"We have an 18-year rule in our laboratory, unbroken until now, that it is unwise to embark on a project in which the first step requires the evolution of the starting material for steps 2 to 20," Liu said. "But in this case, we thought the potential usefulness of an adenine base editor was worth the risk."
It took more than two years, but ultimately, they were successful. After lots of trial and error, first author and post doctoral fellow Nicole Gaudelli was able to generate an enzyme that can convert AT base pairs to GC base pairs in human cells with an average efficiency of 53 percent and almost no errors.
It's not perfect, but it's a vast improvement over other methods currently in use to address point mutations.
In the paper, the authors compared their adenine base editor with the more traditional gene editing approach known as homology directed repair, or HDR. They report that their new tool was about 10 times more efficient than HDR, and resulted in at least 100 times fewer undesired products like random insertions or deletions.
The researchers also offered a glimpse at how their editor might be used in the future to combat genetic diseases.
In one experiment, they went after a point mutation that is a common cause of hereditary hemochromatosis, which causes an excessive buildup of iron in a patient's blood that can be fatal. Using their adenine base editor, they were able to correct the mutation in cells derived from a patient with HHC.
In a second example, the team used its new base editor to install a pair of mutations that activate genes that code for the production of fetal hemoglobin. These genes are usually silenced around birth, but they can be used to protect against certain blood diseases like sickle cell anemia if they are allowed to remain active through adulthood.
These early demonstrations are promising, but Liu cautioned that base editors will not be used to address genetic diseases in living humans any time soon. (The aforementioned experiments were all done on cells grown in petri dishes).
Before that can happen, researchers will have to determine the best way to deliver the base editor machinery to the right tissues in the body and into the right cells. They will also have to figure out when in a patient's life is the best time to deliver a certain gene therapy. To that end, his lab is collaborating with other labs that have expertise in genetic diseases.
"A tremendous amount of work is needed before this molecular machine cab be used to treat diseases in humans," he said. "But having a machine is an important starting point."
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