Synergy – Sum is greater than the parts

It’s a big topic I’m sure I’ll cover again in the future, synergy, the name we give to the phenomena that mixtures of things working together seem to have greater power than a simple sum of their component parts.

The idea is old one, from at least Aristotle’s day. Though it is a broad concept encompassing the biological and the social.

Magic bullets

Who knows where the idea that the single magic bullet is better for dealing with complex biological phenomena like disease came along. Though obviously it has been an advantageous meme to the construction and marketing of the contemporary pharmaceutical industry over the last century.

Perhaps it was the advent of modern chemistry that allowed us to separate and isolate individual constituents in long used plant drugs, to distill out their essence. Perhaps it was the germ theory, where we could imagine every disease state was simply down to the presence of a discrete and identifiable (bad) life form in isolation from any other factors. Perhaps it was the discovery of antibiotics and the initial success against the hordes of malevolent bacteria and microbes we imagined invading and destroying our bodies. Perhaps the idea of the pluripotent medicine, the cure for all ills, is something we humans have harboured for millenia. Something we imagine that can guarantee our safety and survival in what can often seem a hostile world.

In some cases for some things, there may well be a single substance that works. Though if you look at most living systems there are numerous strategies at work to survive and thrive, including beneficial relationships with other lifeforms or an array of chemical defenses in the case of plants.

I think it’s fair to say that we now realise that in fact we need the vast array of microbial lifeforms to survive, from those inside our bodies where they seem to have always outnumbered our own cells, to the broader biosphere services they perform. Though of course we don’t need them all and some of them are certainly unwelcome house guests, literally sapping the life out of us.

We can also realise by now that in fact these various lifeforms that can infect our bodies are not static, but like all lifeforms, no matter how small, they are dynamic and respond and adapt to the circumstances they face. Indeed, some of them are giving a new generation a go every 20 minutes or so. Our widespread and untempered use of antibiotics, initially seen as remarkably successful, is now fostering a swathe of multi-drug resistant (MDR) lifeforms.

In terms of pharmacology, there’s a differentiation between aspects we call pharmacokinetics, the ways and means we uptake, metabolise and excrete drug molecules, or pharmacodynamics, the ways and means drug molecules act on our own cells or those pesky germs. Of course, as typical in complex biological systems, the difference between these aspects is not necessarily always clear, but they serve a purpose for describing different ways in which the sum of a mixture is in one way or another altered, particularly made more effective. Plotted below is a representation of synergistic and antagonistic effects, indicated by the decreasing or increasing dose required of the respective drugs (A and B) for the same effect.

Herbal medicines and Malaria.

The idea of synergy in herbal medicines is a hotly contested concept by some. A contest which I believe can only be sustained with ignorance of the complex and common biology of plants and all life on earth.

Following on from the great blog about the history of Sweet Annie (Artemisia annua) and unearthed tombs in China. The use of this herb or its constituents in malaria globally and recent scientific investigations have thrown up further insights into the apparently synergistic role of whole herb medicines versus isolated constituents. This recent review (Open Access) of whole plant extracts in Malaria covers almost all the issues.

According to this recent review Artemisia annua whole herb extracts, as a fresh crushed juice or ethanolic extracts are reported to have a 6-18 fold greater activity against malaria than their artemisinin content would suggest. With casticin, a flavonoid also found in Artemisia annua, reported to increase the action of artemisinin by 3-5 fold alone.

A tea prepared traditionally as per the Chinese Pharmacopoiea gave maximum serum concentrations within 30 minutes, compared to hours for artemisinin alone, with about one fifth as much artemisinin as standard treatment alone (94.5 mg artemisinin in a tea, or 500 mg in a pill). This apparent increased bioavailability being due to the other constituents. Artemisinin being a sesquiterpene is a quite lipophilic substance and not very water-soluble, but you can dissolve more in a whole herb tea than you can alone in water, due to the amphiphilic qualities of other plant constituents, with many natural glycosides having this quality.

Curcumin, the bright yellow pigment from Tumeric, inhibits the metabolism and excretion of artemisinin too and been shown to completely inhibit the recrudesence (return) of malaria in animal models, which is a problem with artemisinin alone. Piperine from Black Pepper increases the bioavailability of curcumin itself by %2000. It also increases the bioavailability of epigallocatechin gallate (EGCG) from Green tea. The latter a known inhibitor of the efflux pumps that characterise many multi-drug resistant (MDR) organisms.

There’s plenty of evidence that synergistic effects, that alter bioavailability and potency of action, are present in whole herb extracts from single herbs (Ginkgo, St John’s Wort, Kava, Valerian, Cannabis) compared to any of the isolated constituents. Or due to different constituents in herb mixtures.

In many ways it has been the lack of sophistication and the reductionist modelling of our science that is the greatest obstacle to further understanding of all these complexities. Only now with the advent of metabolomics and genomic transcription analysis can we begin to look at the cascades and networks of effects that underly all biological systems and phenomena. In many ways this is far greater challenge to scientifically investigate and understand.

Plants themselves develop an array of physical and chemical defenses to survive. Even microbial lifeforms have a range of strategies to deal with potent drugs such as antibiotics.

In a biological sense it seems far more appropriate that we should find and expect an array of compounds, physical or pharmacological strategies, would be more successful than any one thing on its own.

further reading

Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions – Review, P Rasoanaivo, C W Wright, M L Willcox, B Gilbert, (Open Access)

Pharmacokinetic study of artemisinin after oral intake of a traditional preparation of Artemisia annua L. (annual wormwood), K. Rath, K. Taxis, G. Walz, C. H. Gleiter, S.-M. Li and L. Heide,

The importance of pharmacological synergy in psychoactive herbal medicines, M. Spinella,

Review (Part I) – Synergy research: Approaching a new generation of phytopharmaceuticals, H. Wagner, G. Ulrich-Merzenich,

Review (Part II) – New perspectives for synergy research with the “omic”-technologies, G. Ulrich-Merzenich, D. Panek, H. Zeitler, H. Wagner, H. Vetter,

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5 Responses to Synergy – Sum is greater than the parts

  1. dianabuja says:

    Yes, though there is a problem here along Lake Tanganyika: folks have discovered that the mosquito nets are excellent for catching ndagala – a very small indigenous fish that fried whole, and that is much beloved in the country.

    Of course, not only does this remove nets from their intended use – but also the nets capture many fingerlings of other fish breeds and this is adding to the demise of fish in the lake.

    Unlike Lake Victoria, due to war and upheavels there are no regulations in place and-or enforced against these netting practices.

    Solve one problem, another may pop up!

    Interesting about the research and use of Artemisa annua in Africa.

    • dianabuja says:

      Woops, intended to add that there are several organizations working with Artemisa in Burundi – it is a good high altitude plant and we have lots of high altitude here. Though, the germans and italians are working (independently) to ‘extract’ the goodies from the plant, whereas the St. Francis of Assisi folk are working to dev. ways that villagers can use the whole plant in treating malaria, which I think is the pest approach in this impoverished country.

      I’d like to get some to explore uses for livestock in controlling lung worms – which are a big problem here.

      • Nature and Science says:

        One point of my blog was exactly this difference in perspective, the pure ‘active’ ingredient vs the whole plant. Much of this seems directly relevant to Africa more than many other places on this specific topic. It also seems combination therapies are much more common for malaria now as well, for the very reason of beating tolerance by the malaria plasmodium to single compounds/drugs.

        Aside from the clinical and scientific debates, there’s a host of economic and social aspects to what will really be helpful or practical too. Including the empowerment for people to learn about and grow their own medicines I think. When one of the few things they really possess is their land and the knowledge of farming.

        No doubt there are other local medicine plant traditions there too. Though no-other traditional medicines other than Cinchona (source of quinine) and Artemisia annua have as long a history of clinical and scientific support that I’m aware of. Which isn’t to say there aren’t others out there.

        Burundi looks like a speck in the middle of sub-saharan Africa from here. One of the biggest contrasts in terms of people per sq km that you can find between any two countries on earth would be between there and Australia.

        Once established, like many Artemisia, Sweet Annie can become prolific by self-seeding. It’s status as a weed seemingly depends mostly on how much humans use it, if it’s around. I like it’s fine, dark and strongly aromatic foliage, it grows well here generally, but would be considered a pest and introduced weed for the most part. It looks a bit delicate, but is really very hardy.

        All the best

  2. dianabuja says:

    Most interesting – as was the article on whole plant extracts that you reference.

    A couple of years ago I had the misfortune of a terrible case of herpes zoster and following postherpetic neuralgia for which I was in the hospital a couple of months with regular morphire to control. Then, trying lots of stuff for the postherpetic neuralga.

    Although none of the materials that I’ve found on the net say so, the pain was (is) PHANTOM pain. This can be managed with a variety of products. As you say, modern separation of a diseases from complex treatments is in part responsible.

    On malaria treatment ( one disease I’ve never had – good genes, I guess) – the approaches used during the colonial period in Africa are interesting and here are some blogs about them – multìple treatments, some pretty terrible:

    • Nature and Science says:

      Nothing about malaria sounds like fun.
      A kind of fascinating but devastating creature.
      Interesting blogs and some intolerable treatments.

      It seems multiple strategies from mosquito nets to medicines is definitely required for this disease.
      There’s probably more happening with research, cultivation and use of Artemisa annua in Africa than anywhere else these days.
      Stay well.

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