Cells with DNA made in the laboratory produce a new type of protein, a “Holy Grail” for synthetic biology



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In San Diego, a microbe with DNA made in the laboratory has synthesized proteins from molecules never before used by life. (Illustration by Rachel Orr / Washington Post, iStock Images)

Scientists in San Diego have achieved an important goal in the effort to create artificial organisms: a microbe whose genetic material includes some instructions made in the laboratory was able to live, reproduce, and synthesize proteins that included molecules never before used by life.

The development, described Wednesday in an article in the journal Nature, is a step towards a world in which scientists can design organisms capable of producing highly specialized proteins that can be used to improve medicines, build new materials and perhaps even change the functions of the cells.

"It's front-wave stuff, this is the edge of science," said Andrew Ellington, a biochemist at the University of Texas at Austin who was not involved in the research. "W we are learning better how to design living systems."

For four billion years, the history of life on Earth has been written using a limited molecular alphabet. The rungs of the rotating DNA ladder are constructed with only four basic units: adenine, which binds with thymine, and cytosine, which is combined with guanine. These four "letters" – A, T, C and G – define the form and function of each organism on earth, from a bacterium to an elephant, from photosynthesis to camouflage.

When these genetic instructions are transcribed and translated by cellular machinery, they allow the production of proteins, the workhorses of life, which catalyze reactions, transmit signals and form tissues such as cartilage and shells. The basic components of proteins, called amino acids, are only a little more varied than those of DNA; only 20 amino acids are used to synthesize the proteins necessary for all life functions.

In 2014, San Diego scientists, led by chemist Floyd Romesberg of the Scripps Research Institute, rewrote the genetic material of an E. coli strain to include a new base pair, called dNaM and dTPT3 but informally known as X and Y. Although the resulting population of microbes was not stable (they usually lost their X and Y bases after a few days) these were the first organisms in the history of life to include a new pair of bases in their DNA .

It was a completely new type of genetic engineering. Other gene editors modify the DNA of organisms using existing materials, such as Shakespeare, which comes with new idioms. But Romesberg and his colleagues were writing genetic instructions with molecules that life had never seen before: the biological equivalent of Tolkien inventing Elvish.

In their latest experiment, Romesberg's team used that expanded genetic alphabet to teach cells to synthesize "amino acid" proteins: hundreds of molecules that can be found in nature or in the laboratory but that organisms do not use natural form. Semisynthetic cells were able to produce artificial proteins almost as efficiently as their unmodified parents.

"This last step of adding a pair of non-natural bases to add an unnatural amino acid to a protein is a kind of sacred Grail of what we've been trying to do all along," Yorke said. Zhang, a graduate student in the Romesberg lab who designed, performed and badyzed the experiment.

For decades, scientists have been trying to add non-canonical amino acids to proteins in the hope of making these biological warhorses even more powerful. But they had a problem. The translation of the genetic material into a protein product, which is carried out by means of RNA molecules, depends on sequences of three letters called "codons". Each codon corresponds to a particular amino acid, so that when the machinery reads that sequence, it knows exactly which piece of protein to grab. However, with the existing genetic alphabet, the 64 possible codon combinations are already badociated with a specific task. If the researchers wanted the cell to perform a new function, they did not have a unique way of transmitting the demand.

Some scientists have tried to avoid this obstacle by reprogramming one of the cell's "stop" codons, which carry instructions to stop the process of protein production – to be badociated with a new amino acid.

But Romesberg and his colleagues had great ambitions. By adding just two new base units to the genetic instructions of a cell, they would generate dozens of new codon possibilities – "more than we could use" for any practical purpose, Romesberg said.

After testing hundreds of possible base pairs, it landed on dNaM and dTPT3. These units were not only completely alien to life on Earth, but were chemically linked by a completely different link to the one connecting A with T and G with C.

In an interview this week, astrobiologist Steve Benner, who He led the first team to develop a pair of artificial bases almost 30 years ago, expressed doubts that DNA can be fully functional with this unusual base pair link. He suggested that the natural base pairs in Romesberg's E. coli might be "flanking" the facts in the lab, holding the double helix despite the unnatural and uncomfortable insertions. The DNA was effectively damaged, he said, and the fact that the cells did not die is just a testament to the resistance of life.

Romesberg disagreed, noting that the cells designed in his last experiment successfully used the genetic material X and Y. and a non-canonical amino acid to produce large amounts of bright green protein without much loss of efficiency.

"In a sense, the proof is in the pudding," he said. The experiment worked, which would indicate that synthetic DNA also works.

Because the microbes themselves can not produce the X and Y bases or the extraterrestrial amino acid, the scientists had to continually "feed" these molecules into the cells. This is a characteristic, not an error, said Romesberg. On the one hand, he badures that any microbe that escaped from the laboratory would die quickly, dispelling the fears of an artificial life apocalypse in the style of Jurbadic Park.

In addition, it suggests a possible application of these microbes made in the laboratory: vaccines. "I if you put it in a person, the body can no longer survive," Zhang said, making these cells a safe way to train the body to fight infections.

In 2014, Romesberg co-founded a biotechnology company, Synthorx, whose goal is to convert proteins made from non-canonical amino acids into proteins. In the short term, he said, scientists could harvest such proteins from synthetic cells and use them to help in the administration of drugs or to make therapeutic proteins, such as insulin, more effective.

But even more distant … and more attractive: the application not only involves proteins, but the microbes manufactured in the laboratory that produce them: "What happens if you allow bacteria to harbor this information? unnatural recovers the protein and you use it for something interesting? ", Romesberg reflected. " Could you develop organisms that have new properties," such as the ability to extract oil spills or eat cancer cells? " Could we develop cells that can do things that their natural counterparts can not do?"

Maureen McKeague, a synthetic biologist at the Swiss Federal Institute of Technology in Zurich, said that this latest achievement is a synthesis of the work that Romesberg and others have been puzzling for a while. So far, several scientists have developed artificial base pairs and unnatural proteins synthesized, "but this shows that all parties can join, f coding the information and storing it for transcription and translation," he said. [19659003] It also raises some interesting philosophical questions.

"One thing that scientists have always been questioning is whether the only way evolution of biology is the way," said McKeague.

That the Romesberg artificial cells lived, and that they lived even with the unusual bond that binds their base pair aggregates, suggests that it is not. Perhaps, in some distant rocky planet or in the cold oceanic moon, the organisms follow genetic instructions written in an alien alphabet according to a chemistry completely different from ours.

Scientists are just beginning to expand the language of life on Earth. But in the universe, biology can follow an even stranger script.

Read more:

Scientists synthesize cousin of smallpox in ominous progress

Scientists create 'designer yeast' in an important step towards synthetic life

This artificial cell has the smallest genome ever seen, but a third of its genes are a mystery

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