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Scientists bid to create GM embryos

Published 23/04/2015

The researchers used a molecular cut and paste technique to edit DNA at specific locations in order to remove and replace a problem gene
The researchers used a molecular cut and paste technique to edit DNA at specific locations in order to remove and replace a problem gene

A first attempt to create genetically modified (GM) human embryos has been made by Chinese scientists in a move that has prompted a call for a worldwide ban on the creation of "designer babies".

The researchers used a molecular cut and paste technique to edit DNA at specific locations in order to remove and replace a problem gene.

Their aim was to modify the gene responsible for beta-thalassaemia, a potentially fatal inherited blood disorder.

But the experiment, conducted on "non-viable" human embryos, proved unsuccessful. Of 86 embryos treated, only 28 were spliced and a fraction of those were found to contain the replacement genetic material.

Nevertheless, the research published in the online journal Protein & Cell, is hugely controversial because it crosses what for many is a scientific red line.

Commenting on the development, Dr David King, director of the watchdog group Genetics Alert, said: "This news emphasises the need for an immediate global ban on the creation of GM designer babies.

"It is critical that we avoid a eugenic future in which the rich can buy themselves a baby with built-in genetic advantages. If China does not want to get the reputation of being the wild west of the new eugenics it must join the many countries including the UK which would ban such research."

Details of the research were brought to mainstream attention by the journal Nature in an online news article.

It quoted lead scientist Dr Junjiu Huang, from Sun Yat-sen University in Guangzhou, saying: "If you want to do it in normal embryos, you need to be close to 100%. That's why we stopped. We think it's too immature."

The technique, known as CRISPR/Cas9, involved injecting very early single-cell embryos with an enzyme complex that precisely binds and splices DNA.

It can be programmed to target a problem gene which is replaced or repaired by another molecule introduced at the same time.

Although well studied in human adult cells and animal embryos, there have been no published reports until now of its use in human embryos.

Dr Huang's group used the technique to edit a gene called HBB, which codes for the human beta-globin protein. Mutations in this gene are the cause of beta-thalassaemia.

Embryos were obtained from fertility clinics and had an extra set of chromosomes which meant they could undergo the first stages of development without resulting in a live birth.

Dr George Daley, a stem cell biologist at Harvard Medical School in Boston, US, told Nature: "I believe this is the first report of CRISPR/Cas9 applied to human pre-implantation embryos and as such the study is a landmark, as well as a cautionary tale.

"Their (the Chinese team) study should be a stern warning to any practitioner who thinks the technology is ready for testing to eradicate disease genes."

The scientists found a surprising number of "off-target" mutations that were assumed to have been introduced by the editing complex acting on other parts of the genome, or genetic code.

"This effect is one of the main safety concerns surrounding germline gene editing because these unintended mutations could be harmful," said the Nature article.

Germline genes are those that can be passed onto future generations in eggs and sperm.

The rate of mutations was said to be much higher than those seen in gene-editing studies of mouse embryos or human adult cells.

Dr Huang admitted that not all the unintended mutations were likely to have come to light because the study only focused on a portion of the genome.

"If we did the whole genome sequence, we would get many more," he said.

The Chinese scientists maintain that their paper was rejected by the prestigious journals Nature and Science in part because of ethical objections.

Nature declined to comment on the claim to its news journalists, who are editorially independent from the team that publishes scientific research.

Dr Huang is said to be considering several different strategies to reduce the number of off-target mutations which he hopes to test on adult human cells or animal models.

Dr King pointed out that China already had a law compelling women pregnant with a genetically disabled child to have an abortion. Chinese scientists were also allegedly involved in research to identify high IQ genes.

"Western governments must finally put pressure on China to change its policies in this area if it wants to be a respectable part of the international community," Dr King added.

"The research demonstrates the safety pitfalls of these techniques and is entirely unnecessary since there are already many ethical ways to avoid thalassaemia. This research is a classic example of scientific careerism - assuring one's place in the history books even though the research is unnecessary and unethical."

Tampering with the germline is currently illegal in the UK with one exception. In an historic decision taken in February, MPs and peers voted to allow the donor replacement of mitochondrial DNA - genetic material contained in tiny cellular power plants - in order to prevent hereditary diseases.

However, mitochondrial DNA accounts for a minute fraction of the genetic code and is very different from the DNA in the cell nucleus which determines personal traits such as height, eye colour and personality.

British experts said the new research underlined the need for caution when considering applications for powerful gene editing technology.

Alastair Kent, director of Genetic Alliance UK, a charity supporting families with genetic conditions, said: "Families with a life-limiting genetic disease reading of this research will be interested to learn that it has been done, but will be only too aware of the scientific difficulties that will need to be overcome, and the ethical challenges that will need to be resolved, before it could be postulated as a potential therapeutic intervention for use in embryos destined for implantation in a woman through IVF.

"If there is to be further development of this work it will be essential that the experimental data is fully accessible so the methodology can be scrutinised carefully before further work that moves this closer to patients is contemplated.

"Failure to do this will render patients and families vulnerable, and risk bringing the wider field of gene transfer for serious diseases into disrepute."

Dr Philippa Brice, from the genomics think tank the PHG Foundation, said: " This story underlines the urgent necessity for international dialogue over the ethics of germline gene editing in human embryos, well in advance of any progression towards theoretical clinical application.

"Recent calls for a moratorium on any such research to allow time for expert and public consideration of what is and is not ethically, socially and indeed legally acceptable with respect to human germline genetic modification should definitely be heeded."

Professor Darren Griffin, a genetics scientist from the University of Kent, said: " Given the widespread use of the CRISPR/Cas9 system, such announcement was inevitable, sooner rather than later. We clearly have a lot of thinking to do. Germline manipulation is currently illegal in the UK but the question is bound to be asked whether this should change, especially if the safety concerns are allayed.

"If the technology is proved to be safe, then the question moves to whether it crosses a moral boundary to apply this technology in the clinic. Equally, some will ask if the procedure is safe, do we have a moral imperative to make sure that we do it."

Professor Shirley Hodgson, an expert in cancer genetics at St George's, University of London, said: " I think that this is a significant departure from currently accepted research practice. This is because any manipulation of the germline of human embryos is potentially heritable. Can we be certain that the embryos that the researchers were working on were indeed non-viable?

"In the past all the gene therapy research that has been approved by regulatory bodies has been somatic, not germline, because of the potentially unpredictable and heritable effects of germline research. The fact that these researchers found that there were a number of "off-target" mutations resulting from the technique they used is clearly a worry in this context.

"Any proposal to do germline genetic manipulation should be very carefully considered by international regulatory bodies before it should be considered as a serious research prospect."

Coincidentally, news of the Chinese research came as US scientists reported using a different gene editing technique to prevent the transmission of defective mitochondria.

These experiments, carried out at the Salk Institute in La Jolla, were performed on mice, not human embryos.

The "proof of concept" study published in the journal Cell selectively prevented mutated mitochondrial DNA linked to human diseases being passed from female mice to their offspring.

Researcher Dr Alejandro Ocampo said: "The clinical application of our technique does not require donor eggs. We are just performing a single injection into the patient's egg or one-cell embryo, which is technically easier than mitochondrial replacement."

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