By Ben Locwin
A few weeks ago, when the ZMapp drug treatment went from obscure novel therapy to the most famous drug name searched for on Google, history was made. Interestingly, it’s been a history a long time in the making; the first drug treatments created to treat maladies and diseases were derived by early humans from plants, so we’re really taking this story narrative from the beginning of recorded time to now, and have skipped over much of what has occurred in between.
Well-known to many, one of the first treatments derived from plants reliably, aspirin (salicin), was prepared from willow bark. The ancient Egyptians used willow and other salicylate-containing plants at least 1,000-2,000 years BC. Hippocrates himself (from whom we get the Hippocratic Oath) mentioned the use of salicylate tea for fever in about 400 BC. It wasn’t until 1971 that it was demonstrated that aspirin works in part by effecting prostaglandins and thromboxanes.
Digoxin (similar to digitoxin) is derived from the foxglove (Digitalis) plant, and is a cardiotonic medicine (used to treat various heart conditions such as atrial fibrillation). Atropine is derived from the nightshade plant, and is widely used for ocular treatments, dangerously low pulse, as well as certain poisoning events (e.g., nerve gas and organophosphate insecticides).
And of course, our favorite plant-derived drug: the central nervous system-stimulant caffeine. It is extracted from coffee beans, tea (Camellia sinensis) leaves, etc. Caffeine has been keeping us awake for thousands of years of humanity by blocking (antagonizing) adenosine receptors in the brain and encouraging the pituitary gland to signal the adrenal glands to produce more epinephrine (adrenaline).
Interestingly, these four plant-derived drugs are ALL on the World Health Organization’s List of Essential Medicines.
As Albert Einstein observed, “We cannot solve problems at the same level of thinking when we created them.” Greater world population. Greater availability of world travel. Increased exposure probability to novel organisms. The methods and treatments we seek to produce haven’t been fully developed yet. And that’s the challenge: to develop that which has not been developed before. Briefly speaking, the goal is to produce therapeutic proteins whose amino acid sequences match those of the native species and which can be glycosylated–an industry which has been very successful so far using bacterial and mammalian cells. Plant-based therapies, done by transgenic breeding, or ‘pharming’, can produce very similar end-products with a few major benefits: they don’t produce endotoxin, which can be found in mammalian or other cell-based culture, aren’t affected by human pathogens (so they can’t be infected by the people working around them, which is always a huge concern with cell-based therapies), and they can produce post-translational modifications (glycosylation is one of many) required for the complex therapeutic molecules which are desired. There is no evidence that immunogenicity is a greater risk using plant cells compared with mammalian or bacterial cells for therapeutic protein production.
As to how some of this works on a basic level, we at AAPS have provided insight and guidance to the media on ZMapp and transgenic crops more generally.
So why aren’t these therapies available everywhere? There is a lengthy process for drug approvals within the FDA, EMA, MHRA, etc. which substantiates not only the treatments’ efficacy, but also their safety profile. In this particular case, given the humanitarian need for treatment to abate the Ebola outbreak, the World Health Organization (WHO) and UN have determined the use of experimental ZMapp to be ethical in its trial use. There is more on this topic, as well as the bifurcation in public opinions on the genetic modification of crops and how the technology actually works in my piece here.
Additionally, as my colleague Dr. Bell wrote about on this blog, GlaxoSmithKline (GSK) is trialing its Ebola vaccination at the U.S. NIH. The results of this and other work will be interesting; once a patient has been infected with Ebola and survived (such as the case with ZMapp recipients Kent Brantly and Nancy Writebol), they would be immunized against that particular strain (Zaire in this case)–they develop cell-mediated immunity and specialized antibodies. The so-called cross-protection against the other four strains is still a question mark and a target for ongoing study. What we can do and will do is advise on the ongoing research and communicate out in a clear and salient way to the public what the next steps hold for us.