Ergot: the story of a parasitic fungus (1958).

the black out growths on this head of Rye are the scleria of Urgot claviceps peria the scleria from the Greek scaros hard occur on many grain crops and grasses they contain a group of alkaloids of which ergotamine specific in the treatment of migrain and ergometrine of Great Value In Obstetrics are now the most widely used at least as early as the 16th century midwives in Europe Ed Urgot to speed labor and control postpartum hemorrage then this knowledge was largely forgotten it was rediscovered in the new world when John Sterns heard the Tale in Massachusetts early in the 19th century he drew the attention of doctors to its medicinal possibilities and obstetrics but there are two sides to the Urgot story on the one hand there is its value in Therapeutics on the other its poisonous nature for centuries the European peasant has used Ry in his bread and Rye is particularly susceptible to the fungus Frugal inhabit ignorant of the dangers the impoverished peasant often neglected to remove the Urgot from the Rye so the fungus milled with the flour found its way into the bread damp years increase the danger for it is then that the fungus thrives the Harvest poor and each a grain valuable in popular tradition records abound of the sufferings of people especially the poor of fiery burning pains along the limbs mutilations from gangin delirium convulsions hallucinations and in many cases death as long ago as 1095 an order named after St Anthony of Egypt was founded to take care of these sufferers so that the gangrenous condition particularly with the burning pains which preceded it became known as St Antony's fire but several centuries were to elapse before Urgot became suspect a French suggestion by doar in 1676 seems to be the first trustworthy reference to this connection his ideas were not widely circulated and so the outbreaks of Urgot poisoning continued they occurred even in England a country where Ry has never been widely used one outbreak occurred at watsham near bison Edmunds in 1792 in the tower of The Village Church there is a tablet recording the deaths of the wife and children of a poor agricultural laborer the parish register gives a vivid description of their sufferings but it is obvious that Urgot was not suspected as the cause Elizabeth the next daughter aged 14 years was on the next day namely Monday January the 11th 1762 seized only in one leg and foot which he could not set on the floor for 3 weeks but stood all that time upon the other leaning against the chimney after which being taken in the same manner in her other F she lay down one foot mortified and came off at the ankle the other leg near the knee in the London medical times of 1847 there is an account of Mutilation which occurred to a young Irishman who ate rye bread he lost fingers and toes through Gang Green again as recently as 1928 some Jewish immigrants in Manchester were taken ill with characteristic symptoms after eating bread made from Rye which was later proved to have been infected with ergot but perhaps the most disquieting outbreak was that which occurred in France in 1951 disquieting in that it could still occur today from the small town of Pon espri came news of the sufferings of the people there through the newspapers the world learned of the hallucinations convulsions delirium and deaths which had resulted from Urgot poisoning unfortunately the poisoning of Farm stock from Urgot infected grasses other than Ry is still fairly common this heer is typical it is lame as the result of gang green developing in the extremities here it is in the hoof and also in the tail ergots belongs to the group of fungi known as esoms it is therefore related to the Stags horn fungus silaria hypoxylon the devil's bunion delinia concentrica the edible morel moella crapes the vegetable caterpillar a species of CPS the coral spot fungus netria cabina the orange peel fungus a species of Piza and also here shown growing on a crust of bread penicilium notatum the microscopic mold from which penicillin is derived the OT sclerosi is is a tough resting body which when fully developed falls from the ear during the winter it lies on the soil germination depends on this period of exposure to cold in the spring a number of little stalked bodies grow out from the sclerosi the tips of these stalks become globular and pitted with little holes from these holes the spores will eventually be ejected the holes are the openings of small flask-shaped cavities the Perth thesia this is how the perithia appear in a stained section each parath thesium is lined with fungal threads the hyy a single multinucleate hypher elongates and produces a side branch after nuclear division culation takes place between these branches and the nuclei associ in pairs elongation occurs and cell walls are laid down small projections each containing two nuclei grow from the sides of these cells this process is known as hook formation after a further synchronous division Fusion takes place while while the nuclei which have not fused proceed to further hook formation the cell now elongates enormously to form an ascus the diploid nucleus divides to form eight haid nuclei around which the protoplasm Aggregates to form eight cylindrical ascospores each ascus when it has matured ejects its ascospores and they are blown away in the Wind at this time the Ry is coming into flow the ANS three to each flow burst forth and shed their pollen later the feathery stigmas are exposed ascospores carried by the wind adhere to them the ascospores send out hyy which grow down through the fragile tissues of the stigmas and penetrate the ovary soon the fungus will have replaced quite a proportion of the normal ovary tissue this is a longitudinal section through an infected FL in the central mass of the fungus pockets are formed from which enormous numbers of little canidia spores are liberated these canidia spores or canidia are ooid in shape not long and thin like the ASA spores at the same time a strong sugar solution called honey is secreted and slowly Wells out between the florids in these drops of Honey are numerous canidia insects are attracted by the honey Jew which sticks to their bodies and they thus carry the spores to other Ry flow if deposited on the stigmas the spores will germinate as they are doing here and infect the ovaries of more flowers in this way an infection spreads throughout the crop the tissues of infected ovaries instead of developing into grains of Rye become replaced by Fungus the external hyi darken in color spores and honey are no longer produced a new generation of scleria has been formed and the life cycle is complete in August the scleria will be dropping to the ground again next spring each scorum will develop ascores in the heads of which ascospores will be formed these will be ejected and infect the Rye honeydew will be produced later a new crop of scler roia will be formed aot will grow on a variety of cereals and other grasses such as wheat barley Ry grass lini Taz grass disa Cox foot dactus glomerata and Yorkshire fog hus latus the demand for Urgot alkaloids for medicinal uses is increasing and greater quantities are being used annually supplies can only come from the grasslands and cereal Farms of the tempered Zone to The Peasants of some of these areas such as those of Northwest Spain and Portugal the fungus which infects their Rye has now become an important crop The Peasants pick the Urgot by hand from the standing crop and when they feel it will command the highest price take it to dealers in the local Village Market such a village is Aros deales in Northern Portugal close to the Spanish border here are the dealers set up their stalls barter is often the vehicle of trade and few are dealers who inquire whether the Urgot was smuggled across the border these supplies of Urgot are subject to wide variations in quality and price the cause of the constant commercial tug of war between dealer and peasant regularity of Supply can never be guaranteed at a Porto the ergot is dried and inspected before being shipped to Britain and other countries 20 sacks of OT May yield as little as 100 gr of ergometrine the yield depending greatly on the strain of OT thus it is not surprising that a great deal of attention has been paid to the possibility of cultivating Urgot and developing better strains in the laboratory it is possible to dispense with part of the normal life cycle canidia are produced by a melium which has grown under sterile conditions from the scler roia a clorium is washed surface sterilized and rinsed now soft enough to cut easily sections are placed on a nutrient medium in Petri dishes after suitable incubation a melium begins to grow numerous subcultures are prepared first on slopes in test tubes then later in Thompson bottles the canidia are dislodged from the final Culture by shaking with glass balls in water a suspension of spores is thus prepared and is removed by suction pure cane sugar is added to make a 50% solution this fluid is maintained at a low temperature to [ __ ] germination of the spores a trial dilution is prepared to determine the concentration of spores a counting chamber is used for this purpose here through a microscope we see the appearance of the canidia by by counting the spores and a known number of the cells of the counting chamber the concentration in the original suspension can be calculated in the field the stock suspension is diluted according to the calculations made in the laboratory there are various ways of infecting the ears of Rye with the inoculum but this one gives a high percentage of satisfactory results each worker has a felt pad which he dips into his suspension of spores he claps the ears between the felt pad and a Clapper set with needles the Spore suspension is thus forced into the right tissues through holes made by the needles at a later date the ears missed by the Clapping technique are infected with spores obtained from the developing honey Jew under natural conditions this operation is performed by insects and is therefore unpredictable and so man AIDS nature in ensuring completion of the task using brushes with nylon bristles the worker sweeps the h from plant to plant his protective clothing is necessary because of the sticky nature of the honey Jew these techniques achieve two objects they enable known strains of Urgot to be perpetuated and they ensure a heavy and satisfactory crop Sir Henry Dale at that time Dr HH Dale initiated the the pharmacological study of Urgot alkaloids in a paper in 196 he drew attention to the remarkable activity of these compounds his two collaborators Barger and car were thereby enabl to isolate the first of the Urgot alkaloids ergot toxin ergotamine was isolated some 15 years later in action indistinguishable from OT toxin ergotamine has the advantage of being easier to prepare and hence is more widely used in medicine ergometrine a more recent discovery differs in type and action from OT Toxin and ergotamine all the known Urgot alkaloids are derivatives of lysergic acid ergometrine is composed of lysergic acid and D2 aminopropanol while ergotamine is more complex these the two ergot alkaloids most commonly used in medical practice have to be separated from the many other substances contained in Urgot the methods we are about to see are essentially the same as those used in large scale manufacturer the Urgot is ground and mated with sodium bicarbonate and water the mixture is transferred to a percolator and extracted with an organic solvent this percolate containing all the alkaloids is chemically and physically aade then an acid solution is added to the percolate which on shaking takes out the alkaloids the solution is run off and transferred to a vessel where it is treated with alkaline this precipitates the water insoluble alkaloids comprising aot osine a Corine tine and er Christin from the filtrate the water soluble ergometrine is extracted with chloroform after concentration crude ergometrine crystallizes out it is further purified to give ergometrine mate ergotamine is specific against migraine the symptoms of which are unilateral headache visual disturbances nausea and vomiting unfortunately aamine when given by mouth in adequate doses increases the norer and vomiting even when potentiated by caffeine the smaller dose of otaman is still liable to induce these side effects so the potent and Rapid acting antiemetic cycline hydrochloride is added this successfully counters norin vomiting whether due to ergotamine or to the migraine more it allows the dose of ergotamine to be increased migr is a product compounded to meet these requirements the use of Urgot to promote contraction of the uterus and to control postpartum Hemorrhage as we have already said dates from very early times The Midwives of long ago used an aquous extract of Urgot and this type of extract was official in the 19 14 British pharmer in the 1932 revision it was replaced by an alcoholic extract on the ground that the active principles known at that date ergotoxine and ergotamine were soluble in alcohol but scarcely at tall in water many practitioners however after trying the new preparation expressed a preference for the old watery extract their views and incidentally those of many generations of midwives were Vindicated when the obstetrician Dr shasa moer clearly showed by mechanical tracings that the watery extract caused a powerful contraction of the human uterus after childbirth and that this action could not be explained by any of the then known alkaloids and here is Professor chassam Mo to continue the story himself these were exciting days and I vividly recall the details of the hunt for this new active principle of herot I was working at the time with Professor FJ Brown in University College Hospital London and now at Sir Henry Dale's suggestion I also collaborated with the with the chemist the late Dr HW Dudley Dudley preparing the Arrogant fractions and I testing them on the human subject after three years of continuous work Dudley succeeded in 1935 in isolating The elusive principle which at Sir Henry Dale suggested we named eletr Metra being the Greek for uterus our paper described ergometrine as an alkaloid over three times more soluble in water than an alcohol and by far the most potent oxytocic agent yet isolated from OT with the property also of being rapidly absorbed when given by mouth short after the publication of our paper the same alkaloid was described from three other Laboratories where the search for it must have been simultaneously but independently in progress in the United States pharmacopia by the way ergometrine is known as ergonovine and now let us see ergometrine in routine use at University College Hospital this patient is in the second stage of Labor as the child is born ergometrine will be administered its action is to promote contraction and retraction of the uterus thus expelling the placenta and minimizing the risk of postpartum Hemorrhage come in all right LIF up keep breath in let just push down down down CL it's the boy the story of Urgot is not yet ended new strains have been propagated new compounds sought who knows what undiscovered Secrets may still remain within this quite extraordinary fungus w