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Precise "chemical surgery" has been performed on human embryos to remove disease in a world first, Chinese researchers have told the BBC.

The team at Sun Yat-sen University used a technique called base editing to correct a single typo out of the three billion "letters" of our genetic code.

They altered lab-made embryos to remove the disease beta-thalassemia. The embryos were not implanted.

The team says the approach may one day treat a range of inherited diseases.

Base editing alters the fundamental building blocks of DNA: the four bases adenine, cytosine, guanine and thymine.

They are commonly known by their respective letters, A, C, G and T.

All the instructions for building and running the human body are encoded in combinations of those four bases.

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The potentially life-threatening blood disorder beta-thalassemia is caused by a change to a single base in the genetic code - known as a point mutation.

The team in China edited it back.

They scanned DNA for the error then converted a G to an A, correcting the fault.

Junjiu Huang, one of the researchers, told the BBC News website: "We are the first to demonstrate the feasibility of curing genetic disease in human embryos by base editor system."

He said their study opens new avenues for treating patients and preventing babies being born with beta-thalassemia, "and even other inherited diseases".

The experiments were performed in tissues taken from a patient with the blood disorder and in human embryos made through cloning.

Genetics revolution

Base editing is an advance on a form of gene-editing known as Crispr, that is already revolutionising science.

Crispr breaks DNA. When the body tries to repair the break, it deactivates a set of instructions called a gene. It is also an opportunity to insert new genetic information.

Base editing works on the DNA bases themselves to convert one into another.

Prof David Liu, who pioneered base editing at Harvard University, describes the approach as "chemical surgery".

He says the technique is more efficient and has fewer unwanted side-effects than Crispr.

He told the BBC: "About two-thirds of known human genetic variants associated with disease are point mutations.

"So base editing has the potential to directly correct, or reproduce for research purposes, many pathogenic [mutations]."

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The research group at Sun Yat-sen University in Guangzhou hit the headlines before when they were the first to use Crispr on human embryos.

Prof Robin Lovell-Badge, from the Francis Crick Institute in London, described parts of their latest study as "ingenious".

But he also questioned why they did not do more animal research before jumping to human embryos and said the rules on embryo research in other countries would have been "more exacting".

The study, published in Protein and Cell, is the latest example of the rapidly growing ability of scientists to manipulate human DNA.

It is provoking deep ethical and societal debate about what is and is not acceptable in efforts to prevent disease.

Prof Lovell-Badge said these approaches are unlikely to be used clinically anytime soon.

"There would need to be far more debate, covering the ethics, and how these approaches should be regulated.

"And in many countries, including China, there needs to be more robust mechanisms established for regulation, oversight, and long-term follow-up."

Follow James on Twitter.</s>The explosive growth of human genomic data has revealed unprecedented numbers of disease-causing point mutations. Repairing such mutations may offer the best, and in some cases, only cure for genetic diseases. We and other groups have sought to correct disease mutant by combining CRISPR/Cas9 and homology directed repair (HDR) in human tripronulcear zygotes and diploid zygotes. However, low efficiency, mosaicism, off-target cleavage, and unintended homologous recombination (between target site and endogenous homologous genomic DNA sequence) remain obstacles that hamper the clinical applications of such approaches (Kang et al., 2016; Liang et al., 2015; Tang et al., 2017). In a recent report, it was found that diploid human zygotes, distinct from pluripotent cells, tends to repair DNA double strand break (DSB) using endogenous homologous sequence (Ma et al., 2017), consistent with what we have found in human tripronuclear zygotes (Liang et al., 2015). In the study, highly efficient repair of the mutant allele was achieved using the wild-type (WT) allele in heterozygous human zygotes through CRISPR/Cas9 (Ma et al., 2017). However, homozygous mutant embryos could not be repaired in way because of the lack of WT alleles. Additionally, recombination may occur with similar but not identical endogenous sequences, leading to unexpected mutations, as we found in human tripronuclear zygotes in which HBB recombined with HBD (Liang et al., 2015). Using base editors to directly repair point mutations may represent an efficient and highly specific alternative.

The base editor is a RNA-protein complex, adapted from the CRISPR/Cas9 system and cytidine deaminase (Komor et al., 2016). The effector protein is composed of cytidine deaminase (rAPOBEC1), Cas9, and uracil DNA glycosylase inhibitor (UGI). It can deaminate cytidine (C) to uridine (U) without inducing DNA DSB, and finally result in C-to-T (or G-to-A) conversion in the target DNA sequence (Hohmann, 2017; Komor et al., 2016; Liang et al., 2015). Efficient base editing at single-base resolution has been reported in plant, yeast, human cells, mouse zygotes, and human tripronuclear zygotes (Chen et al., 2017; Kim et al., 2017b, c; Komor et al., 2016; Li et al., 2016, 2017a, b; Liang et al., 2017; Lu and Zhu, 2016; Ren et al., 2017; Zhou et al., 2017); Zong et al., 2017). Intriguingly, mouse embryos and pups with 100% point mutation efficiency (free of mosacism), as well as human tripronuclear zygotes has been generated (Kim et al., 2017c; Li et al., 2017a; Liang et al., 2017). However, whether base editors can repair homozygous T>C (or A>G) disease mutant in human embryos remains to be tested.

β-Thalassemia, a common genetic disease in Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia, is a major problem of global health (Cao and Galanello, 2010; Galanello and Origa, 2010; Weatherall, 2010). Genetic mutations, which will lead to the reduction of hemoglobin β chain (β-globin) and erythrocytes, finally cause oxygen shortage, bone deformity, organ dysfunction and even organ failure in many parts of the human body (Cao and Galanello, 2010). Based on the severity of the disease, β-thalassemia can be classified into β-thalassemia minor (also called β-thalassemia carrier), β-thalassemia intermedia, and β-thalassemia major (Cooley’s anemia) (Cao and Galanello, 2010). Without treatment, patients with β-thalassemia major usually die before age 5. Thalassemia major patients require lifelong blood transfusion and iron chelation treatment to survive, often accompanied by numerous complications, including arrhythmia, congestive heart failure, hypothyroidism, hypoparathyroidism, hypogonadism, diabetes, osteoporosis, liver cirrhosis, and infection (Chern et al., 2007; Wu et al., 2017). To date, allogeneic bone marrow transplantation (BMT) is the only curative therapy, but BMT is limited by human leukocyte antigen (HLA) compatibility. β-Thalassemia is mainly caused by mutations in the HBB gene, of which −28 (A>G) mutation is a common defect reducing the transcription of HBB (Orkin et al., 1983). Patients with homozygous or compound heterozygous −28 (A>G) mutation may develop severe anemia or intermedia anemia (Cao and Galanello, 2010; Orkin et al., 1983). Correcting the −28 (A>G) mutation by base editing should help to ameliorate anemia. Here, we report the efficient correction of −28 (A>G) mutation in human primary cells and human embryos by base editors.</s>In the wake of the first gene-edited embryos in the US being created earlier this year, Chinese researchers have employed a different technique to swap a single base in a human embryo's genome.

The precise edit was designed to return functionality to a gene responsible for a component of haemoglobin, which in its mutated form results in an often fatal blood condition called beta-thalassaemia.

A team of researchers from Sun Yat-sen University in Guangzhou, China, used what's called a base editor technique to change a single G back to an A in the DNA code of an embryonic cell's HBB gene.

The change might have been tiny, but in its mutated form HBB can't produce the protein beta-globin needed to build the oxygen-carrying haemoglobin for our red blood cells.

A shortage of haemoglobin means a shortage of oxygen, impeding growth and development and leading to a lifetime of blood transfusions to treat anaemia – if the embryo survives at all.

Beta-thalassaemia is usually a recessive condition, meaning both parents need to contribute a copy of the mutated gene for anaemia to develop in their child.

Correcting the mutations in this gene could help parents carry an embryo to term, or remove the trait from family lines.

About 400 different kinds of code-corruptions can affect HBB.

In this case, the researchers focussed on a single point-mutation that targets a base called cytosine (C) and exchanges it for one called thymine (T).

Each of these letters complements the other two kinds of base – thymine is a jigsaw-puzzle piece that matches adenine (A), while cytosine matches guanine (G).

By swapping a C for a T, the mutation should revert back to the proper 'A' code.

If this base editing technology seems unnecessarily complicated, there's a good reason for doing a genetic do-si-do – it means the strand of DNA isn't being snipped all the way through.

To test if the procedure was feasible, the team created a cell line with pieces of the gene embedded inside and then used two different base editing techniques to change the code.

Satisfied the editing could be done, they took the process to the next level and edited the gene in skin cells from a beta-thalassemia patient.

Researchers transferred the nucleus of the patient's skin cells into 30 mature oocytes – or human egg cells.

One of the techniques was then applied to the 26 cells that survived the cloning procedure, which successfully turned the G to an A in 9 of the embryos, and a G to a C (cytosine) in one.

None of the embryos were developed further or implanted.

Gene editing has been big news in recent years with advances in the application of a technology called CRISPR, which uses enzymes found in bacteria to chew up DNA at a specific location.

Applying this kind of corrective genetic surgery to human embryos could spell an end to a variety of inherited conditions, but so far efforts have been controversial, to say the least.

Questions have developed recently on whether or not the technology produces unwanted mutations, indicating that for all of its promise, it's still early days for this revolutionary engineering tool.

Base editing won't replace CRISPR, but could be a more delicate solution for those solitary mutations.

"We are the first to demonstrate the feasibility of curing genetic disease in human embryos by base editor system," researcher Junjiu Huang told the BBC.

Feasibility is the word here. We're nowhere near a safe operating procedure for repairing genes we consider broken in embryos.

But each careful step, coupled with healthy public debate, brings us a bit closer to an age when debilitating conditions like beta-thalassemia will be notes in a medical history book.

This research was published in Protein & Cell.</s>When the U.S. Food and Drug Administration issued new guidance earlier this month on how companies who handle human cells, tissues and cellular and tissue-based products should report problems to the agency, it was a recognition that the medical industry is heading deeper into uncharted territory.

But FDA Commissioner Scott Gottlieb recognized that it was still early-going, calling the policy "another step forward in our development of a comprehensive framework for regulating cell and tissue products – one that provides clear rules and balances patient protection with the need for efficient oversight of these technologies."

[Also: Genome editing tools set to bring monumental change to healthcare]

As research into novel treatments for cancer and rare disease continues, regenerative medicine is becoming big business, with companies focused on cellular products having raised some $25 billion in financing, according to a recent study from Informa Pharma Intelligence.

"Previously regenerative medicine focused on devices, but now we’re seeing a pipeline shift centered on therapies," said Amanda Micklus, principal analyst of Informa Pharma Intelligence. "This is an exciting time for the field, with new innovations spanning diseases and patients that were previously underserved by currently available treatments. Considering the large size of the pipeline we’re going to see several new discoveries and advances in the space over the next few years.”

[Also: In a precision medicine landmark, FDA approves first gene therapy]

That pipeline shift has seen an uptick in large federal and private sector investment since President Barack Obama signed the 21st Century Cures Act, which created a special status pathway for regenerative medicines through the FDA’s regenerative medicine advanced therapies designation.

There were more than 100 regenerative medicine mergers and acquisitions announced since 2016, with at a total value of $68 billion, according to IPI, with nearly half of such deals involved smaller biotech companies partnering with each other to advance their respective technologies

"Growth in regenerative medicine is being driven by a friendly federal government and enormous market interest, especially from Johnson & Johnson, Celgene and AstraZeneca, the most active large pharma players in the space in terms of number of partnerships," said Micklus. "We’re going to continue seeing major breakthroughs in this space, that can help people where no other help is currently available."

Still controversial, but gene editing is making advancements

Another report from IPA examines the expansive new frontier of gene editing, which is fast evolving thanks to growth in the CRISPR-Cas9 tools. The study spotlights the fact that more than 100 inventors have been granted patents so far.

The technology -- the two halves of the acronym stand for "clustered regularly interspaced short palindromic repeats" and "CRISPR associated protein 9" -- represents just the latest (but so far most hugely promising) generation of gene editing technologies, which center around the use of an RNA molecule to guide the Cas9 endonuclease to a target area editing.

[Also: Start-up working on breakthrough in 3-D printing of human organs]

Scientists such as Yoshizumi Ishino at Osaka University, Emmanuelle Charpentier at University of Vienna, Jennifer Doudna of the University of California and Feng Zhang of Harvard and MIT's Broad Institute have been instrumental in the field's research, and "intellectual property around the foundational US patents in CRISPR/Cas9 has become a contentious issue in the gene editing field," according to IPI.

There are other controversies and hurdles that need to be ironed out for advancements in gene editing to truly take hold, according to the report. For instance, the practice is currently limited to ex vivo applications, but many of the human diseases that could be treated or prevented would need to be targeted in vivo. Unwanted (and often unpredictable) immune reactions and off-target mutations are big concern. And several groups have issued policy statements expressing concern with the ethics of gene editing and recommending caution.

That said, "many companies, such as Bluebird Bio and Homology Medicines, are improving on existing gene-editing technologies to produce more efficient systems," said IPI, and the existing field of gene editing companies is "advancing their assets through several key deals. Several large pharmaceutical companies have become quite active, including Novartis, which has signed agreements with Caribou Biosciences, Intellia Therapeutics, and Celyad."

Nonetheless, "gene editing for the treatment of human disease is still in early stages and represents a very small proportion, just 3 percent of the overall regenerative medicine landscape in comparison to more active treatment modalities within regenerative medicine," according to the report.

Across the gene editing landscape, the most active companies span discovery-stage biotechs to large pharma firms. Most are using CRISPR-Cas9, including Editas Medicine and CRISPR Therapeutics, "which each have ten candidates in development (either as an originator or licensee)," according to the report. Big names such as Shire, Pfizer and Bayer have also staked their claims to the gene editing field.</s>Chinese scientists used an adapted version of a controversial gene-editing technique to correct a disease-causing mutation in human embryos, a medical first cautiously hailed by other experts Thursday.

The team used a so-called "base editor" -- an adaptation of the CRISPR-Cas9 DNA snipping tool -- to correct a single, mutated "letter" among about three billion in the intricate coding of the human genome.

The targeted mutation can cause humans to be born with beta-Thalassaemia, a potentially fatal genetic blood disorder.

"This study demonstrated the feasibility of curing genetic diseases in human... embryos by base editor system," the team wrote in the specialist journal Protein & Cell.

The journal sparked controversy when it published a paper in 2015 in which the same authors reported on experiments with CRISPR-Cas9 to modify the thalassaemia gene.

That paper led to calls for a halt to experiments involving the genetic editing of human embryos.

Many fear such technology could lead to so-called "designer babies" with desired features such as intelligence engineered into their genes.

For the new study, Puping Liang of the Sun Yat-sen University in China, and a team used a technique based on CRISPR-Cas9, which allows scientists to remove and replace a faulty strand of DNA with pinpoint precision.

Instead of using the Cas9 protein as "scissors" to eliminate the mutated "letter", they used an enzyme to change it.

- Can it be improved? -

DNA is the instruction booklet for cells to make and sustain life.

It resembles a zipper-like spiral -- the teeth on each strand are "base pairs" of encoding "letters" that chemically match with each other.

Adenine teams up with thymine to create the A-T base pair, while cytosine pairs with guanine for the C-G pair.

Thalassaemia can be caused by an "A" base letter converted to a "G" in a specific location of the gene.

For the latest study, the team sought to chemically change the "C" partner of the mutant "G", to a "T".

This would cause the errant "G" to automatically convert to an "A", expert Robin Lovell-Badge of the Francis Crick Institute, who was not involved in the study, explained via the Science Media Centre.

The method eliminated the need to cut DNA, and the team were successful about one in five times.

They worked with cloned embryos that were kept alive for just a few days for the purposes of lab experimentation

Observers said the technique appeared to be an improvement on standard CRISPR-Cas9.

"This powerful study sheds new light on precise gene correction for single gene disorders," commented Helen Claire O'Neill of University College London.

"It remains to be seen whether the efficiency... can be improved upon."

For Darren Griffin, a genetics professor at the University of Kent, the paper showed that "the ethical implications of gene manipulation in embryos need a thorough examination where safety is of paramount concern."

US-based scientists in August reported using CRISPR-Cas9 to repair a disease-causing mutation in the DNA of early-stage human embryos.

Last week, British scientists said they had used CRISPR-Cas9 to reveal the role of a key gene in the early development of human embryos.</s>Scientists have cured human embryos of a blood disorder in a first-ever technique that could one day stamp out inherited diseases.

Researchers with Sun Yat-sen University in China performed “chemical surgery” on the lab-made embryos to remove the disease called beta thalassemia, which reduces the production of hemoglobin, according to the BBC.

“We are the first to demonstrate the feasibility of curing genetic disease in human embryos by base editor system,” said researcher Junjiu Huang.

Huang said the study creates the possibility of treating patients and preventing babies being born with beta thalassemia — “and even other inherited diseases.”

The experiment was conducted on tissue taken from a patient with the blood disorder and human embryos made through cloning.

Researchers used a technique called “base editing,” which alters the fundamental building blocks of DNA — adenine, cytosine, guanine and thymine, commonly known by their respective first letters, A, C, G and T.

Beta thalassemia is caused by a fault called a point mutation — a change to a single base in the genetic code.

Researchers used base editing to change a G base to an A — successfully curing the DNA of the blood disorder.

Base editing is an advanced form of gene editing called Crispr, which breaks DNA.

David Liu, who pioneered the technique at Harvard University, said the method is preferred because it creates fewer side effects than Crispr.

“About two-thirds of known human genetic variants associated with disease are point mutations,” said Liu. “So base editing has the potential to directly correct, or reproduce for research purposes, many pathogenic [mutations].”</s>(CNN) In the future, it might be possible to prevent inherited illnesses by making a change to a single faulty gene. That was recently demonstrated in a new study.

For the first time, scientists used a controversial gene-editing technique called base editing to correct a gene mutation in human embryos linked to the hereditary blood disorder beta thalassemia , according to the study published in the journal Protein & Cell in September.

A change to a single base pair in your genetic code, known as a point mutation , can cause beta thalassemia

The scientists noted that the efficiency of repairing mutations in the study was only about 20% -- so they were not 100% successful in effectively editing all of the embryos all of the time. Yet the study findings and the base editing technique are now gaining international attention.

The base editor technique is similar to the powerful gene-editing tool called CRISPR, but there is a major difference.

Base editing uses some of the components of CRISPR, but directly makes changes to a targeted site in DNA without cutting the DNA, said David Liu, core institute member of the Broad Institute and professor of chemistry and chemical biology at Harvard University, who was not involved in the study.

When a cut is made in genomic DNA using the traditional CRISPR approach -- for instance, to disrupt a mutation -- the primary response of a cell is to repair the cut and, in the process, disrupt the DNA at the cut site, Liu said.

"But many human genetic diseases are caused by single point mutations that need to be precisely corrected, rather than disrupted, in order to treat or study the corresponding disease," Liu said. That's where base editing comes in.

"Base editing, in contrast, does not make a double-stranded cut in the target DNA. Instead, base editors directly perform 'chemical surgery' on the target DNA base to convert one base pair to a different base pair, that is, to make a point mutation," said Liu, whose research group at Harvard developed base editing.

"It's important to note that compared to traditional nuclease-mediated genome editing methods such as the use of CRISPR-Cas9, base editing is a complementary -- not necessarily better -- approach, and each approach has its strengths and preferred applications," he said.

About two-thirds of known human genetic variants associated with diseases are point mutations, so base editing has the potential to correct or reproduce such mutations for research purposes, Liu said.

'The future is here'

"The paper itself represents a significant technical advance because, rather than using the classic CRISPR-Cas9 technology previously reported, the current 'base editor' technology is an adaptation that chemically alters the DNA bases themselves," Griffin said about the new study, of which he was not involved.

"While this is undoubtedly a highly significant advance, it is important not to get carried away about its widespread utility if put into clinical practice," Griffin said.

"An embryo would still need to be diagnosed as abnormal (if there were other embryos in the cohort that were normal they would presumably be used instead), then the base editor applied, then re-diagnosed to make sure that it had worked," he said. "In the meantime, the ethical implications of gene manipulation in embryos need a thorough examination where safety is of paramount concern."

The new study involved base editing experiments in cells from beta-thalassemia patients and human embryos. Cloned human embryos were generated in a lab using a technique called nuclear transfer. A total of about 20 embryos were harvested.

"It's interesting work that shows that base editing can directly correct a pathogenic beta-thalassemia mutation in the promoter of the beta-thalassemia gene in cells from beta-thalassemia patients, and in cloned human embryos," Liu said.

Without treatment, patients with the more severe type, known as beta thalassemia major, usually die before age 5, the scientists wrote in the study.

"Our data highlight the tremendous potential of correcting homozygous disease and compound heterozygous mutations by base editing in human somatic cells and embryos," the scientists wrote. "Although we did not achieve 100% repair in human embryos, we and other groups have reported 100% base editing in mouse embryos."

The scientists noted that the base editing wasn't uniform across all cells in the embryos, resulting in mosaic embryos. They also noted in the study that more research is needed to improve the safety of this base editing approach, especially before base editing is ready to use in humans.

"The efficiency of editing was quite low, and the embryo was mosaic as it developed, meaning that only some cells had the hoped-for base change. Both of these inefficiencies have to be overcome for the approach to be useful," said Dana Carroll, a professor of biochemistry at the University of Utah, who was not involved in the study but has used CRISPR in his own research.

"As far as I know, this is the first published study that uses base editing in human embryos, but the embryos are very unusual," he said, referring to how they were made in a lab. "It seems unlikely that the response to the base editor, and other cellular events, are an accurate reflection of what would happen in a natural embryo."

A request for comment from some of the scientists was unsuccessful.

All in all, the scientists noted in the new study that technical, ethic, and societal issues still need to be investigated and discussed thoroughly before base editing could be considered for clinical application.

Meanwhile, Liu said that his own research group has generated additional base editors that could expand the capabilities of the gene-editing technique.

"We will be reporting these developments in due course," he said. "We are hopeful that base editing might advance the study and treatment of genetic diseases, and our laboratory is working hard towards this goal."</s>Chinese scientists have successfully altered the genetic code of a human embryo, an “ingenious” breakthrough that experts believe could be key to eradicating hereditary diseases.

Using a technique known as ‘base editing’, researchers from Sun Yat-sen University in Guangzhou filtered through three-billion ‘letters’ of our genetic code to remove a single error responsible for a potentially deadly blood disorder.

"We are the first to demonstrate the feasibility of curing genetic disease in human embryos by base editor system,”Junjiu Huang, one of the scientists involved in the research, told BBC.

During the experiments, which were carried out on tissues taken from a patient with the blood disorder beta-thalassemia and inserted into cloned human embryos, a strand of DNA was examined to pinpoint the offending base. The team then used base editing, a more advanced form of the Crispr gene-editing technique to repair the faulty gene.

Such is the level of precision involved in base editing that Professor David Liu of Harvard University, a pioneer of the technique, dubbed it “chemical surgery.”

“Base editing has the potential to directly correct, or reproduce for research purposes, many pathogenic [mutations]," Liu said, adding that it is more efficient than Crispr as it has fewer unexpected side-effects.

The study, which has been published in the journal Protein and Cell, presents serious ethical questions for scientists.

While describing parts of the study as “ingenious,” Professor Robin Lovell-Badge of the Crick Institute in London called for robust regulation the techniques employed in gene editing.

"There would need to be far more debate, covering the ethics, and how these approaches should be regulated,” Lovell-Badge said. "And in many countries, including China, there needs to be more robust mechanisms established for regulation, oversight, and long-term follow-up."

The debate is also raging in the US, where the National Academy of Science and the National Academy of Medicine recommended easing the blanket ban on modifying DNA in February this year.

“We’ve always said in the past gene editing shouldn’t be done, mostly because it couldn’t be done safely. That’s still true, but now it looks like it’s going to be done safely soon,” Richard Hynes, a cancer researcher at the Massachusetts Institute of Technology who co-led the committee, told the New York Times.
The journal Protein & Cell publishes Sun Yat-sen University research describing the use of gene therapy in the removal of a version of the inherited blood disorder beta-thalassemia from an artificially-created nuclear transfer-type of cloning-model system of human oocytes. Collectively, this study demonstrated the feasibility of curing this and a range of other inherited diseases using the same genome editing technology of CRISPR.