When Adrien Albert died in Canberra on 29th December 1989, Australia lost an outstanding son. Not only had he introduced and firmly established the discipline of medicinal chemistry within this country but, in so doing, he had contributed greatly to research in heterocyclic chemistry. Little wonder that his early research and scholarship in both areas had been recognized even in 1948 by Sir Howard (later Lord) Florey, who induced the Australian National University to offer Albert the foundation Chair of Medical Chemistry within its newly-established John Curtin School of Medical Research, a position he occupied with distinction until his retirement in 1972 (1). Although a complex person, Albert operated on two simple principles: time was the most precious commodity in life, and, for any who undertook scientific research, the work was infinitely more important than the worker. Those who could share or appreciate these beliefs found in him a stimulating and kindly colleague; those who were irritated by them soon went elsewhere.
Albert was born in Sydney on 19th November 1907. His father, Jacques Albert, was a businessman in the music industry who had come to Australia from the Ukraine, although (probably) of Swiss nationality, while his much younger mother, Mary Eliza Blanche, was Australian born; he had two considerably older half-brothers from an earlier marriage of his father. Jacques did not survive many years, so young Adrien was brought up by his mother and a more distant relative in Sydney. After attending primary schools in Randwick and Coogee, he eventually settled into the Scots College, Sydney, for his secondary education: there he excelled in both music and science, although his youthful enthusiasm for an experimental approach to the latter sometimes proved embarrassing to the school. He matriculated in 1924.
At this stage, Albert was expected to enter the family music-publishing business but he had his sights firmly set on a career in pure science. Eventually a compromise was reached and he undertook the then current course in pharmacy, which involved part-time attendance at Sydney University combined with a type of apprenticeship in a pharmacy. However, having become a State-registered pharmacist in 1928, Albert soon realized that life in a pharmacy consisted of too little science and too much commerce for his liking. Accordingly, after the inevitable wrangle, he returned to Sydney University and completed a BSc with first class honours and University Medal in 1932. He worked briefly in the University's Pharmacy Department where he produced his first papers, and then for a period in a fabric dyeing firm to save some money.
He departed for London in 1934. There he commenced research for the PhD degree under he guidance of W.H. Linnell (2) at the College of the Pharmaceutical Society, part of London University. His research project, on the synthesis of new aminoacridines as potential antiseptics, introduced him to the world of heterocyclic chemistry and led to his life-long fascination with the role of heterocyclic compounds in chemotherapy and medicine.
Because he was forced to live on his meagre savings, supplemented only by a minute income from some part-time dispensing work in London, his meals became irregular and inadequate: this, combined with long hours at the bench, led inevitably to stomach ulceration, haemorrhage, and perforation. Emergency surgical intervention was carried out by a junior registrar at a London hospital in the middle of the night: although his life was saved thereby, he was left with an appalling legacy from which he suffered grievously for the rest of his life, despite later skilled reparative work. However, he graduated PhD (Med) in 1937 and immediately set out on a brief but extensive journey (the harbinger of many in later life) to visit German, French and other European centres of chemotherapeutic research, then located mainly in industrial laboratories.
Albert returned to Australia in 1938 and took temporary teaching positions (offering some research facilities), first in the Pharmacy Department, and subsequently with J.C. Earl in the Organic Chemistry Department of Sydney University. His continuing presence in the latter department was engineered by Earl, using a variety of funding devices, until Albert was appointed as advisor on medical chemistry to the Medical Directorate of the Australian Army in 1942. During this period, he not only continued his earlier acridine antiseptic research with any available co-workers, but also undertook the development of a practical synthesis of the acridine antimalarial, mepacrine ('Atebrin'), and the industrial scale preparation of the antiseptic, proflavine, both of which were needed desperately in the Pacific war zones (3). The Organic Chemistry Department's technical laboratory was given over to the manufacture of proflavine under the direct supervision of Dr Konrad Gibian, an employee of a small but active chemical firm, Timbrol Ltd. Many kilograms were produced under very difficult conditions: all those associated with the makeshift plant (including Gibian and Albert) remained a bright yellow hue for several years afterwards and all paths in the vicinity fluoresced a brilliant green whenever it rained. Proflavine was subsequently replaced by one of Albert's new compounds, aminacrine (9-aminoacridine), but it was produced in an industrial plant under the trade name 'Monacrin'.
Albert was always extremely tall and slim (hence the affectionate nickname, 'the snake' used by his less respectful students) and, at this time, he dressed very nattily in a double-breasted navy-blue suit surmounted by a then-fashionable narrow-brimmed felt hat with a small red or green feather in the band. During a wartime trip to Washington in connection with the mepacrine project, Albert inadvertently sat upon his prized hat all the way across the Pacific in the belly of a bomber: it was never seen again, nor did he ever buy another hat.
Towards the end of the war, Albert's research was at last appreciated by a recently formed funding organization, the (Australian) National Health and Medical Research Council, which began to support his work more adequately. Thus he built up a 'chemotherapy team' which lasted until his departure in late 1947 to join the Wellcome Research Institution in London.
These years had seen the transformation of Albert from a penniless postdoctoral person, with little but potential to offer, into a respected team leader with an established pattern of fundamental research in the burgeoning area of chemotherapy, so recently stimulated enormously by the advent of penicillin and the antibiotic era. His classical experimental studies on the antimicrobial activity of aminoacridines and hydroxyquinolines (with S.D. Rubbo as his chief biological collaborator) had now firmly established the overwhelming importance of physical properties in governing the activity and selectivity of drugs. The chief properties studied were (i) electron distribution governing ionization, the degree of which facilitated or forbade combination of the drug with its receptor, and (ii) steric properties, which controlled access to the correct receptor as well as the fit on arrival. Thus only two of the five possible monoaminoacridines were highly active as antibacterials: the active isomers, 3- and 9-aminoacridine, were those with ionization constants which ensured that they existed mainly as cations at the biological pH of about 7.3, whereas the inactive isomers were less than two percent cations under such conditions. This correlation was subsequently tested rigorously using more than a hundred substituted aminoacridines on more than twenty bacterial species: only those acridines which were greater than fifty percent cations at pH 7.3 emerged as powerful antibacterials. Turning to steric properties, it was shown that any active molecule required a flat area extending over at least three six-membered rings. Thus 4-aminopyridine and 4-aminoquinoline had acceptable ionization constants but lacked sufficient flat area for high activity; likewise, 9-aminoacridine with one of its outer rings hydrogenated (and hence no longer flat) lost its activity although its pKa was still satisfactory; and activity was restored to 4-aminoquinoline by the addition of a coplanar styryl grouping. These findings were of course further tested with other compounds. Albert's expertise in the chemistry of acridines resulted in the publication of an excellent monograph, The Acridines, in 1951 and an updated version some fifteen years later. In reading about acridines, it should be borne in mind that the numbering system was changed by the International Union of Pure and Applied Chemistry about 1950: thus for example,5-aminoacridine became thereafter 9-aminoacridine. Most of Albert's acridine papers and the first edition of his book used the old system but his later papers and the second edition of his book necessarily employed the revised system.
The Wellcome Research Institution in London did not retain Albert's services as a senior research worker for long. On 1st January 1949, he took up his appointment as Professor and Head of the Medical Chemistry Department within the Australian National University. Because no building was available in Canberra, he promptly established his department in hired laboratories on the top floor of the Wellcome Building in Euston Road, London. An appropriate nucleus of staff was engaged and research began about 1st April 1949. As befitted the new era, Albert chose to abandon most former research topics in favour of a new start in purine and pteridine chemistry, an area then pregnant with possibilities following the introduction of 6MP (6-mercaptopurine) and methotrexate as effective anti-leukaemia drugs and the recognition of essential roles for the folic acids in biochemistry. As well as his own bench work, supervision of his new staff, and a deep involvement in planning the new (but yet unnamed) school of medical research for Canberra, Albert now became quite obsessed with the concept of selective toxicity: he had introduced this novel term into pharmacology during a remarkable series of lectures delivered with the encouragement of F.G. Young at University College London during 1948-49. Thus he envisaged an ideal drug as highly toxic to an invading pathogenic organism but minimally toxic to the host: moreover, this concept was applicable not only to human and veterinary medicine, but to pesticides, selective herbicides and such like. This unifying thought was released to a wider audience in the tiny first edition of Selective Toxicity in 1951 and it was progressively developed in successive editions during the next thirty-five years. These books became essential reading for generations of pharmacologists, medicinal chemists, and agricultural chemists, especially in the United States, Japan, and the less conservative parts of Europe.
Despite the enormous enthusiasm of both professor and staff, the new department was not without its vicissitudes. For example, Albert did keep an unusually tight rein on his research staff and this irritated some beyond endurance: one such person even complained formally to Florey (then the de facto director of the unassembled school of medical research) of Albert's perceived shortcomings in human relations, a complaint rejected outright at the time but later followed up tactfully by Florey. Several years later Albert's application for tenure on behalf of an excellent member of his research staff was rejected by the appropriate board in Canberra because of vehement opposition by two influential members, apparently on political grounds. To his lasting credit, Albert campaigned at the highest level, boots and all, against this misguided decision and it was eventually reversed, alas too late to retain the services of the person involved.
At the outset, it was expected that the department would stay in London for perhaps three years but in the event it was there for seven. During that time the new pteridine project produced detailed data on the synthesis, properties and behaviour of hundreds of simple pteridine derivatives, only one of which had been known at the outset. This provided an invaluable sound basis for later and more biologically applied work elsewhere (4). A similar approach to purines was less spectacular, simply because more was known of the basic chemistry to start with. Aspects of related heterocyclic nuclei were studied similarly as required for comparison. Parallel with the above efforts, work continued on the degree of metal-binding by heterocycles, amino acids, and other naturally-occurring substances, mainly in connection with antimicrobial activity. Although the last project proved fascinating at the time, the mathematics involved in calculating stability constants for metal-ligand complexes in solution were so time-consuming and wearisome, that only in later years (during the computer age) did this work bear significant fruit in the hands of Albert's associate, D.D. Perrin.
In 1956 Albert at last received word that the new building in Canberra was ready for occupation. Accordingly, every piece of equipment (down to the last beaker) in the Euston Road laboratories was carefully packed by all available hands and the professor, most of his staff (including families, domestic pets etc.), and a great many packing cases set out in October for Canberra by devious routes. By March 1957, research had recommenced in Wing-D of the new building, which included a sizeable technical-scale laboratory now fully equipped and serviced for pilot-scale production of intermediates or final products for biological or even clinical trial. Unfortunately, Albert's foresight in providing this facility was never fully rewarded: it proved so expensive to operate effectively that it was eventually converted into an animal breeding and holding area.
Research now flourished with a greatly expanded staff but Albert soon noticed that he enjoyed less personal research time at the bench on account of a greatly increased administrative load and necessary attendance at various boards, committees and other such paraphernalia accumulated by universities. However, he pushed ahead, especially with an investigation of covalent hydration in the pteridine series: this was a chemically and biologically important phenomenon he had discovered shortly before leaving London. He now realized that such addition reactions also occurred to other highly-nitrogenous heterocycles and could involve alcohols, the so-called Michael reagents, amines, and even other heterocycles in place of water. All aspects of this area were explored with his customary thoroughness. He also made several in-depth excursions into the very difficult area of hydropteridines and related series, where he developed much needed methods of synthesis and proof of configuration for such products, prone to facile prototropy. Because of its fundamental importance to any understanding of the physical and biological properties of heterocyclic compounds, Albert now returned to his studies of ionization. For example, he and his colleague, G.B. Barlin, studied tautomeric equilibria of hydroxy-, mercapto-, and amino-heterocycles in solution by using the twin tools of ionization constant measurement and ultraviolet spectra. In addition he produced the first and second editions of Ionization Constants, an invaluable manual covering the background, practical measurement, and interpretation of ionization data. Usually in connection with one or other of the above themes, Albert sometimes reverted to regular synthetic and/or degradative studies of specific pteridines or related heterocyclic compounds. In addition, he produced a slim and subsequently a more detailed edition of Heterocyclic chemistry, the first general text to classify heterocyclic systems logically as paraffinic (fully reduced), ethylenic (partly reduced), p-deficient heteroaromatics (e.g. pyridine), and p-excessive heteroaromatics (e.g. pyrrole) (5). This period also saw the publication of no less than four editions of Selective Toxicity (vide supra) as well as sundry papers and reviews on drug action.
Several years before retirement, Albert became involved (in connection with his covalent hydration studies) with a little known but potentially interesting system, the v-triazolo[4,5-d]pyrimidines: these he insisted 'for simplicity' in naming as 8-azapurines (with purine numbering) against all the rules of systematic nomenclature, the advice of his colleagues, and the wrath of editors. After toiling to make some required derivatives by the usual route from pyrimidines, he began to study alternative synthetic routes from 1,2,3-triazoles, even though such intermediates were by no means easy to produce at that time. His efforts prospered and by the end of 1972 he felt that he had mastered the chemistry sufficiently to begin the preparation of more specific derivatives as potential anti-neoplastic agents and the like.
About 1970 occurred one of the greatest disappointments of Albert's life. An ad hoc review committee recommended the closure of his beloved department, not on account of any apparent shortcomings in quality or quantity of scientific work emerging but on the grounds of a perceived lack of relevance to then current trends in medical research. However, on the advice of Faculty Board, the university eventually decided to compromise by continuing the discipline of medicinal chemistry within the John Curtin School as a slowly diminishing Medical Chemistry Group with more applied guidelines. This flew in the face of Albert's basic philosophy that the relationship between physico-chemical properties and biological activities in molecules was more important to the ultimate development of medicinal chemistry than was any direct search for new or improved drugs. His general distress was clearly expressed during his valedictory lecture on 25th October 1972 but only a hint of his feelings remained evident in the published excerpts (4). In fact, the proposed group was established in 1973 and continued vigorously under a new head until it was phased out thirteen years later (6).
Although he had the foresight and good fortune to arrange a Visiting Fellowship (with laboratory and office facilities, as well as some technical assistance) within the Research School of Chemistry for 1973 onwards, retirement proved a grievous blow to Albert. For some time he went about lamenting his fate as 'a discard on the scrapheap' and blaming the university for this state of affairs. However, he eventually began to rationalize the situation, to count his blessings, and to settle down to a productive retirement. This process, the recovery of self-esteem, was greatly assisted by several invitations from the United States to deliver the Patton, Blicke, and Smissman Lectures on various campuses and (in particular) to become a well-paid Visiting Professor in A.P. Grollman's Department of Pharmacological Sciences of the State University of New York at Stony Brook, on no less than six occasions.
Thus he continued his studies on the 8-azapurines and their precursors with whatever help he could muster, first in the Research School of Chemistry in Canberra, then at Stony Brook, and finally in the Department of Chemistry in Canberra from 1981. In addition, he maintained a steady output of helpful review-type papers on various facets of drug activity as well as a few others specifically on pteridines. He also produced the sixth and then the truly definitive last edition of Selective Toxicity (1985); a third edition (with E.P. Serjeant) of Ionization Constants (1984), complete with computer programs for hassle-free calculation of overlapping ionization constants and the like; a small volume, The Selectivity of Drugs; and a completely new book, Xenobiosis (on foods, drugs and poisons in the human body), a work already acclaimed as a masterpiece by life scientists and intellectual lay people alike and one which earned him the Olle literary prize from the Royal Australian Chemical Institute. At the time of his death, Albert was working actively on a totally new but yet untitled short version of his earlier heterocyclic chemistry text, this time aimed specifically at undergraduate teaching: it may yet be finished by an appropriate co-author.
As might be gleaned from the foregoing pages, Albert was a prodigious worker at the bench and an organizer of his own and his staff's time into the right channels. He disliked administrative work of all sorts and its cessation was the only good aspect of retirement evident to him. Because of his medical condition, he was unable to start work before 10 o'clock each morning but he seldom ceased work much before midnight, even on the weekends. Much of his writing and planning was done in the evening hours and his assistants and research students usually found long and detailed suggestions for the coming day's work (in characteristically minute handwriting) on their benches when they arrived each morning. Although he was careful to monitor the research area and general approach of his more senior staff, he seldom interfered in their day-to-day work other than to make general suggestions which were usually spot-on and readily accepted. Moreover, unlike some heads of departments, he was meticulous in discouraging the use of his name on papers to which he had made no substantial experimental or planning contribution. Thus, for example, many Parts of the Pteridine Studies series are missing from Albert's bibliography simply because he was not included thereon as an author: nevertheless, in all cases he had made at least minor contributions to the work by way of useful suggestions. However, he did insist, quite correctly, on his right to criticize constructively every paper, review or book to be submitted by any member of his staff for publication.
To anyone who was doing his or her job effectively, Albert was invariably polite and courteous but to any who appeared slack or inefficient (be it in the laboratory, a bank, a restaurant, or indeed anywhere) he could be terse in the extreme. Partly for this reason but mainly because he took great pains in preparing and delivering lectures, he was an excellent teacher of undergraduates. However, for much of his life he avoided teaching in favour of using the time for research, so that it was only in the late thirties and during the eighties that he was seen in this role. As a young man Albert was mildly misogynistic and clearly believed that a woman's place was in the home or in a secretarial or service role. More than once he seriously considered marriage but decided quite objectively that a wife and family would use up valuable time which could be better spent on research. Eventually he did realize and admit that the gender of a scientist was irrelevant but, with a few notable exceptions, he still avoided female co-workers.
Albert was an inveterate traveller providing there was a worthwhile conference or scientific contact at the end of each journey: moreover, he always delivered a well prepared and topical talk at any host institution or meeting and he invariably had telling points to make in any discussion. Thus he was an excellent roving ambassador for Australian science. He was particularly welcome in the United States where his brand of chemical pharmacology at the molecular level was accepted much earlier than in the more conservative European countries. He lectured and made friends in almost every country where heterocyclic chemical and/or drug research was at all developed. He was reasonably proficient in German, French and Italian along with some knowledge of Russian and most other major European languages. His last journey, to an International Pteridine Symposium in Zürich and subsequently to Britain and the Netherlands, was completed less than three months before his death.
Although research always came first, Albert did relax in moderation. He had an extensive knowledge and love of music coupled with considerable skill as a pianist: as might be expected, his playing was completely accurate but sometimes wanting in emotional content. He derived great enjoyment from his piano in early life and middle age but unaccountably disposed of it subsequently, possibly because of some imagined minor inadequacy in his own performance. Instrumental music, in particular that of Bach, Schumann and Schubert appealed to him greatly but he was not overly fond of lieder or choral music. His abilities as a visual artist were confined to photography (essentially a record of his travels) and to cartoons: his depictions of the canine adventures of Woofred and his wife, Ima Bitch, frequently appeared in the most unexpected places during the London years to the surprise and delight of close associates. Unusual plants and flowers fascinated Albert: although he grew only mundane indoor plants, his knowledge of Australian flora was extensive and proved invaluable for entertaining foreign visitors during a short bushwalk or visit to the botanic gardens. Perhaps because of his phenomenal memory and wide reading, he had a knowledge of clinical medicine far beyond matters connected with drug therapy: not being medically qualified, he was unable to make much practical use of this knowledge but medical practitioners often found him several steps ahead of them in diagnosis and up-to-date treatment of some disease or pathological condition.
Besides the Patton, Blicke, and Smissman lectureships and the Olle prize, already mentioned, Albert was the recipient of many honours. He was elected to Fellowship of the Australian Academy of Science in 1958; he was chosen for the inaugural Royal Society of Chemistry (Australian) Lectureship in 1960 and for the Royal Society of NSW Liversidge Research Lectureship in 1964; a biennial Adrien Albert Lectureship was endowed in his honour by the Royal Australian Chemical Institute in 1985; he received the Order of Australia (AO) in 1989; and in the very month of his death he received with genuine delight an invitation from his alma mater to accept a DSc (honoris causa) conferred posthumously on 31st March 1990 in the presence of his next-of-kin and two lifelong friends.
In early December 1989, Albert's health suddenly deteriorated markedly and he died three weeks later of complications resulting from a long-standing resistant Staphylococcus aureas infection, possibly exacerbated by a (genetic) Marfan syndrome condition.
This memoir was originally published in Historical Records of Australian Science, vol.8, no.2, 1990. It was written by D.J. Brown, formerly Reader in Medical Chemistry, Visiting Fellow in the Research School of Chemistry, Australian National University.
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