liu lab base editing
We need to do many more things. “We still have to deliver that machine, we have to test its safety, we have to assess its beneficial effects in animals and patients and weigh them against any side effects. They also used ABE7.10 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. “That was a tough call, because at that point we had been working well over a year on the project, and it was very exciting that we were seeing any base editing on A•T base pairs in DNA at all.”The team restarted its efforts with several additional rounds of evolution and engineering, now testing their adenine base editors against 17 genetic sequences that included all possible combinations of DNA bases surrounding the target A, Liu said. Additional research is needed to enable the adenine base editor to target as much of the genome as possible, as Liu and his students previously did through engineering variants of BE3.At first glance, Liu said, it might appear as though developing the adenine base editor would be a straightforward process: Simply replace the enzyme in BE3 that performs the “chemical surgery” to transform C into U with one that could convert A into I (inosine), a nucleotide that behaves similarly to G. Unfortunately, he said, there is no such enzyme that works in DNA, so Liu and colleagues made the unusual choice to evolve their own DNA adenine deaminase, a hypothetical enzyme that would convert A to I in DNA.“This wasn’t a small decision, because we’ve had a longstanding rule in the lab that if step one of your project is to evolve the starting material that’s needed for the rest of the project to begin, that’s not a very good project, because it’s really two major projects,” Liu said. We changed the selections to force a base editor that would process all sites, regardless of their sequence,” Liu said. Following three rounds of evolution and engineering, the adenine base editors were working deceptively well, until the team discovered that the system would only work on certain DNA sequences.“At that point we could have pulled the trigger and reported a base editor that works well only at certain sites, but we thought the sequence requirements would really limit its usefulness and discourage others from moving the project forward, so we went back to the well of evolution. “But Nicole has amazing instincts about how to interpret the results from each stage of protein evolution, and after seven generations of evolution, she succeeded in evolving a high-performance A base editor, which we call ABE7.10.”The road that led to the adenine base editor required more than just evolving the starting material. “What we’ve developed is a base editor, a molecular machine, that in a programmable, irreversible, efficient, and extremely clean way can correct these mutations in the genome of living cells. Gene editing comes in all shapes and sizes—and achieves all sorts of different outcomes. But having the machine is a good start.”© 2020 by the President and Fellows of Harvard College The final ABE7.10 variant edited sites with an average efficiency of 53 percent, and produced virtually no unwanted products.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. DNA base editing(Liu lab) Technique has potential to help reverse the most common type of disease-associated mutations. Technique has potential to help reverse the most common type of disease-associated mutationsIn addition to Liu, the study was led by Nicole Gaudelli, a postdoctoral fellow in Liu’s lab; Alexis Komor, a former postdoctoral fellow in Liu’s lab who is now an assistant professor at the University of California, San Diego; graduate student Holly Rees; and former postdoctoral fellows Ahmed H. Badran and David I. Bryson.The new system transforms A•T base pairs into G•C base pairs at a target position in the genome of living cells with surprising efficiency, the researchers said, often exceeding 50 percent, with virtually no detectable byproducts such as random insertions, deletions, translocations, or other base-to-base conversions.
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