Reflections on drug research

One of the more striking characteristics of human civilization has been his attempts to use his intelligence to seek relief from his various bodily ailments. His original efforts were entirely empirical like a game of ‘Blind Man's Buff’. There is a record of these early activities in a museum in Heidelberg which authentically recreates the official pharmacies of folk-lore medicine that operated in Germany from the 14th to the 18th centuries. In their day, these pharmacies administered the official pharmacopoeias, the currently accepted list of remedies and nostrums of the day. The museum shows how the pharmacopoeias kept changing. As products fell into disfavour, new products appeared to fill the gaps. We now know that many diseases will ameliorate for a time by giving biologically inert-substances – placebos. So, from a therapeutic point of view, were these drugs intrinsically useless? Probably most of the remedies were indeed worthless. But folk medicine had its successes; some of them are still used in modern medicine. The roots of the belladonna plant are a source of atropine, the leaves of the foxglove are a source of digitalis, and the seeds of a common poppy provide morphine. How people originally found out about the therapeutic properties of these plants is truly a mystery. This empirical approach to therapeutics based on trial and error did not give way to an empirical one based on scientific knowledge until the middle of the 19th century. In 1856, William Perkin, then 18 years old, was doing amateur chemistry experiments on the top floor of his parent's home in London (Harrow, 1921). At that time, London was heated and lit by gas derived from the distillation of coal, a process that produced by-products, including coal tar. Professor Hofmann, Perkin's tutor, had shown him how naphtha extracted from coal tar could be converted to the artificial alkaloid known as naphthalidine, and Perkin was trying to convert this artificial alkaloid into a drug, the natural alkaloid, quinine. Quinine had come to Europe from South America in the 17th century where its antimalarial properties had been discovered by folk medicine. It was in short supply and very expensive but vitally important to prevent malaria which was rampant in many parts of the world. Perkin's experiment failed but he did produce a magnificent new colour – mauve, the first aniline dye. Mauve led to a whole new industry for synthesizing artificial dyestuffs and thence to the development of explosives, perfumes, photography and modern therapeutic drugs. After Perkin's experiment, the next contribution of dyestuffs to medicines came from Paul Ehrlich who was born 2 years before Perkin made his great discovery. By the time Ehrlich went to university, he had developed a passion for the microscopy of animal tissues, mounted on glass slides and stained with aniline dyes. Although he was not the first to use aniline dyes to stain tissues, he was the first to develop a theory on the staining process. He graduated in medicine when he was 24 and his graduation thesis on ‘On the theory and practice of histological staining’ was remarkable. His early ideas about the chemical affinity of dyes would lead him on to his work with von Behring on antitoxins and his concepts of serum therapy. Due to his work on antitoxins he developed his ideas about receptors (Maehle et al., 2002). He imagined that cells sprouted finger-like processes that, with specific receptors expressed on their surfaces, could bind toxin molecules on a one-to-one basis. This receptor idea turned out, years later, to be the basis for the invention of many new drugs. Then he discovered that living cells in tissue culture, as distinct from pieces of dead tissue fixed in blocks of wax, could be selectively stained by another dyestuff, methylene blue. From this, he developed the idea of chemotherapy as a concept-driven goal. What he wanted was to find dyestuffs, like methylene blue which would selectively bind to receptors on the surface of living cells but which, unlike the blue dye, would be toxic and would kill the cell. He knew that many dyestuffs were organic compounds of the well-known poison arsenic. He therefore set out to screen organic arsenicals for with the that had been discovered to be the of he He first that the to an organic and a toxic was – in chemical he that was not the that but a and to from this, he its chemical ideas that he had developed in a of the chemistry of new was into with the was then the next was was a then he wanted to know the was the toxic a he as the therapeutic in he found a that was and had a therapeutic et al., It was the that he had and and as the known as Ehrlich was truly the of modern and of the modern was another still a he the in and first the of with gas and He his the and an and In he a of as and was by Ehrlich to their dyes in He of new in – and In this he discovered the of but was that a that was in would be in his fell with a In he with and made a He one about this experiment until the of human were in was the of and the The most to has been Paul a who his and his in the by from a that had been into medicine in as an for and was found to properties and of its properties could be for its wanted to he could the is a and he knew that chemistry was he to its and the properties of the new molecules The first known as the is when a is with an and its In the a of in in a is The tissue but when an is to the these are By synthesizing and new compounds these he a of the specific chemical for the properties – now them and are the of modern he by new drugs. were a and a and are still drugs as from years of was of an of chemical that he to as as his knew had his of chemical blocks that had for him in the From then led to and and he and to new drugs. one has great and a of to discovery. from molecules that knew had for tissue new compounds in whole in in and used the of these to new molecules based on ideas about used the approach that had as the basis of Although of them had an for their to lead to a invention based on that were were – and one to them from their – with their as as was to their – not the of a but the of that a was 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