The lexicon of life is so limited. If only scientists could expand its repertoire of building blocks, they could revolutionise our ability to build huge, complex proteins that could lead to a new generation of drugs, molecular machines and wonder materials.
All living things on Earth are built from proteins created from the same 20 chemical units, called amino acids. Now, scientists at the Medical Research Council’s Laboratory of Molecular Biology, Cambridge, are getting closer to developing polymers composed of new amino acids beyond those canonical 20.
Of the 400-plus scientists currently working in the laboratory, the largest space is reserved for a team run by Jason Chin, which has assembled tools to synthesise polymers far beyond the complexity of anything currently made by chemists. Chin’s team has done this by redesigning the ribosome – a molecular factory found in all living cells that synthesises proteins, turning genes into flesh and blood since the dawn of life four billion years ago.
While industrial methods assemble simple chemical units to make polymers, like stringing beads on a thread, the ribosome shuffles the 20 basic amino acids to sculpt elaborate 3D proteins such as enzymes, molecular machines, light sensors and more inside living things. Chin’s work paves the way for an engineered ribosome that could assemble a much larger repertoire of amino acids into molecules that, with tens of thousands of amino acids and millions of atoms, could rival the size and complexity of anything in nature.
To do this, Chin has overcome a key problem in turbocharging the ribosome: it is so central to life that even modest tinkering can be lethal. Over the past 15 years, he has created the tools to build an “orthogonal ribosome” to work alongside the real thing while leaving the original to take care of key cellular functions. “Loosely speaking, it’s like running one operating system inside another,” he says.
Consisting of half a million or so atoms, a ribosome is a confection of protein and RNA – thought to be the genetic material of the first life on Earth. Two key RNA molecules and more than 50 proteins form two basic parts of the ribosome: the “brain”, known as 30S, which reads genetic code in the form of messenger RNA; and the larger 50S “heart” that turns the messenger RNA’s information into protein with the help of transfer RNAs, which carry amino acids. Essentially, the ribosome matches messenger RNA to transfer RNA, assembling the latter’s cargo of amino acids in the right order to make a protein.
Chin can evolve new ribosomes by using robots to select cells with beneficial mutations in the genes responsible for the two RNAs in the ribosome. “Once you have discovered an orthogonal ribosome, making it is not that difficult,” he says.
There are various ways to expand the lexicon. Nature’s ribosomes read three “letters” of genetic code at a time, known as a codon, of which there are 64 different combinations. However, there are only 20 amino acids because some are specified by more than one codon. One approach, therefore, is to use only one codon for each of those 20 amino acids, so the remaining 40 or so others can be put to other uses. To reassign two of the six codons naturally used to specify the amino acid serine in the gut bacteria E. coli, for example, 18,000 changes would have to be made to the bug’s four-million “letter” genetic recipe. You can think of the result of this genetic alteration as a compressed zip file – only the freed-up space is used to specify new amino acids with the aid of new transfer RNAs and enzymes.
In May, Chin’s team reported such an accomplishment in the journal Nature, compressing the entire E. coli genome to produce an edit of the organism that uses two fewer codons than the usual number, along with other changes. “This is the largest synthetic genome by a factor of four, and the first demonstration that life can use a reduced number of codons to encode amino acids in proteins,” Chin says.
In a more radical approach, Chin has also evolved ribosomes that can read many more codons. “We made a ribosome with a bigger ‘reading head’ to read four letters at a time: quadruplet codons,” he says. That yields 256 blank codons to assign to existing or new amino acids, which Chin says could “address problems in biology that would otherwise be impossible.”
This year, Chin expects to combine these various advances to explore basic biology and create useful polymers. One potential application could be in a new kind of gene therapy, where an orthogonal ribosome is implanted in a patient to expand the repertoire of drugs to treat disease.
While conventional synthetic drugs are small molecules that are quickly cleared from the body, and GM versions of natural proteins can be chewed up by the body’s immune system, orthogonal ribosomes could mint polymers with precise and long-lasting effects. One day, an orthogonal ribosome could even be evolved within a living thing, such as a mouse that has been modified to develop human-like disease. “That way, we can discover from a library of polymer sequences what has the most effect on disease by direct in vivo discovery,” says Chin.
Engineering ribosomes, he says, goes further towards synthetic biology than conventional genetic modification: “This is pretty transformational, and could mark a revolution in our ability to evolve, manufacture and discover polymer sequences.”
Roger Highfield is the Science Director of the Science Museum Group and a member of the Medical Research Council
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