‘Genetic cures are going to be realized within my lifetime’
By Justin Matlick, Hutchinson Center science writer
Gene therapy is one of the most exciting potential cures we’re pursuing here at Fred Hutch. But even though I hear about it every day, the idea of editing the molecules in a person’s DNA seems impossibly complicated. So I paid a visit to Dr. Barry Stoddard—one of the field’s leading researchers—to see if he could help me understand how gene therapy actually works. His first piece of advice: “Think of it like molecular white out.”
Stoddard is pioneering a therapy called targeted gene correction. While this is years away from being applied to people, the idea is to zero in on a mutation within a gene that’s causing a disease, cut around it, and insert new instructions that corrects the mutation and makes the gene behave.
“We’re basically editing the gene so it acts normally,” Stoddard says.
The first trick is to precisely target the exact region of a gene that’s malfunctioning – no small feat considering that, if you stretched a person’s DNA out into a single thread, it would extend to the moon and back about 23 thousand times. Ask Stoddard how his laboratory actually does this, and he introduces a funny paradox: to pursue some of the world’s most advanced cures, Stoddard is taking lessons from its most primitive organisms.
It turns out that bacteria, fungi and other single cell organisms are in a perpetual battle to dominate the microbe universe. To do this, they manufacture proteins—called ‘homing endonucleases ‘and ‘TAL effectors’—that are designed to infiltrate their enemies, attach themselves to a specific location in their DNA, and then surreptitiously reprogram their genetic instructions. Stoddard’s lab is repurposing these proteins so they can perform a similar task in humans.
“It’s like introducing a mole into the CIA,” Stoddard says, “except we’re the good guys.”
This is where things get complicated. Every homing endonuclease and TAL effector has a unique physical structure that allows it to latch onto the DNA molecule it targets. Stoddard’s lab has to rearrange the atoms —that’s right, they’re manipulating atoms—on the protein’s surface so they attach to the right defective gene. Then it can write over it with a copy of a gene that works correctly.
“It might sound complex, but it boils down to using basic chemistry to modify these proteins,” Stoddard says. “Once you’ve done it for years it actually becomes kind of easy.”
Stoddard is investigating how to apply targeted gene correction to everything from HIV to Parkinson’s disease. Some of his latest work uses the technique to try and combat cystic fibrosis (CF), which is a particularly good candidate because it’s almost always caused by a single mutation in a single gene. Stoddard’s team developed homing endonucleases that target that mutation. Now they’re working with John Engelhardt, of the University of Iowa, to test them.
While there are lots of difficult hurdles that must be crossed before the therapy could be applied to humans, Stoddard believes it’s only a matter of time before targeted gene correction is used to treat a wide variety of diseases.
“There’s no end to the potential application of homing endonucleases and TAL effectors to treat human disease,” he says. “And whether it’s this approach or another one, it’s very clear to me that genetic cures are going to be realized within my lifetime.”