Alexander Todd - A Time to Remember

Needless to say, I took part in the wartime Anglo-American cooperative research project on penicillin, but I was not involved in the early stages and our efforts beginning in, I think, 1943, were on a relatively modest scale. Looking back at it now, I find it rather amusing that, by showing that penicillin readily formed a sulphoxide, we did indeed establish that it was a true lactam; furthermore, our sulphoxide has, in recent years, sprung into prominence as a starting material for much synthetic work on beta-lactam antibiotics in general. I confess that I got little pleasure from our penicillin work, and that, I believe, for two reasons. In the first place I found the constant stream of research reports from all participants in the cooperative venture, amounting almost to a flood, very distracting, and, indeed, counterproductive in that they hampered the free development of my own ideas. Secondly -and this applied in variable degree to all our war work - I have always found it difficult to do good research unless the subject is one in which I have a strong personal interest. I think this latter point applies to many academic research scientists, and that is why they are usually not very efficient in industrial contract work. Indeed, my advice to an industrial firm with a research problem which it wishes to solve expeditiously, is to do it within the firm, taking external advice as appropriate but not to contract it out to a university. I know, of course, that in recent years several industrially oriented units for contract research have been set up in a number of universities; but these are quite different in outlook and staffing from normal university departments, and have had variable fortunes. I still think that the proper place for industrial research is in industry.

I have already explained how chance in the shape of George Barger introduced me to the vitamin field; from that introduction grew an interest in vitamins, and especially in the chemical reasons for their importance. These interests are at the heart of what most people would probably regard as my main contributions to research - the chemistry of vitamins, of nucleosides, nucleotides, coenzymes and nucleic acids. Such a view is entirely reasonable, since there can be little doubt that our nucleotide work and the establishment of the chemical structure of nucleic acids form the base on which molecular biology and modern genetics have developed in such spectacular fashion during the past quarter of a century. Yet, in addition, I have always had a deep interest in natural colouring matters - an interest triggered by my association with Robert Robinson in research on the beautiful red and blue colouring matters of flowers known by the generic name of anthocyanins. As a result, I have, during my career, done a good deal of work on natural colouring matters and especially on those remarkable pigments found in aphids, those well-known sucking insects which are the bane of many gardeners' lives; I shall recount something of that research later.

In Manchester we had laid the ground for our foray into the field of nucleotide coenzymes. We had developed new methods for nucleoside synthesis and for phosphorylation of nucleosides with dibenzyl phosphorochloridate, and had discovered a new method for phosphorylating amines using diesters of phosphorous acid and polyhalogen compounds. (This latter reaction was, in fact, accidentally discovered by F. R. Atherton when he tried to remove acid impurities from a solution of dibenzyl hydrogen phosphite in carbon tetrachloride by shaking it with ammonia; the whole mixture set to a semi-solid mass of dibenzyl phosphoramidate.) I need not elaborate in detail, but during the first few years in Cambridge we had effected the first of our coenzyme syntheses — that of adenosine triphosphate (ATP), the substance which is involved in phosphate transfer and acts as the necessary reservoir of energy for muscular activity in animals. We also not only settled the structure of the known natural nucleosides and nucleotides by synthesis, but established their stereochemical configuration as well.

Already in 1938 when I started work in this field I was of the opinion that nucleic acids might be involved in the transmission of hereditary characteristics as had been suggested by the earlier work of Griffith on pneumococcal transformation; Avery's demonstration in 1944 that deoxyribonucleic acid (DNA) was the transforming factor seemed to me to settle the issue. Curiously enough Avery's work - so beautiful and, to me, so convincing - did not convince everybody. In the summer of 1946 I attended a symposium on nucleic acids held in Cambridge by the Society of Experimental Biology to which I agreed to contribute a paper on 'The structure and synthesis of nucleotides'. At that symposium I remember a violent argument between E. Stedman, who stoutly maintained that histones and not nucleic acids were the carriers of hereditary characteristics, and a number of others and notably Caspersson who, like me (and with better evidence), was a proponent of nucleic acid. I think it was really at that meeting that I first met and talked with the main operators in the biology and biochemistry of nucleic acids, and heard from Astbury about his X-ray studies. My interest was aroused, and I began - again for the first time -seriously to consider the chemical structural problems presented by the two types of nucleic acid - ribonucleic (RNA) and deoxyribonucleic (DNA). The time was in any case propitious, because we were just on the point of completing our first ATP synthesis and we now knew sufficient about phosphates and their behaviour to make nucleic acids, chemically speaking, a bit less daunting than they were to most people at that time. So we began to think about the problem a bit, and to study the behaviour of simple nucleotides alongside our coenzyme work.

I was, of course, familiar with most of the chemical literature on nucleic acids and their component nucleotides. As a result of his work extending over many years, P. A. Levene had substantially clarified the structure of the simple nucleotides and nucleosides which can be obtained by hydrolysis, and deduced correctly that the nucleic acids were made up of nucleotides linked together in some way through phosphate residues. But he had, based on analytical methods we now know to have been inaccurate, reckoned that only two nucleic acids existed - one from plants (RNA) and one from animals (DNA) and that each was composed of four nucleotides present in equal amounts. More unfortunate still, he supported the idea that the nucleic acids might be simply tetranucleotides which formed colloidal aggregates in solution. From the moment I read his claims and views I found myself in total disagreement. For one thing, there was already some evidence to suggest molecular weights of 500 000 or more for DNA, and, in any case, its general properties suggested strongly that it was a macromolecular substance like protein or one of the polymeric materials studied by Staudinger, and even then appearing in commerce in the form of synthetic rubber and synthetic fibres. Nor could I accept the idea that we were dealing with polymerised tetranucleotide units; on the evidence available I had doubts about the constant composition of both types of nucleic acids and the claimed existence of only two acids. These views were, of course, fully confirmed during the years that followed, but belief in the so-called 'tetranucleotide hypothesis' was, in my view, largely responsible for the slowness with which biochemists and biologists came to realise the importance of the nucleic acids in hereditary transmission. I have sometimes wondered whether the ready acceptance of the tetranucleotide hypothesis by many biochemists was not, perhaps, due to their belief that proteins with their manifold properties would be found to be responsible for all life processes, and they accordingly felt no need to look any further!