A new type of DNA editing enzyme, developed in HHMI Investigator David Liu’s lab, lets scientists directly and permanently change single base pairs of DNA from A•T to G•C. The process could one day enable precise DNA surgery to correct mutations that cause human diseases.
DNA editing just got a sharp, new pencil. Researchers have built an enzyme that can perform a previously impossible DNA swap, directly changing the DNA base pair from an A•T to a G•C. The new enzyme, known as a base editor, may one day enable genome surgery that erases harmful mutations and writes in helpful ones, Howard Hughes Medical Institute (HHMI) Investigator David Liu and colleagues report October 25, 2017, in the journal Nature.
The new system is a “really exciting addition to the genome engineering toolbox,” says Feng Zhang, an HHMI-Simons faculty scholar and molecular biologist at the Broad Institute of MIT and Harvard, who was not involved in the study. “It’s a great example of how we can harness natural enzymes and processes to accelerate scientific research.”
Some genome editing tools, such as CRISPR/Cas9, cut both strands of DNA and rely on the cell’s own molecular machinery to fill in the gap with the desired DNA sequence. Base editors are, in a sense, more precise tools. “CRISPR is like scissors, and base editors are like pencils,” says Liu, a chemical and molecular biologist at Harvard University and the Broad Institute.
Those pencils can rewrite the individual chemical units of DNA, known as bases. Each base on one strand of DNA joins its partner base on an opposing strand, so that the base adenine pairs with thymine (A•T), and guanine pairs with cytosine (G•C). Last year, Liu and colleagues described a base editor that could change C•G base pairs into T•A. But researchers didn’t have the ability to convert A•T to G•C, until now.
Going in, Liu and his team knew that the project was risky, because the first step involved creating an enzyme that didn’t yet exist. Postdoctoral researcher Nicole Gaudelli took on the challenge, relying in part on evolution to create an enzyme that could do the job. Gaudelli started with an enzyme called TadA that’s able to convert adenine to a molecule called inosine (which cells treat as guanine), but in transfer RNA rather than in DNA. She made larger libraries of TadA mutants into bacterial cells and required them to convert A to inosine in antibiotic resistance genes in order to survive in the presence of antibiotics. Surviving bacteria encoded TadA mutations that imparted the ability to perform the adenine-to-inosine conversion on DNA.
This evolution in the lab paid off. Soon enough, the researchers saw that some bacterial colonies were able to fix their own mutations with chemical surgery and survive the antibiotic challenge. Along with other tweaks, the researchers attached the enzyme to a molecule called Cas9 nickase. That add-on allows the base editor to find the right spot to cut along a DNA strand and snip the opposing strand of DNA ? a nick that prompts the cell to insert the correct partner base pair to match the new one, thereby completing the swap of A•T to G•C.
Along with several related enzymes, the most tricked-out version, called ABE7.10, is an efficient chemical surgeon, turning A•T into G•C in both human and bacterial genomes. The enzyme operates with greater than 50 percent efficiency and few, if any, by-products such as undesired mutations.
Mutations in which a G•C mutates into an A•T account for nearly half of the roughly 32,000 single point mutations associated with human diseases. Experiments in Liu’s study hint at the promise of the new genome pencil. ABE7.10 reversed a G-to-A mutation associated with a genetic iron-storage disease known as hemochromatosis in cells taken from patients. In a different experiment, ABE7.10 added a mutation that restored the function of a hemoglobin gene in human cells. That mutation is known to confer protection against blood diseases including sickle cell anemia.
“CRISPR is like scissors, and base editors are like pencils.”
The results are an early step. “We are hard at work trying to translate base editing technology into human therapeutics,” Liu says, but many hurdles remain. Safety, efficiency, and base editor delivery methods still need to be better understood before base editing can be used to tweak the human genome. “Having a machine that can make the change you want to make is only the start,” Liu says. “You still need to do all this other work, but having the machine really helps.”
Learn more: New Enzyme Rewrites the Genome
The Latest on: DNA surgery
- Report says aging voting machines a concern in Alabamaon July 19, 2019 at 7:35 pm
A report published Thursday on election security says states need more federal money to safeguard elections from outside threats. It says Alabama election officials cited a need to replace voting ... […]
- 'Encore entrepreneurs': How New York might embrace its aging populationon July 19, 2019 at 3:11 pm
New York is getting old — but that may not be a bad thing. From 2007 to 2017, New Yorkers over the age of 65 were the fastest growing segment of the population in the state. Over that decade, the ... […]
- The Women in My Life Taught Me to Love Agingon July 19, 2019 at 2:41 pm
We are ageless because we choose to be. Share on Pinterest On my 25th birthday, I paced around the house tending to minuscule tasks waiting for a single phone call. This was not just any call, but the ... […]
- Successful Aging: We moved to be closer to our grandkids, but now my husband wants to move backon July 19, 2019 at 10:07 am
Q. My husband and I recently retired, sold our home in Southern California and moved to Colorado to be closer to our son and grandchildren. That was my husband’s idea. I actually am tired of moving, ... […]
- This Obscure, Potentially Dangerous Drug Could Stop Agingon July 19, 2019 at 6:50 am
Louis is a 27-year-old assembly-line worker in Three Rivers, Michigan. He has no health problems and rarely sees a doctor. Yet for a man in his prime, Louis thinks a lot about cheating death. He ... […]
- Mariah Carey Says She Won't 'Acknowledge' the FaceApp Aging Featureon July 18, 2019 at 6:52 pm
The latest viral trend around social media is FaceApp's "old" feature, in which users can upload a photo of themselves to see how they would look as elders. A number of celebrities have taken part, ... […]
- Mariah Carey Doesn't 'Acknowledge' the FaceApp Aging Challenge & Instead Responds with Iconic Memeon July 18, 2019 at 4:49 pm
Amid a week where Instagram and Twitter timelines are being flooded with celebrities sharing photos of what they might look like in old age using the “old” filter on the FaceApp, Mariah Carey ... […]
- 'You don't exist to me': Mariah Carey refuses FaceApp aging challengeon July 18, 2019 at 1:46 pm
FaceApp? Mariah Carey isn't interested. Many celebs have taken to social media to give a glimpse of what they could look like in a few decades through FaceApp, an iOS and Android mobile app that ... […]
- Fewer Inspections for Aging Nuclear Plants, Regulators Proposeon July 18, 2019 at 8:00 am
Want climate news in your inbox? Sign up here for Climate Fwd:, our email newsletter. WASHINGTON — A new report by staff members of the Nuclear Regulatory Commission, which oversees the safety of the ... […]
- Transcriptome analysis identifies a robust gene expression program in the mouse intestinal epithelium on agingon July 18, 2019 at 3:29 am
Despite the fact that the intestinal tract is critical for life and health, there is limited knowledge on how intestinal health is maintained throughout lifespan. Many age-related intestinal disorders ... […]
via Google News and Bing News