Adding New DNA Letters Make Novel Proteins Possible

An anonymous reader quotes a report from The Economist: The fuzzy specks growing on discs of jelly in Floyd Romesberg’s lab at Scripps Research in La Jolla look much like any other culture of E. coli. But appearances deceive — for the dna of these bacteria is written in an alphabet that has six chemical letters instead of the usual four. Every other organism on Earth relies on a quartet of genetic bases: a (adenine), c (cytosine), t (thymine) and g (guanine). These fit together in pairs inside a double-stranded dna molecule, a matching t and c, g. But in 2014 Dr Romesberg announced that he had synthesised a new, unnatural, base pair, dubbed x and y, and slipped them into the genome of E. coli as well. Kept supplied with sufficient quantities of X and Y, the new cells faithfully replicated the enhanced DNA — and, crucially, their descendants continued to do so, too. Since then, Dr Romesberg and his colleagues have been encouraging their new, “semisynthetic” cells to use the expanded alphabet to make proteins that could not previously have existed, and which might have properties that are both novel and useful. Now they think they have found one. In collaboration with a spin-off firm called Synthorx, they hope to create a less toxic and more effective version of a cancer drug called interleukin-2.

Interleukin-2 works by binding to, and stimulating the activity of, immune-system cells called lymphocytes. The receptor it attaches itself to on a lymphocyte’s surface is made of three units: alpha, beta and gamma. Immune cells with all three form a strong bond to interleukin-2, and it is this which triggers the toxic effect. If interleukin-2 can be induced to bind only to the beta and gamma units, however, the toxicity goes away. And that, experiments have shown, can be done by attaching polyethylene glycol (PEG) molecules to it. The trick is to make the PEGs stick. This is where the extended genetic alphabet comes in. Using it, Synthorx has created versions of interleukin-2 to which PEGs attach themselves spontaneously in just the right place to stop them linking to the alpha unit. Tested on mice, the modified molecule has exactly the desired anti-tumor effects. Synthorx plans to ask permission for human trials later this year.

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