Reflections on drug research

Empirical approaches, discovery and invention 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 inertsubstances – 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 BJP British Journal of Pharmacology DOI:10.1111/j.1476-5381.2010.01019.x www.brjpharmacol.org