Dr Neil “Ned” Kelly is a popular speaker for the Monmouth u3a Science and Technology group, and last month he brought his unique blend of humour, expertise and insight to bear on the subject of pharmaceutical origins and development.
Historically of course drugs have come from nature, from plants, microorganisms and perhaps more surprisingly animals, though that is changing. We know of historical use of herbs and roots in folk medicine as curatives and preventatives, some of which have developed into modern medicines and some of which have be related as insufficiently effective or in some cases positively dangerous; those folk remedies would not have undergone clinical trials for efficacy and safety of course…
When one starts to try to identify what exactly it is that is the active component of historical cures, we can run into, Ned reminded us, the post hoc ergo propter hoc fallacy: assumption that one thing caused another simply because it preceded it. His example was the idea that if we have a headache we feel “better” after a “cure”. Perhaps we do. Perhaps it was effective, perhaps we feel better because we think we should (placebo effect) or because someone is listening to us. Or would the headache have got better anyway?
Ned reminded us of the incredibly valuable tenet correlation is not causation via an example of hay fever and icecream sales showing strong temporal correlation. Does icecream cause hayfever? Of course not; they actually both independently correlate with it being summer.
After this sally into fallacy avoidance, Ned reminded us of perhaps the best-known plant-derived drugs: digitalis from foxgloves and aspirin (salicylic acid) originally from willow bark (genus Salix), and of course opium and its derivatives from opium poppies and cannabinoids now used to treat MS, from hemp plants. Perhaps less well-known are the leukaemia drugs vincristine and vinblastine derived from the periwinkle plant (genus Vinca). Statins are well known; less well-known is that they are derived from compounds found in mushrooms, red yeast rice and fermented Chinese tea. Warfarin is another plant-based drug: in the 1920s, cattle and sheep in North America began to die from internal bleeding for no apparent reason. The disease was most common in damp climates when the cattle ate sweet clover hay that had become mouldy; it was discovered that the mouldy hay contained a substance called coumarin that reacted with a fungus to produce a blood-thinning molecule called dicoumarol, of which warfarin is a synthesised optimised analogue.
Some animal-derived medicines we are probably familiar with: earlyuse of pig insulin to treat type 2 diabetes; this is an example of a drug which is now synthesised rather differently. Pig insulin is not as effective as human insulin, so now it is made by splicing the insulin production gene from humans into the e coli bacterium. Heparin, a widely used anticoagulant, was originally isolated from dog liver cells and later from pigs, though the product is not optimal and attempts are underway to synthesis it in vitro. Aprotinin is a blood loss preventative derived from bovine lung tissue, and there is a whole series of drugs from snake venoms, such as the common blood pressure medicine perindopril and the analgesic mambalgins from black mamba venom. We of course have anticoagulants such as hirudin and its artificial analogue bivalrudin. And even Draculin from vampire bat saliva.
Ned went through the history of these developments, some down to serendipity, which Ned defined for us as “a farmer looking for a needle in a haystack and finding his daughter”…Serendipity played a major role in the discovery of both vincristine and aprotinin, as well as warfarin as we have mentioned. Famously it lead to Fleming’s discovery of penicillin and the whole of modern antibiotics. More infamously viagra was being trialled for coronary heart disease prevention when its better known effects were reported, and minoxidil was being trialled as an ulcer treatment but is now used as a vasodilator and hair loss restorer, a side effect noticed in the clinical trial.
Nowadays much novel drug development is via designer molecule construction, based on initial screening of thousands of potential candidate molecules by in vitro assay, and increasingly AI is being used to predict target molecules.
Increasingly drug development is turning to antibodies, and specifically monoclonal antibodies, which are specific to one antigen. A clue is that such drugs end in the letters “mab”, such as Lecanemab used for Alzheimers and Dostarlimab and Nivolumab used against certain cancers.
Ned’s conclusion was that drugs actually come from all over the place.
Phil Chadwick
