Molecular Circuits Learn to Trigger Targeted Cancer Cell Death

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An international team of researchers has learned to use micro-RNA circuits to trigger targeted cell death in HeLa cells, widely used cultured cervical cancer cells, orginally taken from a woman who died long ago. Although it is too late for this information to help Henrietta Lacks, it is possible that this approach -- or something like it -- may be used to trigger the large-scale suicide of a wide range of cancer cells eventually.

Xie has developed a genetic “logic circuit” that prompts cells to kill themselves if the levels of five molecules match those of a cancer cell. Yaakov Benenson, who led the study, says, “In the long term, the circuits’ role is to act like miniature surgeons that can identify and destroy cancer cells.” That is a very long way off, but the study is a promising step in the right direction.

Xie worked with HeLa cells, a common line of cervical cancer cells taken from a tobacco farmer called Henrietta Lacks in 1951. Since then, they have become one of the most important tools in modern medicine. Xie identified five small molecules called microRNAs that act as a signature for HeLa cells, separating them from healthy ones. Two of the microRNAs are unusually common in HeLa; three are unusually rare.

Next, Xie created five genetic switches that would only flip if their respective microRNAs were found at the right levels. The switches control a gene called Bax, an executioner that compels a cell to kill itself. If the circuit is introduced into a cell that carries the molecular signature of HeLa, all five switches flip, Bax is roused into action, and the cell automatically self-destructs.

Xie rigged his circuit so that Bax could be restrained by each of the three microRNAs found at low levels in HeLa cells. The gene would only activate if all three molecules were largely absent; any one of them could stay the executioner’s hand. Meanwhile, the two microRNAs that are common in HeLa actually lift restraints on Bax, by blocking genes that keep it in check. Again, the circuit needs high levels of both of these molecules. If either is absent, Bax is held back.

This clever set up means that all five switches must to be flipped before the executioner carries out it bloody work. The cell only dies if it meets every one of five conditions. And Xie found that his circuit worked in practice. It activated Bax at far higher levels in HeLa cells and selectively killed them while leaving other lineages of laboratory cells unharmed. _Discover

Article abstract from Science

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Al Fin research oncologists and molecular biologists feel that Benenson's approach is more than a bit awkward and prone to breaking down. But he is working at a level of gene regulation which should prove relatively safe, as it moves closer to clinical research. And he is working at a level of complexity which should prove fertile for learning more about the molecular networks of cancer.

Expect some fascinating developments to come from this line of research.