What makes the Salk Institute so prestigious

Engineers of Life (2) : The genetic protective wall

It was the tiniest riddle in the world. In the summer of 2010, Craig Venter, researcher, entrepreneur, child prodigy and enfant terrible of molecular biology, stepped before the press and presented a bacterium whose genome was artificially produced. In the more than one million bases, the letters of the genome, not only the identity of the bacterium was coded. Venter had also placed a few encrypted messages in the DNA thread, 50,000 times thinner than a human hair. Among other things, the sentence was hidden there: "What I cannot create, I cannot understand either."

The saying comes from the physicist Richard Feynman and he comes across again and again in the field of synthetic biology. Because it is the aim of these researchers not to simply observe and describe life, but to recreate it, to create it. Venter believes that he has achieved exactly that: With a team of scientists, he processed the genetic material of the Mycoplasma mycoides bacterium on the computer, recreated the sequence from the four building blocks of our genetic material and then transplanted it into a living cell of the Mycoplasma capricolum bacterium. The bacterium bowed to the gene dictation and transformed into the related species. "The first cell whose parents were a computer," Venter announced proudly.

The experiment was a technical masterpiece. Many companies can now deliver short snippets of DNS for a few dollars. But assembling genomes of this length is still extremely time-consuming and expensive: Venter's prestige project cost 40 million dollars and kept the researchers busy for years. But the germ slime in the Petri dish is not yet artificial life. And apart from four places where Venter's researchers have placed their names and a few quotations in the genome, the sequence corresponds to its natural model.

"Basically, he just copied the genome," says geneticist George Church in his light-flooded Boston office. He looks like a nice uncle: gray hair, white beard, understanding eyes. But the Harvard professor has been at the forefront of every technological revolution in genetics for 30 years. “Venter's experiment was technically interesting, but it didn't advance our understanding a bit,” he says. “It just wasn't radical enough.” Where Venter has copied what was already there, Church and others want to fundamentally rewrite the genome. You want to change the language of life in such a way that other living beings can no longer understand it.

Venter's experiment impressively demonstrated one principle of modern biology: the genetic material is nothing more than a program that the cell executes. The key to understanding this program is the genetic code, the only universal language of life on our planet (see box). It determines how the bases A (denin), C (ytosin), G (uanin) and T (hymin) of a genetic material are translated into proteins, those small working molecules that allow the cell to grow and move, signals to process, in short: to live.

Every three bases stand for one amino acid. Biologists call these pairs of three codons. However, there are only 64 possible codons and only 20 amino acids. So most amino acids have several codons. CGU, CGC, CGG and CGA, for example, all four code for the amino acid arginine. Researchers like Church want to use this duplication: “In theory, it is possible to replace all CGUs in the genome of a living being with CGCs. The proteins would still be built correctly. But CGU would no longer be needed, ”he says. The researchers could then simply delete the molecules that CGUs recognize and translate into arginine. Or they could fill the vacancies in the genetic code with another amino acid that does not occur in nature. This enables chemical reactions to take place that nature never invented.

Church now claims to have done just that. He chose the rarest codon in the E. coli bacterium: TAG only occurs 314 times there. “Now it doesn't even happen,” he says. For this Church had 314 short pieces of DNA synthesized, 90 bases long, which corresponded to the sequence of the genetic material, with one difference. Where TAG is written in the normal bacterium, TAA is written in the genetic material fragments. "If you treat these snippets correctly and put them in the cell, they will exchange for the old piece of DNA," says Church. Up to eight sections can be changed at the same time. If the researchers repeat the procedure often enough, at some point there will be a bacterium in which all 314 TAG positions have been replaced by TAA.

The work has not yet been published, but researchers are already discussing the results. “I've heard about it and I'm very excited to see what the data will look like,” says Lei Wang from the Salk Institute in San Diego. Nedilijko Budisa from the Technical University of Berlin has also heard of the work. He warns, however, that clearing a codon is a massive encroachment on the cell. “This redundancy of codons also makes sense,” says the chemist. Because the translation molecules of the particularly rare codons are also less common. This creates a short pause in the construction of the protein. "This allows the already finished part of the protein to fold into a certain shape," explains Budisa. If a rare codon is replaced by a more common one, there could be problems with the folding of the proteins. “It damages some cells so much that they are barely alive,” says Budisa. Church believes these problems are solvable. “We're still studying the properties of our cells,” he says. "But even if there is a growth defect, we will find it and fix it."

Such cells could also help evolutionary biologists to solve an age-old riddle: How did the genetic code develop? After all, it is as old as life itself: 4 billion years. Because all living beings share the genetic code, changes to it have a completely different advantage: They make the cells immune to viruses. The tiny pathogens only bring bare genetic material with them; they use the machinery of the cell to translate them into proteins. If this is changed in such a way that it no longer uses certain codons at all, it can no longer implement the instructions for the virus. "With every codon that the cell no longer recognizes, more viruses become powerless until the cell is immune to all viruses at some point," says Church.

It works both ways. “These cells are, so to speak, in a parallel world,” says Budisa. They can no longer exchange their genetic information with other living beings, they have a genetic firewall. “That could be extremely important in the future when more and more artificial living things are used for industrial purposes,” he says. Many chemicals are already produced industrially by bacteria. If viruses infect the cells, the entire production can be paralyzed. “The genetic firewall could prevent that and at the same time make it impossible for modified genes to spread in the environment,” says Budisa.

It is unclear where the changes will lead: In theory, pets or even people who are immune to viruses are conceivable. Whether this will also be possible in practice and whether someone will one day do it is a completely different question. "That shouldn't be decided by scientists, but by society," says Budisa. However, this requires that people grapple with research that is just emerging. It is reminiscent of another sentence that Venter had hidden in his designer genome: "To see the world not as it is, but as it could be."

The next episode is about researchers who want to turn cells into factories.

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