Changing our DNA: “The age of human therapeutic gene editing is here”

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Changing our DNA: "The age of human therapeutic gene editing is here"

While Rose spent her short life helping to break down the stigma attached to a devastating illness, geneticist David Liu has devoted his career to developing ways to alter the genetic code that governed her life at such a tender age has cost.

“That a single misspelling in her DNA 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 of Transformative Technologies in Healthcare at Harvard University.

“I didn’t have a chance to meet Adelia before she passed away in January. But every Progeria patient I’ve met has been warm, charming, articulate and deeply inspirational,” Liu told CNN.

An 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-pitched voice, and stiffness in the joints.
In his Harvard lab, Liu and his team have invented new ways to repair mutated genes that do less damage to DNA than previous technologies. One of his lab’s innovations is called Base Editor, which he used to cure progeria in mice last year. There are four bases in DNA: adenine (A), cytosine (C), guanine (G), and thymine (T). These form definite pairs: A with T and G with C.

Liu hopes the tool will soon be used in human clinical trials to reverse progeria in humans.

“The base editor goes into the cells of the animal, looks for the error that is a C into a T in progeria, and turns the T back into a C,” Liu said ahead of his presentation on the topic at the Life Itself conference, a health and wellness event presented in partnership with CNN.

“And that’s it. We never get back into the patient — it’s a one-time treatment that permanently fixes the mutation that causes the disease,” said Liu, who is also vice faculty chair at MIT and Harvard’s Broad Institute, a biomedical and genomics professor Research Center in Cambridge, Massachusetts.

Six months after announcing success with Progeria, Liu and scientists at St. Jude Children’s Research Hospital announced that they had used basic editors to reverse sickle cell disease in mice.

“The age of human therapeutic gene editing is not yet to come. It’s already here,” Liu said.

The benefit of a “nick”

Scientists edit genes using enzymes engineered to target a specific sequence in DNA, cutting out the offending genetic material and inserting replacement DNA. For decades, however, known methods of altering our genetic code were clumsy, often missing the mark, or cutting off too much or too little genetic material.

What is CRISPR and why is it controversial?
The advent of CRISPR systems in the 1990s, and in particular CRISPR-Cas-9 in 2013, heralded a new, more elegant way of editing genes. CRISPR uses so-called guide RNA to bring the Cas-9 enzyme to a more precise place on the DNA strand to make the cut.
After years of scrutiny, the U.S. Food and Drug Administration approved CRISPR-Cas-9 for use in human clinical trials for sickle cell disease in 2021. Clinical trials are also underway to test the safety of gene editing in a blood disorder called beta-thalassemia, liver congenital amaurosis, a form of hereditary childhood blindness, blood cancers, leukemia and lymphoma, type 1 diabetes and HIV/AIDS , just to name a few.
In 2021, researchers reported that they had successfully treated a rare, painful condition called transthyretin amyloidosis in six people with a single treatment. The deadly disease causes a protein called TTR to fold into clumps and attack the heart and nerves. The study, published in August, reported that TTR levels had fallen by an average of 87% in some people after treatment.
A researcher runs a CRISPR-Cas-9 process at the Max Delbrück Center for Molecular Medicine in Berlin.

However, like older editing technologies, CRISPR-Cas-9 cuts both strands of DNA, which has some downsides, Liu said. For one, some cells reverted the changes after they were made, he said, “so the overall efficiency of editing was very low.”

Liu’s team discovered that if you cut just one strand of the DNA double helix using CRISPR-based technology and “nodded” the other, the cell was more likely to make the corresponding change to the second strand without complaint — and with fewer errors.

Editing larger DNA sequences

Liu and his team also invented another type of CRISPR-based tool called the Prime Editor that could do larger, more complex edits to DNA than basic editors couldn’t.

Unethical experiments' painful contributions to contemporary medicine
In tests using lab-grown human cells, Liu’s team used prime editing to correct the genes responsible for Tay-Sachs disease, a deadly neurological disorder that occurs in the first few months of life. Children with Tay-Sachs typically die within a few years of the onset of symptoms.

“One analogy I like to use is that the original CRISPR-Cas_9 is like scissors cutting DNA. Basic 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 real search and replace on larger sequences.”

Only a third of the 75,000 known “spelling errors” that cause genetic diseases can be corrected by the base’s editors, Liu said. “But add our chief editor, and the two of them can finally free us from being bound to the vast majority of misspellings in our DNA,” he said.

“We have to make sure that all these different technologies go through clinical trials very carefully,” Liu added. “But if they prove safe and effective, one could envision not only treating rare misspellings that cause serious genetic diseases, but perhaps even treating gene variants that we know cause terrible diseases like Alzheimer’s.” disease or high cholesterol.”

In a 2019 blog post, former director of the National Institutes of Health, Dr. Francis Collins, who called Prime editing “revolutionary”. 80 characters long.”

But Collins added, “It’s unclear whether prime editing can insert or remove DNA the size of full-length genes — which can contain up to 2.4 million letters.”

Scientists have unlocked the vitamin D potential of tomatoes, a study says

Genetic editing will not be a solution to all of life’s diseases, Liu warned. For example, infections and cancer cells are two areas that are not well suited for gene editing, since you would have to touch every cell to stop the disease.

“But for many genetic diseases, we often only have to edit 20% or 30% of the tissue to save the genetic disease,” Liu said. “We’ve seen that in progeria and sickle cell anemia in mice. A little bit of editing can go a long way in saving these diseases in animals, and we think in humans, too.”

Correction: A previous version of this story incorrectly attributed comments made by Liu during the Life Itself conference. They came from an interview.

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Changing our DNA: “The age of human therapeutic gene editing is here”

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Changing our DNA: "The age of human therapeutic gene editing is here"

While Rose spent her short life helping to break down the stigma attached to a devastating illness, geneticist David Liu has devoted his career to developing ways to alter the genetic code that governed her life at such a tender age has cost.

“That a single misspelling in her DNA 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 of Transformative Technologies in Healthcare at Harvard University.

“I didn’t have a chance to meet Adelia before she passed away in January. But every Progeria patient I’ve met has been warm, charming, articulate and deeply inspirational,” Liu told CNN.

An 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-pitched voice, and stiffness in the joints.
In his Harvard lab, Liu and his team have invented new ways to repair mutated genes that do less damage to DNA than previous technologies. One of his lab’s innovations is called Base Editor, which he used to cure progeria in mice last year. There are four bases in DNA: adenine (A), cytosine (C), guanine (G), and thymine (T). These form definite pairs: A with T and G with C.

Liu hopes the tool will soon be used in human clinical trials to reverse progeria in humans.

“The base editor goes into the animal’s cells, looks for the error that is a C into a T in progeria, and changes the T back into a C,” Liu said Tuesday at the Life Itself conference, a health and safety conference Health Forum wellness event presented in partnership with CNN.

“And that’s it. We never get back into the patient — it’s a one-time treatment that permanently fixes the mutation that causes the disease,” said Liu, who is also vice faculty chair at MIT and Harvard’s Broad Institute, a biomedical and genomics professor Research Center in Cambridge, Massachusetts.

Six months after announcing success with Progeria, Liu and scientists at St. Jude Children’s Research Hospital announced that they had used basic editors to reverse sickle cell disease in mice.

“The age of human therapeutic gene editing is not yet to come. It’s already here,” Liu told the Life Itself audience.

The benefit of a “nick”

Scientists edit genes using enzymes engineered to target a specific sequence in DNA, cutting out the offending genetic material and inserting replacement DNA. For decades, however, known methods of altering our genetic code were clumsy, often missing the mark, or cutting off too much or too little genetic material.

What is CRISPR and why is it controversial?
The advent of CRISPR systems in the 1990s, and in particular CRISPR-Cas-9 in 2013, heralded a new, more elegant way of editing genes. CRISPR uses so-called guide RNA to bring the Cas-9 enzyme to a more precise place on the DNA strand to make the cut.
After years of scrutiny, the U.S. Food and Drug Administration approved CRISPR-Cas-9 for use in human clinical trials for sickle cell disease in 2021. Clinical trials are also underway to test the safety of gene editing in a blood disorder called beta-thalassemia, liver congenital amaurosis, a form of hereditary childhood blindness, blood cancers, leukemia and lymphoma, type 1 diabetes and HIV/AIDS , just to name a few.
In 2021, researchers reported that they had successfully treated a rare, painful condition called transthyretin amyloidosis in six people with a single treatment. The deadly disease causes a protein called TTR to fold into clumps and attack the heart and nerves. The study, published in August, reported that TTR levels had fallen by an average of 87% in some people after treatment.
A researcher runs a CRISPR-Cas-9 process at the Max Delbrück Center for Molecular Medicine in Berlin.

However, like older editing technologies, CRISPR-Cas-9 cuts both strands of DNA, which has some downsides, Liu said. For one, some cells reverted the changes after they were made, he said, “so the overall efficiency of editing was very low.”

Liu’s team discovered that if you cut just one strand of the DNA double helix using CRISPR-based technology and “nodded” the other, the cell was more likely to make the corresponding change to the second strand without complaint — and with fewer errors.

Editing larger DNA sequences

Liu and his team also invented another type of CRISPR-based tool called the Prime Editor that could do larger, more complex edits to DNA than basic editors couldn’t.

Unethical experiments' painful contributions to contemporary medicine
In tests using lab-grown human cells, Liu’s team used prime editing to correct the genes responsible for Tay-Sachs disease, a deadly neurological disorder that occurs in the first few months of life. Children with Tay-Sachs typically die within a few years of the onset of symptoms.

“One analogy I like to use is that the original CRISPR-Cas_9 is like scissors cutting DNA. Basic 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 real search and replace on larger sequences.”

Only a third of the 75,000 known “spelling mistakes” that cause genetic diseases can be corrected by grassroots editors, Liu said. “But add our chief editor, and between the two of them they can finally free us from being bound to the vast majority of misspellings in our DNA,” he told the Life Itself audience.

“We have to make sure that all these different technologies go through clinical trials very carefully,” Liu added. “But if they prove safe and effective, one could envision not only treating rare misspellings that cause serious genetic diseases, but perhaps even treating gene variants that we know cause terrible diseases like Alzheimer’s.” disease or high cholesterol.”

In a 2019 blog post, former director of the National Institutes of Health, Dr. Francis Collins, who called Prime editing “revolutionary”. 80 characters long.”

But Collins added, “It’s unclear whether prime editing can insert or remove DNA the size of full-length genes — which can contain up to 2.4 million letters.”

Scientists have unlocked the vitamin D potential of tomatoes, a study says

Genetic editing will not be a solution to all of life’s diseases, Liu warned. For example, infections and cancer cells are two areas that are not well suited for gene editing, since you would have to touch every cell to stop the disease.

“But for many genetic diseases, we often only have to edit 20% or 30% of the tissue to save the genetic disease,” Liu said. “We’ve seen that in progeria and sickle cell anemia in mice. A little bit of editing can go a long way in saving these diseases in animals, and we think in humans, too.”

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