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application of the doctrine of signatures in Europe, or the Alain Li-Wan-Po
pharmacopoeia of the Chinese Yellow Emperor. For this
lecture, delivered in the grand city of Madrid at the kind personalised; the doctors that their diagnoses were specific
invitation of the Spanish Royal Academy of and the pharmacists that their medicines were specifics.
Pharmaceutical Sciences, I would like to begin here. For it The emptiness of those claims have resonated down the
was the Jesuit Cardinal Juan de Lugo, a Madrilenian, centuries. Pasteur and Koch, and later Paul Ehrlich and
trained at your famous University of Salamanca, only a Emil von Behring, established the methodology for
few miles from here, who brought the first truly effective validating such claims using the microscope and specific
medicine, the first ‘miracle’ drug, to the attention of the stains, and Behring’s serum therapy against diphtheria was
old world while serving as the Director of the apothecary the first truly effective antibody therapy. Jenner had
at the Santo Spirito Hospital in Rome. That medicine, the earlier, of course, developed the first vaccine which
cinchona bark or quinine, has saved countless lives since eventually eliminated smallpox worldwide on an empirical
those mid-seventeenth century days when Father basis before the cause was identified.
Bartholmé Tafur, the Peruvian Jesuit brought a small stock
from San Pablo for his Jesuit superior. As demand grew, a VARIABILITY IN HUMAN RESPONSE
Spanish Royal Order was issued in 1751 for the
establishment of a Royal monopoly for trading cinchona One of the great puzzles for the early non-charlatan
bark, with supplies located in the Royal Pharmacy here in physicians was the wide variability in their patients’
Madrid. responses to medicines. With the benefit of hindsight,
some of the reasons are obvious: (i) natural variability in
There would not be another miracle medicine until the the chemical composition of plants (e.g. the variable
late nineteenth century although the therapeutic value of pungency of Spanish chilies even of the same variety, and
opium had been discovered centuries earlier, both in the variation in the quality of wine, give some clear clues), (ii)
East and West, and morphine was isolated as a pure misdiagnosis (e.g. of fevers), (iii) adulteration, deliberate
medicinal chemical by Friedrich Sertürner in 1804 (1). or through ignorance, and (iv) variable dosing.
The age of modern synthetic medicines is perhaps best Paracelsus (2) knew of the importance of dosing,
anchored to the late 19th century with heroin and aspirin, stating, ‘All substances are poisons ... The right dose
both derivatives of naturally-occurring molecules; differentiates a poison and a remedy.' Arthur Koestler, the
morphine and salicin (the salicylic acid glucoside prodrug) colourful writer, once imprisoned in Seville during the
respectively. However, compared to the next revolution, tumultuous period of your National history, knew after he
brought about by the Pasteur’s and Koch’s discovery and failed in a suicide attempt. ‘Trying to commit suicide is a
proof of the microbial basis of many of the most gamble the outcome of which will be known to the
devastating diseases, those advances were modest in terms gambler only if the attempt fails, but not if it succeeds,’ he
of lives saved though not necessarily of pain avoided. said when he tried again years later. Sadly, the dose and
drug combination he chose did work that time, both for
THE BIRTH OF MODERN PERSONALISED him and his wife in their double suicides.
MEDICINE If drug response is so variable, then it is obvious that
personalizing their use would potentially improve therapy
The medical and pharmaceutical professions have (Figure 1).
always claimed that their clinical practice was
Figure 1 From one-size-fits-all to personalized therapy.
THE BIRTH OF PHARMACOGENETICS variation’ with ‘inheritance.’ This extension is important
as we inherit not only our genes from our parents but also
Pharmacogenetics can be defined as the study of the our microbiome and our cultures, including our diet and
impact of genetic variation on response to biologically our preferences, all of which may affect the action of the
active substances (pharmacons). More generally, the term drugs we take.
pharmacogenetics can be enlarged by substituting ‘genetic
94 @Real Academia Nacional de Farmacia. Spain
