CHEMISTRY AND THE ART OF HEALING

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<ul><li><p>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</p><p>Your use of the JSTOR archive indicates your acceptance of the Terms &amp; Conditions of Use, available at .http://www.jstor.org/page/info/about/policies/terms.jsp</p><p> .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.</p><p> .</p><p>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.</p><p>http://www.jstor.org </p><p>This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions</p><p>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</p></li><li><p>CHEMISTRY AND THE ART OF HEALING </p><p>The Sir William Jackson Pope Memorial Lecture by </p><p>FRANZ BERGEL , Ph.D., D.Sc ., F.R.I.C. , F.R.S. , </p><p>Professor of Chemistry y University of London , Institute </p><p>of Cancer Research: Royal Cancer Hospital , delivered to the Society on Wednesday 2</p></li><li><p>APRIL 1964 CHEMISTRY AND THE ART OF HEALING </p><p>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 !' </p><p>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. </p><p>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. </p><p>ATOMS AND MOLECULES IN SPACE </p><p>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). </p><p>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 (</p></li><li><p>JOURNAL OF THE ROYAL SOCIETY OF ARTS APRIL 1 964 </p><p>Table I. From atoms to whole organisms </p><p>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. </p><p>PRIMARY, SECONDARY, TERTIARY AND QUATERNARY STRUCTURES </p><p>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 </p><p>322 </p><p>This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions</p><p>http://www.jstor.org/page/info/about/policies/terms.jsp</p></li><li><p>APRIL 1964 CHEMISTRY AND THE ART OF HEALING </p><p>Table II. Molecular organization </p><p>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 </p><p>323 </p><p>This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions</p><p>http://www.jstor.org/page/info/about/policies/terms.jsp</p></li><li><p>JOURNAL OF THE ROYAL SOCIETY OF ARTS APRIL 1 964 </p><p>Figure i . Stereochemical models constructed by Dr. J . H. Lister and Mr. A. L. Steward of the Chester Beatty Research Institute </p><p>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. </p><p>324 </p><p>This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions</p><p>http://www.jstor.org/page/info/about/policies/terms.jsp</p></li><li><p>APRIL 1964 CHEMISTRY AND THE ART OF HEALING </p><p>THE FOUR STRUCTURAL TYPES AND THE ART OF HEALING </p><p>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. </p><p>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. </p><p>SECONDARY STRUCTURES OF DRUGS AND RECEPTORS </p><p>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 </p><p>325 </p><p>This content downloaded from 91.238.114.227 on Sat, 28 Jun 2014 10:40:28 AMAll use subject to JSTOR Terms and Conditions</p><p>http://www.jstor.org/page/info/about/policies/terms.jsp</p></li><li><p>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 analges...</p></li></ul>