts of the field of which I tried to give you a hurriedly drawn picture, from the ideas of Pasteur, van Hoff via Beckett-Pfeiffer-Ing to Monod-Jacob- Hinshelwood and the molecular biologists. In a considerable number of instances the speculations reflected the true state of affairs, in others the ideas had to be modified to accommodate further experimental evidence. But often this science of stereochemistry, so ingeniously nurtured by Sir William Pope and from another direction by yourself, has provided us with many advances, which the Art of Healing can and ought to utilize for its own most vital ends.

    REFERENCES

    i E. B. Chain, 'Academic and Industrial Contributions to Drug Research', J. Roy. Soc . Arts , 1963, cxi, 856.

    2. Chemistry in the Service of Medicine , ed. F. N. L. Poynter, Pitman Med. Pubi. Coy., London, 1963.

    H. H. Dale, An Autumn Gleaning , p. 82, Pergamon Press, London, iq;4. 4. E. C. Dodds. 'The Debt of Chemistry to Medicine', .7. Roy. Soc. Arts , 1046, civ, 671. 5. See G. W. Wheland, Advanced Organic Chemistry , p. i3off., 2nd ed., John Wiley &

    Sons, New York, 1949. 6. J. H. van 4 Hoff, The Arrangement of Atoms in Space , 2nd ed., Longmans, London, 1898. 7. See E. J. Ambrose, The Stereochemistry of Compounds of High Molecular Weight , in

    Progress in Stereochemistry y 7, ed. W. Klyne, p. 250, Academic Press, New York, 1954. 8. F. Sanger, Science , 1959, 129, 1340. 9. R. Schwyzer and P. Sieber, Total Synthesis of Adrenocorticotropic Hormone ,

    Nature , 1963, 199, 172. 10. See Biological Structure and Function at the Molecular Level , ed. V. A. Engelhardt, The

    Macmillan Company, New York, 1963. li. A. H. Beckett, 'Stereochemical Factors in Biological Activity', in Progress in Drug

    Research . I. 455. Birkhuser Verlag, Basel- Stuttgart, 1959. 12. A. D. Macdonald and G. Woofe; F. Bergel, A. L. Morrison and H. Rinderknecht,

    'Analgesic Action of Pethidine Derivatives and Related Compounds', Brit . J. Pharmacol ., 1946, I, 4.

    13. A. H. Beckett and A. F. Casey, J. Pharm. Pharmacol ., 1954, 6, 986.

    331

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • JOURNAL OF THE ROYAL SOCIETY OF ARTS APRIL 1 964 14. J. H. Burchenal, H. F. Oettgen, J. A. Repput and V. Coley, 'The Effect of Actinomycins and their Derivatives on a Spectrum of Transplanted Mouse Leukemia' , in 'The

    Actinomycins and their Importance in the Treatment of Tumors in Animal and Man', ed. F. N. Furness, Ann. New York Acad. Sci ., 89, Art. 2, 4QQ.

    15. A. B. Mauger and Roy Wade, 'Synthetic Studies of Actinomycin Analogues', Ann. Rep. Brit. Emp. Cancer Campgn., 1962, 40, 24.

    16. See S. Frber, G. D'Angio, A. Evans and A. Mitus, 'Clinical Studies of Actinomycin D with Special Reference to Wilm's Tumor in Children', Ann. New York Acad. Sci., 89, Art. 2, 421.

    17. bee Cj. . Gause and M. G. Brazhnikova, Lancety il, 1944, 715. i. bee b. Bergel, Optical btereospecmcity of Anti-Cancer Agents , If Farmaco, 1964 (m press).

    19. bee H. C. Reilly, bome Aspects of Azasenne, o-diazo-5-oxo-L-norleucine and - 2- thienylalanine', in Aminoacids and Peptides with Antimetabolic Activity , ed. G. E. W. Wolstenholme and C. M. O'Connor, p. 62, J. & A. Churchill, London, 1958.

    20. J. M. Buchanan, 'The Interference of Azaserine in purine biosynthesis', ibid., 75. 21. P. Brookes and P. D. Lawley, J. chem. Soc., 1961, 539, 3923; J. Mol. Biol., 1962, 4, 216. 22. See M. Eigen and others, 'Helix-to-Random Coil Change takes less than a Micro-

    second', Chem . Eng. News, 1963, 2nd Dec., 38. 23. J. Monod, J. P. Changeux and F. Jacob, 'Allosteric Proteins and Cellular Control

    Systems', J. Mol. Biol., 1963, 6, 306. 24. A. C. R. Dean and C. Hinshelwood, 'Some basic Aspect of Cell Regulation', Nature ,

    1964, 201, 232. 25. See J. C. Kendrew, 'The Structure of Globular Proteins', in Biological Structure and

    Function at the Molecular Level, ed. V. A. Engelhardt, p. 1, The Macmillan Co., New York, 1963; M. F. Perutz, 'Relation between Structure and Sequence of Haemoglobin'. Nature . 1062. IQ4. Q14..

    26. F. Schapira, J-. Dreyfus and G. Schapira, 'Anomaly of Aldolase in Primary Liver Cancer', Nature , 1963, 200, 994.

    27. O. H. Lowry, J. V. Passonneau, D. W. Schuh and M. K. Rock, 'The Measurement of Pyridine Nucleotides by Enzymatic Cycling'. J. Biol. Chem.. 1061. 246, 274.6.

    28. F. Bergel, et al., 'Interaction of Carbonyl Groups and Biologically Essential Sub- stituents', Pts. I-IV, J. chem. Soc ., 1959, 1431; ibid., 4047, 4051; 1962, noi.

    29. F. Bergel and M. A. Peutherer, 'Interaction of Carbonyl Groups and Biologically Essen- tial Substituents', Pts. V and VI, J. chem. Soc., 1964, in press. 30. See D. Wnnch, Chemical Aspects of the Structure of Small Peptides, Munksgaard,

    Copenhagen, i960.

    DISCUSSION

    the chairman: I was fascinated with Professor Bergel's lecture, particularly his analysis of the factors to be taken into consideration when deciding on a drug for the relief of pain. After a lifetime of work on this sort of problem, I have come almost to the end of hope, because whenever you get an orderly series of compounds that appear to fit in, if you go on, then the next compound you make completely upsets the theory. I think it was Rutherford, or Sir Henry Tizard, who said that if you really want to get on quickly as a young man the only thing to do is three experiments ; then you can construct a curve and derive a mathematic formula. If you do a fourth you would not be able to do it !

    If you take the group of compounds in which my colleagues and myself have been interested for so many years, namely the synthetic oestrogens, there are many examples of a certain orderliness in activity, but again one compound completely breaks any theory of relationship between structure and activity. What is so extra- ordinarily difficult to explain is that a substance like stilboestrol, which really bears no chemical relationship whatsoever to the naturally occurring hormones, is more active biologically than they are and is excreted practically unchanged.

    the lecturer: I did touch for 'one microsecond' on the Monod- Jacob hypothesis of small molecules and their influence on proteins, but I did not mention the dis- integration of glutamic acid dehydrogenase by oestrone, among others, changing the glutamate activity of the enzyme to alanine specificity. This is fascinating, and may help to explain the mechanism of oestrogens. The other possibility is that some of

    33*

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • APRIL 1964 CHEMISTRY AND THE ART OF HEALING

    these compounds which you, Mr. Chairman, have put on the map of the chemical world can influence cell penetration phenomena. I think it would be useful to investigate whether these hormones really belong to the group of small molecules which can produce confirmational changes by attaching themselves to the surface of proteins.

    sir SELWYN SELWYN-CLARKE, K.B.E., C.M.G., M.C., M.D., F.R.c.p. (Member of Council of the Society): Professor Bergel mentioned the successful treatment of malignant melanoma by the use of melphalan in regional perfusion. He also described certain of the acetyl aminocyl compounds not carrying what he referred to as the cytotoxic 'war head* (nitrogen mustard group M) as having an anti-tumour effect. I have noticed in patients under this treatment most unpleasant side effects because of the action of the nitrogen mustard group on the rapidly proliferating cells of the alimentary tract, and I wonder whether Professor Bergel could tell us whether this group which does not carry this cytotoxic 'war head* is in fact as efficacious in dealing with melanoma?

    Secondly, reference was made by Professor Bergel in passing to leukaemia. I wonder whether he would indicate whether the melphalans are of any use in the treatment of that distressing disease?

    the lecturer: I said that the optical configuration of the amino-acid which did not carry the 'war-head', the mustard group, had seemingly a greater influence on the overall activity of the dipeptides than the melphalan moiety. The melphalan itself still has the mustard group, so none of these compounds is in fact without these cytotoxic groups. This gives me an opportunity to say that I personally, and perhaps some of my colleagues, have the idea that the alkylating agents will one day (looking back perhaps from the year 2100) be considered as the 'bows and arrows' of cancer chemotherapy: they have side effects; they are not yet selective enough; they will attack any kind of dividing cell in a growing tissue, and it is only slowly that by work, such as that carried out by my colleagues Dr. W. C. J. Ross and his collaborators, certain changes are effected which might make these drugs more selective. I would say that alkylating agents will be abandoned inside the next generation, particularly when our molecular biologists, or scientists like Dr. Kirby, Drs. Bookes and Lawley and others, will have isolated some nucleic acids from normal tissues, and shown that these compounds have some transforming activities; instead of killing the tumour cell they may bring it like a delinquent back into the social life of the bdy.

    Whether they can penetrate the cellular membrane is another matter. My colleague Dr. Stock is at the moment studying the physical chemical principles underlying the combination of similar polyacids with polybases to see whether such combination which enables viruses to get into a mammalian cell may also do the same for what one might call large molecules of therapeutic value.

    To answer your second question, Sir Selwyn, leukaemia can of course be divided into lymphatic and myelogenous, and also into chronic and acute forms. As far as the chronic lymphatic type goes, the compound made by Ross some years ago called chlorambucil has some effect. It has no effect on the chronic myelogenous leukaemia where Myleran, one of the brain children of Dr. Timmis, is effective. As for acute forms, I would say that hardly any of these alkylating agents would do the job. There, one has to use so-called antimetabolites, e.g., anti-purines or antifolics and cortisone, or blood transfusions. One can only hope that in this field the work of one of my colleagues, Dr. Harrap, who is looking for biochemical changes during the process of leukaemia progression, might perhaps lead to something more helpful than these agents of the 1960s.

    major w. v. G. fuge, M.B.E., M.I.E.E., A.M.I .MECH.E. : I should like to ask a general question. It has been said that all life is chemical. One reads of the wonderful advances

    333

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

  • JOURNAL OF THE ROYAL SOCIETY OF ARTS APRIL 1 964 also being made in organic chemistry in connection with plastics and resins, and of how very sensitive organic chemical analysis is now. If all differences are, in the ultimate, chemical, is there any hope that chemical analysis will be developed to the stage when it may be possible to ascertain every single chemical compound in cancer cells, and every chemical compound in healthy cells, and ascertain the difference? And also to ascertain the chemical difference which prevents skin grafting? A long time ago it was thought that all blood was the same.

    the lecturer : As a chemist and an optimistic chemist, I would say, yes, it depends on the time factor. It certainly depends on the recognition not only of the straight- forward composition of the chemical constituents but also of their steric arrangements, which molecular biology is now teaching us. We do not know yet what regulates this kind of steric arrangement. As far as the immune response to grafting is concerned, modest progress has been made. I am not criticizing the people who are working at this. It is wonderful what they have achieved. They can suppress, temporarily, with the help of chemicals, such as mercaptopurine and some of the alkylating agents like cyclophosphamide and aminochlorambucil, the immune response of a human patient; they have then transplanted into this human patient a kidney which not necessarily arises from a twin brother or twin sister. They are at a very early stage in the development of these organ transplantations.

    the chairman : I am sure that you would wish me to express our great thanks to Professor Bergel. He has given us a lecture which we shall certainly remember. Professor Bergel, those of us who have followed your work have admired it for many years, for you have made signal contributions. We sincerely hope that you will go on doing so and that your work in the chemo-therapeutic attack on cancer will be successful.

    The vote of thanks to the Lecturer was carried with acclamation. sir SELWYN SELWYN-CLARKE : It is my privilege to propose a vote of thanks to

    Sir Charles Dodds. I am sure you will agree with me that the choice of him as our chairman was a particularly happy one. He was appointed the Courtauld Professor of Biochemistry in Middlesex Hospital Medical School at the very early age of 26. In 1942 he was elected a Fellow of the Royal Society for his outstanding contribution to the practice of medicine, and in particular for his work on the synthesis of stilboestrol and allied compounds referred to by Professor Bergel. I would ask you to join with me, first of all in offering him our warm congratulations on the honour of a baronetcy conferred upon him by Her Majesty The Queen at the beginning of this month, and, secondly, in thanking him for chairing this meeting.

    The vote of thanks to the Chairman was carried with acclamation, and the meeting then ended .

    334

    This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions

    http://www.jstor.org/page/info/about/policies/terms.jsp

    Article Contentsp. 320p. 321p. 322p. 323p. 324p. 325p. 326p. 327p. 328p. 329p. 330p. 331p. 332p. 333p. 334

    Issue Table of ContentsJournal of the Royal Society of Arts, Vol. 112, No. 5093 (APRIL 1964), pp. 285-382FORTHCOMING MEETINGS [pp. 285-286]ANNUAL RECEPTION [pp. 286-287]SWINEY PRIZE PRESENTATION [pp. 287-288]MEETINGS IN MANCHESTER [pp. 288-289]TRUSTS OF THE SOCIETY [pp. 289-290]MEETING OF COUNCIL [pp. 290-291]INDUSTRIAL ART BURSARIES [pp. 292-305]VETERINARY MEDICINE ON THE FARM [pp. 306-319]CHEMISTRY AND THE ART OF HEALING [pp. 320-334]THE IMPERMANENCE OF PAINTINGS IN RELATION TO ARTISTS' MATERIALS [pp. 335-352]THE ECOLOGICAL APPROACH TO PEST AND DISEASE PROBLEMS OF CACAO IN WEST AFRICA [pp. 353-371]GENERAL NOTES [pp. 372-373]OBITUARY [pp. 373-374]NOTES ON BOOKSReview: untitled [pp. 374-375]Review: untitled [pp. 375-376]Review: untitled [pp. 377-378]Review: untitled [pp. 378-379]Review: untitled [pp. 379-380]Review: untitled [pp. 380-381]

    FROM THE JOURNAL OF 1864 [pp. 381-381]Back Matter