October 16, 2014, by Editor

To cure all ills

This week’s blog is the fourth one from our  Emeritus Professor, Malcolm Stevens FRS:

I returned to Nottingham to embark on my PhD research on 1st October, 1960, on one of those magical still days which show the autumnal glories of the University campus at its best, a scene which has attracted and bewitched generations of past students (and their parents) and, doubtless, students yet to be recruited. I have always had a compelling urge to collect and hoard conkers and the horse chestnut trees on campus always obliged in dispensing their bounty to coincide with the arrival of new students. A fresh conker, polished on the trousers reveals one of the most glorious textures and hues of nature.

I was still happily ensconced in my Lenton lodgings just a brief cycle ride to the Pharmacy Department on Clifton Boulevard. I recall watching the TV show ‘Twenty Questions’ with my landlady and landlord, although it was never the same after the curmudgeonly chairman Gilbert Harding was sacked in 1960 for drunkenness and rudeness on air. Although the Department was sited in quiet and solitary exile on the very edge of campus, over the next few years the area vibrated to the thud of pile drivers seeking solid ground to support the emerging academic fortresses of Chemistry, Physics and Engineering which became ‘Science City’ as it is known today. The newcomers, possibly encouraged by the foundingVC, who as an Oxbridge Classics don barely concealed his hostility to the very thought of pharmacists working in his brave new University, delighted in ‘kicking sand’ in the faces of their poor relations. It took a further 25 years before the roles were reversed – convincingly so, and in spades.

Four of my degree contemporaries also stayed on to join the vestigial departmental research enterprise. Whereas they all seemed to have defined projects I was never quite sure what my research targets were. My funding came from Boots and I assumed that it was linked to drug discovery in some way: my supervisor Prof Bill Partridge airily suggested we might explore the synthesis of some small heterocyclic compounds which, with luck, might cure all the ills which mankind was heir to! The keen but gullible Stevens went along with that. (As the supervisor of scores of research students of my own in later years I hope I gave them a rather more convincing reason to spend three years in postgraduate poverty.)

The starting material required for my synthetic work to cure all diseases was anthranilonitrile (o-aminobenzonitrile). This could not be purchased at the time and had to be synthesised by pyrolysis of isatin β-oxime, a reaction originally discovered by Partridge. The process involved putting the oxime in a large open round-bottomed flask, spot heating the glass with a bunsen flame and then retiring quickly behind a reinforced glass screen to watch the fireworks. The heated spot eventually spread producing a necrotic bubbling magma from which anthranilonitrile could be isolated in 65% yield. Amazing eh? Partridge increased the scale of the reaction with each new recruit so testing their ‘bottle’ for research; when it was my turn the scale had increased to 250g! As nothing was known about the mechanism of this reaction the bushy-tailed Stevens decided to ingratiate himself with his supervisor by cracking its secrets. Accordingly, late one night, an experiment was devised whereby the reaction, sensibly on a much smaller scale, was now contained in a sealed flask with the effluent gases trapped by passing them through various diagnostic reagents. Spot-heating was followed by the evolution of water – actually super-heated steam! – and, in the brief moment before the contents of the flask erupted violently, lime water was seen to go cloudy. I didn’t report this clandestine work to my supervisor, but given the information that the only reaction products were anthranilonitrile, water and carbon dioxide, any decent organic chemist could work out the mechanism. Go on chemists try it. Now this experience taught me a valuable lesson: my research destiny was to go from A to B along as straight a line as possible, leaving exploration of the oft more interesting mechanistic by-ways and cul-de-sacs to others.

My work often involved the synthesis of cyano compounds and, in the absence of an IR spectrometer, it was necessary for me to process them to the corresponding amides and acids to confirm their structures. To obtain NMR spectra we had to send compounds to ICI in Alderley Park where one of Partridge’s former students worked. To change the recording wavelength on our in-house, but venerable, Unicam SP200 UV spectrometer one had to manually rotate a prism. I spent most of weekday evenings laboriously recording the UV spectra of my products; each one took about 2 hours. (Actually there is one of these antique devices in the Science Museum, I understand). To lighten the routine I played bridge in the evenings with other postgrads while we were waiting for our reactions to reach end-points. Such quick-fit as could be afforded was guarded as if it was the crown jewels and there were several lacerations incurred by trying to drive glass tubing through corks. None of us wore safety glasses; solvents, including benzene, were routinely evaporated on the bench; and the fume cupboards operated on the principle of convection only. My project drifted on rather aimlessly but I gained a reputation from my struggling contemporaries of being lucky and able to synthesise anything I set my mind to. I amassed a large collection of vials containing beautifully-crystalline compounds, all neatly labelled as only pharmacists can. Over time my molecules, although small, became engorged with nitrogen atoms, often to the point of being unstable and the first intimation of a type of structure which was to become a block-buster drug over four decades later was becoming apparent.

Outside of work there were some notable historical events: in Jan 1961 JFK became President of the USA carrying the hopes of the world’s youth with him; then in April of that year Yuri Gargarin, the first human is space, piloted his Vostok spacecraft in an orbit of earth; and finally, lest I forget, later that year I got married to Val, the girl from school, who danced like a dream, sang like an angel and who could “act the drawers off Sarah Bernhardt” as thespians are wont to claim. Our nuptials didn’t make world news, but did necessitate a move out of my Lombard St. lodgings firstly to a small flat on Derby Rd looking across Lenton Park to Lenton church and thence, in October 1962, to a tiny cottage on Salthouse Lane off Beeston High Rd. Being so close to FB Hall we were invited by the warden, Miss Spellman, to become members of FB Senior Common Room. We were invited to many Hall events and became ‘moral tutors’ to a group of the students. So sixties! I missed my former landlady’s cheerful “eh up mi duck” every morning and her apple pies on Sundays. The Beeston move coincided with the ‘Cuban Missile  Crisis’ but as we had no radio or television at the time we were blissfully unaware of the high stakes poker game being played by Kennedy and Khrushchev with nuclear war a strong possibility. With exemplary timing the Beatles’ ‘Love me do’ became their first hit.

It was in the early 1960s that I became deeply politicised: I attended a big rowdy Union meeting in the Portland Building protesting against apartheid which was addressed by all of the local political firebrands. But what I remember most was the music played before and after – Rimsky-Korsakov’s ‘Scheherazade’. I fell in love with it and it was the first LP I ever bought. The satirical television programme ‘That Was The Week That Was’ fronted by the young David Frost in 1962 and 1963 had plenty of ammunition to lampoon the aristocratic Tory Party, notably during the ‘Profumo Affair’ of 1963. Then the general election of 1964 came after “thirteen years of Tory misrule” according to Harold Wilson, the then Leader of the Labour Party. I attended an old-style political rally addressed by Wilson in the Albert Hall in Nottingham just before the election when he talked, inspiringly, about a Britain transformed in “the white heat of the technological revolution.” And then there was a barnstorming eve-of-poll alcohol-fuelled performance by George Brown in Slab Square extorting the “brothers to unite for victory”.  He was a consummate master of the politics of the gutter; only Lord Hailsham for the Tories could compete in the common abuse stakes. They were both wonderful entertainers.

By the final year of my research a theme was emerging and I mined a productive seam of bicyclic compounds with multiple nitrogen atoms; some of these compounds displayed modest antitumour activity in a rat sarcoma model maintained in the Cancer Research Laboratories adjacent to the Pharmacy Department. I sometimes assisted with the injections of these animals. They were not the docile, inbred white rats familiar to researchers today: rather they were large, grey and ill-tempered, probably only a generation or so out of the sewers. I received many a slashing bite from these sullen creatures in the name of research. As was the practice in my lab, writing up my thesis started after Christmas in my third year. A pliant secretary typed out my masterpiece at the cost of one shilling/page including making four carbon copies; this seemed a fortune at the time. My personal copy was the fourth carbon copy and even in 1963 practically unreadable. All of the several hundred chemical structures had to be drawn by hand with a Rotring pen and stencil and then glued into each copy of the text. What a contrast to the beautifully crafted theses which are produced by students on their computers nowadays. Nevertheless the thesis was ready for submission by the 1st May deadline followed by my oral exam soon thereafter. My external examiner, Prof John Stenlake from Strathclyde University and a co-inventor of the neuromuscular-blocking drug atracurium besilate, also commented that my work did not seem to have an overarching theme but, as he only had 45 minutes to examine the theses of my contemporary Sandy Slorach and myself before rushing to catch his train northward, he fortunately didn’t dwell on the matter. Many of today’s students have to endure a three or four hour ordeal in their PhD oral: I suspect that nowadays examiners see a PhD oral as more of a personal ego-trip (for the examiner) and in their keenness to impress with their omniscience forget the anxiety and distress often imposed on the suffering student and his/her supervisor. On the other hand I do recall one student who was most upset that her exam was only four hours and complained that she was being short-changed – but then she was Chinese.

So, in mid-1963 with a freshly minted PhD in my pocket I faced the burning question: what next? I did make overtures to move to Canberra in Australia to work with a notable medicinal chemist there by name of Adrien Albert. He was rather under-rated internationally despite many pharmaceutical innovations to his name: his discovery of the activity of antibacterial acridines led him to identify the importance of the ionisation state of drugs in determining their biological action; he was the first to introduce the term ‘pro-drug’ to describe molecules that are chemically- or metabolically-activated to the true bio-active species; and his introduction of the terms ‘pi-deficient’ or ‘pi-excessive’ to describe the different properties of, for example, pyridine or pyrrole, respectively, have allowed generations of pharmacy students to make sense of the otherwise baffling concept of aromaticity in heterocyclic chemistry. When I became Head of Pharmacy at Aston University in 1983 I was able to invite Albert to spend a year on sabbatical where, in his robust 80s, he taught final-year pharmacy students a lecture course based on his book ‘Selective Toxicity’. My own copy of this book is still a most treasured possession.

I set aside all thoughts of Australia when I was offered a post-doctoral fellowship funded by the British Empire Cancer Campaign in Nottingham. This was to be the start of a long relationship with the Charity and its successors. The position allowed me to explore the promising synthetic leads that had emerged towards the end of my PhD project; in addition I expanded my biological knowledge and developed the skills of paper writing and conference presentation – a solid research apprenticeship for a career in drug discovery no less. Referees’ reactions to my papers have changed over the decades: my earliest efforts were praised for their sound science and imaginative chemistry, but my writing style was once criticized for being “flowery”, whatever that means. Fifty year on I get plaudits for my “poetic” writing but am occasionally panned for dodgy science. This change is telling me something!

It was not all work however: my wife and I had a large circle of friends across campus and in theatrical circles in town, and were avid party goers. Barely a week went by without us slinking into the kitchen of our host with a bottle of lousy headache-provoking Sauterne or, worse, Matteus Rose. (Does anyone remember those potions?) We learned the mean trick of dumping our bottle on the table and drinking better produce that other more discerning, or prosperous, revellers had brought.  Nottingham really did swing in 1965 and Yates’s was the place to be seen on Friday and Saturday nights. I recall one regular, a striking six foot tall blonde dream who did her hair in the popular beehive style of the day –  and that added another nine inches! I believe she was involved somehow with ‘Birdcage’, Nottingham’s first boutique. She wore the shortest of skirts and high-heeled thigh-length boots and had the ultimate in accessories: a borzoi dog. In utter contrast, drinkers were entertained by background music from a trio of veteran musicians who affected a style of playing gems from the shows – ‘The Student Prince’, ‘The Desert Song’, ‘Rose-Marie’ and the like – in a wobbly, slightly off-key style. They were real pros and mightily chuffed if you requested a special number from their considerable repertoire. Would it work today, I wonder?

Before leaving Nottingham my wife and I hosted a summer party in our tiny cottage on Salthouse Lane. It became memorable for a game of poker which started late and finished just as dawn was breaking.On the final hand I was dealt the king, jack, ten and nine of spades and a nothing. I changed the nothing and drew…. the queen of spades! A royal flush no less. If that wasn’t enough, and the chances of such a hand are less than 1 in 100,000, I was playing the hand against two opponents each with a full house. As a good host I eventually took pity on my friends but still made enough to pay for all the drink and food. I took this exceptionally rare event as a good omen as I prepared to complete my first incarnation in Nottingham and depart for a lectureship to a strange, far-off, foreign land. Scotland.

Malcolm Stevens 15th Oct, 2014

Posted in Pharmaceutical Research