While Rose spent her short life helping to break down the stigma attached to a devastating illness, geneticist David Liu has dedicated his career to developing ways to alter the genetic code that took her life at such a tender age.
“That a single misspelling in her DNA ended Adalia’s life so early is a loss for all of us,” said Liu, a professor of chemistry and chemical biology and director of the Merkin Institute of Transformative Technologies in Healthcare at Harvard University.
“I did not get the chance to meet Adalia before she passed away in January. But every progeria patient I have met has been warm, charming, articulate and profoundly inspiring,” Liu told CNN.
In his Harvard lab, Liu and his team have invented new ways to repair mutated genes that are less damaging to DNA than prior technologies. One of his lab’s major innovations is a base editor, a tool that can correct misspellings in the four most common bases in DNA, Liu told an audience at Life Itself, a health and wellness event presented in partnership with CNN.
“These misspellings in our DNA collectively caused thousands of disorders that affect millions of millions of people and their families,” Liu said.
These four DNA bases — adenine (A), cytosine (C), guanine (G) and thymine (T) — form specific pairs that are always supposed to be matched with each other: A with T, and G with C.
“The base editor goes into the cells of the animal, looks for the mistake, which in progeria is a C to a T and changes the T back into a C,” said Liu, who is also vice-chair of faculty at the Broad Institute of MIT and Harvard, a biomedical and genomic research center in Cambridge, Massachusetts.
Liu’s team further discovered that base editors worked especially well if you “nick” the unedited strand of the DNA double helix, coaxing the cell to copy the desired edit onto the second strand.
“And that’s it. We never come back into the patient — it’s a one-time treatment that permanently fixes the mutation that causes the disease,” Liu said.
“The age of human therapeutic gene editing isn’t just coming. It’s already here,” Liu told the Life Itself audience.
The next generation of gene editors
Scientists edit genes by using enzymes that have been engineered to target a specific sequence in DNA, cut out the offending genetic material and insert replacement DNA. For decades, however, known methods of modifying our genetic code were clumsy, often missing their target or cutting too much or too little genetic material.
CRISPR-Cas9 evolved in bacteria to disrupt the genes of infecting viruses by cutting both strands of DNA, essentially shutting the gene down, Liu explained to the audience.
Editing larger sequences of DNA
Cutting a double helix to silence a gene, however, did not solve the problem of the many genetic diseases that need a computer-like “find and replace” solution, Lui told the audience.
The discovery of base editors, which could convert one letter into another, solved only a part of that problem. What was needed was an editor which could accomplish larger, more complex edits to DNA that base editors could not.
Enter the next generation: premium editing.
“An analogy I like to use is that the original CRISPR-Cas_9 is like scissors that cut DNA. Base editors are like pencils that precisely correct letters by changing them to one of four different letters,” Liu explained. “And prime editors are like molecular word processors that do a true search and replace of larger sequences.”
Only a third of the 75,000 known “misspellings” that cause genetic disease can be corrected by base editors, Liu said. “But add in our prime editor, and between the two they can finally liberate us from being beholden to the vast majority of misspellings in our DNA,” he said.
“We have to make sure all of these different technologies go through clinical trials very carefully,” Liu added. “But if they prove to be safe and efficacious, then one could imagine treating not just rare misspellings that cause grievous genetic diseases, but perhaps even treating gene variants we know contribute to terrible diseases like Alzheimer’s disease or high cholesterol.”
However, Collins added, “It’s unclear if prime editing can insert or remove DNA that’s the size of full-length genes — which may contain up to 2.4 million letters.”
Genetic editing will not be a solution for all of life’s illness, Liu cautioned. For example, infections and cancer cells are two areas that are not well matched for gene editing, because you would need to touch each cell to stop the illness.
“But with many genetic diseases, we often only need to edit 20% or 30% of tissue to rescue the genetic disease,” Liu said. “That’s what we saw with progeria and sickle cell disease in mice. A little bit of editing can go a long way to rescue these diseases in animals, and we think in people as well.”
Correction: An earlier version of this story incorrectly attributed comments by Liu as made during the Life Itself conference. They were from an interview.
Correction: An earlier version of this story misstated the number of base pairs that make up human DNA.
Update: This story has been updated to reflect Lui’s statements at the Life Itself event and clarify details from the original version.