Tuesday, December 3, 2013

The Poison and the Remedy


“Among the evil things created by Angro Maynes are noxious grasses that cause pregnant women to drop the womb and die in childbirth.” –sacred books of Parsees on ergot between 400 and 300 BC.4

Secondary metabolites produced by the Claviceps genus of fungi have a rich cultural and medical history rooted in their effects on humans—be them deadly, therapeutic, or abused to reach euphoria. Evidence exists dating to 1100 BC China that this group of compounds known as ergot alkaloids has been used in practices for their beneficial effects on humans, particularly in obstetrics.4 They became known to the European world in the Middle Ages in an agricultural disaster, parasitizing cereals and causing mass poisonings of tens of thousands of consumers.4 In the same regions of Europe, it was later manipulated in small doses by midwives to induce labor and limit postpartum bleeding, while in larger doses was used to cause abortions.3,4 The hallucinogenic qualities of the ergot alkaloid ergotamine—a synthetic derivative of which we know as the recreational drug LSD—were first discovered in the 1940s,3 growing in popularity through successive decades.  This paradox of good and bad and something blurred between exemplifies our ability to finely manipulate the natural world as our knowledge of it grows—source and dosage in this case is everything.

Ergot growth caused
by Claviceps purpurea
The manufacturer of ergot alkaloids, Claviceps, is a group of fungi with a host range consisting of around 600 plant species.3 Most notable are the agriculturally valuable cereals such as wheat, rye, and barley on which fungal spores may land and grow branch-like hyphae into.3 Once the spores have penetrated the exterior of the plant, they colonize the ovaries where the disease course begins to manifest macroscopically.3 Between three and five weeks post-infection, a small limb known as the sclerotium, more commonly as ergot, will begin to protrude from the spike of the plant.3 This is when and where our alkaloids are generated.

Today our harvested cereals are cleaned to prevent contamination with the fungus and its metabolites—though it still occurs, often discovered in flour.5  More recently it has been observed in newer strains of rye that are thought  to  exhibit a lower  degree of resistance than that developed in older strains.5 Claviceps infection is not limited to plants humans depend on agriculturally and intoxication is not limited to us either. Cattle have also been gravely affected by the toxicity of fungus-infected grasses, wiping out entire herds at a time and having significant ecological and economical impacts.1

The connection between the effects of these fungal metabolites on humans and consumption of blighted grains was first recorded in 1597, followed by further observations of the connection throughout both the 17th and 18th centuries.3 Despite many having pinned down the source, it wasn’t until 1918 that large-scale industrial production of the compounds began,3 exploiting their effects in regulated doses for a variety of pharmaceuticals. Be it migraines, hypertension, or even Parkinson’s disease, the therapeutic capacity of these fungal metabolites has demonstrated success when used properly.3 Structurally they resemble the neurotransmitters norepinephrine, dopamine, and serotonin,2 each of which has psychological and physiological effects on the body that may counteract the others. The drugs derived from ergot can therefore be used in a variety of treatment courses. Depending on the type, they can cause smooth muscle stimulation, vasoconstriction, and either stimulation or inhibition of dopamine and serotonin receptors.2,3 The vasoconstrictive alkaloids present an example of dosage effect; they prevent hemorrhage and are ultimately the cause of gangrenous limbs resulting from toxic doses, while they as well are used in the treatment of migraines in small, controlled doses.3

The pharmatech industry has continued and still growing interest in ergot alkaloids as the scope of their applications has broadened. Claviceps was initially manipulated in industry via field production where spores from the fungus were directly introduced to host plants, primarily rye.3 The infection would be allowed to run its course and ergot would then be harvested from which our almighty compounds could be isolated and purified. Today this method is still in practice alongside collection from grain mills.3 The supply of these metabolites, however, has become less and less capable of matching climbing demand using these processes. Large vessel liquid culturing has since been employed as an alternate method of acquisition;5 however this is complicated by the knowledge that most Claviceps species produce ergot alkaloids only in the parasitic phase of their life cycle, thus requiring a host.

Genetic modification of Claviceps is an approach recently taking shape to increase yield of the secondary metabolites. A group of genes termed the EAS cluster codes for many of the necessities of ergot alkaloid biosynthesis.3 Since many of these genes have already been identified, the expression levels could potentially be modified with relatively common genomic strategies, once they are successfully adapted to Claviceps. Up-regulating the genes could mean increasing the amount of biosynthesis components, which could push the production of the targeted ergot alkaloid upward. With advances such as these, demand could be met more easily and the benefits of ergot alkaloids could be taken to an even larger scale.

Neurotoxicity, migraine relief, agonizing convulsions, hallucinations, gangrene of limbs, abortion, and decreased or increased blood pressure: all results of ergot alkaloid consumption, varied in type and dosage. Produced by the parasitic group of fungi Claviceps, ergot contains secondary metabolites from the organism that fulfill a wide variety of pharmaceutical applications. The discovery of ergot alkaloids was not without devastation, however, as it was consumption of toxic doses as well as unpredictability of concentrations in natural sources that caused the death of several thousand people. Today the risks are far fewer than the benefits. The scope in application of ergot alkaloids is not ceasing in expansion either, as specialization through chemical and genetic alterations becomes possible. Considering this and what we already know of the versatility of their pharmaceutical uses, it begs an interesting question several scientists are asking: what more might these fungal pathogens have to offer us?

1. D. J. Scheider, et al. “First report of field outbreaks of ergot alkaloid toxicity in South Africa.” Onderstepoort Journal of Veterinary Research. 1996, 63(2):97-108.
2. G. Emilien, et al. “Dopamine receptors—physiological understanding to therapeutic intervention potential.” Pharmacology & Therapeutics. 1999, 84: 133-156.
3. H. Hulvova, et al. “Parasitic fungus Claviceps as a source for biotechnological production of ergot alkaloids.” Biotechnology Advances. 2013, 31:79-89.
4. P. L. Schiff. “Ergot and its alkaloids.” American Journal of Pharmaceutical Education. 2006, 70(5): Article 98.
5. P. Tudzynsk, et al. “Biotechnology and genetics of ergot.” Applied Microbiology and Biotechnology. 2001, 57(5-6):593-605.

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