Montezuma's Final Act?


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Prof. David Mirelman and his research team. Antisense















When the Spaniards conquered Mexico in the early 16th century, they were met with an unexpected form of resistance: life-threatening dysentery, which they called "Montezuma's revenge" (Montezuma being the exalted leader of the Aztecs at that time). Tourists traveling to developing countries sometimes go through the same experience.

Today we know that one of the main causes of this disease is an amoeba found in sewage-contaminated drinking water and poorly sanitized food. Amoeba-caused disease claims the lives of thousands yearly and afflicts millions more, mainly in impoverished communities. 
Unfortunately, the means to fight amoebic disease remain very limited. Because affected populations usually reside in poor countries pharmaceutical companies do not have sufficient economic incentive to invest in developing new therapies. Now a Weizmann team has succeeded in engineering an amoeba that could become the basis for a pioneering vaccine against amoebic disease.


Kiss of Death

Amoebas are parasites that settle in the victim's intestine, where they reproduce and attack mucosal cells in the intestines' linings. In the early 1980s Profs. Carlos Gitler and David Mirelman of the Weizmann Institute's Biological Chemistry Department received a joint research grant from the Rockefeller Foundation to study dysentery-causing amoebas. Mirelman focused on lectins, the proteins that enable amoebas to attach themselves to intestinal cells. Gitler, who had immigrated to Israel from Mexico where he personally witnessed amoeba-related suffering, discovered that amoebas kill human cells by injecting a small protein into their membranes. Gitler called this protein an amoebapore; the killing phenomenon was coined "the amoeba kiss of death."  Gitler hoped to produce antibodies that could be used against the amoebapore. However, the anti-bodies proved ineffective because they couldn't reach the amoebapore, which passed directly from the amoebas into the intestinal cells without being exposed.
Some 15 years later, technological advances encouraged Mirelman to make an attempt to study the amoebapore's role in the development of disease. Mirelman and team members Rivka Bracha and Yael Nuchamowitz isolated the gene encoding the amoebapore, made a copy of the gene and reversed the orientation of its components (called nucleotides). They then reintroduced the reversed gene (called "anti-sense") into the amoeba, creating an organism that carries both the original ("sense") amoebapore gene and the antisense gene. When the original amoebapore gene starts getting expressed, the anti-sense gene does the same. The resulting two molecules (called messenger RNAs) fit together perfectly, clinging to each other like two sides of a zipper. As a result, neither of the messenger RNA molecules is available for producing the amoebapore protein.
illustration of Amoebae protest
Using this technique the scientists managed to block some 60% of amoebapore production in the amoebas. The engineered amoebas  were much less aggressive than their original counterparts. Yet the scientists went further: In follow-up research they managed to completely block the gene that encodes the lethal protein, in effect developing a new breed of "silenced" amoebas incapable of making amoebapore and therefore much less harmful to human cells.
Now the scientists are trying to see whether the silenced amoebas can be used as a vaccine against aggressive amoebas (similar to the way weakened viruses or bacteria are used as vaccines). If successful, this first vaccination of its kind will open the way to ending the suffering of millions affected by the amoeba parasite.
Prof. David Mirelman is the incumbent of the Besen-Brender Chair of Microbiology and Parasitology. His research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; Erica A. Drake, Scarsdale, NY; Robert Drake, the Netherlands; Mr. and Mrs. Henry Meyer, Wakefield, RI; the M.D. Moross Institute for Cancer Research; and Claire Reich, Forest Hills, NY.
While attending a conference in China around ten years ago, Mirelman asked local Chinese doctors what they prescribed to patients suffering from intestinal diseases. They told him of an ancient remedy that has been used for almost five thousand years, consisting of an alcohol extract made from freshly crushed garlic cloves. They even jotted down the precise recipe. Surprised to hear that this extract cured patients from the infecting microorganisms without ill effects, Mirelman decided to investigate it. Upon returning to the Weizmann Institute, he prepared the solution and found that a specific molecule, allicin, which is found in fresh garlic extracts, kills amoebas by inactivating some of their crucial enzymes. Though the same molecule can affect enzymes in human cells, they, unlike their amoebic counterparts, are able to reactivate these enzymes. The key to reactivating them lies in a substance called glutathione, which exists in mammalian cells but not in amoebas and most other microorganisms. Efforts to develop therapies for amoebic disease based on these findings are currently under way.

Prof. Mirelman on the Great Wall of China. Garlic cure