David Liu, chemist: "We can correct the vast majority of DNA errors that cause genetic diseases"

American chemist David Liu has revolutionized medicine with his gene-editing tools.CASEY ATKINS

Harvard University Magazine published almost a couple of decades ago that one of its professors, chemist David Liu, had been banned from Las Vegas casinos when he was 29 years old, after winning too much money playing blackjack.

Asked if it's an urban legend, Liu smiles.

“It is partially true.

He was actually 21 years old and it wasn't just one night,” he replies between laughs.

The chemist was a young prodigy.

At the age of 26, he was a professor at Harvard.

At 31 he was already a professor.

For fun, he used math in his head to gain an advantage at blackjack, a card game in which 21 points win.

At the age of 43, in 2016, his team invented base editors, a tool for precisely modifying DNA that is revolutionizing medicine.

Three months ago,

“Her cancer is in complete remission,” Liu celebrates.

The operating manual of a human being, present in every cell, is a text with more than 3,000 million chemical letters.

Errors in this DNA cause cancer and a multitude of diseases.

Liu wants to rewrite this human book to eliminate typos.

The Californian chemist, born in Riverside 49 years ago, compares his base editors to a pencil with an eraser, capable of removing a single letter and replacing it with another.

More information

The woman cured with gene editing: "My supercells have changed my life"

Alyssa's medical team, from University College London, used base editors to modify a donor's white blood cells to help them attack the girl's cancer cells.

David Liu's amazing techniques have outdated previous gene-editing tools, including those known as CRISPR, invented in 2012 and winners of the 2020 Nobel Prize in Chemistry. The researcher likens the original CRISPR to a pair of scissors, useful for inactivating genes in such a way rough, but not to rewrite accurately.

His own pencil with eraser is already being surpassed.

In 2019, Liu announced a new tool: quality editing.

“It's like a word processor: you can search for a specific sequence and replace the entire sequence with another sequence that you want,” he explains by videoconference.

The quality editors of him,

Ask.

There are 20 million new cases of cancer every year in the world.

How many of these patients could benefit from database publishers or quality publishers?

Answer.

Cancer is not a disease, there are hundreds of diseases.

And each of them presents different molecular changes that cause it.

I think the strategy used with Alyssa holds great promise for patients with T-cell leukemia and possibly other blood tumors, but it's too early to know what role these tools might play in other types of cancer.

Base editors have achieved complete remission of leukemia for Alyssa, a 13-year-old British girl.UCL

Q.

This seemed like science fiction in 2016, even to you.

A.

These database editors and quality editors do not exist in nature.

They are engineered molecular machines.

It seems incredible to me that human beings are taking control so quickly of our genomes and of the misspellings that cause genetic diseases.

Q.

There are 400 million people affected by one of the 7,000 diseases caused by mutations in a single gene.

His colleague Fyodor Urnov, from the University of California at Berkeley, wondered three months ago: "Why aren't we already curing them?"

He maintains that the main obstacles are not technical, but legal, financial and organizational.

A.

I agree.

There are still significant technical and scientific challenges, such as learning to modify DNA in ways that would be therapeutic, but that we don't know how to do.

And, of course, we still don't know how to get to certain tissues in the body.

But I agree with Fyodor that there are manufacturing, regulatory, and other non-scientific barriers that will need to be addressed if we are to maximize the benefit of these technologies to society.

Q.

Are many people going to die from obstacles that are not scientific?

A.

If someone dies from a disease, it is the fault of the disease, not the regulatory bodies.

Regulators don't kill anyone.

The goal is to ensure that these treatments are as effective as possible, but also that they are safe.

The history of medicine is littered with examples where well-meaning doctors and scientists did not fully understand the side effects of their experimental therapies and ended up harming patients.

The goal is to prevent this from happening.

The history of medicine is littered with examples in which well-meaning doctors ended up harming patients.

Q.

How many letters do you receive from parents with children with genetic diseases?

R.

About five or ten letters every week.

We try to answer all.

In the early days of base editors, technology could fix few of the single letter mutations we were told about, but now there is almost always a technology to fix the bug, either with base editors or quality editors.

In some cases, however, it has not been shown that correcting the error can actually cure the patient.

In some genetic diseases it is late, because the damage appears very soon.

In many cases, unfortunately, I have to explain to the people who send us the letters that it takes very solid science to link a genetic mutation to a disease.

And you also need good animal models that mimic that disease.

For most of these diseases there is no

so it's hard to prove whether gene editing can work.

And of course, even if there are animal models, it takes years of work to show that correcting a mutation can correct the disease.

I understand that it can be frustrating for a patient's family to know that we know of a technology that can correct an error in DNA that could be the cause of the genetic disease affecting their son or her daughter.

However, gene editing technology is not enough on its own.

So the good news is that we already have technologies that can correct the vast majority of DNA errors that cause known genetic diseases.

But, although this is an important step, we need the rest of the steps to develop therapeutic strategies.

even if there are animal models, it takes years of work to show that correcting a mutation can correct the disease.

I understand that it can be frustrating for a patient's family to know that we know of a technology that can correct an error in DNA that could be the cause of the genetic disease affecting their son or daughter.

However, gene editing technology is not enough on its own.

So the good news is that we already have technologies that can correct the vast majority of DNA errors that cause known genetic diseases.

But, although this is an important step, we need the rest of the steps to develop therapeutic strategies.

even if there are animal models, it takes years of work to show that correcting a mutation can correct the disease.

I understand that it can be frustrating for a patient's family to know that we know of a technology that can correct an error in DNA that could be the cause of the genetic disease affecting their son or daughter.

However, gene editing technology is not enough on its own.

So the good news is that we already have technologies that can correct the vast majority of DNA errors that cause known genetic diseases.

But, although this is an important step, we need the rest of the steps to develop therapeutic strategies.

I understand that it can be frustrating for a patient's family to know that we know of a technology that can correct an error in DNA that could be the cause of the genetic disease affecting their son or daughter.

However, gene editing technology is not enough on its own.

So the good news is that we already have technologies that can correct the vast majority of DNA errors that cause known genetic diseases.

But, although this is an important step, we need the rest of the steps to develop therapeutic strategies.

I understand that it can be frustrating for a patient's family to know that we know of a technology that can correct an error in DNA that could be the cause of the genetic disease affecting their son or daughter.

However, gene editing technology is not enough on its own.

So the good news is that we already have technologies that can correct the vast majority of DNA errors that cause known genetic diseases.

But, although this is an important step, we need the rest of the steps to develop therapeutic strategies.

So the good news is that we already have technologies that can correct the vast majority of DNA errors that cause known genetic diseases.

But, although this is an important step, we need the rest of the steps to develop therapeutic strategies.

So the good news is that we already have technologies that can correct the vast majority of DNA errors that cause known genetic diseases.

But, although this is an important step, we need the rest of the steps to develop therapeutic strategies.

P.

Fyodor Urnov, in the same article published in

, estimated that it takes four years and about $10 million to get a gene-editing drug.

A.

Ten million sounds right, even a low number.

I would say it can cost between a million and 100 million dollars.

And four years seems very fast to me.

It seems like an ambitious deadline to start a clinical trial, but not to obtain the authorization of a drug.

It's an important point of view, so that people realize that when they read a story that a treatment works in an animal, there are still years of work to do before that treatment is available to patients.

Q.

Who can invest $10 million to develop a drug that can only be used in a person with a specific mutation?

A.

That is one of the main issues facing our field.

We are already working on some strategies to try to solve this problem.

I think there are a few ways that a gene-editing agent can be used to treat many different mutations and even many different genetic diseases.

I hope we can report some news about it soon.

A gene-editing drug can cost anywhere from $1 million to $100 million.

Q.

After Alyssa's cancer goes into remission, what's next?

A.

There are four ongoing clinical trials with database publishers.

One of them is that of Alyssa, from University College London.

The first trial to administer base editors directly into patients [not into their cells in the lab] is a collaboration between the companies Verve and Beam, to reduce skyrocketing bad cholesterol levels linked to the PCSK9 gene.

The Beam-101 trial, against sickle cell disease and beta thalassemia, is already enrolling patients.

And there is also another clinical trial underway in China to treat beta thalassemia.

I hope that Alyssa is the prelude to many more positive results.

Q.

When will the quality editors be tested in a human clinical trial?

R.

You would have to ask Prime Medicine, the company that is developing treatments with quality publishers.

They hope to have an investigational drug in 2024, so I expect clinical trials to start soon, in a few years [David Liu is co-founder of companies Beam Therapeutics and Prime Medicine].

Q.

How do you imagine medicine in 10 years?

A.

I would be disappointed if, 10 years from now, we didn't have enough clinical trials, both with database publishers and quality publishers.

And I hope we'll have the first drugs approved that are molecular machines capable of going into a patient's cell and specifically changing a bug that causes a genetic disease.

Or, as the companies Verve and Beam are doing, make a precise change that lowers your risk of serious illness.

If we do another interview in 2033, I hope that the first drugs that allow us to take control of our genomes are approved, without depending so much on errors in our DNA that determine the genetic destiny of so many millions of people.

I hope that in 10 years the first drugs that will allow us to take control of our genomes will be approved.

Q.

You tweeted the other day that people are happy accidents.

R.

I meant random in evolution.

Organisms evolve and their mutations are partially random.

For a gene to evolve one way or another can be considered a happy accident.

Evolution depends on chance events that make the results stochastic, difficult to predict.

In that sense, the fact that humans have evolved as they have is a bit of a matter of luck, or bad luck, depending on one's perspective.

As [American biologist] Stephen Jay Gould said, if you rewind the movie of life and start all over again from the first organism in the primordial soup, rewatching evolution over billions of years, I'd be surprised if it all ends with us. speaking in this interview.

The odds are overwhelming that you would end up with very different results.

Q.

So you don't see the hand of a God anywhere in the DNA?

A.

It is a difficult question to answer.

No comment [laughs].

Q.

You supported a moratorium on germ line editing [heritable modifications that are carried out in the eggs, sperm or embryos themselves when they are only one cell], to prevent the creation of genetically modified babies.

It was in 2019. Do you still support the moratorium?

A.

It's not a simple black-and-white thing, as it is with most important issues, but I think there's very little reason to edit the germ line these days.

I do anticipate that there will be more cases in the future, especially when somatic cell editing [cells that are neither egg nor sperm] has been tried more and there are even approved drugs.

That might be a better time to discuss the pros and cons of germline gene editing.

For now, I think the ethical and scientific stakes are too high to justify the small number of hypothetical cases in which germline editing might be considered necessary.

Q.

What kind of cases do you envision in the future?

A.

Well, in the future there may be more willingness to edit the germ line.

Once somatic cell gene editing is mature enough that there is a high degree of confidence in its safety and efficacy, I think people will naturally reconsider germline editing.

Currently, I don't think it should be a priority.

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