gene editing

Gene-editing is Science mag’s breakthrough of 2015

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Gene-editing is Science mag's breakthrough of 2015
A gene-editing technique known as CRISPR was named by the influential US journal Science as 2015’s breakthrough of the year

A gene-editing technique known as CRISPR was named Thursday by the influential US journal Science as 2015’s breakthrough of the year, due to its potential to revolutionize health and medicine.

The method has stirred controversy, particularly after Chinese researchers earlier this year announced they had deliberately edited the DNA of nonviable human embryos from a .

Concerns over such research—and the prospect of altering humans to promote certain, desirable traits—recently prompted global scientists to urge researchers to steer clear of interfering with embryos destined for pregnancy, citing the risks of introducing permanent changes into the population.

But many are excited about the “superior ability of CRISPR to deliver a gene to the right spot compared to its genome editing competitors -– as well as the technique’s low cost and ease of use,” said the journal Science.

“Clinical researchers are already applying it to create tissue-based treatments for cancer and other diseases,” wrote managing news editor John Travis.

“CRISPR may also revive the moribund concept of transplanting animal organs into people.”

Thousands of labs, and scientists have already begun exploiting the three-year old technique, he said.

“It’s only slightly hyperbolic to say that if scientists can dream of a genetic manipulation, CRISPR can now make it happen,” said Travis.

The technique, first announced in 2012, experienced a “massive growth spurt last year,” Travis said, describing it as a “molecular marvel.”

Marcia McNutt, editor-in-chief of the Science family of journals, said in an accompanying editorial that “in two ‘ time CRISPR will have brought to many diverse fields in biology the enduring level of excitement and optimism that immunotherapy has brought to cancer patients.”

Immunotherapy, a host of techniques which harness the body’s immune cells to fight cancer, was named Science’s breakthrough of 2013.

But the lay public was less enthusiastic about CRISPR, according to online visitors who voted on the top 10 picks of the year on Science’s website.

To 35 percent of voters, the flyby of Pluto by an unmanned NASA probe called New Horizons was the top breakthrough of the year, offering views in unprecedented detail of the distant dwarf planet.

CRISPR followed with 20 percent of online votes.

Gene editing has saved the life of a girl with “incurable” leukaemia

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Researchers in the UK have successfully treated Layla, a baby girl with leukaemia, using a gene-editing therapy that had previously only been trialled in mice. Doctors say it’s too soon to declare her cured, but she’s now living healthily and cancer free.

The therapy involved using mass-produced gene-edited cells to attack the leukaemia in her body, and it was the first time it had been tried in a human. But because Layla’s case had been declared incurable and doctors had exhausted all other options, her parents were granted permission to use the experimental treatment on compassionate grounds.

Layla’s results will be presented at the American Society of Hematology in December, and represent the first time that a human life has been saved by gene-editing – despite many years of promising trials using the technique.

“As this was the first time that the treatment had been used, we didn’t know if or when it would work and so we were over the moon when it did,” said Paul Veys, Layla’s lead clinician at the Great Ormond Street Hospital (GOSH) in London. “Her leukaemia was so aggressive that such a response is almost a miracle.”

While this is only one case study, what’s really exciting is that it’s the first evidence that using edited versions of generic, non-personalised cells could work as an effective therapy, paving the way for more affordable and accessible treatment options for a range of cancers.

Layla was born in the UK, and was diagnosed with what’s known as acute lymphoblastic leukaemia – an aggressive cancer of the bone marrow – at just three months old. She underwent several rounds of intense chemotherapy, a bone marrow transplant, and took part in an experimental trial all before her first birthday, but the cancer came back.

That’s when her doctors heard about a new type of gene editing being tested at University College London. Normally gene editing works by taking immune T-cells from a patient’s body and then genetically engineering them to attack cancerous cells before placing them back in the body.

This is already being trialled in humans, and results so far suggest that it can be effective. But it’s also incredibly expensive and time consuming, and it won’t work for patients like Layla, who have already undergone extensive treatment for leukaemia and don’t have enough healthy T-cells left to work with.

Instead the researchers at University College London, led by Waseem Qasim, have been working on an ‘off-the-shelf’ therapy, which could be quickly and cheaply given to patients without having to first collect their cells.

In this approach, a healthy person donates a whole bunch of T-cells, which are then modified to make sure they’re safe to transfer, creating what the researchers call UCART19 cells.

To create these cells, Qasim and his team use a pair of ‘molecular’ scissors, known as TALEN proteins, to switch off certain receptors, ensuring that the UCART19 T-cells only attack leukaemia cells, and not healthy ones. They also removed genes to make the cells invisible, so that they wouldn’t be destroyed by other leukaemia drugs.

“The approach was looking incredibly successful in laboratory studies,” said Qasim, “and so when I heard there were no options left for treating this child’s disease, I thought ‘why don’t we use the new UCART19 cells?'”

Layla was given 1 ml of the cells, and then spent the next weeks in isolation while the T-cells attacked her cancer cells. Two months later, once the doctors confirmed that the leukaemia cells had all been removed, she was given another bone marrow transplant.

She’s now recovering well at home and is having regular check ups. And the best part is that once the final bone marrow transplant was done, Layla’s own immune system kicked back in and destroyed the UCART19 cells, so there was no trace left of the gene-editing.

The researchers have now scheduled a proper clinical trial of the UCART19 cells, funded by biotech company Cellectis, to start in early 2016. In addition to making sure the treatment works, these trials will ensure that the modifications made to the T-cells can’t be passed on, and aren’t toxic to a wider group of patients.

“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Qasim. “But, this is a landmark in the use of new gene engineering technology and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukaemia and other cancers.”

Gene-editing record smashed in pigs.

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Geneticist George Church has co-founded a company that is developing genetically modified pigs to grow organs for human transplant.

For decades, scientists and doctors have dreamed of creating a steady supply of human organs for transplantation by growing them in pigs. But concerns about rejection by the human immune system and infection by viruses embedded in the pig genome have stymied research. Now, bymodifying more than 60 genes in pig embryos — ten times more than have been edited in any other animal — researchers believe they may have produced a suitable non-human organ donor.

The work was presented on 5 October at a meeting of the US National Academy of Sciences (NAS) in Washington DC on human gene editing. Geneticist George Church of Harvard Medical School in Boston, Massachusetts, announced that he and colleagues had used the CRISPR/Cas9 gene-editing technology to inactivate 62 porcine endogenous retroviruses (PERVs) in pig embryos. These viruses are embedded in all pigs’ genomes and cannot be treated or neutralized. It is feared that they could cause disease in human transplant recipients.

The gene-edited pigs will be raised in isolation from pathogens.

Church’s group also modified more than 20 genesin a separate set of pig embryos, including genes that encode proteins that sit on the surface of pig cells and are known to trigger a human immune response or cause blood clotting. Church declined to reveal the exact genes, however, because the work is as yet unpublished. Eventually, pigs intended for organ transplants would need both these modifications and the PERV deletions.

Preparing for implantation

“This is something I’ve been wanting to do for almost a decade,” Church says. A biotech company that he co-founded to produce pigs for organ transplantation, eGenesis in Boston, is now trying to make the process as cheap as possible.

Church released few details about how his team managed to remove so many pig genes. But he says that both sets of edited pig embryos are almost ready to implant into mother pigs. eGenesis has procured a facility at Harvard Medical School where the pigs will be implanted and raised in isolation from pathogens.

Jennifer Doudna, a biochemist at University of California, Berkeley, who was one of the inventors of CRISPR/Cas9 technology, is impressed by the number of edited genes. If the work holds up, she says, it could be useful for synthetic-biology applications where genes can be switched on and off. In microorganisms, creating these circuits requires the insertion or modification of multiple genes that regulate one another.

Cutting multiple genes will also be useful for human therapies, says George Daley, a stem-cell biologist at Harvard Medical School, because many diseases with a genetic component involve more than one gene.

Targeted gene editing enters clinic

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Patients with HIV first to receive experimental gene therapy.


A gene-therapy method that specifically disrupts a single gene may have had its first success in the clinic, potentially boosting immune-cell counts in a small number of patients with HIV. The results, presented on 28 February at the Conference on Retroviruses and Opportunistic Infections in Boston, Massachusetts, mark an important therapeutic test for enzymes known as zinc finger nucleases — small proteins that can be designed to bind to and edit specific DNA sequences by virtue of their zinc-bearing structures.

“If they did this several times in a given patient, you could establish a high percentage of resistant cells.”


The study, a phase I safety trial, tested a zinc finger enzyme developed by Sangamo BioSciences in Richmond, California. It included six men with HIV who were already taking the standard regimen of antiretroviral drugs. The drugs had kept the virus at bay, but their immune-cell counts remained abnormally low. Researchers removed a sample of CD4+ T cells, the type of immune cells affected by HIV, from each man and used Sangamo’s enzyme to disrupt the CCR5 gene, which encodes a protein that HIV uses to enter CD4+ cells. The engineered cells were then infused back into the patients. Immune-cell counts subsequently rose for five of the six patients who received the therapy.

“It’s very exciting,” says John Rossi, a molecular biologist at the City of Hope’s Beckman Research Institute in Duarte, California. “If they did this several times in a given patient, you could establish a high percentage of resistant cells.”

The inspiration for targeting the CCR5 gene comes from the small percentage of people who, thanks to a natural mutation in the gene, are resistant to most types of HIV infection. At the meeting on Monday, Jacob Lalezari of Quest Clinical Research in San Francisco, California, reported that the engineered cells migrated throughout the body and thrived in the gut mucosa — a key reservoir of HIV. No serious side effects were seen.

The zinc finger nuclease technique is promising for the treatment of many diseases beyond HIV, says Patrick Aubourg, who studies gene therapy at France’s national biomedical agency INSERM in Paris. The method could replace the more common technique of inserting modified genes into the genome, in which researchers have less control over the gene in question. But he cautions that the technique still has a relatively low efficiency and might have off-target effects.

Meanwhile, Rossi, who is himself embarking on an HIV study that will use Sangamo’s zinc finger nucleases, says that it is not yet clear whether the patients’ CD4+ cell count rose because of the CCR5 disruption or because the extracted cells were activated as part of the protocol for growing them outside the body. And because levels of HIV were already below the threshold of detection in these patients, it is too early to say what effect the therapy could have on patients that have more of the virus. Researchers do not yet know what fraction of a person’s CD4+ cells would need to be HIV-resistant to significantly rein in the virus’s spread and liberate patients from a lifetime of antiretroviral drugs.”It’s going to take a while to put all of those pieces together,” says Carl June, who studies T cells at the University of Pennsylvania in Philadelphia, and is an investigator on another HIV trial involving Sangamo’s nuclease. “But it’s at least conceivable now.”

source: nature