Two teams of researchers reported Wednesday they have come up with more precise ways to edit human genes, offering new hope to treat or even cure thousands of genetic diseases.
One team even reversed a hereditary disease, in cells in a lab.
Nothing's quite ready for use in actual patients, but the reports show there's more than one way to fix a broken genetic code. And the more precise the method, the less likely it is to cause side-effects or unexpected outcomes.
One new approach is a variation of a gene-editing method called CRISPR, and alters RNA instead of DNA, meaning it can be reversed. Another technique changes DNA, and would be permanent.
Each makes a change in just a single letter of the genetic code. But it's an important letter, accounting for about half the simple, single-point mutations known to cause human disease.
Human DNA is made up of four compounds called bases: adenine (A), thymine (T), guanine (G) and cytosine (C). In the double-helix, ladderlike structure of DNA, A always pairs with T and G always pairs with C.
"Each of us carries two sets of 3 billion base pairs of DNA, one set from mom and one set from dad, in almost all of our cells," David Liu, a researcher at the Broad Institute of Harvard and the Massachusetts Institute of Technology who led one of the study teams, told reporters.
"This human genome is predominantly made of just four letters: A, C, G and T."
Various combinations of these four compounds spell out the instructions for amino acids, which in turn make up the proteins produced by cells.
So a mistake in one can cause a disease. "More than human 50,000 genetic changes are currently known to be associated with diseases," said Liu, whose team's experiments are reported in the journal Nature.
Genetic variations known as "single nucleotide polymorphisms" cause sickle cell disease; beta-thalassemia, some types of Alzheimer's and cystic fibrosis, for instance.
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In one case, the researchers changed an A to a T — and found it can have profound effects.
"This class of mutation, changing G-C to A-T, accounts for about half of the 32,000 known pathogenic point mutations in humans," Liu said.
Liu's team fixed this mistake in human cells and reversed one disease in the lab — hereditary hemochromatosis. It's caused by a single mistake when what's supposed to be a G is an A on one particular gene. It causes too much iron to build up in the blood and can cause arthritis, liver disease, diabetes and heart abnormalities.
Liu's team invented an approach called base editing.
"We used this method to remove the DNA that causes the disease in cells from patients with hereditary hemochromatosis," Liu said.
A second researcher at Broad, Feng Zhang, led a team that used a different method to make a similarly precise repair. They used a variation of a method called CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats.
It's a technique learned from bacteria, which use it as a defense. CRISPR can be used to slice out a piece of DNA.
But this variation slices RNA instead. DNA is the genetic recipe. RNA is the genetic system for translating the instructions, so while changing something's DNA has permanent effects, changing RNA is temporary.
Zhang's team used their variation to also change RNA product from an A to a T. Their report was published in the journal Science.
"Manipulating RNA potentially poses fewer ethical concerns than editing DNA, as the effects would not necessarily be permanent," said Dr. Helen O'Neill, who directs the program in reproductive science at University College London and who was not involved in the research.
Liu said both methods will be useful.
"When the goal is simply to fix a point mutation, base editing offers a more efficient and cleaner solution," he said. "CRISPR is like using scissors; base editors are like pencils."
Either approach might be used to correct an inherited genetic defect in an embryo, for instance, so it could later be implanted in the mother's womb to grow.
The idea of replacing faulty genes is not new, but gene therapy has not been easy. Cutting out and replacing DNA can be messy and if it's not done precisely, it can cause side-effects and even kill people. Or it just plain doesn't work at all.