Two research teams have created a kind of "synthetic" life: bacteria that build proteins with amino acids found in no other organisms on the planet. The new work, reported in the 20 April issue of Science ( pp. 498 and 501), could open a new branch of molecular biology, allowing researchers to create souped-up drugs and other proteins that incorporate the previously unused amino acids.
Life is picky. Organisms incorporate only 20 amino acids into proteins, while chemists can make hundreds of such building blocks. Researchers have long wanted to use these amino acids to create proteins that can carry out new functions. They can do it in test tubes by chemically attaching unnatural amino acids to molecular shuttles called transfer RNA (tRNA) molecules that then ferry their cargo to molecular machines called ribosomes that add them to growing proteins. But getting living organisms to take those steps has proven impossible, until now.
In living organisms, proteins called aminoacyl tRNA synthetases (aaRSs) link amino acids to their corresponding tRNAs. So one group, led by chemist Peter Schultz at The Scripps Research Institute in La Jolla, California, genetically engineered an aaRS that grabs hold of an unnatural amino acid (called O-methyl-L-tyrosine) and links it to a tRNA partner. The team also had to engineer their tRNA to recognize the product of a unique genetic code they inserted into a gene--a code that told the E. coli machinery to insert the unnatural amino acid into the protein. It worked: The bug inserted the novel amino acid nearly 100% of the time it was called on to do so.
The other group, led by chemical biologist Paul Schimmel at Scripps and Philippe Marlière at Evologic in Evry, France, chose a different approach. About half of all aaRSs carry out an editing function that double-checks to make sure the proper amino acid is linked to the right tRNA. If the editor finds a mistake, it clips off the incorrect amino acid, giving the tRNA a new chance to load the right one. So Schimmel and his colleagues simply mutated the editing portion of one aaRS, a change that allowed it to load unnatural amino acids onto tRNAs, which were then readily incorporated in proteins.
The new studies are "important milestones for the field," says David Liu, a chemist at Harvard University in Cambridge, who has also worked on incorporating unnatural amino acids into proteins.