Ricin

• 1. Introduction

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  Ricin is a protein made inside the seeds of the castor oil plant, Ricinus communis, and it ranks as a highly potent toxin. A single molecule that reaches the inside of a living cell can disable roughly 1500 of the cell's protein-making machines every minute. A cell that cannot make protein cannot survive. Yet the same seeds are crushed in huge quantities to make castor oil, and some people have swallowed beans in the dozens and lived. How can a molecule so efficient prove so awkward to use? What exactly does it do once it gets inside? And why has it turned up in an umbrella, in envelopes and in a television drama?

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• 2. Two Chains

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  Inside the endosperm of a castor seed, the plant builds ricin from one long precursor chain of 576 amino acid residues. The first 35 residues form a signal peptide, which steers the chain into the endoplasmic reticulum and is then cut away. In that compartment the chain is decorated with sugars, and an enzyme helps form a disulfide bond between cysteines 294 and 318. After more sugar decoration in the Golgi apparatus, the chain travels to protein storage bodies. There an endopeptidase removes a short linker, residues 303-314, and leaves two finished pieces. The A chain has 267 residues and the B chain has 262. A single disulfide bond holds them together.

  Biochemists file ricin under the type 2 ribosome-inactivating proteins, which are also called holotoxins. Type 1 members of the family are a single chain that does its own catalytic work. Type 2 members split the labour between two different chains that form a heterodimer. Ricin's finished shape is a globular, sugar-decorated complex of about 60-65 kDa. The A chain weighs about 32 kDa and the B chain about 34 kDa. Overall, it closely resembles abrin-a, an isomer of abrin.

  The A chain is an N-glycoside hydrolase with three structural domains. About half of it is folded into alpha-helices and beta-sheets. The three domains together form a pronounced cleft, and that cleft is the active site. The B chain is a lectin shaped like a barbell, with two lobes of three subdomains each and no helices or sheets at all. At least one subdomain in each lobe holds a sugar-binding pocket. Neither half is dangerous alone. Barley, for example, makes only an A chain, and that chain cannot enter a cell without the B chain to carry it. The disulfide bond between the two matters enormously, because it must be broken chemically before the A chain can do any harm.

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• 3. Cell Sabotage

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  A cell's outer surface can hold between a million and a hundred million ricin molecules at once, all gripped by the B chain. That chain recognizes complex sugars ending in N-acetylgalactosamine or in beta-1,4-linked galactose. Ricin's own mannose-type sugars also let it stick to cells that carry mannose receptors. Because the grip is so widespread, the cell pulls ricin inside through nearly every kind of membrane pocket it has. Those routes include clathrin-coated pits, caveolae and macropinocytosis.

  Inside, vesicles carry the toxin to endosomes, then to the Golgi apparatus, and onward in reverse to the endoplasmic reticulum. The acid in endosomes does little to it. Ricin stays stable across a wide range of acidity, so being sent to endosomes or lysosomes offers the cell almost no protection.

  The critical step happens in the endoplasmic reticulum. There a protein called protein disulfide isomerase cuts the A chain free from the B chain, which unblocks the A chain's active site. The freed A chain partly unfolds and tucks into the membrane, where it passes for a misfolded protein. The cell's quality-control pathway, known as ERAD, then ejects it into the cytosol. Chaperones named GRP94, EDEM and BiP have been proposed as helpers in that exit.

  Normally a protein thrown out this way is tagged with ubiquitin and destroyed by proteasomes. Ubiquitin attaches at lysine residues, and the A chain has very few of them, so it largely escapes the tag. In the cytosol, the chaperones Hsc70 and Hsp90 and a proteasome subunit called RPT5 help it fold into its working shape.

  Its target is the 28S ribosomal RNA of the large 60S subunit of the ribosome. There the A chain removes a single adenine, at position 4324, and leaves the RNA backbone intact. The adenine sits inside a highly conserved run of 12 nucleotides, 5'-AGUACGAGAGGA-3', called the sarcin-ricin loop. The loop is how the ribosome binds elongation factors, so losing that one base shuts the ribosome down quickly and for good.

  The exact chemistry is still not settled. Tyrosines at positions 80 and 123, glutamic acid at position 177 and arginine at position 180 are the key residues. Studies of mutant A chains showed that Arg180 and Glu177 drive the catalysis rather than the grip on the substrate. Mozingo and Robertus proposed a model from X-ray structures. In it, Arg180 donates a proton to the adenine and breaks its bond to the sugar, and Glu177 steadies the charged intermediate that results.

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• 4. Beans And Bodies

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  Because ricin does not dissolve in oil, very little of it ends up in castor oil. Processors also heat the extracted oil above 80 C to denature any trace that remains. What stays behind after pressing is a solid residue called the cake, oil cake or press cake, and it can hold up to 5% ricin. Cakes from coconut, peanuts and sometimes cotton seeds can feed cattle or fertilize fields. Castor cake cannot feed cattle unless autoclaving first deactivates the ricin. Animals have died from accidentally eating castor cake that was meant as fertilizer.

  In mice, the median lethal dose by injection into the abdomen is around 22 micrograms per kilogram of body mass. Swallowing ricin is far less toxic. The estimated lethal oral dose for a human is about one milligram per kilogram. The pulp of eight beans counts as dangerous to an adult, and 5-20 beans could prove fatal. Even so, deaths from eating the seeds are rare, for two reasons. The seed coat is hard to digest, and the stomach deactivates some of the ricin. Swallowing beans whole rarely kills. They need to be thoroughly chewed.

  The survival rate after eating castor beans is 98%. In 2013 a 37-year-old woman in the United States survived after eating 30 beans. In another case a man blended 200 beans with juice, drank the mixture and survived. Two researchers, Rauber and Heard, studied early twentieth-century case reports. They concluded that public and professional ideas about ricin's toxicity "do not accurately reflect the capabilities of modern medical management".

  Symptoms come late, because the damage is a failure to make protein. After eating the toxin, stomach and gut symptoms can begin within six hours, though they do not always appear. Effects on the central nervous system, adrenal glands, kidneys and liver show up two to five days after exposure. The gut lining becomes inflamed and bleeds, which leads to severe nausea, vomiting, diarrhea and difficulty swallowing. Victims may pass bloody stool or vomit blood. The loss of fluid drops blood volume and can cause organ failure and shock. Death typically comes three to five days after swallowing the toxin.

  Breathing ricin produces a different picture. A cough and fever come first, and fatal fluid in the lungs or respiratory failure can follow. Skin or airway exposure can also trigger an allergic reaction, with swollen eyes and lips, wheezing and blistering skin. Doctors confirm poisoning by measuring ricin or a related compound called ricinine in blood, plasma or urine, using immunoassay or liquid chromatography combined with mass spectrometry.

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• 5. Treatments And Vaccines

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  No antidote has yet become standard care. As of 2006, the British Armed Forces had developed one that was still untested on humans. As of 2005, a US military antidote had proved safe and effective in lab mice and had some human testing. Monoclonal antibodies are under scientific investigation as another possible treatment. For now, doctors rely on supportive care to limit the damage. That can include intravenous fluids and electrolytes, airway management, assisted ventilation, and drugs for seizures and low blood pressure. If the poison was swallowed recently, activated charcoal or gastric lavage can clear the stomach. With treatment most patients recover well, although survivors often suffer long-term organ damage.

  Vaccination is possible by injecting an inactive form of the A chain. The body makes antibodies against it, and the protection lasts for several months. Two vaccines built on modified A chains, RiVax and RVEc, have completed Phase I clinical trials and proved safe. RVEc is also known as RTA1-33/44-198. A company called Soligenix, Inc. licensed RiVax from Vitetta and colleagues at UT Southwestern. It proved safe and immunogenic in mice, rabbits and humans across two successful clinical trials. It also won a US patent and orphan drug status in the US and the EEC. As of 2019 it was still in clinical trials in the US, backed by grants from the National Institute of Allergy and Infectious Diseases and the US Food and Drug Administration.

  Some researchers have eyed ricin as a cancer drug as well. Because it is a protein, it can be attached to a monoclonal antibody that homes in on tumour cells. The obstacle is that ricin's signals for entering cells are spread throughout the protein. A drug carrying any of them would be taken up by healthy cells too and kill them. Bacterial toxins have proven more practical. Diphtheria toxin, for example, is used in denileukin diftitox, an FDA-approved treatment for leukemia and lymphoma. A more promising idea for ricin uses its harmless B subunit as a delivery vehicle that carries antigens into cells and boosts their immune effect. That approach could matter for vaccines delivered through mucous membranes.

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• 6. Weapons And Controls

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  During World War I, the United States studied ricin as either a toxic dust or a coating for bullets and shrapnel. The dust cloud never worked well enough to develop. The coated projectiles would have broken the Hague Convention of 1899, which makes it especially prohibited "to employ poison or poisoned arms".

  In World War II, the United States and Canada tested ricin in cluster bombs. Mass production was planned, and several field trials tried different bomblet designs. The verdict was that it was no more economical than phosgene. That judgement compared the finished weapons and did not turn on ricin's toxicity. The military gave it the symbol W, and later WA. Interest lingered briefly after the war, then faded when the US Army Chemical Corps began a programme to weaponize sarin.

  Ricin is easy to make but a poor battlefield weapon. It is several orders of magnitude less toxic than botulinum or tetanus toxin, though those are harder to obtain. To reach the median lethal dose across 100 square kilometres would take about 8 tonnes of ricin. Anthrax would need only kilogram quantities. Many ways of spreading ricin would produce enough heat to ruin it. A contaminated area stays dangerous only until the bonds between the two chains break, which takes two or three days. Anthrax spores can stay lethal for decades. Jan van Aken, a German weapons expert, wrote in a report for The Sunshine Project that Al Qaeda's ricin experiments suggest it could not produce botulinum or anthrax.

  The plant itself resists control. The castor bean is a common ornamental, and it can be grown at home with no special care. The 1972 Biological Weapons Convention and the 1997 Chemical Weapons Convention both list ricin as a schedule 1 controlled substance. Even so, more than a million metric tons of castor beans are processed every year, and about 5% of that ends up as waste with negligible amounts of undenatured toxin.

  In the United States, ricin sits on the select agents list of the Department of Health and Human Services, so researchers who use it must register. Investigators holding under 1000 mg are exempt. It is also an extremely hazardous substance under Section 302 of the Emergency Planning and Community Right-to-Know Act, which imposes strict reporting duties on facilities that make, store or use significant amounts.

  The Soviet Union held weaponized ricin. The KGB built weapons with it that were used beyond the Soviet bloc, and one case became far better known than the rest.

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• 7. Umbrella And Pellets

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  On a London street in 1978, the Bulgarian dissident Georgi Markov was shot in the leg with a tiny pellet containing ricin. The weapon was a modified umbrella that fired the pellet with compressed gas. The attackers were Bulgarian secret police. Markov died in hospital a few days later. His body went to a special poison branch of the British Ministry of Defence, which found the pellet during the autopsy. His is the only successful murder with ricin that the record describes.

  Markov had defected from Bulgaria some years earlier. He then wrote books and made radio broadcasts that sharply criticized the Bulgarian communist regime, which made the secret police the prime suspects. At the time, many believed Bulgaria could not have made such a pellet and that the KGB supplied it. The KGB denied any part. Later, two high-profile KGB defectors, Oleg Kalugin and Oleg Gordievsky, confirmed that it had been involved.

  Ten days before the attack on Markov, another Bulgarian defector, Vladimir Kostov, felt a sting in his lower back on an escalator of the Paris metro. He developed a fever and recovered. After Markov's death, doctors examined the wound and removed a ricin-laced pellet identical to the one used against Markov. Part of its original wax coating was still attached. Only a little ricin had leaked out, enough to cause some symptoms. That small dose let his body build antibodies against further poisoning.

  The Russian writer Aleksandr Solzhenitsyn also developed ricin-like symptoms after an encounter with KGB agents in 1971, and he survived.

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• 8. Letters And Plots

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  On the 29th of May 2013, two anonymous letters sent to New York City Mayor Michael Bloomberg held traces of ricin. A third went to the offices of Mayors Against Illegal Guns in Washington, D.C. A letter to President Barack Obama was also reported at the same time. The actress Shannon Richardson was charged and pleaded guilty that December. She was sentenced to 18 years in prison and ordered to pay restitution of US$367,000.

  On the 2nd of October 2018, two letters suspected of containing ricin were sent to the Pentagon. One was addressed to Secretary of Defense James Mattis and the other to Chief of Naval Operations Admiral John Richardson. On the 23rd of July 2019 a letter arrived at Pelican Bay State Prison in California claiming to hold a suspicious substance. Authorities confirmed it contained ricin, and nobody was harmed.

  In 2020, some Czech media reported, citing intelligence information, that a person with a Russian diplomatic passport had arrived in Prague carrying ricin. The aim was said to be the assassination of three politicians. One was Zdeněk Hřib, mayor of Prague, who had helped rename the square called Pod Kaštany, where the Russian embassy stands, after the opposition politician Boris Nemtsov, who was assassinated in 2015. Another was Ondřej Kolář, mayor of the Prague 6 district, who had helped remove a statue of Marshal Konev. The third was Pavel Novotný, mayor of the Řeporyje district. All three received police protection. Russian president Vladimir Putin denied the reports. Czech president Miloš Zeman later called Hřib's protection an attempt by an insignificant politician to gain attention, and he confused ricin with castor oil, which is not poisonous.

  German police thwarted attempted ricin attacks in 2018 and in 2023, after tip-offs believed to have come from the US FBI. In 2025, security agencies in the Indian state of Gujarat arrested three men who were allegedly plotting a terrorist attack with ricin.

  The television series Breaking Bad used ricin as a plot device, and its popularity inspired several real criminal cases. Kuntal Patel of London tried to poison her mother with abrin, a similar toxin, after her mother interfered with her marriage plans. Daniel Milzman, a 19-year-old former Georgetown University student, was charged with making ricin in his dorm room, intending to use it on another undergraduate he had a relationship with. Mohammed Ali of Liverpool tried to buy 500 mg of ricin on the dark web from an undercover FBI agent. He was sentenced on the 18th of September 2015 to eight years in prison. The poison's literary career is older than any of these cases, because Agatha Christie used ricin as a plot device in her 1929 short story The House of Lurking Death.

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