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May
25

A Dying Breed

If you have ever wondered how the pill you are taking for your disease originated, then nowadays you don’t have to go far to find out, as a quick search of Wikipedia will return the molecule, who makes it, and a wide array of prescribing information and warnings. This has not always been the case, for many of the FDA approved drugs the histories have been buried in the scientific literature, passed on as oral histories or folklore even in the relatively recent field of pharmacology. You are also likely the beneficiary of some of the best molecule discoveries of the 20th century. These treatments were commonly developed by a wide array of scientists around the world working in the golden age for drug discovery. The probability is high that if you are an older reader you are taking many drugs simultaneously, and this may come with a panoply of side effects and foods to avoid. Besides understanding these interactions, we are also still learning of potential use of the same drugs against different diseases to what they were approved for. Today’s drug for one disease may be tomorrow’s cure for something else. A quick glimpse back to viagra, reminds us that it was intended for a totally different indication originally.

Those in search of medicines are the true heroes and rightly hailed in “The Drug Hunters“, which regales us with the many rich tales surrounding the drugs we take for granted, as deftly relayed by Donald Kirsch and Ogi Ogas. The authors should be commended for providing a whirlwind tour of the histories of some of the greatest hits in the cannon of drug discovery (and also the greatest misses) but leaves one wondering if this book signifies the epitaph. Their insights are deftly woven together from the author’s own hunting for antibiotics in soil, heavy emphasis on several well known treatments derived from plants, and the  deconstruction of natural products that lead to the eventual birth control pill. The latter is an epic caper on which complete volumes have been written but here from an angle that’s surprisingly topical. The rich outsider funding scientific research by the poor researcher makes for an entertaining counterpoint, leaving you to root for this unlikely team that ultimately lead to the contraceptive reaching clinical trials and reshaping society.

Some of the stories of discovery corrected the many ‘single inventor’ misconceptions that still linger and rightfully insert the co-discoverers that were omitted. Some errors rankle, like who is the biggest producer of insulin, which I believe is in fact Novo Nordisk. This in itself would make a useful addition to the otherwise excellent chapter on insulin, how a Danish company now leads the way for diabetic treatment. What is missed is perhaps telling at least to someone in the field. X-ray crystallography is all but ignored as is computational drug design and these combined efforts have lead to great life changing blockbusters like Gleevec and other kinase inhibitors for cancer. A number of key rules of thumb to help with drug discovery and productivity have originated over the last twenty years including ‘Lipinski’s rule of 5’ which has helped our understanding of the molecular properties to influence how drugs are absorbed. Recent drug disasters are given short shrift, for example the French drug BIA 10-2474 killed a clinical trial participant in 2016 and injured several others and is not even named, but this links directly to the story of drugs for pain and endorphins. Cannabinoids get no mention and yet the press is overloaded with the stories of cannabis used to treat various rare diseases. In fact, perhaps the most distressing omission is the way that rare diseases are omitted all together and the focus is on drug discovery for bigger diseases. We are in a new age, rare is big and common diseases are probably less profitable. There are pricing pressures and healthcare costs have rocketed, yet the train wreck ongoing in the US is not discussed. Also the massive fines incurred by pharma misdeeds are avoided and these have to impact drug discovery and shape the evolution of the industry. The drug discovery process has perhaps also been flipped on its head. We now have an array of different treatment modalities, from gene therapies, enzyme replacements, antisense oligonucleotides, CRISPR and beyond. Small molecules are no longer the main attraction that they once were. Also, the ones pushing for treatments for rare diseases are likely the parents, they are now the modern day drug hunters hoping for a cure. Indeed, scientists trained as lone drug hunters are almost extinct, they are being substituted and the tools for drug discovery changed. We are in a new collaborative era, where big pharma companies focus on hunting and buying small companies for their molecules at skyrocketing prices and purchase vouchers that get them a faster review at the FDA. So, what is perhaps needed is some impetus to excite the next generation rather than dwell on the past. The drug hunters offers a glimpse of how it was possible to discover a drug, with much more information buried in detailed notes. It also represents a cautionary tale of what can go wrong. Repeating the maxim that developing a drug is a $1.5bn dollar exercise will inspire few new to drug discovery. Unless you are curious, lucky, foolish or stupendously wealthy then the development of new drugs may well be left to the likes of the Bill and Melinda Gates and Chan Zuckerberg foundations that made their money with software and now want to impact healthcare. Ironically, we cannot program drug hunting…yet, but we are increasingly seeing the same machine learning algorithms used widely by the technology companies knocking at the door of the pharmaceutical industry. A case of one industry trying to shape another in its own image. The Drug Hunters of tomorrow will not be remembered in books like this as they will be anonymous autonomous machines, as we perfect the Byzantine process of drug discovery to address the over 7000 rare diseases, let alone the more common ones like Alzheimer’s disease and cancer which still defy human efforts to treat, them with or without moonshots.

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