When invited, back in the heady days of late summer, I eagerly agreed to present a short talk on the use of genomics in phytomedicine at OneNucleus' Genesis 2011 conference. But when it came to preparing the talk I put it off until the last possible moment. Not only was my knowledge of phytopharmacology (where the active substances come from plants) somewhat limited, connotations of herbal remedies of dubious efficacy was a turn off. I should not have worried, however, as plenty of 'real' medicines originated as plants. Indeed, it is only in the last 20 years of high throughput screening and lipinski rules that rational drug design has taken over from natural sources in drug discovery.
My research into phytomedicine turned out be be rather rewarding. It became apparent, as I scoured the somewhat sparse literature on the subject, that phytomedicine is well-suited to being studied using high-throughput genomic techniques. This is true both from the angle of lead discovery/optimisation, and also target discovery/mode of action. Slides of the talk are available.
Starting with the search for lead candidates, bioactive molecules from plants are effectively proteins/metabolites, and, given a reference sequence, can be traced back to their genomic origins. Biosynthesis of the active compounds can similarly be related to gene expression and plant pathways. Significantly, phytmedicinal traits and be selected for or genetically engineered like any other plant phenotype. There are already phytomedicinal plants such as Cannabis with sequenced genomes that are being investigated in this way (e.g. Medicinal Genomics), and there are tens if not hundreds of species whose genomes would be similarly useful. Another interesting effort is that of the Noble Foundation who are using a systems biology approach applied to the model plant Medicago trunculata to investigate saponin biosynthesis.
The study of phytopharmacology is similar in many respects to that of 'standard' pharmacology, and is tractable via the same genomic techniques. The phytomedicinal exception to this is synergy. Synergistic interaction means that the effect of two or more chemicals taken together is greater than the sum of their separate effects. These can be pronounced in plant extracts, meaning that a single isolated ingredient will not always reproduce efficacy of the plant extract. The Cannabis-based Sativex, for instance, is a complex plant extract that was approved in 2010 as a medicine in the UK and is more effective than synthetic THC. Although the biological explanation of synergistic effects is far from clear, and unbiased whole genome assays seem like a promising approach to their study (in breast cancer treatment, for example).
From what I saw from the Genesis Botanical/Natural Products Stream, the ancient study of phytopharmacology still promises great rewards, but suffers from some very modern issues;
- It is not in vogue in mainstream phara,
- Synthetic homeologues of bioactive plant compounds are not always efficacious,
- The mode of action of bioactive plant compounds is often unclear,
- The mode of action of synergistic interaction is even less clear,
- Standardisation of plant extracts to the extent required for medical approval hugely challenging,
- IP issues can be complex (there are always IP issues).
Is there set to be a resurgence in phytomedicine driven by genomic technologies? Only time will tell.
- Will Spooner, CTO