Biotechnology: Jumping genes in the service of research

The “genetic scissors” Crispr-Cas were discovered over ten years ago, for which the Nobel Prize in Chemistry was awarded in 2020. In contrast to methods of “classic genetic engineering,” which introduce foreign DNA into a relatively arbitrary location in a cell’s genome, Crispr-Cas can specifically modify a very specific DNA sequence. This is called “genome editing”. Although this opportunity offered a huge advantage for basic research and technology development, it was error-prone and the insertion of foreign DNA sequences challenging.

At the end of June, two different groups of researchers presented a new method in the journal “Nature” that would make it easier to insert long DNA sequences into the genome, rotate existing sequences, or cut them out completely. Another advantage of the new method is that, unlike conventional genome editing, it does not work via breaks in the DNA. With Crispr-Cas as well as with the even older Talen and zinc finger methods, these are cemented by the cell’s own repair mechanisms, which can lead to unwanted changes to the genome.

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Self-cutting genes

In one of the Specialist article Patrick Hsu from the University of California Berkeley and colleagues describe a technique for producing so-called programmable recombinases. These are enzymes that catalyze the rearrangement of genetic material.

The recombinases used by Hsu are part of transposons derived from bacteria – so-called jumping genes that can cut themselves out of the DNA and reinsert them at another location. They were discovered in corn plants in the 1940s and 1950s by the American Barbara McClintock. Because her discovery was not taken seriously by the scientific community, she stopped publishing her results in 1953. It was only decades later that her discovery was confirmed by others, and in 1983 McClintock became the only woman to receive the Nobel Prize in Medicine.

Building bridges with RNA

After cutting itself out of the DNA, the transposon IS110 used in the current study forms a “bridge RNA” that guides the enzyme to its site of action. This RNA bridge contains an area that recognizes the DNA that is to be inserted. A second area binds to the location in the genome into which the foreign genetic material is to be inserted.

The recombinase is programmable because RNA can be easily changed in the laboratory – including bridge RNA – and thus the function and target sequences of the enzyme can also be changed. An accompanying article from Hiroshi Nishimasu’s group at the University of Tokyo illuminates the structures of the recombinase using cryo-electron microscopy and provides a detailed overview of the mechanism of action. The researchers show how exactly the DNA strands of the cell’s own DNA and the foreign DNA that is to be inserted are cut and put back together.

So far only experiments with bacteria

A News Article in Nature describes the discovery as an “exciting advance” and points to the possibility of finding additional programmable functions hidden in transposons. However, it is still unclear whether the new method will make it beyond basic research.

There are two hurdles for use outside of bacteria: On the one hand, it is questionable whether the bacterial system can be transferred to eukaryotic cells (i.e. those of plants and animals). On the other hand, the length of the recognition sequence in the bridge RNA is not long enough. Since human and plant genomes are much larger than bacterial ones, there are several possible target sequences purely statistically. Researchers are already working on extending this recognition sequence in order to minimize the risk of unwanted changes at other locations in the genome.

Unwanted changes, so-called off-target effects, are also known from Crispr-Cas, which is more precise than previous genetic techniques, but not as perfect as it is sometimes portrayed. Since the genome of living organisms has evolved from copies and changes of sections, many genetic sections are similar, making targeted changes difficult.

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