Changing our DNA: ‘The era of therapeutic human gene editing is here’

While Rose has spent her short life helping to break the stigma associated with a devastating disease, 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 one misspelling in her DNA that ended Adalia’s life so early is a loss for all of us,” said Liu, professor of chemistry and chemical biology and director of the Merkin Institute for Transformational Technologies in Health Care at Harvard University.

“I didn’t get the chance to meet Adalia before she passed away in January,” Liu told CNN. “But every patient I’ve met from premature aging has been so warm, charming, clear, and so inspiring.”

11-year-old Adalia plays with her phone in her room in 2017. In addition to premature aging, other symptoms of progeria include dwarfism, lack of body fat and muscle, hair loss, visible veins, a high tone of voice, and stiffness in the joints.

In his Harvard lab, Liu and his team have devised new ways to repair mutated genes that are less harmful to DNA than previous techniques. One of his lab’s major innovations is a base editor, a tool that can correct misspellings in the four most common grammars in DNA, Liu told an audience at Life Itself, a health and wellness event presented in partnership with CNN.

“Together, these misspellings in our DNA have caused thousands of disorders affecting hundreds 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 correspond to each other: A with T and G with C.

Last year, Liu and his team used a basic editor to manipulate misplaced genes of premature aging in mice. He hopes that clinical trials for children with progeria will begin in the near future.

“The base editor goes into the animal’s cells, looks for the error, which is in premature aging from C to T and changes T back to C,” said Liu, who is also the vice president of the faculty at Broad University. MIT and Harvard, a research center in biomedicine and genomics in Cambridge, Massachusetts.

Liu’s team further discovered that the rule editors worked especially well if you “cut” the unmodified strand of the DNA double helix, persuading the cell to copy the desired modification onto the second strand.

“That’s it,” Liu said. “We never go back to the patient — it’s a one-time treatment and permanently fixes the mutation that’s causing the disease.”

Six months after declaring success with Progeria, Liu and scientists at St. Jude Children’s Research Hospital announced that they used the core editors Reversing sickle cell disease in mice.

“The era 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 using enzymes that are designed to target specific sequences in DNA, cutting off the offending genetic material and inserting alternative DNA. However, for decades, known methods of modifying the genetic code have been clumsy, often missing their target or cutting too much or too little genetic material.

What is CRISPR and why is it so controversial?
The arrival of CRISPR systems in the 1990s, in particular CRISPR Case 9 In 2013, he heralded a new, more elegant way to edit genes. CRISPR technology uses what’s called a guide RNA to deliver the Cas-9 enzyme to a more precise location on the DNA strand to make the cut.

Liu explained to the audience that CRISPR-Cas9 technology was developed in bacteria to disrupt virus infection genes by cutting both strands of DNA, essentially shutting down the gene.

After years of examination, the US Food and Drug Administration has approved the use of CRISPR-Cas-9 technology in 2021 Human clinical trials For sickle cell disease. Clinical trials are also underway to test the safety of gene modification in a blood disorder called beta thalassemiaAnd the congenital libera form of inherited childhood blindness, leukemias blood cancer And the Lymphomatype 1 diabetes, and HIV/AIDS, to name a few.
In 2021, researchers reported that they had successfully modified a rare and painful condition called transtretin amyloidosis in six people with one treatment. The fatal disease causes a protein called TTR to clump and attack the heart and nerves. the study, Posted in AugustIn some subjects, reported levels of TTR decreased by an average of 87% after treatment.
A researcher performs the CRISPR-Cas-9 procedure at the Max-Delbrueck Center for Molecular Medicine in Berlin.

Editing larger strands of DNA

Lowe told the audience that cutting the double helix to silence the gene did not solve the problem of many genetic diseases that needed a computer-like solution.

The discovery of basic editors, who could convert one character to another, solved only part of this problem. What was needed was an editor who could make larger and more complex modifications to DNA that base editors could not.

Enter the Next Generation: Initial Editing.

unethical experiments & # 39 ;  Painful contributions to today's medicine

“The analogy I like to use is that the original CRISPR-Cas_9 is like scissors that cut DNA. Grammar editors are like pencils that accurately correct letters by changing them to one of four different letters,” Liu explained. “And raw editors are like molecular word processors that do real search and replacement of larger sequences.”

Liu said only a third of the 75,000 misspellings known to cause genetic diseases could be corrected by grammar editors. “But add our chief editor, and between the two they can finally free us from being beholden to the vast majority of misspellings in our DNA,” he said.

In tests using human cells grown in the lab, Liu’s team used preliminary editing Gene Correction Responsible for Tay-Sachs disease, a fatal neurological disorder that attacks in the first few months of life. Children infected with Tay-Sachs usually die within a few years after symptoms begin.

“We have to make sure that all of these different technologies are subject to clinical trials very carefully,” Liu added. “But if it proves safe and effective, one could imagine treating not only the rare misspellings that cause serious genetic diseases, but perhaps even treating genetic variants that we know contribute to terrible diseases like Alzheimer’s or high cholesterol.”

in 2019 blog postDr. Francis Collins, former director of the National Institutes of Health, called the initial editing “revolutionary,” saying that Liu and his team “used their new system to insert new segments of DNA up to 44 letters long and remove segments that were at least 80 letters long.”

However, Collins added, “It is unclear whether the initial editing can insert or remove DNA the size of full-length genes – which may contain up to 2.4 million letters.”

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Liu warned that genetic modification would not be a solution to all life’s ills. For example, infection and cancer cells are two mismatched areas of gene editing, because you’d need to touch each cell to stop the disease.

“But with many genetic diseases, we often only need to modify 20% or 30% of tissues to salvage the genetic disease,” Liu said. “That’s what we’ve seen with progeria and sickle cell disease in mice. A little modification can go a long way to saving these diseases in animals, and we’re thinking in humans as well.”

revision: An earlier version of this story incorrectly attributed Liu’s comments as made during the Life Itself conference. They were from an interview.

revision: An earlier version of this story misspelled the number of base pairs that make up human DNA.

Modernization: This story has been updated to reflect Lui’s statements at the Life Itself event and to clarify details from the original version.