THE LOVELY CASTOR BEAN, by O’Neill Curatolo

Mr. Sherlock Holmes was an expert in the poisons of his time and even carried out forensic chemistry research in his Baker Street rooms. Regardless, his solution of poison-related murder cases generally pivoted on macroscopic diagnostic procedures such as smelling the corpse’s lips, as in A Study in Scarlet, or observing a corpse’s alkaloid-induced tetanic grin, the risus sardonicus, as in The Sign of the Four. The drugs involved were typically described no more specifically than “a powerful vegetable alkaloid” or “some strychnine-like substance.” Of course, this predated the advent of forensic laboratories and the explosion of biochemical knowledge that occurred later in the 20th Century. The array of tools available for the deceitful murderer today would no doubt fascinate Holmes, though luckily the products of 20th and 21st Century biochemistry and cell biology are generally just outside the available reach of those with a near-term desire to kill. Ah, but those with time and the right resources have a wonderful new toolkit!

Consider, for example, the beautiful castor bean, from the plant Ricinus communis. About the breadth of a fingernail, it has a hard, shiny, black-and-brown mottled shell whose beauty has enticed generations of admirers to string these beans together to make necklaces. Unfortunately, from time to time, an unlucky child has chewed one of these necklaced beads and has become very ill—and occasionally worse. For the castor bean holds a secret in its interior: the potent poison ricin.

In 1976, when I was a biochemistry graduate student, I became interested in plant proteins called lectins, which could bind red blood cells together. These proteins attached to the red cell surface membrane and crosslinked red cells to each other, forming an agglutinated mass. I was interested in using plant lectins to probe the structure and function of cell membranes in general, and after perusing the scientific literature on the subject, decided to isolate the lectin from Ricinus communis, called, not surprisingly, Ricinus communis agglutinin (RCA).

As protein isolations go, this was relatively straightforward, and in a late part of the procedure I used a chromatography method to separate RCA from a similar contaminant protein called ricin. I saved the RCA, and poured the ricin down the drain. Little did I know that at approximately the same time, probably in Russia, another equally earnest young biochemist was carrying out a similar isolation, but saving the ricin and discarding the RCA.

About one year later, on September 7, 1978, a forty-nine-year-old Bulgarian dissident named Georgi Markov was waiting for a bus near Waterloo Bridge in London, when he felt a sting in the back of his right thigh. He noticed a man pick up his umbrella from the ground and rush off. Within hours, Mr. Markov became ill and was taken to St. James’ Hospital, Balham, where a puncture bruise in his thigh was noted. He exhibited multiple confusing symptoms, rapidly declined, and died three days after his injury.

On autopsy, a 1.5 mm diameter sphere was removed from the puncture wound in his thigh. Scientists at the Government Chemical Defence Establishment at Porton Down concluded that the pellet delivered ricin, based on the small dose possible in the tiny sphere, Mr. Markov’s symptoms and rapid death, and the known high toxicity of ricin. It was not possible to isolate or identify any residual poison from the sphere utilizing late 1970s technology.

While the attacker was never identified, the authorities generally concluded that Mr. Markov had been injected using a weaponized umbrella by the Bulgarian Secret Police to silence his dissident radio broadcasts. Years later, former Russian KGB agent defectors confirmed KGB involvement in the assassination.

When I read about the Markov case, I vowed that I would wear rubber gloves and take other precautions if I ever isolated castor bean proteins again.

The record on assassination attempts similar to the Markov case is sketchy at best. While it has been purported that six other ricin pellet injection attacks occurred in the 1970s-1980s, public evidence is lacking. In one case, a CIA/KGB double agent claimed to have been injected with a poisonous pellet in Tyson’s Corner, Virginia. This was followed by a high fever and delirium. There are multiple inconsistent accounts of this case and no public investigation has ever been described.

A more famous case did not involve an injected pellet, but has been purported to involve a skin prick with a gel containing ricin. In 1971, the Russian dissident Alexander Solzhenitsyn was in a grocery in the town of Novocherkassk when a KGB agent surreptitiously exposed him, probably superficially on his skin. Solzhenitsyn was not aware of being pricked, but felt skin discomfort on the left side of his body as the day progressed and developed skin blisters by the next morning. He developed a high fever and agonizing pain and was sick for two to three months. A physician observed that Solzhenitsyn’s symptoms were consistent with skin poisoning by ricin.

So what is ricin and why is it so toxic?

The castor plant Ricinus communis is grown commercially and the beans are pressed to produce castor oil, which is non-toxic and has a wide variety of medical and non-medical applications. The press-cake left after oil isolation contains the protein ricin, and is toxic if eaten (as is the intact bean). There are numerous reports of horse, cattle, and poultry fatalities from unintentional and intentional press-cake poisoning.

Oral consumption by humans of the castor bean press-cake, or of isolated ricin, results primarily in local gastrointestinal (GI) effects—severe diarrhea and vomiting. Because ricin is a protein, its molecular size is too large to be absorbed across the intestinal wall and thus little or no ricin can reach the bloodstream. Furthermore, the GI tract contains enzymes that degrade dietary proteins into amino acids that can be absorbed as nutrients.

The protein ricin also undergoes such digestion after oral dosing as if it were a dietary protein, and consequently, only a small amount of the protein is available for a brief period of time to poison the cells of the GI wall. Regardless, this is enough to wreak havoc and the victim may die if diarrhea-induced dehydration is not dealt with. Modern hospitals are well-equipped with the knowledge to deal with dehydration and the reinstatement of proper electrolyte balance, as is typically done for diseases such as cholera and ebola. If an orally-dosed ricin victim is hospitalized quickly, the prognosis today is generally good.

If ricin is injected under the skin or directly into the bloodstream, the situation is very different. The toxic protein will rapidly travel through the lymph and bloodstream to almost all organs of the body.

In a conceptual way, one may think of the ricin molecule as resembling a tiny football. At one end, the so-called “Ricin B-Chain” is a Trojan horse of sorts, which binds to cell surfaces, facilitating ingress of the entire protein into the interior of the cell. The other end of the tiny football, the so-called “Ricin A-Chain,” is the business part of the protein, which once inside the cell inactivates ribosomes, which are the biochemical machines that carry out protein synthesis within the cell.

This inactivation occurs by cleavage of a specific chemical bond in one of the biopolymers that make up the structure of the ribosome. One ricin molecule can permanently inactivate 1500 ribosomes per minute, quickly shutting down manufacture of all the proteins the cell needs to thrive and survive. The cell quickly dies. Because ricin possesses a generally promiscuous Trojan horse capability, it can bind to most cell types in the body, dragging the deadly protein into cells of the kidney, liver, heart, and virtually all organs.

This is catastrophic and irreversible. What a dastardly design!

Thus, from a medical perspective, the toxicity of ricin is much greater after injection, as the toxin has easy access to almost all organs of the body. The median lethal dose (LD50) of ricin is about 20 micrograms per kilogram body weight when dosed by injection and about 1 milligram per kilogram body weight when swallowed.

For a 70 kilogram (155 pound) human, these values correspond to a total dose of 1.4 milligrams when injected and 70 milligrams when swallowed. To put this in perspective, 1.4 milligrams is about the size of a pinhead. Potent stuff!

Now the teleological question—why does ricin exist? In general, plant toxins likely exist to protect the plant from predators. In the case of the castor plant, the toxin is present in the leaves and the seeds, and is known to be poisonous to aphids and various types of plant-boring worms.

In Doyle’s The Sign of the Four, a blow-pipe was used to fire an alkaloid-soaked thorn into a victim’s scalp. Over one hundred years later, with more potent biologic poisons, this general approach appears to still be viable.

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O’Neill Curatolo is a biophysicist who holds 36 U.S. Patents. His suspense novel Campanilismo (2013) chronicles the activities of drug industry physicians and scientists in ethically murky waters in New Jersey, Kuala Lumpur, and Malaysian Borneo. A sequel titled Too Many Hats will be released in 2018.