The human genetic code is about 3 billion letters long. That's a lot of information, and these "letters"—the genetic bases adenine, cytosine, thymine, and guanine—are stored in nearly every one of the cells that makes up your body in the form of DNA.
Errors in the replication process do occur. It's fortunate this happens—these errors are the source of the genetic diversity that we see in nature—but from the perspective of human health, these mistakes can have very serious consequences, including debilitating illnesses like Tay-Sachs disease, sickle cell anemia, and cystic fibrosis.
Now, scientists have devised a way to fix a certain class of genetic errors by re-shaping the very molecules that form the basis of the genetic code. A new type of engineered enzyme called an ABE, or adenine base editor, is described in a paper published Wednesday in the journal Nature. This tool differs from other genetic editing techniques like CRISPR/Cas9, because it does not require the DNA to be physically cut. As useful as CRISPR is, the cutting mechanism can result in the insertion of errors in the code, and thus, deleterious effects. ABEs are "clean," meaning they don't affect the surrounding DNA.
"CRISPR is like molecular scissors while base editors are like pencils"
In a separate but related paper published Wednesday in Science, Feng Zhang of MIT, who's one of the original architects of CRISPR, announced that his lab has modified CRISPR to edit the same types of errors out of RNA, which is closely related to DNA. He and his colleagues call this new platform REPAIR.
The breakthrough described in Nature was the result of two years of relentless effort by researchers in the lab of David Liu, the Director of the Merkin Institute for Transformative Technologies in Healthcare at Harvard University. Liu's group genetically engineered an enzyme that literally rearranges the atoms of one kind of DNA base to turn it into another, all without disrupting the genetic material that surrounds it.
This means that ABEs can turn A-T base pairs into G-C base pairs. Because many genetic illnesses are caused by such single-base mutations, such technology could be particularly useful down the road.
"Standard genome editing methods, including the use of CRISPR…are especially useful when the goal is to insert or delete DNA bases," said Liu at a press briefing in Houston on Tuesday. "But when the goal is simply to fix a point mutation, base editing offers a more efficient and cleaner solution. A useful analogy is that CRISPR is like molecular scissors while base editors are like pencils."
More than 50,000 human diseases, including sickle-cell anemia and phenylketonuria, are the result of a single change in the genetic code—one letter out of three billion. So it would be incredibly useful to have a technique whereby this so-called point mutation can be repaired without messing around too much with the surrounding DNA.
Take for example a disease called hereditary hemochromatosis, or HHC. This genetic ailment causes the body to absorb too much iron from the diet, which is stored in the body's tissues. The result: fatigue, joint pain, heart abnormalities and, in some cases, death. Current treatments for HHC are tragically medieval—a common remedy is to regularly bleed patients to remove excess iron from their systems.
Indeed, one of the main achievements of Liu's lab is that they were able to successfully change the point mutation implicated in HHC to the normal version of the gene, in human cells that were derived from a patient with the disease.
The future applications of Liu's technology, once introduced into living humans, could potentially be very important. As noted in the press briefing, fully 32,000 human genetic diseases are directly repairable using the technique, many of them lethal and lacking any reasonable treatment options. But much needs to be done before base-pair editing can be applied to humans.
The first problem is that, in an adult patient, some way must be found to deliver Liu's enzyme to the appropriate tissue at the appropriate time. But, if a genetic test were to reveal that a fetus could be at risk of developing a genetic disease, the editing technique could theoretically be applied to a developing embryo, wiping out the chance the child would carry that genetic burden. In the future, such an "edited human" could even be raised in an artificial womb. But that's very far down the line.
"A great amount of additional work is needed in order to use this [technique] in a human therapeutic context," said Liu.
"For example, one has to develop a good delivery approach to getting [it] into the right tissues, into the right cell, at the right stage of the patient's life, which is very dependent on the disease," he added. "One has to test the safety, carefully, and the efficacy of using the editor. One has to do a lot of these tests in animal models of the human disease before one progresses to test in human patients. A tremendous amount of work is still needed before these molecular machines can be used to treat human disease in patients. But having a this technology is an important starting point."
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