1 + 1 = 5

Before there were drugs, there were herbs. Before pharmacies, traditional plant knowledge.

Our grandmothers and great-grandfathers, and theirs before them, knew what root to chew on for a sour stomach, what flower makes a soothing tea, and what spices prevent spoilage. They may not have fully understood the chemistry behind the properties they took advantage of, neither could they have been aware of the sensitive chemical reactions that took place between the root and their microbiome, the soft petals and neurotransmitters, and the influence of a seemly simple leaf on a collection of pathogens.

Pharma has developed numerous drugs either inspired by, or directly synthesized from, nature. It has been indicated that nearly half the drugs approved since 1994 are directly related to natural products [1]. These new drugs treat everything from cancer to diabetes [2]. Some of the most effective drugs were discovered from plants such as Taxol for breast cancer (Taxus brevifolia), Vinblastine for Hodkin's lymphoma (Catharanthus roseus), as well as Quinine (Cinchona spp.) and Artemisinin (Artemisia annua) for malaria [3]. Herbal medicine has seen an increase in demand over the past few decades all over the world [4-6]. Over the past two decades about two thirds of the drugs approved by the Food and Drug Administration (FDA) were based on or directly collected from natural products [7]. However even with this apparent movement toward natural products and herbal medicine, there are still hurdles to face when researching them [2].

Plants are difficult to experiment with as they have collections of active compounds [8-10], mixing and reacting together to build the benefits we reap [3]. A chemical symphony so to speak, from a grand orchestra. But just as an audience member cannot always decipher what instruments are holding the melody, scientists also face a difficulty identifying the harmonizing notes from those in the crescendo.

Today we have a beautifully standardized method of delivering specific drugs. It works. Its necessary, but its not all there is. Medicine can be monitored by single compounds, scientists understand how to work with single compounds [2,8]. Having a single point of focus makes for clean experiments. Lets complicate things for ourselves, to make life simpler.

Multiple studies have bared witness to single compounds having less activity than when tested along their full plant profile [11-13]. Why? Because a team is better than one. In a living breathing system, it’s a requirement to be as efficient as possible. Researchers may identify a very active compound, however something else within the plants matrix may increase penetrability, operate on a related target, or make it easier for the compound to link with its target [11, 14-15].

This is where research in synergies is based. Synergy is the relationship between two or more compounds that enhance a given effect [11, 14-15], this is so that 1 + 1 does not equal 2, but 3 or 5! Lets imagine we have a compound, A, that reduces inflammation. Compound B does not. When combined (A + B), we could anticipate that the mixture would work only as well as A does against inflammation. A synergistic relationship would show A + B having a greater effect against inflammation than A alone. Compound B may help A be better absorbed into the skin for example, a property that would not help the inflammation on its own.

This is not a new development in science, however it does bring the attention back onto the botanical world. Single compound drugs are easier to administer yes, but also easier to overcome [15, 16-17], leading to increased doses and longer treatment times [17]. Take the example of bacterial resistance. We have seen a gross increase in resistance to our antibiotics, single compound drugs [17-19]. Perhaps our future utilizes combinations of antimicrobial drugs with multiple targets [16]. Establishing hurdles for bacteria to develop resistance: they may be able to overcome drug A, but not drug B simultaneously [16, 20-21]. Our prefect green chemists can inspire us yet again to change our system of medicine.

We already see this what our ancestors would prescribe. Multiple herbs, with diverse components, and a much needed boost to our immune system [22]. It may be that the next generation may utilize raw plant materials in their true chemical form, or combinations of drugs that act as harmonizing notes to a known melody (played by a once effective drug). Only time will show what plants might teach us next.


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  2. Harvey, A. L. (2008). Natural products in drug discovery. Drug discovery today, 13(19-20), 894-901.

  3. Thomford, N. E., Senthebane, D. A., Rowe, A., Munro, D., Seele, P., Maroyi, A., & Dzobo, K. (2018). Natural products for drug discovery in the 21st century: innovations for novel drug discovery. International journal of molecular sciences, 19(6), 1578.

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  5. Banjari, I., Misir, A., Šavikin, K., Jokić, S., Molnar, M., De Zoysa, H. K. S., & Waisundara, V. Y. (2017). Antidiabetic effects of Aronia melanocarpa and its other therapeutic properties. Frontiers in nutrition, 4, 53.

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  9. Gurley, B. J., Yates, C. R., & Markowitz, J. S. (2018). “… Not intended to diagnose, treat, cure or prevent any disease.” 25 years of botanical dietary supplement research and the lessons learned. Clinical Pharmacology & Therapeutics, 104(3), 470-483.

  10. Kellogg, J. J., Paine, M. F., McCune, J. S., Oberlies, N. H., & Cech, N. B. (2019). Selection and characterization of botanical natural products for research studies: a NaPDI center recommended approach. Natural product reports, 36(8), 1196-1221.

  11. Caesar, L. K., & Cech, N. B. (2019). Synergy and antagonism in natural product extracts: when 1+ 1 does not equal 2. Natural product reports, 36(6), 869-888.

  12. D’Ascola, A., Irrera, N., Ettari, R., Bitto, A., Pallio, G., Mannino, F., ... & Squadrito, V. (2019). Exploiting Curcumin Synergy With Natural Products Using Quantitative Analysis of Dose–Effect Relationships in an Experimental In Vitro Model of Osteoarthritis. Frontiers in Pharmacology, 10.

  13. Britton, E. R., Kellogg, J. J., Kvalheim, O. M., & Cech, N. B. (2017). Biochemometrics to identify synergists and additives from botanical medicines: a case study with Hydrastis canadensis (goldenseal). Journal of natural products, 81(3), 484-493.

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  16. Canu, A., & Leclercq, R. (2001). Overcoming bacterial resistance by dual target inhibition: the case of streptogramins. Current Drug Targets-Infectious Disorders, 1(2), 215-225.

  17. Bbosa, G. S., Mwebaza, N., Odda, J., Kyegombe, D. B., & Ntale, M. (2014). Antibiotics/antibacterial drug use, their marketing and promotion during the post-antibiotic golden age and their role in emergence of bacterial resistance. Health, 2014.

  18. Fair, R. J., & Tor, Y. (2014). Antibiotics and bacterial resistance in the 21st century. Perspectives in medicinal chemistry, 6, PMC-S14459.

  19. Lieberman, J. M. (2003). Appropriate antibiotic use and why it is important: the challenges of bacterial resistance. The Pediatric infectious disease journal, 22(12), 1143-1151.

  20. Allahverdiyev, A. M., Kon, K. V., Abamor, E. S., Bagirova, M., & Rafailovich, M. (2011). Coping with antibiotic resistance: combining nanoparticles with antibiotics and other antimicrobial agents. Expert review of anti-infective therapy, 9(11), 1035-1052.

  21. Rezzoagli, C., Archetti, M., Mignot, I., Baumgartner, M., & Kümmerli, R. (2020). Combining antibiotics with antivirulence compounds can have synergistic effects and reverse selection for antibiotic resistance in Pseudomonas aeruginosa. PLoS biology, 18(8), e3000805.

  22. Kiyohara, H., Matsumoto, T., & Yamada, H. (2004). Combination effects of herbs in a multi-herbal formula: expression of Juzen-taiho-to's immuno-modulatory activity on the intestinal immune system. Evidence-Based Complementary and Alternative Medicine, 1.

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