New 'superbug' made by CRISPR is invincible to all viruses

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Ricky Joseph

Is it possible to reprogram life at will? For synthetic biologists, yes. The core code of biology is simple. The letters of DNA, in groups of three, are translated into Lego-like blocks of amino acids that produce proteins. Proteins build our bodies, regulate our metabolism, and allow us to function as living things. Designing custom proteins often means you canredesigning small aspects of life - for example, getting a bacterium to pump out life-saving drugs like insulin.

All life on Earth follows this rule: a combination of 64 triplet DNA codes, or "codons," are translated into 20 amino acids.

But wait, math doesn't add up. Why wouldn't 64 dedicated codons produce 64 amino acids? The reason is redundancy. Life evolved so that multiple codons often produce the same amino acid.

So what happens if we go into those redundant "extra" codons of all living things and insert our own code instead?

A team at Cambridge University recently did just that. In a technological tour de force, they used CRISPR to replace more than 18,000 codons with synthetic amino acids that don't exist anywhere in the natural world. The result is a bacterium that is virtually resistant to all viral infections-because it lacks the normal protein "door handles" that theviruses need to infect the cell.

But that's just the beginning for the superpowers of life engineering. Until now, scientists have only been able to introduce a single engineered amino acid into a living organism. The new work opens the door to hacking multiple existing codons at once, copying at least three synthetic amino acids at the same time. And when that's 3 out of 20, that's enough to fundamentally rewritelife as it exists on Earth.

We have long thought that "releasing a subset of ... codons for reassignment could improve the robustness and versatility of genetic code expansion technology," wrote Drs. Delilah Jewel and Abhishek Chatterjee at Boston College, who were not involved in the study. "This work elegantly transforms that dream into a reality."

Hacking the DNA Code

Our genetic code underlies life, inheritance and evolution. But it only works with the help of proteins.

The program of translating genes, written in the four letters of DNA, into the real building blocks of life depends on a complete cellular decryption factory.

Think of the letters A, T, C, and G of DNA as a secret code, written on a long wrinkled piece of paper wrapped around a scroll. Groups of three "letters," or codons, are the crux-the code for the amino acid a cell makes. A messenger molecule (mRNA), a kind of spy, stealthily copies the DNA message and returns to the cellular world, shuttling the message to the protein factory of thecell - a kind of central intelligence organization.

There, the factory recruits multiple "translators" to decipher the genetic code into amino acids, aptly named tRNAs. The letters are grouped into three, and each tRNA translator physically drags its associated amino acid into the protein factory, one by one, so that the factory eventually makes a chain that rolls up into a 3D protein.

But like any robust code, nature has programmed redundancy into its DNA-to-protein translation process. For example, the DNA codes TCG, TCA, AGC, and AGT all code for a single amino acid, serine. While it works in biology, the authors wondered, what if we hacked into that code, hijacked it, and redirected some of life's directions using amino acidssynthetics?

Hijacking the Natural Code

The new study sees nature's redundancy as a way to introduce new capabilities into cells.

For us, one question was "could you reduce the number of codons that are used to encode a particular amino acid, and thus create codons that are free to create other monomers [amino acids]?" asked lead author Dr. Jason Chin.

For example, if TCG is for serene, why not release the others-TCA, AGC, and AGT-for something else?

It's a great idea in theory, but a truly daunting task in practice. It means the team has to go into a cell and replace every codon they want to reprogram. A few years ago, the same group showed that this is possible in E. Coli, the lab and pharmaceutical favorite insect. At that time, the team made an astronomical leap in synthetic biology by synthesizingIn the process, they also played with the natural genome, simplifying it by replacing some amino acid codons with their synonyms-say, by removing TCGs and replacing them with AGCs. Even with the modifications, the bacteria were able to thrive and reproduce easily.

It's like taking a very long book and figuring out which words to replace with synonyms without changing the meaning of the sentences - so the edits don't physically harm the survival of the bacteria. One trick, for example, was to delete a protein called "release factor 1," which makes it easier to reprogram the UAG codon with a new amino acid. Previous work has shown that this canassign new building blocks to natural codons that are truly "blank" - that is, they don't naturally encode anything anyway.

A synthetic creature

Chin's team took this much further. It prepared a method called REXER (replicon excision for enhanced genome engineering through programmed recombination) - yes, scientists are all for backcronyms - which includes the gene editing tool CRISPR-Cas9. With CRISPR, they precisely extracted large parts of the E. coli bacterium genome made entirely from scratchinside a test tube, and then replaced more than 18,000 occurrences of "extra" codons that code for serine with synonymous codons.

Since the trick only targeted the redundant protein code, the cells were able to go about their normal business - including serum production - but now with multiple free natural codons. It's like replacing "hi" with "oy", making "hi" now free to be assigned a completely different meaning.

The team next did a housecleaning. They removed the cells' natural translators - the tRNAs - which normally read the now-deleted codons without harming the cells. They introduced new synthetic versions of the tRNAs to read the new codons. The engineered bacteria were then naturally grown inside a test tube to grow faster.

The results were spectacular. The superpowered strain, Syn61.Δ3(ev5), is basically an X-Men bacteria that grows quickly and is resistant to a cocktail of different viruses that normally infect bacteria.

"Since all biology uses the same genetic code, the same 64 codons and the same 20 amino acids, that means viruses also use the same code...they use the machinery of the cell to build the viral proteins to reproduce the virus," Chin explained.Now that the bacterial cell can no longer read nature's standard genetic code, the virus can no longer enter the machinerybacterial to reproduce, meaning that the engineered cells are now resistant to being hijacked by almost any viral invader."

"These bacteria can be turned into renewable, programmable factories that produce a wide range of new molecules with novel properties, which could have benefits for biotechnology and medicine, including the manufacture of new drugs such as new antibiotics," Chin said.

Despite the viral infection, the study rewrites what is possible for synthetic biology.

"This will enable numerous applications," Jewel and Chatterjee said, such as completely artificial biopolymers, that is, biologically compatible materials that could change entire disciplines, such as medicine or brain-machine interfaces. In this case, the team was able to tie together a chain of artificial amino acid building blocks to make a type of molecule that forms thebase of some medications, such as those for cancer or antibiotics.

But perhaps the most exciting prospect is the ability to dramatically rewrite existing life. Similar to bacteria, we - and all life in the biosphere - operate with the same biological code. The study now shows that it is possible to overcome the hurdle of just 20 amino acids that make up the building blocks of life by exploiting our natural biological processes.

Next, the team is looking to further reprogram our natural biological code to encode even more synthetic protein building blocks in bacterial cells. They will also move into other cells - mammals, for example, to see if it is possible to compress our genetic code.

This article appeared first on Singularity Hub, translated by SOCIENTIFIC.

Ricky Joseph is a seeker of knowledge. He firmly believes that through understanding the world around us, we can work to better ourselves and our society as a whole. As such, he has made it his life's mission to learn as much as he can about the world and its inhabitants. Joseph has worked in many different fields, all with the aim of furthering his knowledge. He has been a teacher, a soldier, and a businessman - but his true passion lies in research. He currently works as a research scientist for a major pharmaceutical company, where he is dedicated to finding new treatments for diseases that have long been considered incurable. Through diligence and hard work, Ricky Joseph has become one of the foremost experts on pharmacology and medicinal chemistry in the world. His name is known by scientists everywhere, and his work continues to improve the lives of millions.