PHOTOGRAPHY:^ (PREVIOUS^ SPREAD)^ KLAUS^ THYMANN;^(THIS^ PAGE)^ MACIEKJASIKTo do this, Chin has overcome a key problem with the ribosome: it is so
central to life that even modest tinkering can be lethal to the cell. Over the
past 15 years, he has created the tools to build an “orthogonal ribosome” to
work alongside the real thing, leaving the original to take care of key cellular
functions. “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. 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 50S “heart” that turns
the messenger RNA’s information into a protein with the help of transfer
RNAs, which carry amino acids. The ribosome matches messenger RNA to
transfer RNA, assembling the latter’s cargo of amino acids in the right order.
Chin can evolve new ribosomes by using robots to select cells with beneficial
mutations in the genes responsible for the two RNAs. “Once you discover
an orthogonal ribosome, making copies of it isn’t 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
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 as a compressed zip file – and the freed-up
space is used to specify new amino acids.
In May, Chin’s team reported such an accom-
plishment 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.
Chin has also evolved ribosomes that can read bigger
codons. “We made a ribosome with a bigger ‘reading
head’ to read four letters at a time,” 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. 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: 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.
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 CouncilJason Chin, a programme leader at the
Medical Research Council Laboratory of
Molecular Biology, shot by WIRED in May 201901709-19-STopener.indd 15 10/07/2019 11: