A is for Arsenic (16 page)

The eserine story

Physostigma venenosum
is a climbing perennial plant that produces large fruits, each of which contains two or three beans. The use of this bean as a poison was once common in the south-eastern part of Nigeria known as Calabar, and the beans are commonly known as Calabar beans. When the active compound within the Calabar bean was isolated it was named
physostigmine. The local name for the bean was
eséré
, so the same compound is also known as eserine.
⁴⁹

The plant, and the poisonous properties of its beans, was well known in West Africa, but it was only brought to the attention of the wider world by Scottish missionaries who arrived in Calabar in the 1840s. Rather melodramatically, the missionaries named it the Ordeal Bean of Old Calabar. They discovered a tradition of trial by ordeal for crimes such as witchcraft, murder and rape. Guilt or innocence was determined by the accused drinking a concoction of poisonous beans. If they were guilty, the beans would poison them and they would die, but if they were innocent they would be spared death. However, anyone who showed ill effects but survived was subsequently sold into slavery. The method of preparing the poison varied. Sometimes the whole bean was used, while at other times the beans would be mashed in water, and the accused would be required to drink the resulting milky liquid. These trials by bean were known locally as ‘chop nut'.

There may be more to this trial by poisonous bean than initially meets the eye. Guilty people may have been more inclined to chew the beans slowly and prolong the moment before they had to swallow. Chewing would release more of the poison than if the bean was swallowed whole. Or, if a drink was given, the guilty might sip it cautiously. The end result was the same; slow administration of the poison and a longer exposure time, giving the body more opportunity to absorb the poison. Innocent people would swallow their beans quickly, safe in the knowledge that they were not guilty. The whole bean would take longer to digest, and less of the poison would be released. Alternatively, the beans could cause gastric irritation, inducing vomiting that saw the poison largely removed before it could be absorbed.

Other theories have been suggested that throw a different light on the trials. Those responsible for acquiring the beans and preparing them would be expected to have a greater knowledge of native plants and their effects on humans than the general populace. Half a Calabar bean can constitute a lethal dose, but the quantity of poison it contains varies depending on ripeness. Beans could be harvested at different times to affect the result of the trials, and the beans themselves could be doctored to give the desired result. The small brown beans could also have resembled non-toxic varieties, and a substitution could have been made that might have gone unnoticed by the accused.

Local people were so confident in chop nut that many actively volunteered to swallow the poisonous concoctions to prove their innocence. The missionaries claimed that thousands gathered at witch trials to swallow beans
en masse
. The beans were also used in duels as well as in trials. Combatants would cut a bean in two, and each eat a half. They would continue to eat the divided beans until one or other (though quite often both) died as a result. The missionaries estimated that the Calabar bean was responsible for 120 deaths in the region every year.

The missionaries were keen to collect samples of the bean, as well as of the whole plant, to send back home. Collectors travelling around the world had brought exotic delights such as the coffee bean and cinchona bark (which contains the active component, quinine, used in the treatment of malaria) to Europe. These discoveries had given us new foods and medicines, in addition to a range of plants to adorn gardens. Many people built careers out of collecting exotic specimens and selling them to buyers in Europe, but the missionaries in Nigeria were having problems tracking down samples of the
eséré
bean and the plant it came from. Initially they could only obtain a few leaves. Eventually the Reverend Hope Waddell, a missionary who had been apprenticed to a pharmacist before he became ordained, discovered that the king in Calabar had ordered the wholesale destruction of the plants except for a
few specimens kept under close guard, for use in administering local justice. In 1855 Waddell smuggled a few beans out of the country and sent them to Robert Christison (1797–1882), a celebrated Edinburgh toxicologist. Christison managed to grow a few plants from the beans, but none would flower. It wasn't until 1859 that flowering specimens were brought from Nigeria for study; the king in Calabar had either relaxed his bean embargo or some unscrupulous soul had found a way around his strict controls.

Christison was interested in the medical effects of the beans, and he took the then traditional method of testing toxins by swallowing a quarter of one. The beans, Christison noted, had a very bland taste and he initially suspected they were harmless. In his own words he was ‘much mistaken'. The most dramatic effect Christison experienced was his heart slowing, and he suggested that death may be caused by paralysis of the heart. Some years later, in 1897, John Uri Lloyd (1849–1936), an American pharmacist, suggested that the bean could be used to execute condemned criminals, as the poison appeared to act painlessly. The suggestion was not taken up.

In 1863, the ophthalmologist Douglas Argyll Robertson (1837–1909) published a paper describing the effects of an extract of the bean on the pupils of the eye, and this spurred further research. Eserine was the first known miotic, a compound that causes the pupil to contract. Robertson openly admitted that he had been told about the unusual properties of eserine by a physician friend, Thomas Fraser (1841–1920), who detailed the process of extraction in his doctoral thesis. Even after he had completed this, Fraser continued to carry out rigorous and detailed studies on eserine's properties, and other scientists joined in. By the late nineteenth century many alkaloids had been extracted from Calabar beans, but the structures of these compounds were not elucidated for another 30 years or more. In the meantime, researchers could only judge the contents of their extracts by their physiological effects, and there were still problems with extracting the active compound from the bean and storing it without degradation;
eserine is unstable in water and decomposes to form eseroline. Eseroline has a very different effect on the body, delivering pain relief through its interaction with opioid receptors (see page
here
), amongst other diverse effects. Despite the problems faced by Victorian Calabar-bean researchers, many discoveries were made.

Scientific interest in the Calabar bean is reflected in Agatha Christie's novel
Curtain
. One of the characters in the novel, Dr John Franklin, a research chemist, conducts experiments with extracts of the bean. Christie goes into a detailed description of the poison and its uses (but here she calls it physostigmine). Dr Franklin is assisted by Judith, the daughter of Captain Hastings, friend of Hercule Poirot and narrator of
Curtain
. He quotes his daughter talking about the research: ‘She referred learnedly to the alkaloids physostigmine, eserine, physovenine, and geneserine, and then proceeded to the most impossible-sounding substance, prostigmin or the methyl carbonic ester of 3-hydroxyphenyl trimethyl ammonium, etc., etc.'

Agatha Christie's science is good here, and there are only minor errors in her list of alkaloids. The confusion is understandable, though, as many of these compounds had undergone numerous name changes over time. As we've seen, physostigmine and eserine are the same compound, but Christie might have been confusing eserine with eseramine, which is also present in the bean. Another compound she lists, prostigmin (now known as neostigmine), is a synthetic derivative of eserine. Neostigmine was first prepared in 1931, in an effort to modify eserine into a compound that was more stable in water but that retained the same physiological effects. This work was successful, and the resulting compound was found to be a more effective miotic agent than the parent compound.

Of the other alkaloids Christie mentions, geneserine is the second commonest alkaloid within the Calabar bean (only 35 per cent as much as the quantity of eserine). Geneserine is sometimes prescribed as drops to be taken orally for the treatment of digestive disorders such as dyspepsia and constipation.
Meanwhile physovenine, also mentioned by Christie, has been found to be effective in treating the symptoms of Alzheimer's disease.

In
Curtain
, Dr Franklin claims that there are two types of beans that resemble each other very closely. He claims the second type contains all the same alkaloids as the Calabar bean but with one extra, and that this additional alkaloid neutralises the effects of the others. The existence of a plant similar to
Physostigma venenosum
is hinted at in the correspondence of a Mr William Milne, who was living in Calabar in the 1860s. One species was ‘largely cultivated for putting into streams to kill fish, and another is sold in the markets for Calabar chop'. It would make sense if the species used to kill fish was less toxic to humans than
Physostigma venenosum
– people would want to eat the fish, after all.

Dr Franklin goes on to describe how the bean was used in West African ordeal trials, and his belief that those in the inner circle knew of the second type of bean, and used it in a secret ritual. These people never came down with ‘Jordanitis', a disease Christie seems to have invented to give a reason for Franklin's research and his possession of many bottles of potentially lethal extracts of the Calabar bean.

To obtain the poison, the murderer in
Curtain
had no need to travel to Africa or to fake a prescription; all they had to do was take a bottle of an extract from Franklin's laboratory. The contents of the bottle are added to an after-dinner cup of coffee. Several hours pass before the victim – the doctor's wife, Barbara – starts to exhibit the effects of the poison, and she dies the following morning. There are no details of the symptoms experienced by Mrs Franklin other than the fact that she is taken ‘violently ill'. Little is done to treat Mrs Franklin, although there is plenty of time to call a doctor; a doctor would be likely to have the antidote to eserine poisoning available, in the form of atropine (which we first encountered on page
here
). The use of atropine as an antidote for eserine, and
vice versa
, was first proposed by Thomas Fraser back in the 1870s. The effect of contracting the pupil and
slowing the heart were directly opposing to the effects of atropine, and each compound could therefore be used to counteract the other's actions. Some doubt was thrown on Fraser's theory because he carried out his atropine/eserine experiments on rabbits, the only mammal he could obtain easily in the quantities he needed; unfortunately, rabbits have a particularly high tolerance of atropine.

However, atropine antidotes were successfully used in several cases of eserine poisoning, and
vice versa
. Two cases of mass Calabar bean poisoning occurred in Britain, the first of these in 1864 and the second in 1871. Despite the best efforts of the king in Calabar, some beans were smuggled out of the country and brought to Britain on ships. Some of the beans were dropped at Liverpool docks during the unloading process, where they were found by some children, who ate them. A total of 57 children became ill, but all but one were saved through prompt treatment with atropine. Even if atropine is not immediately available, the patient can be supported with artificial respiration. Mrs Franklin seems to have been particularly unfortunate.

The main symptoms exhibited by the children at the Liverpool docks, and presumably by Mrs Franklin in
Curtain
, were tremors, involuntary defecation and urination, pinpoint pupils, difficulty in breathing and a slow pulse. The Liverpool children were apparently quite docile and far from distressed by their situation, and they did not cry or seem unduly agitated during their time in hospital. This supports earlier descriptions of the painless effects of this poison. Individually, the poisoning symptoms can be attributed to a wide variety of diseases and toxins, but this combination is characteristic of eserine and related compounds.

How exactly eserine produced these effects on the body was unknown to Victorian scientists, but there was a lot of speculation. For example, the tremors were clearly the result of interference with the nerves, but was this a result of direct action on the spinal cord or a secondary effect as a consequence of interaction with nerve endings? These scientists were working at a time when the mechanisms of nerve function
were still a mystery, so it is hardly surprising that they struggled to explain how eserine interacted with the body. When the mechanism of nervous signalling was determined in the 1920s, eserine provided scientists with vital clues to solving the mystery.