Bacteriophages — viruses that look like the lovechild of a New Age crystal and the Lunar Lander — have been preying on bacteria for billions of years. But a bacterium is far from helpless; in fact, its immune system is so good it has been borrowed by humans to do genome editing with the famous CRISPR system.
Another mysterious component in bacteria, called a retron, has puzzled scientists for years, but now, Science reports, we finally know exactly what it's for — and how we could use it to level up genome editing.
A Cellular Cyanide Pill
A retron is a packet of proteins and genes found in some bacteria: it contains a DNA/RNA hybrid; an enzyme called reverse transcriptase; and a special protein that varies with the retron.
This, it turns out, is a weapon.
"They really are a remarkable biological entity, yet nobody knew what they were for," UT Austin biophysicist Ilya Finkelstein told Science, a mystery that's lasted 30 years.
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A team from Israel's Weizmann Institute of Science had a hunch that retrons were used to defend against bacteriophage viruses. Their research, published in Cell, demonstrates that retrons are a failsafe, a kind of cellular cyanide pill that ensures if its other defenses fail, the infected bacteria dies before the phages can use it to crank out enough copies to infect other bacteria around them.
The researchers focused on one specific retron, called Ec48 (which totally sounds like a cute little Star Wars droid). This retron "guards" another known anti-phage weapon in the bacteria, called RecBCD.
Phages and bacteria have been in an arms race longer than you can imagine, so phages had to figure out a way around RecBCD to survive. But bacteria have a failsafe. If a phage successfully disarms RecBCD, the retron swings into action, taking its weaponized protein to the bacteria's membrane, causing the cell to self-destruct.
"Thus, the Ec48 retron forms a second line of defense that is triggered if the first lines of defense have collapsed," the authors wrote.
CRISPR is really good at acting like an x-acto knife, cutting up the parts of the genome we want it to — but it isn't as adept at inserting new genetic code into the DNA.
Which is where the retron comes in.
The key is the reverse transcriptase. To simplify it, reverse transcriptase creates DNA from an RNA blueprint. Retrons' reverse transcriptase can whip up lots of the DNA we want, which can then be inserted into the genome where CRISPR cuts it. Put them together, and you may have a tool that combines CRISPR's cutting with retron's copy/pasting.
Retrons are a failsafe, a kind of cellular cyanide pill that ensures if its other defenses fail, the infected bacteria dies before the phages can use it to crank out enough copies to infect other bacteria around them.
"Because CRISPR-based systems and retrons have different strengths, combining them is a highly promising strategy," Anna Simon, a synthetic biologist at Strand Therapeutics, told Science.
Weizmann’s Rotem Sorak, an author on the Cell paper, told Science that retrons appear “quite efficient tools for accurate and efficient genome editing.”
Some of those tools have already been developed: CRISPEY, from Hunter Fraser’s lab at Stanford, has been used to make yeast mutants, and two other teams — led by famed Harvard geneticist George Church and synthetic biologist Timothy Lu across the way at MIT — have done similar experiments with bacteria, although those papers are currently preprints.
But there is, of course, a catch: retron genome editing hasn’t been shown to work in mammalian cells, yet — the same situation was CRISPR in, eight years ago.