Ricin
Overview
Ricin from the castor oil plant
Castor oil plant
The castor oil plant, Ricinus communis, is a species of flowering plant in the spurge family, Euphorbiaceae. It belongs to a monotypic genus, Ricinus, and subtribe, Ricininae. The evolution of castor and its relation to other species are currently being studied.Its seed is the castor bean which,...

 Ricinus communis, is a highly toxic, naturally occurring protein. A dose as small as a few grains of salt can kill an adult. The LD50 of ricin is around 22 micrograms per kilogram (1.76 mg for an average adult, around 1/228 of a standard aspirin tablet (0.4 g gross) in humans if exposure is from injection
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...

 or inhalation
Inhalation
Inhalation is the movement of air from the external environment, through the air ways, and into the alveoli....

. Oral exposure to ricin is far less toxic and lethal dose can be up to 20–30 milligrams per kilogram.
Ricin is poison
Poison
In the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....

ous if inhaled
Inhalation
Inhalation is the movement of air from the external environment, through the air ways, and into the alveoli....

, injected
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...

, or ingested
Ingestion
Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in the substance through the mouth into the gastrointestinal tract, such as through eating or drinking...

, acting as a toxin by the inhibition of protein synthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...

.
Encyclopedia
Ricin from the castor oil plant
Castor oil plant
The castor oil plant, Ricinus communis, is a species of flowering plant in the spurge family, Euphorbiaceae. It belongs to a monotypic genus, Ricinus, and subtribe, Ricininae. The evolution of castor and its relation to other species are currently being studied.Its seed is the castor bean which,...

 Ricinus communis, is a highly toxic, naturally occurring protein. A dose as small as a few grains of salt can kill an adult. The LD50 of ricin is around 22 micrograms per kilogram (1.76 mg for an average adult, around 1/228 of a standard aspirin tablet (0.4 g gross) in humans if exposure is from injection
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...

 or inhalation
Inhalation
Inhalation is the movement of air from the external environment, through the air ways, and into the alveoli....

. Oral exposure to ricin is far less toxic and lethal dose can be up to 20–30 milligrams per kilogram.

Toxicity

Ricin is poison
Poison
In the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....

ous if inhaled
Inhalation
Inhalation is the movement of air from the external environment, through the air ways, and into the alveoli....

, injected
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...

, or ingested
Ingestion
Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in the substance through the mouth into the gastrointestinal tract, such as through eating or drinking...

, acting as a toxin by the inhibition of protein synthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...

. It is resistant, but not impervious, to digestion by peptidases
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

. By ingestion, the pathology of ricin is largely restricted to the gastrointestinal tract where it may cause mucosal injuries; with appropriate treatment, most patients will make a full recovery. Because the symptoms are caused by failure to make protein, they emerge only after a variable delay from a few hours to a full day after exposure. An antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....

 not yet tested on humans has been developed by the UK military, and a vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 has been developed by the US military, and has had some human testing, and so far shown to be safe, and effective when lab mice were injected with ricin-antibody rich blood mixed with ricin. Symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...

atic and supportive treatment is available. Long term organ
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...

 damage is likely in survivors. Ricin causes severe diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

 and victims can die
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....

 of shock. Death typically occurs within 3–5 days of the initial exposure. Abrin
Abrin
Abrin is a toxalbumin that is found in the seeds of a plant called lucky bean, rosary pea or jequirity pea. Abrin is similar to but far more deadly than ricin, a toxin found in the seeds of the castor oil plant.-Physical Properties:...

 is a similar toxin, found in the highly ornamental rosary pea.

Deaths caused by ingestion of castor plant seeds are rare, partly because of the indigestible capsule, and partly because ricin can be digested (although it is resistant). The pulp from eight beans is considered toxic for an adult. A solution of saline
Saline (medicine)
In medicine, saline is a general term referring to a sterile solution of sodium chloride in water but is only sterile when it is to be placed intravenously, otherwise, a saline solution is a salt water solution...

 and glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 has been used to treat ricin overdose. Rauber and Heard have written that close examination of early 20th century case report
Case report
In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrence....

s indicates that public and professional perceptions of ricin toxicity "do not accurately reflect the capabilities of modern medical management."

Overdosage

Most acute poisoning episodes in humans are the result of oral ingestion of castor beans, 5-20 of which could prove fatal to an adult. Victims often manifest nausea, emesis, diarrhea, tachycardia, hypotension and seizures persisting for up to a week. Blood, plasma or urine ricin concentrations may be measured to confirm diagnosis.

Biochemistry

Ricin is classified as a type 2 ribosome inactivating protein
Ribosome inactivating protein
A ribosome inactivating protein is a protein synthesis inhibitor that acts at the ribosome..A number of bacterial and plant toxins act by inhibiting protein synthesis in eukaryotic cells. The toxins of the Shiga and ricin family inactivate 60S ribosomal subunits by an N-glycosidic cleavage which...

 (RIP). Whereas Type 1 RIPs consist of a single enzymatic protein chain, Type 2 RIPs, also known as holotoxins, are heterodimeric glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

s. Type 2 RIPs consist of an A chain that is functionally equivalent to a Type 1 RIP, covalently connected by a single disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

 to a B chain that is catalytically inactive, but serves to mediate entry of the A-B protein complex into the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....

. Both Type 1 and Type 2 RIPs are functionally active against ribosomes in vitro, however only Type 2 RIPs display cytoxicity due to the lectin
Lectin
Lectins are sugar-binding proteins that are highly specific for their sugar moieties. They play a role in biological recognition phenomena involving cells and proteins. For example, some viruses use lectins to attach themselves to the cells of the host organism during infection...

 properties of the B chain. In order to display its ribosome inactivating function, the ricin disulfide bond must be reductively cleaved.

Structure

The tertiary structure of ricin was shown to be a globular, glycosylated
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...

 heterodimer of approximately 60-65 kDA. Ricin toxin A chain and ricin toxin B chain are of similar molecular weight, approximately 32 kDA and 34 kDA respectively.
  • Ricin A Chain (RTA) is an N-glycoside hydrolase
    Glycoside hydrolase
    Glycoside hydrolases catalyze the hydrolysis of the glycosidic linkage to release smaller sugars...

     composed of 267 amino acids. It has three structural domains with approximately 50% of the polypeptide arranged into alpha-helices and beta-sheets. The three domains form a pronounced cleft that is the active site of RTA.
  • Ricin B Chain (RTB) is a lectin
    Lectin
    Lectins are sugar-binding proteins that are highly specific for their sugar moieties. They play a role in biological recognition phenomena involving cells and proteins. For example, some viruses use lectins to attach themselves to the cells of the host organism during infection...

     composed of 262 amino acids that is able to bind terminal galactose
    Galactose
    Galactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....

     residues on cell surfaces. RTB form a bilobal, barbell-like structure lacking alpha-helices
    Alpha helix
    A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...

     or beta-sheets
    Beta sheet
    The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...

     where individual lobes contain three subdomains
    Protein domain
    A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...

    . At least one of these three subdomains in each homologous lobe possesses a sugar-binding pocket that gives RTB its functional character.


Many plants such as barley
Barley
Barley is a major cereal grain, a member of the grass family. It serves as a major animal fodder, as a base malt for beer and certain distilled beverages, and as a component of various health foods...

 have the A chain but not the B chain. People do not get sick from eating large amounts of such products, as ricin A is of extremely low toxicity as long as the B chain is not present.

Entry into the cytosol

The ability of ricin to enter the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....

 depends on hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...

ing interactions between RTB amino acid residues and complex carbohydrates on the surface of eukaryotic cells containing either terminal N-acetyl galactosamine
Galactosamine
Galactosamine is a hexosamine derived from galactose with the molecular formula C6H13NO5. This amino sugar is a constituent of some glycoprotein hormones such as follicle-stimulating hormone and luteinizing hormone...

 or beta-1,4-linked galactose residues. Additionally, the mannose
Mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. Mannose is a C-2 epimer of glucose. It is not part of human metabolism, but is a component of microbial cell walls, and is therefore a target of the immune system and also of antibiotics....

-type glycans of ricin are able to bind cells that express mannose receptor
Mannose receptor
The mannose receptor is a C-type lectin carbohydrate binding protein primarily present on the surface of macrophages and dendritic cells. It helps recognize pathogens that have mannose on their surface, and triggers one pathway of the complement system....

s. Experimentally, RTB has been shown to bind to the cell surface on the order of 106-108 ricin molecules per cell surface.

The profuse binding of ricin to surface membranes allows internalization with all types of membrane invagination
Invagination
Invagination means to fold inward or to sheath. In biology, this can refer to a number of processes.* Invagination is the morphogenetic processes by which an embryo takes form, and is the initial step of gastrulation, the massive reorganization of the embryo from a simple spherical ball of cells,...

s. Experimental evidence points to ricin uptake in both clathrin
Clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...

-coated pits, as well as clathrin-independent pathways including caveolae
Caveolae
In biology, caveolae , which are a special type of lipid raft, are small invaginations of the plasma membrane in many vertebrate cell types, especially in endothelial cells and adipocytes....

 and macropinocytosis. Vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...

 shuttle ricin to endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...

s that are delivered to the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....

. The active acidification of endosomes are thought to have little effect on the functional properties of ricin. Because ricin is stable over a wide pH range, degradation in endosomes or lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...

s offer little or no protection against ricin. Ricin molecules are thought to follow retrograde transport via early endosomes, the trans-Golgi network, and the Golgi to enter the lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...

 of the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...

 (ER).

For ricin to function cytotoxically, RTA must be reductively cleaved from RTB in order to release a steric block of the RTA active site. This process is catalysed by the protein PDI (protein disulphide isomerase) that resides in the lumen of the ER. Free RTA in the ER lumen then partially unfolds and partially buries into the ER membrane, where it is thought to mimic a misfolded membrane-associated protein. Roles for the ER chaperones GRP94 and EDEM have been proposed prior to the 'dislocation' of RTA from the ER lumen to the cytosol in a manner that utilizes components of the endoplasmic reticulum-associated protein degradation (ERAD
ERAD
Endoplasmic-reticulum-associated protein degradation designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome....

) pathway. ERAD normally removes misfolded ER proteins to the cytosol for their destruction by cytosolic proteasomes. Dislocation of RTA requires ER membrane-integral E3 ubiquitin ligase complexes, but RTA avoids the ubiquitination that usually occurs with ERAD substrates because of its low content of lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

 residues, which are the usual attachment sites for ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...

. Thus RTA avoids the usual fate of dislocated proteins (destruction that is mediated by targeting ubiquitinylated proteins to the cytosolic proteasomes). In the mammalian cell cytosol, RTA then undergoes triage by cytosolic molecular chaperones that results in its folding to a catalytic conformation that de-purinates ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

s, thus halting protein synthesis.

Ribosome inactivation

Study of the N-glycosidase activity of ricin was pioneered by Endo and Tsurugi who showed that RTA cleaves a glycosidic bond within the large rRNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...

 of the 60S
60S
60S is the large ribosomal subunit in eukaryotes. It corresponds to 50S in prokaryotes.It consists of the following:* 5S* 28S* 5.8SThe following is a list of proteins contained within the 60S ribosome:...

 subunit of eukaryotic ribosomes. They subsequently showed RTA specifically and irreversibly hydrolyses the N-glycosidic bond of the adenine
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...

 residue at position 4324 (A4324) within the 28S
28S ribosomal RNA
28S ribosomal RNA is the eukaryotic nuclear homologue of the prokaryotic 23S ribosomal RNA; this is the structural RNA for the large component of eukaryotic cytoplasmic ribosomes, and thus one of the basic components of all eukaryotic cells....

 rRNA, but leaves the phosphodiester backbone of the RNA intact. The ricin targets A4324 that is contained in a highly conserved sequence
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...

 of 12 nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

s universally found in eukaryotic ribosomes. The sequence, 5’-AGUACGAGAGGA-3’, termed the sarcin-ricin loop, is important in binding elongation factor
Elongation factor
Elongation factors are a set of proteins that facilitate the events of translational elongation, the steps in protein synthesis from the formation of the first peptide bond to the formation of the last one.Elongation is the most rapid step in translation:...

s during protein synthesis. The depurination event rapidly and completely inactivates the ribosome, resulting in toxicity from inhibited protein synthesis. A single RTA molecule in the cytosol is capable of depurinating approximately 1500 ribosomes per minute.

Depurination reaction

Within the active site of RTA, there exist several invariant amino acid residues involved in the depurination
Depurination
In molecular genetics, depurination is an alteration of DNA in which the purine base is removed from the deoxyribose sugar by hydrolysis of the beta-N-glycosidic link between them. After depurination, an apurinic site is formed where the sugar phosphate backbone remains and the sugar ring has a...

 of ribosomal RNA. Although the exact mechanism of the event is unknown, key amino acid residues identified include tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...

 at positions 80 and 123, glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...

 at position 177, and arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

 at position 180. In particular, Arg180 and Glu177 have been shown to be involved in the catalytic mechanism, and not substrate binding, with enzyme kinetic
Enzyme kinetics
Enzyme kinetics is the study of the chemical reactions that are catalysed by enzymes. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction investigated...

 studies involving RTA mutants. The model proposed by Mozingo and Robertus, based x-ray structures, is as follows:

  1. Sarcin-ricin loop substrate binds RTA active site with target adenine stacking against tyr80 and tyr123.
  2. Arg180 is positioned such that it can protonate N-3 of adenine and break the bond between N-9 of the adenine ring and C-1’ of the ribose
    Ribose
    Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....

    .
  3. Bond cleavage
    Bond cleavage
    Bond cleavage, or scission, is the splitting of chemical bonds.If the two electrons in a cleaved covalent bond are divided between the products, the process is known as homolytic fission and free redicals are generated by homolytic cleavage the process is known as homolytic fission or homolysis...

     results in an oxycarbonium ion on the ribose, stabilized by Glu177.
  4. N-3 protonation of adenine by Arg180 allows deprotonation
    Deprotonation
    Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...

     of a nearby water molecule.
  5. Resulting hydroxyl
    Hydroxyl
    A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...

     attacks ribose carbonium ion
    Carbonium ion
    A carbonium ion is a carbocation of the penta- or tetracoordinated nonclassical type such as an ion of the type R5C+.- Methanium:The parent compound methanium or CH5+ is protonated methane and a superacid. This ion exists as a reactive intermediate in the interstellar medium and can be produced in...

    .
  6. Depurination of adenine results in a neutral ribose on an intact phosphodiester RNA backbone.

Manufacture

Ricin is easily purified from castor oil
Castor oil
Castor oil is a vegetable oil obtained from the castor bean . Castor oil is a colorless to very pale yellow liquid with mild or no odor or taste. Its boiling point is and its density is 961 kg/m3...

 manufacturing waste. The aqueous phase left over from the oil extraction process is called waste mash. It contains about 5-10% ricin by weight. Separation requires only simple chromatographic techniques.

Patented extraction process

A process for extracting ricin has been described in a patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....

. The described extraction method is very similar to that used for the preparation of soy protein isolates.

The patent was removed from the United States Patent and Trademark Office
United States Patent and Trademark Office
The United States Patent and Trademark Office is an agency in the United States Department of Commerce that issues patents to inventors and businesses for their inventions, and trademark registration for product and intellectual property identification.The USPTO is based in Alexandria, Virginia,...

 (USPTO) database sometime in 2004. Modern theories of protein chemistry cast doubt on the effectiveness of the methods disclosed in the patent.

Potential medicinal use

Some researchers have speculated about using ricins in the treatment of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, as a so-called "magic bullet" to destroy targeted cells. Because ricin is a protein, it can be genetically linked to a monoclonal antibody to target malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...

 cells recognized by the antibody. The major problem with ricin is that its native internalization sequences are distributed throughout the protein. If any of these native internalization sequences are present in a therapeutic, then the drug will be internalized by, and kill, untargeted epithelial cells as well as targeted cancer cells.

Some researchers hope that modifying ricin will sufficiently lessen the likelihood that the ricin component of these immunotoxin
Immunotoxin
An immunotoxin is a human-made protein that consists of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell...

s will cause the wrong cells to internalize it, while still retaining its cell-killing activity when it is internalized by the targeted cells. Generally, however, ricin has been superseded for medical purposes by more practical fragments of bacterial toxins, such as diphtheria toxin
Diphtheria toxin
Diphtheria toxin is an exotoxin secreted by Corynebacterium diphtheriae, the pathogen bacterium that causes diphtheria. Unusually, the toxin gene is encoded by a bacteriophage...

, which is used in denileukin diftitox
Denileukin diftitox
Denileukin diftitox is an antineoplastic agent, an engineered protein combining Interleukin-2 and Diphtheria toxin. This can bind to Interleukin-2 receptors and introduce the diphtheria toxin into cells that express those receptors, killing the cells...

, an FDA-approved treatment for leukemia and lymphoma. No approved therapeutics contain ricin.

A promising approach is also to use the non-toxic B subunit as a vehicle for delivering antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

s into cells thus greatly increasing their immunogenicity
Immunogenicity
Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal.- Immunogenicity :The ability to induce humoral and/or cell-mediated immune responses....

. Use of ricin as an adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...

 has potential implications for developing mucosal vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

s.
Ricinine has some insecticidal effects on three insect pests as well as a hepatoprotective activity.
Ricinine, when administered to mice at low doses has memory-improving effects.
The signs of intoxication caused by ricinine can be used as chemical model of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

 in the screening of anticonvulsant drugs.

Incidents involving ricin

Ricin has been involved in a number of incidents, including the high-profile assassination of Georgi Markov
Georgi Markov
Georgi Ivanov Markov was a Bulgarian dissident writer.Markov originally worked as a novelist and playwright, but in 1969 he defected from Bulgaria, then governed by President Todor Zhivkov...

 using a weapon disguised as an umbrella.

The ingestion of Ricinus communis cake is responsible for fatal ricin poisoning in animals.

Use as a chemical/biological warfare agent

The United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 investigated ricin for its military potential during the First World War. At that time it was being considered for use either as a toxic dust or as a coating for bullet
Bullet
A bullet is a projectile propelled by a firearm, sling, or air gun. Bullets do not normally contain explosives, but damage the intended target by impact and penetration...

s and shrapnel. The dust cloud concept could not be adequately developed, and the coated bullet/shrapnel concept would violate the Hague Convention of 1899
Hague Conventions (1899 and 1907)
The Hague Conventions were two international treaties negotiated at international peace conferences at The Hague in the Netherlands: The First Hague Conference in 1899 and the Second Hague Conference in 1907...

 (adopted in U.S. law at 32 Stat.
United States Statutes at Large
The United States Statutes at Large, commonly referred to as the Statutes at Large and abbreviated Stat., are the official source for the laws and concurrent resolutions passed by the United States Congress...

 1903), specifically Annex § 2, Ch.1, Article 23, stating "...it is especially prohibited...[t]o employ poison or poisoned arms". The First World War ended before the U.S. weaponized ricin.

During the Second World War the United States and Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...

 undertook studying ricin in cluster bomb
Cluster bomb
A cluster munition is a form of air-dropped or ground-launched explosive weapon that releases or ejects smaller sub-munitions. Commonly, this is a cluster bomb that ejects explosive bomblets that are designed to kill enemy personnel and destroy vehicles...

s. Though there were plans for mass production
Mass production
Mass production is the production of large amounts of standardized products, including and especially on assembly lines...

 and several field trial
Field trial
A field trial is a competitive event at which hunting dogs compete against one another. There are field trials for retrievers, pointing dogs and flushing dogs. Field trials are usually organized by kennel clubs or other gun dog organizations...

s with different bomblet concepts, the end conclusion was that it was no more economical than using phosgene
Phosgene
Phosgene is the chemical compound with the formula COCl2. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles...

. This conclusion was based on comparison of the final weapons rather than ricin's toxicity (LCt50
LD50
In toxicology, the median lethal dose, LD50 , LC50 or LCt50 of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration...

 ~40 mg·min/m3). Ricin was given the military symbol
Chemical weapon designation
Chemical, biological, and radiological warfare agents are sometimes assigned what is termed a military symbol. Military symbols evolved out of the First World War from the British in part for secrecy, and to simplify reference to chemicals by something other than a chemical name...

 W or later WA. Interest in it continued for a short period after the Second World War, but soon subsided when the U.S. Army Chemical Corps began a program to weaponize sarin
Sarin
Sarin, or GB, is an organophosphorus compound with the formula [2CHO]CH3PF. It is a colorless, odorless liquid, which is used as a chemical weapon. It has been classified as a weapon of mass destruction in UN Resolution 687...

.

The Soviet Union
Soviet Union
The Soviet Union , officially the Union of Soviet Socialist Republics , was a constitutionally socialist state that existed in Eurasia between 1922 and 1991....

 also possessed weaponized ricin. There were speculations that the KGB
KGB
The KGB was the commonly used acronym for the . It was the national security agency of the Soviet Union from 1954 until 1991, and was the premier internal security, intelligence, and secret police organization during that time.The State Security Agency of the Republic of Belarus currently uses the...

 even used it outside of the Soviet bloc; however, this was never proven. In 1978, the Bulgaria
Bulgaria
Bulgaria , officially the Republic of Bulgaria , is a parliamentary democracy within a unitary constitutional republic in Southeast Europe. The country borders Romania to the north, Serbia and Macedonia to the west, Greece and Turkey to the south, as well as the Black Sea to the east...

n dissident Georgi Markov
Georgi Markov
Georgi Ivanov Markov was a Bulgarian dissident writer.Markov originally worked as a novelist and playwright, but in 1969 he defected from Bulgaria, then governed by President Todor Zhivkov...

 was assassinated by Bulgarian secret police
Secret police
Secret police are a police agency which operates in secrecy and beyond the law to protect the political power of an individual dictator or an authoritarian political regime....

 who surreptitiously 'shot' him on a London
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...

 street with a modified umbrella
Bulgarian umbrella
The Bulgarian umbrella is the name of an umbrella with a hidden pneumatic mechanism which shot out a small poisonous pellet containing ricin....

 using compressed gas to fire a tiny pellet contaminated with ricin into his leg. He died in a hospital a few days later; his body was passed to a special poison branch of the British Ministry of Defence (MOD) that discovered the pellet during an autopsy
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...

. The prime suspects were the Bulgarian secret police: Georgi Markov had defected
Defection
In politics, a defector is a person who gives up allegiance to one state or political entity in exchange for allegiance to another. More broadly, it involves abandoning a person, cause or doctrine to whom or to which one is bound by some tie, as of allegiance or duty.This term is also applied,...

 from Bulgaria some years previously and had subsequently written books and made radio broadcasts which were highly critical of the Bulgarian communist regime. However, it was believed at the time that Bulgaria would not have been able to produce the pellet, and it was also believed that the KGB had supplied it. The KGB denied any involvement although high-profile KGB defectors Oleg Kalugin
Oleg Kalugin
Oleg Danilovich Kalugin , is a former KGB general. He was a longtime head of KGB operations in the United States and later a critic of the agency.-Early life and the KGB career:...

 and Oleg Gordievsky
Oleg Gordievsky
Oleg Antonovich Gordievsky , CMG , is a former Colonel of the KGB and KGB Resident-designate and bureau chief in London, who was a secret agent of the British Secret Intelligence Service from 1974 to 1985.-Early career:Oleg Gordievsky attended the Moscow State Institute of International...

 have since confirmed the KGB's involvement. Earlier, Soviet dissident
Dissident
A dissident, broadly defined, is a person who actively challenges an established doctrine, policy, or institution. When dissidents unite for a common cause they often effect a dissident movement....

 Aleksandr Solzhenitsyn
Aleksandr Solzhenitsyn
Aleksandr Isayevich Solzhenitsyn was aRussian and Soviet novelist, dramatist, and historian. Through his often-suppressed writings, he helped to raise global awareness of the Gulag, the Soviet Union's forced labor camp system – particularly in The Gulag Archipelago and One Day in the Life of...

 also suffered (but survived) ricin-like symptoms after a 1971 encounter with KGB agents. See also: Alexander Litvinenko
Alexander Litvinenko
Alexander Valterovich Litvinenko was an officer who served in the Soviet KGB and its Russian successor, the Federal Security Service ....

.

Despite ricin's extreme toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...

 and utility as an agent of chemical/biological warfare, it is extremely difficult to limit the production of the toxin. The castor bean plant from which ricin is derived is a common ornamental
Ornamental plant
Ornamental plants are plants that are grown for decorative purposes in gardens and landscape design projects, as house plants, for cut flowers and specimen display...

 and can be grown at home without any special care, and the major reason ricin is a public health threat is that it is easy to obtain. Under both the 1972 Biological Weapons Convention
Biological Weapons Convention
The Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological and Toxin Weapons and on their Destruction was the first multilateral disarmament treaty banning the...

 and the 1997 Chemical Weapons Convention
Chemical Weapons Convention
The Chemical Weapons Convention is an arms control agreement which outlaws the production, stockpiling and use of chemical weapons. Its full name is the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction...

, ricin is listed as a schedule 1 controlled substance. Despite this, more than 1 million tonne
Tonne
The tonne, known as the metric ton in the US , often put pleonastically as "metric tonne" to avoid confusion with ton, is a metric system unit of mass equal to 1000 kilograms. The tonne is not an International System of Units unit, but is accepted for use with the SI...

s of castor beans are processed each year, and approximately 5% of the total is rendered into a waste
Toxic waste
Toxic waste is waste material that can cause death or injury to living creatures. It spreads quite easily and can contaminate lakes and rivers. The term is often used interchangeably with “hazardous waste”, or discarded material that can pose a long-term risk to health or environment.Toxic waste...

 containing high concentrations of ricin toxin.

Ricin is several orders of magnitude less toxic than botulinum or tetanus toxin
Tetanospasmin
Tetanus toxin is an extremely potent neurotoxin produced by the vegetative cell of Clostridium tetani in anaerobic conditions, causing tetanus. It has no known function for clostridia in the soil environment where they are normally encountered. It is also called spasmogenic toxin, tetanospasmin or...

, but the latter are harder to come by. Compared to botulinum or anthrax
Anthrax
Anthrax is an acute disease caused by the bacterium Bacillus anthracis. Most forms of the disease are lethal, and it affects both humans and other animals...

 as biological weapons or chemical weapons, the quantity of ricin required to achieve LD50 over a large geographic area is significantly more than an agent such as anthrax (tons of ricin vs. only kilogram quantities of anthrax). Ricin is easy to produce, but is not as practical nor likely to cause as many casualties as other agents. Ricin is inactivated (the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 changes structure and becomes less dangerous) much more readily than anthrax spore
Spore
In biology, a spore is a reproductive structure that is adapted for dispersal and surviving for extended periods of time in unfavorable conditions. Spores form part of the life cycles of many bacteria, plants, algae, fungi and some protozoa. According to scientist Dr...

s, which may remain lethal for decades. Jan van Aken, a Dutch expert on biological weapons, explained in a report for The Sunshine Project that Al Qaeda's experiments with ricin suggest their inability to produce botulin or anthrax.

Ian Davison
Ian Davison
Ian Davison is a British unemployed lorry driver, white supremacist, and neo-Nazi who was arrested in 2009 for planning terrorist attacks. Davison's then-18-year-old son Nicky, a milk man's assistant, was also arrested at the same time....

, a British white supremacist and neo-Nazi, was arrested in 2009 for planning terrorist attacks involving ricin.

In 2011 the United States government discovered information that terrorist groups were attempting to obtain large amounts of castor beans for weaponized ricin use.

On November 1, 2011 the FBI arrested 4 North Georgia
Georgia (U.S. state)
Georgia is a state located in the southeastern United States. It was established in 1732, the last of the original Thirteen Colonies. The state is named after King George II of Great Britain. Georgia was the fourth state to ratify the United States Constitution, on January 2, 1788...

 men and charged them in plots to purchase explosives, a silencer and to manufacture the biological toxin ricin from castor beans.

External links

  • Canola oil: Does it contain toxins? from Mayo Clinic
    Mayo Clinic
    Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...

  • Castor bean information at Purdue University
    Purdue University
    Purdue University, located in West Lafayette, Indiana, U.S., is the flagship university of the six-campus Purdue University system. Purdue was founded on May 6, 1869, as a land-grant university when the Indiana General Assembly, taking advantage of the Morrill Act, accepted a donation of land and...

  • ricin information at Department of Health (United Kingdom)
    Department of Health (United Kingdom)
    The Department of Health is a department of the United Kingdom government with responsibility for government policy for health and social care matters and for the National Health Service in England along with a few elements of the same matters which are not otherwise devolved to the Scottish,...

  • ricin information at Cornell University
    Cornell University
    Cornell University is an Ivy League university located in Ithaca, New York, United States. It is a private land-grant university, receiving annual funding from the State of New York for certain educational missions...

  • Medical research on ricin at BBC
    BBC
    The British Broadcasting Corporation is a British public service broadcaster. Its headquarters is at Broadcasting House in the City of Westminster, London. It is the largest broadcaster in the world, with about 23,000 staff...

  • Chemical Review at United States Army
    United States Army
    The United States Army is the main branch of the United States Armed Forces responsible for land-based military operations. It is the largest and oldest established branch of the U.S. military, and is one of seven U.S. uniformed services...

  • Ricin - Emergency Preparations at CDC
    Centers for Disease Control and Prevention
    The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

  • BioHealthBase Bioinformatics Resource Center Ricin bioinformatics resource
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