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Researchers have developed “prime editing,” a true search-and-replace function for DNA

 

Conceptual illustration of two cans, one regular Crispr, one Prime

 
 
MS TECH

Biotechnology / CRISPR

The newest gene editor radically improves on CRISPR

Researchers have developed “prime editing,” a true search-and-replace function for DNA.

Oct 21, 2019

For all its well-earned fame, the gene-editing tool CRISPR is, in reality, pretty hard on the genome. It’s a pair of DNA scissors that cuts the double helix, and what’s called “editing” is actually a cell’s hasty attempt to patch things back together. That introduces errors: critics have even called these unpredictable changes a form of “genome vandalism.”

So researchers are searching for ways to make CRISPR live up to its reputation as a real search-and-replace function for genes. In the words of David Liu, a Harvard University biologist, the ultimate aspiration of genome engineers is “the ability to make virtually any targeted change in the genome of any living cell or organism.”

Today, in the latest—and possibly most important—of recent improvements to CRISPR technology, Liu is introducing “prime editing,” a molecular gadget he says can rewrite any type of genetic error without actually severing the DNA strand, as CRISPR does.

The new technology uses an engineered protein that, according to a report by Liu and 10 others today in the journal Nature, can transform any single DNA letter into any other, as well as add or delete longer stretches. In fact, Liu claims it’s capable of repairing nearly any of the 75,000 known mutations that cause inherited disease in humans.

CRISPR 1.0 is harnessed most often to disable genes—making it useful for research and possibly in treating a subset of diseases where a DNA delete button is what’s called for. More extensive gene replacements are also possible with this tool but aren’t easy to control.  

The new technology, which delivers a wider menu of edits with more finesse, is already worth untold sums of money. Even before the paper was published, a syndicate of venture capitalists, including Newpath, Google’s venture arm, and F-Prime, had formed a company, Prime Medicine, and bought rights to it from the Broad Institute, where Liu has a lab.

The company is very new—no location yet, no employees—so we’ll have to wait to learn if it’s going to be the latest to try to develop CRISPR drugs or will do something else. Robert Nelsen, a partner at Arch Venture Partners, a fund also involved in the deal, emailed to say he couldn’t offer more detail. “Amazing time in the scientific world,” he wrote. “We are not saying anything at this time.”

How does prime editing work?

It is a type of CRISPR because it employs the same bacterial miracle protein, Cas9, which can zero in on a predetermined location in a plant or animal genome, finding its way among billions of letters. But unlike CRISPR classic, prime editing doesn’t break the DNA helix.

Liu and his group kept the part of Cas9 that serves as a homing mechanism but removed the scissors part—a component called a nuclease. In its place they spliced another enzyme, reverse transcriptase, well known in biology textbooks because it’s what chugs along your chromosomes when your cells divide, spooling out a new copy.

A document editor really is the right image if you want to picture how Liu’s new engineered molecule works. First, researchers add a bit of genetic text they want to put into a genome (think of that as the “copy” command). Cas9 then acts like the cursor, finding the right position in the DNA. Last, reverse transcriptase acts like a “paste” command, copying in the genetic text prepared by the scientists.

Liu’s team, including postdoc Andrew Anzalone, tried prime editing on cells in their lab. They say they fixed the error that causes sickle-cell disease (one wrong letter), the one that leads to Tay-Sachs disease (four extra letters), and a mutation that’s a common cause of cystic fibrosis (three missing letters).

The original CRISPR can be made to do some of these tricks too, but with low odds of accurate results, which is why for the last several years Liu’s lab had been trying to extend the technology’s abilities.  An earlier invention, base editing, allowed them to transmute certain individual DNA letters into others. Yet not every type of change was possible. Prime editing, they say, could conceivably repair most inherited DNA errors found in the human species that causes genetic disease.

The big sums involved in the scramble to commercialize editing super-tools is evident in the IPO plans of Beam Therapeutics, a separate company Liu founded to work on base editing, which has helped advance prime editing too. The Harvard researcher’s financial stake in that gene-editing startup, which is aiming to treat blood diseases like sickle-cell, is expected to be worth more than $50 million when Beam goes public.

The promise to potentially resolve the entire spectrum of inherited human ailments is huge, but in practice it’s still distant. Editing tools are not like aspirin, a small molecule that slips easily into cells. The prime editor is, in molecular terms, gigantic—so getting it into people’s cells is going to require something like gene therapy. 

The research was paid for by the government and philanthropists and carried out at Harvard and the nonprofit Broad Institute. The system will be made available for just a few dollars through a clearinghouse, AddGene, to anyone who wants to use it for basic science.

Since CRISPR 1.0, base editing, and prime editing each have some pros and cons, Liu expects all to remain in use. With prime editing, not every cell takes up the wanted change—meaning that it’s not yet as efficient as researchers would like.

“This is the beginning rather than the end,” Liu told journalists in a conference call arranged by Nature. “If CRISPR is like scissors, base editors are like a pencil.  Then you can think of prime editors like a word processor, capable of precise search and replace … All will have roles.”

As genome editing becomes more potent, controversies around certain potential uses—say, to make designer babies, genetic pesticides, or even bioterror weapons—are likely to be sharpened.

Liu didn’t reply to questions about whether the powerful new tool has any downsides or how financial incentives are shaping the choice to create, and widely share, these means of changing the molecule all life is based on.

Xinjiang schools used to separate children from families

China Muslims: Xinjiang schools used to separate children from families

 
Media captionThe BBC’s John Sudworth meets Uighur parents in Turkey who say their children are missing in China

China is deliberately separating Muslim children from their families, faith and language in its far western region of Xinjiang, according to new research.

At the same time as hundreds of thousands of adults are being detained in giant camps, a rapid, large-scale campaign to build boarding schools is under way.

Based on publicly available documents, and backed up by dozens of interviews with family members overseas, the BBC has gathered some of the most comprehensive evidence to date about what is happening to children in the region.

Records show that in one township alone more than 400 children have lost not just one but both parents to some form of internment, either in the camps or in prison.

Formal assessments are carried out to determine whether the children are in need of “centralised care”.

Alongside the efforts to transform the identity of Xinjiang’s adults, the evidence points to a parallel campaign to systematically remove children from their roots.

Hotan Kindness Kindergarten
Image captionThe Hotan Kindness Kindergarten, like many others, is a high security facility

China’s tight surveillance and control in Xinjiang, where foreign journalists are followed 24 hours a day, make it impossible to gather testimony there. But it can be found in Turkey.

In a large hall in Istanbul, dozens of people queue to tell their stories, many of them clutching photographs of children, all now missing back home in Xinjiang.

“I don’t know who is looking after them,” one mother says, pointing to a picture of her three young daughters, “there is no contact at all.”

Another mother, holding a photo of three sons and a daughter, wipes away her tears. “I heard that they’ve been taken to an orphanage,” she says.

In 60 separate interviews, in wave after wave of anxious, grief-ridden testimony, parents and other relatives give details of the disappearance in Xinjiang of more than 100 children.

Missing in China; some of the family portraits handed to us in Turkey by Uighur parents looking for information about their children back home in Xinjiang

They are all Uighurs – members of Xinjiang’s largest, predominantly Muslim ethnic group that has long had ties of language and faith to Turkey. Thousands have come to study or to do business, to visit family, or to escape China’s birth control limits and the increasing religious repression.

But over the past three years, they have found themselves trapped after China began detaining hundreds of thousands of Uighurs and other minorities in giant camps.

The Chinese authorities say the Uighurs are being educated in “vocational training centres” in order to combat violent religious extremism. But evidence shows that many are being detained for simply expressing their faith – praying or wearing a veil – or for having overseas connections to places like Turkey.

For these Uighurs, going back means almost certain detention. Phone contact has been severed – even speaking to relatives overseas is now too dangerous for those in Xinjiang.

With his wife detained back home, one father tells me he fears some of his eight children may now be in the care of the Chinese state.

“I think they’ve been taken to child education camps,” he says.

Map

New research commissioned by the BBC sheds light on what is really happening to these children and many thousands of others.

Dr Adrian Zenz is a German researcher widely credited with exposing the full extent of China’s mass detentions of adult Muslims in Xinjiang. Based on publicly available official documents, his report paints a picture of an unprecedented school expansion drive in Xinjiang.

Campuses have been enlarged, new dormitories built and capacity increased on a massive scale. Significantly, the state has been growing its ability to care full-time for large numbers of children at precisely the same time as it has been building the detention camps.

And it appears to be targeted at precisely the same ethnic groups.

Graph

In just one year, 2017, the total number of children enrolled in kindergartens in Xinjiang increased by more than half a million. And Uighur and other Muslim minority children, government figures show, made up more than 90% of that increase.

As a result, Xinjiang’s pre-school enrolment level has gone from below the national average to the highest in China by far.

In the south of Xinjiang alone, an area with the highest concentration of Uighur populations, the authorities have spent an eye watering $1.2bn on the building and upgrading of kindergartens.

Mr Zenz’s analysis suggests that this construction boom has included the addition of large amounts of dormitory space.

Xinhe County Youyi Kindergarten
Image captionXinhe County Youyi Kindergarten has space for 700 children, 80% of whom are from Xinjiang’s minority groups

Xinjiang’s education expansion is driven, it appears, by the same ethos as underlies the mass incarceration of adults. And it is clearly affecting almost all Uighur and other minority children, whether their parents are in the camps or not.

In 2018 work began on a site for two new boarding schools in Xinjiang’s southern city of Yecheng (known as Kargilik in Uighur).

INTERACTIVEUse the slider button to see how the school has developed

May 2019

Yechung County Number 11 and Number 10 Middle School

April 2018

Yechung County Number 11 and Number 10 Middle School

 

Yecheng County Middle Schools 10 and 11

Dragging the slider reveals the pace of construction – the two middle schools, separated by a shared sports field, are each three times larger than the national average and were built in little more than a year.

In April last year, the county authorities relocated 2,000 children from the surrounding villages into yet another giant boarding middle school, Yecheng County Number 4.

Government propaganda extols the virtues of boarding schools as helping to “maintain social stability and peace” with the “school taking the place of the parents.” And Mr Zenz suggests there is a deeper purpose.

“Boarding schools provide the ideal context for a sustained cultural re-engineering of minority societies,” he argues.

Just as with the camps, his research shows that there is now a concerted drive to all but eliminate the use of Uighur and other local languages from school premises. Individual school regulations outline strict, points-based punishments for both students and teachers if they speak anything other than Chinese while in school.

And this aligns with other official statements claiming that Xinjiang has already achieved full Chinese language teaching in all of its schools.

 
Media captionThe BBC visits the camps where China’s Muslims have their “thoughts transformed”

Speaking to the BBC, Xu Guixiang, a senior official with Xinjiang’s Propaganda Department, denies that the state is having to care for large numbers of children left parentless as a result.

“If all family members have been sent to vocational training then that family must have a severe problem,” he says, laughing. “I’ve never seen such a case.”

But perhaps the most significant part of Mr Zenz’s work is his evidence that shows that the children of detainees are indeed being channelled into the boarding school system in large numbers.

There are the detailed forms used by local authorities to log the situations of children with parents in vocational training or in prison, and to determine whether they need centralised care.

Mr Zenz found one government document that details various subsidies available to “needy groups”, including those families where “both a husband and a wife are in vocational training”. And a directive issued to education bureaus by the city of Kashgar that mandates them to look after the needs of students with parents in the camps as a matter of urgency.

Schools should “strengthen psychological counselling”, the directive says, and “strengthen students’ thought education” – a phrase that finds echoes in the camps holding their parents.

It is clear that the effect of the mass internments on children is now viewed as a significant societal issue, and that some effort is going into dealing with it, although it is not something the authorities are keen to publicise.

 
Media captionThe BBC has found new evidence of the increasing control and suppression of Islam in China

Some of the relevant government documents appear to have been deliberately hidden from search engines by using obscure symbols in place of the term “vocational training”. That said, in some instances the adult detention camps have kindergartens built close by, and, when visiting, Chinese state media reporters have extolled their virtues.

These boarding schools, they say, allow minority children to learn “better life habits” and better personal hygiene than they would at home. Some children have begun referring to their teachers as “mummy”.

We telephoned a number of local Education Bureaus in Xinjiang to try to find out about the official policy in such cases. Most refused to speak to us, but some gave brief insights into the system.

We asked one official what happens to the children of those parents who have been taken to the camps.

“They’re in boarding schools,” she replied. “We provide accommodation, food and clothes… and we’ve been told by the senior level that we must look after them well.”

Hotan Sunshine Kindergarten
Image captionHotan Sunshine Kindergarten, seen through a wire fence

In the hall in Istanbul, as the stories of broken families come tumbling out, there is raw despair and deep resentment too.

“Thousands of innocent children are being separated from their parents and we are giving our testimonies constantly,” one mother tells me. “Why does the world keep silent when knowing these facts?”

Back in Xinjiang, the research shows that all children now find themselves in schools that are secured with “hard isolation closed management measures.” Many of the schools bristle with full-coverage surveillance systems, perimeter alarms and 10,000 Volt electric fences, with some school security spending surpassing that of the camps.

The policy was issued in early 2017, at a time when the detentions began to be dramatically stepped up. Was the state, Mr Zenz wonders, seeking to pre-empt any possibility on the part of Uighur parents to forcibly recover their children?

“I think the evidence for systematically keeping parents and children apart is a clear indication that Xinjiang’s government is attempting to raise a new generation cut off from original roots, religious beliefs and their own language,” he tells me.

“I believe the evidence points to what we must call cultural genocide.”