Book review: The Drug Hunters

Authors: Donald Kirsch and Ogi Ogas

Link: https://www.amazon.com/Drug-Hunters-Improbable-Discover-Medicines-ebook/dp/B01HDVCRY0/

This book is the authors' attempt to explain what the job of "drug hunter" is, specifically to explain how hard it is (partly to counter the "pharma is evil" narrative). The book takes a historical perspective, roughly covering different "eras" of drug hunting where the "hunting" was done in different places.

Note first the term "hunter": this is different than "inventor" or "designer". This word choice is (at least partially) intentional. For most of human history, there was no notion that new drugs could be created, just found in nature. And, the vast majority of drugs ever created were "found" rather than "designed": either a substance produced by plant/animal/fungus/etc was found and found to have a certain therapeutic effect, or somebody was testing artificial substances to see what happened and happened to find a therapeutic effect.

The basic eras of drug hunting were:

• Plant era: in ancient times basically all drugs came from plants and were discovered by trial and error. Plants secrete all sorts of substances and people naturally try eating different plants, so randomly discovering therapeutic properties is not too surprising. People had no really understanding of why anything worked though. Example drug: quinine (anti-malarial drug extracted from the bark of a tree).
• Alchemy/chemical era: trying new chemicals synthesized by alchemists, again with no idea why anything worked. Example drug: ether (an anesthetic).
• Synthetic chemistry era: people use new chemical synthesis methods to improve on natural drugs. Example drug: aspirin (modified version of salicylic acid, where the modification of adding an acetyl group reduced unpleasant gastrointestinal side effects while preserving pharmacological activity).
• "Magic bullet" era: drugs were designed to achieve a specific effect in the body (eg killing a microorganism). The pre-requisite for this era was having some understanding of what actually caused disease (mostly germs), otherwise obviously nothing can be intentionally designed. Paul Ehrlich was studying dyes and had the idea of a "magic bullet", a chemical that just targets and kills the pathogen (something he suspected might be possible because there were microscopy dyes that only stained pathogens and not animal cells). Example drug: arsphenamine (aka salvarsan), a drug against syphilis.
• "Regulation" era: not an era of discovery per se, but in the 1930s-40s governments (particularly the US government) started to regulate drugs to ensure they were safe. This obviously improved safety but made development and testing more costly. Notable drug disaster: Elixir Sulfanilamide, which was a drug mixed with toxic diethylene glycol (intended to give it a sweet flavor).
• "Science" era: for most of history pharmacy was a "pre-scientific field", basically just a list of effects without any organizing principles or clear conceptual frameworks. Gilman and Goodman wrote an influential textbook that tried to describe all known drugs scientifically, forming the basis for pharmacy to be a more scientific field (like it is now).
• "Microbe" era: starting with penicillin, scientists screened compounds from microscopic organisms (bacteria and fungi). Example drugs: penicillin and streptomycin. The chapter ends with a commentary of how antibiotic discovery is not commercially attractive to big pharma, which is a huge shame.
• "Animal" era: medicines from animals, like hormones and antibodies. Example drug: insulin.
• "Epidemiological" era: using insights from epidemiology to understand causes of disease, and therefore how one might treat it. The chapter (chapter 10) discusses cholera and John Snow, although no drug was invented for Cholera at this time. Example drugs: Diuril and Captopril as anti-hypertensive agents. They were known to lower blood pressure, but this was only linked to cardiovascular health by the "Framingham Heart Study" which overturned medical opinion that hypertension was good.

(NOTE: these eras are not sequential, some of them overlap, especially the later ones)

In the end there are 2 chapters which don't really fit into any of these eras: the story of how the birth control pill was invented and a collection of stories about drug discovery where luck played a huge part.

Overall I'd highly recommend the book. The anecdotes are great, and it provides great context for the past of drug discovery, which was mostly about "screening" and "luck". It implies that the current efforts from companies like Recursion to do drug design are 1) historically anomalous 2) very very difficult. I don't think we should be deterred, just aware of the past. Overall I'd highly recommend this book to anybody in pharma / drug discovery / AI for drug discovery.