Gunning for the parasites

From a book meant for reading rather than reference I seek inspiration; inspiration to reflect on the subject matter, and which perhaps makes a contribution, however insignificant, to the topic.

When I was a medical student at St Mary's Hospital Medical School in Paddington, I came across a book in the library by John Krantz and Jelleff Carr titled The Pharmacological Principles of Medical Practice . This book combines a thoughtful history of pharmacology and a plentiful helping of the folklore of drugs derived from natural products with the science of pharmacology and its clinical application through modern therapeutics. It is heady stuff, and looking back it undoubtedly influenced me towards my career in clinical pharmacology.

I began this review as journey work, but halfway through the introduction The Elusive Magic Bullet hit the spot and imperceptibly I began reading it for fun and interest and found John Mann's account of the search for the perfect drug inspirational. There is so much of interest in this book that I cannot do justice to it all. It caused me to reflect on the drug discoveries I have witnessed career and the landmark discoveries to which I have been close.

For example, one day in 1953 I was in a practical bacteriology class when the lecturer asked me to take a written message to Professor Fleming. Alexander Fleming was then professor of bacteriology, the world-renowned discoverer of penicillin ( pace Oxford), still basking in the Nobel prize and world adulation. I went across to the great man's room, now marked by a plaque on the north east tower of the old St Mary's. Clutching the note, I knocked on the door and on hearing a Scottish grunt went in. Fleming was seated at the very bench depicted in Mann's book, just as I remember it, even to the green carved dado and the packet of Gold Flake cigarettes. He quickly looked at the note, turned and asked me: "Boy, do you know how to plate out on agar?", referring to the process of transferring a bacteriological specimen to an agar culture plate to grow and thereby identify the bacteria. I mumbled something incoherent. He got up from his bench. "Sit down here, lad, and I'll show you how." Then he proceeded to teach me how to do it, by making me do it. There cannot be many people who have been tutored in this fundamental bacteriological craft by Alexander Fleming.

Penicillin is as close to the concept of a magic bullet as one can get. The term was created by Paul Ehrlich, a giant of medical science: "Magic bullets which aim exclusively at the dangerous intruding parasites, strangers to the organism, but do not touch the organism itself and its cells."

The book relates the fascinating history of the development of anti-infective chemotherapy (mainly bacteria and viruses), vaccination and immunisation from the late 1880s to the present day. In my view this field has been the medical miracle of the 20th century. The story is peppered with great names and Nobel prizewinners: Koch (TB), Ehrlich (immunity), Domagk (prontosil), Fleming, Florey, Chain (penicillin), Waksman (streptomycin), Hodgkin (Nobel prize for structure of vitamin B12 but carried out important X-ray crystallographic studies on penicillin G in 1945).

There is a chapter on the chemotherapy of cancer illustrating the strange mix of serendipity and directed science that is slowly giving way to a completely rational approach to drug therapy, that is the magic bullet should be aimed at a specific target, predetermined by an understanding of the molecular pathology of the disease. However, there is a precondition for the magic bullet: that the process to be manipulated for therapeutic ends is not a crucial one for the function of normal cells and tissues. Bacteria, viruses, parasites, fungi and other infective organisms are in various ways quite different from normal cells. Cancer cells are different in terms of growth control and some metabolic processes, but sometimes not all that different in rapidly changing cell types, such as the gut lining, bone marrow and lymphatic tissue. Often, anti-cancer chemotherapy is not that specific, and it is these rapidly turning over tissues that suffer, leading sometimes to severe adverse effects such as nausea, vomiting, diarrhoea, anaemia, immuno-suppression and infection. Again the field attracts Nobel prizes: Huggins (hormonal control of prostatic cancer), Elion and Hitchins (for general principles in drug discovery, but particularly for drugs affecting nucleic acid synthesis).

One field in which amazingly fast drug discoveries have been made and in which the use of drugs is governed remarkably by all the lessons learned from anti-infective chemotherapy in the past century is anti-viral drug therapy in HIV infection (Aids). While it is true that many anti-HIV drugs have serious adverse effects, nevertheless by judicious combinations of anti-viral drugs that act as magic bullets hitting different targets on the virus, the replication of the virus can be greatly slowed, as can the progression of the disease in the patient.

An unfortunate property of HIV is its ability to mutate; mutations can render it resistant to anti-HIV drugs. Resistance to anti-infective agents has been known since the days of sulphonamides. For instance, the multiple drug treatment approach now seen with HIV has been a routine principle for more than 40 years in the treatment of tuberculosis in an attempt to avoid resistance. Mann deals with this problem of resistance to magic bullets in a most lucid way.

In a seamless journey, we are well prepared by the author for the exciting application of gene technology and the new genomics to the control of infectious disease and its utilisation in the production of immunogenic proteins of pathogenic viruses. There is also a real sense of an adventure. This is a story of people starting scientific work largely in the dark, inventing whole fields of biological science, having the courage to back their considerable wits, picking up the serendipitous observation and running with it, asking deceptively simple questions, focusing, and coming up eventually with quite simple answers. Mann puts all this over without once adopting an attitude of arrogance about the superiority of science: an unpleasant feature of much popular biological science writing today. He keeps up the pace, the excitement and the promise for the future.

Who should read The Elusive Magic Bullet ? It requires a good deal of biological and a little chemical knowledge, certainly post A level and maybe even second-year undergraduate level. I would suggest: medical students, pharmacy students and undergraduates in all the biological sciences and medicinal chemistry, and all the graduates in those fields who would like to read about one of the great human discovery stories of the 20th century. Who knows, this book may inspire some impressionable young mind to embark on a similar adventure in the new century.

David Grahame-Smith is professor of clinical pharmacology, University of Oxford.