Bioterrorism: Fast And Sensitive Way To Detect Ricin
ScienceDaily (Apr. 8, 2009) — Scientists at Albert Einstein College of Medicine of Yeshiva University have developed a simple, accurate, and highly sensitive test to detect and quantify ricin, an extremely potent toxin with potential use as a bioterrorism agent.
Ulrich Elling - scientist in the group of Josef Penninger - working in the lab with one of his colleagues. (Credit: Copyright: IMBA/Hans Krist)
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Vern Schramm, Ph.D.Ricin, a protein extracted from castor beans, can be in the form of a powder, mist, pellet or solution.
When injected or inhaled, as little as one-half milligram of ricin is lethal to humans.
No antidote is available.
The most infamous ricin attack occurred in London in 1978, when Bulgarian dissident Georgi Markov died after being stabbed with an umbrella that injected a ricin-coated pellet into his leg.
The ricin assay described in the journal article was developed in the laboratory of Vern Schramm, Ph.D., professor and Ruth Merns Chair of Biochemistry at Einstein and corresponding author. The assay detects small amounts of ricin more accurately and faster than ever before.
Users of the assay would place samples of potentially adulterated food, or swabs used to wipe potentially contaminated surfaces, into a few drops of a mixture of reagents; the mixture will emit light if ricin is present, with higher luminescence indicating greater concentrations of the toxin.
Dr. Schramm believes the assay's most immediate application is for discovering drugs that could serve as antidotes for ricin poisoning.
"Previously we had to rely on laborious, multi-step methods to see if a compound was preventing ricin from working, which is probably why no antidote to ricin has yet been discovered," explained Dr. Schramm.
After ricin enters cells, it kills them by interfering with their ability to make proteins─a basic cellular function.
Ricin does this by disrupting ribosomal RNA (the key component of ribosomes, the cell's protein manufacturing "machines").
The ricin attack causes ribosomal RNA to release a molecule of adenine.
Dr. Schramm's assay detects and quantifies ricin by measuring the amount of adenine released by cells.
"Our lab's expertise is in enzymes," says Dr. Schramm.
"One day I realized we could use a specific enzyme to convert the adenine released by ricin into ATP─a molecule whose presence can be easily detected by an already-available assay based on the light-emitting gene from fireflies.
In retrospect, like many scientific advances, it's such a simple idea that I'm surprised it wasn't thought of earlier."
Ricin has also been used as an anticancer agent by linking it to antibodies that home to tumors and deliver the ricin 'warhead' to kill cancer cells.
Einstein scientists indicate that detection of ricin in cancer trials may be an early use of this technology.
While the researchers emphasize that the ricin detection method is now laboratory-based, they also predict that relatively minor changes will be needed to make detection of ricin by light practical for field and clinical applications.
Albert Einstein College of Medicine has filed a patent application on the ricin detection method and is interested in licensing the technology to a company or organization that would develop it further for drug discovery and public health applications.
http://www.sciencedaily.com/releases/2009/04/090408104538.htm~~~~~~~~~~~~~~
Ricin is an extremely potent poison that can easily be purified from the widely available castor beans.
Security experts say an amount roughly equivalent to half a grain of rice is enough to kill an adult, making it 1,000 times more poisonous than cyanide.
There are currently no known antidotes for Ricin, and the ease of production of this tasteless, odorless plant toxin is why ricin is feared for its immense bioterrorism potential.
http://www.sciencedaily.com/releases/2011/07/110722112048.htm~~~~~~~~~~~~~~~~~
Science News
...How Deadly Food Poisoning And Bioterrorism Toxins Can Be Tamed
ScienceDaily (Mar. 6, 2008) — A powerful plant toxin widely feared for its bioterrorism potential may one day be tamed using findings about how the toxin attacks cells.
The findings may also help scientists combat food poisoning episodes such as those recently caused by bacteria-tainted produce and ground meat.
Biotechnology researchers at Rutgers University have discovered that ricin, extracted from abundant castor beans, kills cells by a previously unrecognized activity that appears to work in concert with its ability to damage protein synthesis.
While those earlier known effects still harm cells, it’s the newly discovered and more stealthy activity that the researchers now believe delivers the knockout punch.
Ricin toxin is feared as a bioterror agent because it can be easily purified from the waste of castor oil production and there are no known antidotes. It is poisonous if inhaled, ingested or injected.
Symptoms can show up within hours, including difficulty breathing, nausea, vomiting and diarrhea. Death can result within days from low blood pressure, severe dehydration, respiratory failure and eventually, failure of organs such as the liver and kidneys.
Those who survive severe ricin poisoning may still have permanent or long-lasting organ damage.
Writing in the March 7 issue of the Journal of Biological Chemistry, Rutgers plant biology and pathology professor Nilgun Tumer and her colleagues report that ricin tricks a cell into turning off a natural defense mechanism that destroys foreign proteins.
If ricin did not first deactivate the cell’s defenses, the cell would be able to turn on a stress response to get rid of the toxin.
The discovery allows scientists to explore new ways to disarm ricin.
“Because there are no specific medical treatment options for ricin intoxication, we felt it essential to dig deeper into the mechanism of ricin-induced cell death,” said Tumer.
“The new mechanism we discovered provides new targets for possible therapeutic agents.”
Tumer discovered that ricin is inhibiting a cell defense mechanism known as unfolded protein response or UPR.
Proteins that a cell synthesizes need to have their long molecular chains folded in a precise pattern.
The UPR causes proteins that don’t fold, or that fold incorrectly, to be degraded and removed from the place in a cell where folding occurs, known as the endoplasmic reticulum (ER).
When the toxic ricin A protein enters a cell, it takes a reverse pathway, being transported to and unfolded in the ER.
At this point, the UPR should initiate a cell stress response that degrades the unfolded proteins, hence acting as the cell’s first line of defense.
A piece of the ricin A protein molecule, however, signals the ER to shut down its UPR and the cell’s stress response needed for survival.
Tumer verified this mechanism by testing it with a mutant form of the ricin A protein molecule. The mutant lacked the signal that caused the UPR to shut down.
When Tumer introduced the mutant protein into yeast cells, she found that the UPR triggered the necessary stress response.
“At first, we thought ricin might be triggering the stress response and preventing it from turning off, which causes cell damage in some cancers and type II diabetes,” Tumer said.
But in experiments with the mutant form of ricin A protein, the stress response was turning on and off properly.
“Then we discovered that the wild ricin A protein was inhibiting the stress response,” she said.
Tumer noted that toxins secreted by some strains of E. coli bacteria, including those blamed for high-profile food poisoning cases recently involving spinach, lettuce and fast-food hamburgers, appear to have a similar mechanism to ricin.
Further study is needed to verify this and find ways to combat the toxin.
http://www.sciencedaily.com/releases/2008/03/080306140857.htm~~~~~~~~~~~~~~~~~~~
How the Bioweapon Ricin Kills:
Scientists Solve Mystery Through Revolutionary New Technology
ScienceDaily (Dec. 1, 2011) — A key protein that controls how the deadly plant poison and bioweapon ricin kills, has finally been identified by researchers at the Institute of Molecular Biotechnology in Vienna, Austria.
The discovery was made using a revolutionary technology that combines stem cell biology and modern screening methods, and reported on 2 December 2011 in the scientific journal Cell Stem Cell.
Shocking news spread in August this year.
Al Quaida, a terror organization, was reported to be producing bombs containing the poison ricin to attack shopping centers, airports, or train stations.
Since the First World War, ricin has had a gruesome reputation as a bioweapon. It is one of the deadliest plant based poisons in the world.
Even a tiny amount can kill a person within two to three days after getting into the bloodstream. And it comes from the humble castor oil bean, available in many health food shops or online.
How the poison works
Castor oil is a powerful laxative, used medicinally for centuries, but the raw beans also contain small amounts of the poison ricin. So far no antidote is available.
But now Ulrich Elling, a scientist on the research team led by Prof Josef Penninger at the Institute for Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences in Vienna, has identified a protein molecule called Gpr107.
This protein in the targeted cells is essential for the deadly effect of ricin. In other words, cells which lack Gpr107 are immune to the poison.
Ulrich Elling is optimistic, saying "Our research suggests that a specific antidote could now be developed by making a small molecule to block the Gpr107 protein."
New technology allows screening of the entire mammal genome
The researchers at IMBA were able to find in just a few weeks what others have been trying to find for decades.
Their rapid success was made possible by a pioneering new method of genetic research developed largely by Ulrich Elling and Josef Penninger.
With this new method, an entire mammal genome can be screened for mutations within a reasonable time frame.
Until now, screening methods for mice, rats and other mammals have focused on finding one single mutation.
This was done using a technique called RNA interference or by breeding a suitable 'knock-out mouse' to study the effect of removing a single gene.
But RNA interference doesn't always work, and breeding a knock-out mouse takes years and considerable effort.
That's why Josef Penninger sees this powerful technology as a revolution in biomedicine.
"We've now succeeded in combining the genetics of yeast, which has a single chromosome set that allows instant gene mutation, with stem cell biology," he says.
"For decades researchers have been looking for a system in mammals which would allow scientists to reconstruct millions of gene mutations simultaneously.
We have solved the puzzle and even broke a paradigm in biology -- we managed to make stable mouse stem cells with a single set of chromosomes and developed novel tools to use such stem cells to rapidly check virtually all genes at the same time for a specific function."
This new technology helped Ulrich Elling in unraveling the toxic effect of ricin.
He tested the poison in thousands of different mutations of mouse stem cells, and discovered that 49 different genetic mutations were present in one single protein, Gpr107.
Obviously, a mutation in this protein saved the cells.
Combination with stem cell research reveals broad range of applications
The incredible potential in this discovery becomes even clearer in the light of stem cells' ability to transform into any cell in the human body.
Josef Penninger is excited.
"The possible uses of this discovery are endless.
They range from fundamental issues, like which genes are necessary for the proper function of a heart muscle cell, to concrete applications as we have done in the case of ricin toxicity."
Penninger's team is already working on its next projects, including studies on how tumor cells acquire resistance to chemotherapy, a key issue in the development of cancer, and how nerve cells can regenerate, to offer hope in cases of paraplegia.
http://www.sciencedaily.com/releases/2011/12/111201125025.htm