Don’t mess with me: a supermicrobe might look like this Chris Bickel/Science

It’s not finished yet. But if it is, it will be the greatest feat of genetic engineering by far.

A team in the US is part-way towards recoding the E. coli bacterium to work with a different genetic code from all other organisms on Earth. That means making more than 62,000 changes to its genome.

“We take on projects other groups say are impossibly expensive – or just plain impossible,” says the team leader George Church at Harvard Medical School in Boston, for whom this project is one step towards even more ambitious creations.


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The recoded E. coli could have all kinds of industrial uses. It should be better in several ways: resistant to all existing viruses, unable to swap genes with other organisms and capable of producing proteins unlike any found in nature.

Building blocks

Normal proteins have the 20 natural amino acids as their building blocks. The recoded E. coli will make proteins with up to four additional artificial amino acids. “That’s going to challenge the creativity of the scientific community,” says team member Marc Lajoie at the University of Washington, Seattle.

Making an organism virus-resistant gives it a huge advantage. But the recoded E. coli will be unable to grow unless fed one of those artificial amino acids, so it shouldn’t spread in the wild. “Biocontainment is our number one priority,” says Church.

Church ultimately wants to make farm animals and human stem cells that are resistant to all viruses. Such cells could be used for producing vaccines and for transplants. It is very difficult to make people resistant to viruses, cancer and ageing, Church says, but we could create tissues and organs for transplant with these properties.

Genetically engineered microbes are ever more widely used in industry. At first, only simple changes could be made. In the 1970s, for instance, a human gene was added to E. coli so it could be used to “brew” insulin for people with diabetes.

Nowadays, brewers are adding or tweaking dozens of genes, to create microorganisms that can churn out everything from saffron and vanilla flavouring to antimalarials and opium.

Trouble brewing?

But the worry is that drastically modified microbes will escape from factories or swap genes with wild microbes. Imagine, for instance, if a microbe churning out a drug like opium started colonising the guts of people.

Viruses can also wreck batches of growing microbes if they infect the vats. “Companies don’t like to talk about it,” Church says.

In theory at least, changing microbes’ genetic code could solve these problems. In a gene coding for a protein, each sequence of three DNA letters – called a triplet codon – either specifies which amino acid should be added to the chain next, or tells the protein-making machinery to stop when a protein is complete.

There are four different DNA letters (A, T, G and C) so there are 64 different triplet codons (AAA, AAT and so on). But because there are only 20 amino acids, there’s a lot of redundancy. For instance, the codons TAG, TAA and TGA all mean stop.

If every TAG in a genome was altered to TAA or TGA, it wouldn’t alter any of the protein recipes. But it would free up the TAG codon, so it could be used for specifying an artificial amino acid.

Church was part of a group that has already done this. In 2013, they finished editing the genome of one strain of E. coli to replace every one of the 314 instances of TAG.

Last year, the biologists went on to show that the freed-up TAG could be made to specify any one of several artificial amino acids. What’s more, they altered genes so that essential proteins would work only if they included the artificial amino acid at certain points. This meant these strains of E. coli could only grow if their culture medium contained those artificial amino acids. In other words, these bacteria cannot escape from labs or factories.

Piece by piece

Now Church’s team has revealed their progress towards on a far more ambitious project: changing seven codons in E. coli. Because this requires making more than 62,000 DNA changes, it cannot be done by gene editing. Instead, the team designed the genome on a computer and then synthesised the DNA in short pieces around 2000 DNA letters long.

These short segments have been stitched together to make 87 longer segments 50,000 DNA letters long. The final step will be to put them together to create a complete, 4-million-letter long E. coli genome. But before they do that, Church and his team are checking that all the genes still work, by inserting these segments into a living bacterium and deleting the equivalent sequence.

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As expected, changing codons sometimes has lethal effects. For instance, one change to an essential gene altered the binding of a protein that controls gene activity. But so far only 13 deadly flaws have been found in the 2200 genes that have been checked so far – just over half the total – and these have all been fixed.

When will it be finished? The betting pool among the team ranges from 4 months to 4 years, says Church. But unexpected problems could yet put a spanner in the works.

If it does succeed, Church’s team won’t be the first to create a bacterium with a genome synthesised by scratch. That honour goes to a team at the J. Craig Venter Institute in La Jolla, California.

Minimal genome

But Venter’s team created a microbe with a stripped down, minimal genome. Altering the genetic code as Church’s team are doing is far more challenging.

Although seven codons have been altered, the peculiarities of the genetic code mean only four could be used to specify artificial amino acids. “The genetic code is weird,” says Lajoie.

The recoded E. coli will be made freely available to other researchers. Companies will be able to license it on a non-exclusive basis, Church says.

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And many may want this since changing seven codons should be enough to make it completely resistant to all viruses. Viruses cannot make their own proteins, but instead hijack the machinery of the cells they infect. A recoded E. coli will still start producing viral proteins if it is infected, but there will be so many errors in those proteins that no new viruses will be produced.

Making animals resist viruses in the same way will be a far greater challenge. The human genome is 6 billion letters long compared to the 4 million of E. coli, for instance.

But a group of biologists including Church are trying to raise $100 million to synthesise the entire human genome from scratch.

The initial plans do not include altering the genetic code, but if this Human Genome Project-Write goes ahead, it would pave the way for doing so.

Journal reference: Science, DOI: 10.1126/science.aaf3639

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