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A team of researchers led by David Liu, Professor of Chemistry and Chemical Biology at Harvard University, developed an adenine base editor (ABE) capable of rearranging the atoms in a target adenine (A), one of the four bases that make up DNA, to resemble guanine (G) instead, and then tricking cells into fixing the other DNA strand to make the change permanent. The result is that an A•T base pair is changed to a G•C base pair. The new system is described in a paper published in the journal Nature.
The "base editor" is a molecular machine that directly converts one building block of DNA into another. DNA sequences contain four "base" chemicals that pair up on the molecule's twin-stranded double helix in specific ways. As such, edits made to the DNA using the new tools are far more precise than the leading and most famous technology, CRISPR. To compare the two, David Liu uses the analogy of scissors and pencils, with CRISPR being the scissors, snipping out targeted chunks of DNA and pasting in new ones, while base editors are pencils, making corrections and tweaking individual base pairs in DNA in place without cutting anything out.2,4
The new system, called Adenine Base Editor or ABE7.10, transforms A•T base pairs into G•C base pairs at a target position in the genome of living cells with surprising efficiency, often exceeding 50 percent, with virtually no detectable byproducts such as random insertions, deletions, translocations, or other base-to-base conversions. The adenine base editor can be programmed by researchers to target a specific base pair in a genome using a guide RNA and a modified form of CRISPR-Cas9 that no longer cuts double-stranded DNA.
What's CRISPR?
| (c) Cambridge University Press |
CRISPR, adapted from a primitive bacterial immune system, does its handiwork by first cutting the double-stranded DNA at a target site in a genome. Base editing, in contrast, does not cut the double helix, but instead uses enzymes to precisely rearrange some of the atoms in one of the four bases that make up DNA or RNA, converting the base into a different one without altering the bases around it. That ability greatly increases the options for altering genetic material.3
CRISPR/Cas9 relies on machinery in the cell that’s linked to cell division, so it can only be used when cells are actively replicating. If we want to fix a mutation in the brain or muscle cells — which don’t replicate — we hit major roadblocks.4 Also, any human diseases are caused by the mutation of a single base. CRISPR has difficulty correcting these so-called point mutations efficiently and cleanly, so base editing could provide a more effective approach.3
Together guanine (G), adenine (A), thymine (T) and cytosine (C) make up the letters of the genetic code. The human genome has 3 billion of these “base pairs,” and their precise order determines not just the structure of proteins but their quantity and the circumstances of their production — like ramping up antibodies in response to an infection. Despite the vast library of protein recipes in the human genome, there is little margin for error.4
The new system converts the DNA base-pair A-T to G-C, a microscopically small effect that has massive implications for science and medicine.2 Being able to make this type of conversion is particularly important because approximately half of the 32,000 disease-associated point mutations already identified by researchers are caused by a mutation by a change from a G•C base pair to a A•T base pair. 4 Fixing these mistakes requires a tool that can find a one in 3 billion target and tweak it without introducing any new errors, an arduous and tedious task.4
About 300 times a day in every human cell, a spontaneous chemical reaction converts a cytosine (C) base into uracil (U), which behaves like thymine (T). While there are natural cellular repair mechanisms to fix that spontaneous change, the machinery is not perfect and occasionally fails to make the repair. The result can be the mutation of the G•C base pair to an A•U or A•T base pair, which can lead to certain genetic diseases.
Using these base editors, researchers can now correct all the so-called “transition” mutations — C to T, T to C, A to G, or G to A — that together account for almost two-thirds of all disease-causing point mutations, including many that cause serious illnesses that currently have no treatment. Additional research is needed to enable the adenine base editor to target as much of the genome as possible.
To demonstrate the adenine base editor’s potential, Liu and colleagues used ABE7.10 to correct a mutation that causes hereditary hemochromatosis in human cells. They also used it to install a mutation in human cells that suppresses a disease, recreating the so-called “British mutation” found in healthy individuals who would normally develop blood diseases like sickle cell anemia. The mutation instead causes fetal hemoglobin genes to remain active after birth, protecting them from the blood diseases.
This new base editor, a molecular machine, is programmable, irreversible and efficient in correcting mutations in the genome of living cells. While the development of the adenine base editor is an exciting development in base editing, more work remains before base editing can be used to treat patients with genetic diseases, including tests of safety, efficacy, and side effects.
Where do we go from here?
Though this is an amazing advance in science of managing genetic diseases, it will need more time and effort before this technology finds itself into human clinical trials, and beyond. But we have to be careful here though; with the publication of a paper from David Liu's group last year, a group in China has already used DNA base editing to correct a disease-causing mutation in human embryos cloned from a patient with a genetic blood disorder.3
Researchers worry that genome editing could accidentally affect the wrong part of the genome—a change that would be permanent with a DNA base editor.3
How does editing RNA compare to DNA editing?
With the above concerns regarding DNA editing and CRISPR, REPAIR, the technique that edits RNA, sounds more promising.
1. Researchers can target single bits of ephemeral RNA, which will make the changes transient, even reversible. So this system could fix genetic mutations without actually touching the genome. Once you stop editing the RNA, the edited material will get degraded over a period of time, and whatever changes were made to the cell will also disappear.4
2. The transient nature of REPAIR edits would be useful in treating diseases caused by temporary changes in cell state, such as local inflammation, Type 1 diabetes, or psoriasis. If you only want to edit a protein when there’s inflammation and stop when the inflammation is gone, you can.
3. Researchers could also expose cells to the RNA editor during a treatment course and then stop, for example, if science advances such that a better treatment becomes available.4
4. REPAIR doesn’t depend on other components in the cell, so it can modify the RNA and lead to the desired change we want in a broad variety of tissues, including the brain and the muscles.
References:
1. Harvard Gazette (majority of the information is referenced from this publication)
2. The Independent
3. Science
4. Vox
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