John writes …
‘Cardiff scientists look at honey as drug alternative’ (1) – a headline that intrigued both me and Dave Piper of Trans World Radio (TWR-UK), leading to his request to interview me about it (2). On the surface it seems rather strange or even crazy but there are good reasons why it may not be as strange as it appears. I will return to this later but first I want to look more generally at our dependence on plants for important pharmaceuticals.
The World Health Organisation (WHO) publishes a long list of Essential Medicines, last updated in 2021 (3); over 100 of them were first derived from or are still extracted from flowering plants, including the examples I discuss below. In the immortal words of Michael Caine ‘Not a lot of people know that’. Over the millennia of human existence, people have turned to the natural world for help in combatting a wide range of ailments from everyday aches and pains to serious illnesses. Many of these folk remedies were not, as we would now say, ‘evidence-based’: they did not actually work. Equally however, many have now been shown to point to the existence of genuinely therapeutic chemicals, as shown by four examples. I have discussed them in some detail because I really want our readers to understand how dependent we are on the natural biodiversity of the plant kingdom – a feature that is constantly under threat.
Aspirin. Accounts of the use of extracts of willow (Salix) leaves and bark to relieve pain and to treat fevers occur as far back as 2,500 BCE, as evidenced by inscriptions on stone tablets from the Sumerian period. Willow bark was also used by the ancient Egyptians while Hippocrates (460-377 BCE) recommended an extract of willow bark for fever, pain and child-birth. The key chemical in willow has the common name of salicin, first purified in the early 19th century. In the human body, this is metabolised to salicylic acid which is the bioactive compound that has the medicinal effects. Meadowsweet (Spirea ulmaria) leaves also contain salicin and the medicinal properties of this plant had led in earlier centuries to the Druidic Celts regarding it as sacred.
Salicylic acid was synthesised in the lab for the first time in 1859 and the pure form was used with patients shortly after that. Unfortunately, the acid has a very unpleasant taste and also irritates the stomach so is not ideal for use as a regular medication. However, in 1897, a team led by Dr Felix Hoffman at Friedrich Bayer and Co. in Germany managed to synthesise a derivative, acetyl-salicylic acid which has a less nasty taste and is much less of an irritant than the parent compound. After successful clinical trials, the compound was registered as aspirin in 1899. This was the first drug to be made synthetically and the event is regarded as the birth of the pharmaceutical industry. Interestingly, the place of acetyl-salicylic acid in the WHO list is based, not on its pain-killing properties but on its action as a blood-thinner.
Morphine. Morphine is a powerful narcotic and pain killer that is synthesised by the opium poppy (Papaver somniferum); extracts of the plant, known as opium, have been used medicinally and recreationally for several thousand years, both in Europe and in what we now call the Middle East. Indeed, as long ago as 4,000 BCE in Mesopotamia, the poppy was called the ‘plant of joy.’ In Europe, the medicinal use of opium, often as a tincture or as a solution in alcohol was popularised from the 16th century onwards. In addition, the seeds or extracts of seeds, often in the form of a poppy seed cake or mixed with milk or honey have been given to babies and small children to help them sleep (4) (the Latin name of the plant means sleep-inducing poppy).
The active ingredient of opium is morphine which was first isolated by a German pharmacist, Freidrich Sertürner in 1803. It was thus the first medicinally active ingredient to be isolated from a plant (as opposed to salicylic acid – see above – which was the first to be chemically synthesised). It was originally called morphium, after the Greek god of dreams, Morpheus but the name was changed to morphine when Merck started to market it in 1827. Over the past 15 years methods have been developed for its chemical synthesis but none of these are as yet anything like efficient enough to meet the demand for the drug and so it is still extracted from plant itself.
Artemisinin. In China, extracts of the sweet wormwood plant (Artemisia annua) have been used to treat malaria for about 2,000 years. The active ingredient was identified as an unusual and somewhat complex sesquiterpene lactone (illustrated, for those with a love of organic chemistry!) which was named artemisinin. It was added to the WHO list after extensive clinical trials in the late 20th century.
Artemisinin has not been chemically synthesised ‘from scratch’ and initial efforts to increase production involved attempts to breed high-yielding strains of A. annua. However, it proved more efficient to transfer the relevant genes into the bacterium Escherichia coli or yeast cells, both of which can be grown on an industrial scale (5). The genetically modified cells synthesise artemisinic acid which is easily converted into artemisinin in a simple one-step chemical process.
Vinblastine and Vincristine. These two anti-cancer drugs were isolated from leaves of the Madagascar periwinkle (6) (which is not actually confined to Madagascar). The original Latin name for this plant was Vinca rosea (hence the names of the two drugs) but is now Catharanthus roseus. In Madagascar, a tea made with the leaves had been used as a folk remedy for diabetes and the drug company, Eli Lilly took an interest in the plant because of this. However, controlled trials in the late 1950s and early 1960s gave, at best, ambiguous results and no anti-diabetic compounds were found in leaf extracts. However, the company did detect a compound that prevented chromosomes from separating and thus inhibited cell division. The compound was named vincristine. Further, a research team at the University of Western Ontario discovered a similar compound with similar inhibitory properties; this was named vinblastine. Because the two compounds inhibit cell division, they were trialled as anti-cancer drugs and are now part of an array of pharmaceuticals which may be used in chemotherapy (7). In past 15 years, both have been chemically synthesised from simple precursors but we still rely on extraction form plants for the bulk of the required supply.
I also want to emphasise that these are far from being the only anti-cancer drugs derived from plants, discussed by Dr Melanie-Jayne Howes of the Royal Botanic Gardens, Kew (8). As she says, plants are far better at synthetic chemistry than humans!
Back to the beginning.
In the book we describe the natural world as a network of networks of interacting organisms. Given that context, we need to think about the natural function of these compounds that humans make use of in medicine. A brief overview suggests that many of them have a protective role in the plant. This may be protection against predators or disease agents or against the effects of non-biological stresses. Thinking about the former brings us back to the topic that I started with, namely looking for ‘drug alternatives’. The story starts with another interaction, namely that the fungus Penicillium notatum synthesises a compound that inhibits the growth and reproduction of bacteria; that compound was named penicillin and was the first antibiotic to be discovered (in 1928). However, as with the examples of drugs from plants mentioned earlier, we see hints of the existence of anti-biotics in ancient medical practices. In China, Egypt and southern Europe, mouldy bread had been used since pre-Christian times to prevent infection of wounds and the practice of using ‘moulds’ (probably species of Penicillium or Rhizopus) to treat infections was documented in the early 17th century by apothecary/herbalist/botanist John Parkinson who went on to be appointed as Apothecary to King James I. It is not just plants that supply us with essential drugs: the fungus kingdom also comes up with the goods.
Antibiotics are a subset of the wider class of anti-microbials, chemicals that are effective against different types of micro-organisms, including micro-fungi, protists and viruses. Artemisinin, mentioned above, is thus an anti-microbial. Many anti-microbials are – or were initially – derived from natural sources while others have been synthesised by design to target particular features of particular micro-organisms. There is no doubt that their use has saved millions of lives. However, we now have a major problem. The over-use of antibiotics and other anti-microbials in medicine, in veterinary medicine and in agricultural animal husbandry has accelerated the evolution of drug-resistant micro-organisms against which anti-microbials are ineffective. The WHO considers this to be a major threat to our ability to control infectious diseases and hence there is a widespread search for new anti-microbials.
The search is mainly focussed on the natural world although there are some attempts to design drugs from scratch using sophisticated synthetic chemistry. The Cardiff team who headlined this article are looking at plants and at products derived from plants. The ‘drug alternatives’ mentioned in the BBC headline refer to the team’s hopes of finding new anti-microbials. They have noted that in earlier centuries, honey had been used in treating and preventing infection of wounds and they wonder whether it contains some sort of anti-microbial compound. The plants that have contributed to a batch of honey can be identified by DNA profiling of any cellular material, especially pollen grains, in the honey. The team is especially interested in honey derived or mainly derived from dandelion nectar because dandelions synthesise a range of protective chemicals and in herbal medicine are regarded as having health-giving properties. So … the hunt is on and we look forward to hearing more news from Cardiff in due course.
All images by John Bryant, except those credited otherwise.
(1) Cardiff scientists look at honey as drug alternative – BBC News.
(3) World Health Organisation model list of essential medicines – 22nd list, 2021.
(4) This was certainly practised in parts of central Europe in the mid-20th century.
(5) See J. A. Bryant & L. La Velle, Introduction to Bioethics (2nd edition), Wiley, 2018, p. 200.
(6) See J.A. Bryant & L. La Velle, Introduction to Bioethics (2nd edition), Wiley, 2018, pp. 241-242.
(7) Interestingly, a recent paper claims that traditional Indian medicine has made use of the anti-tumour properties of C. roseus: Mishra & Verma, International Journal of Research in Pharmacy and Pharmaceutical Sciences, 2017, Vol. 2, pp. 20-23.
(8) Plants and the evolution of anticancer drugs – Royal Botanic Gardens Kew.
John Bryant and Graham Swinerd comment on biology, physics and faith.