Daily Archives: August 3, 2017

Weve always said in the past gene editing shouldnt be done, mostly because it couldnt be done safely, said Richard Hynes, a cancer researcher at the Massachusetts Institute of Technology who co-led the committee. Thats still true, but now it looks like its going to be done safely soon, he said, adding that the research is a big breakthrough.

What our report said was, once the technical hurdles are cleared, then there will be societal issues that have to be considered and discussions that are going to have to happen. Nows the time.

Scientists at Oregon Health and Science University, with colleagues in California, China and South Korea, reported that they repaired dozens of embryos, fixing a mutation that causes a common heart condition that can lead to sudden death later in life.

If embryos with the repaired mutation were allowed to develop into babies, they would not only be disease-free but also would not transmit the disease to descendants.

The researchers averted two important safety problems: They produced embryos in which all cells not just some were mutation-free, and they avoided creating unwanted extra mutations.

It feels a bit like a one small step for (hu)mans, one giant leap for (hu)mankind moment, Jennifer Doudna, a biochemist who helped discover the gene-editing method used, called CRISPR-Cas9, said in an email.

Scientists tried two techniques to remove a dangerous mutation. In the first, genetic scissors were inserted into fertilized eggs. The mutation was repaired in some of the resulting embryos but not always in every cell. The second method worked better: By injecting the scissors along with the sperm into the egg, more embryos emerged with repaired genes in every cell.

When gene-editing components were introduced into a fertilized egg, some embryos contained a patchwork of repaired and unrepaired cells.

Gene-editing

components inserted

after fertilization

Cell with

unrepaired

gene

Mosaicism in

later-stage embryo

When gene-editing components were introduced with sperm to the egg before fertilization, more embryos had repaired mutations in every cell.

Gene-editing components

inserted together with sperm,

before fertilization

In 42 of 58

embryos

tested, all

cells were

repaired

Uniform

later-stage embryo

When gene-editing components were introduced into a fertilized egg, some embryos contained a patchwork of repaired and unrepaired cells.

Gene-editing

components inserted

after fertilization

Cell with

unrepaired

gene

Mosaicism in

later-stage embryo

When gene-editing components were introduced with sperm to the egg before fertilization, more embryos had repaired mutations in every cell.

Gene-editing

components inserted

together with sperm,

before fertilization

In 42 of 58

embryos

tested, all

cells were

repaired

Uniform

later-stage embryo

I expect these results will be encouraging to those who hope to use human embryo editing for either research or eventual clinical purposes, said Dr. Doudna, who was not involved in the study.

Much more research is needed before the method could be tested in clinical trials, currently impermissible under federal law. But if the technique is found to work safely with this and other mutations, it might help some couples who could not otherwise have healthy children.

Potentially, it could apply to any of more than 10,000 conditions caused by specific inherited mutations. Researchers and experts said those might include breast and ovarian cancer linked to BRCA mutations, as well as diseases like Huntingtons, Tay-Sachs, beta thalassemia, and even sickle cell anemia, cystic fibrosis or some cases of early-onset Alzheimers.

You could certainly help families who have been blighted by a horrible genetic disease, said Robin Lovell-Badge, a professor of genetics and embryology at the Francis Crick Institute in London, who was not involved in the study.

You could quite imagine that in the future the demand would increase. Maybe it will still be small, but for those individuals it will be very important.

The researchers also discovered something unexpected: a previously unknown way that embryos repair themselves.

In other cells in the body, the editing process is carried out by genes that copy a DNA template introduced by scientists. In these embryos, the sperm cells mutant gene ignored that template and instead copied the healthy DNA sequence from the egg cell.

We were so surprised that we just couldnt get this template that we made to be used, said Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University and senior author of the study. It was very new and unusual.

The research significantly improves upon previous efforts. In three sets of experiments in China since 2015, researchers seldom managed to get the intended change into embryonic genes.

And some embryos had cells that did not get repaired a phenomenon called mosaicism that could result in the mutation being passed on as well as unplanned mutations that could cause other health problems.

In February, a National Academy of Sciences, Engineering and Medicine committee endorsed modifying embryos, but only to correct mutations that cause a serious disease or condition and when no reasonable alternatives exist.

Sheldon Krimsky, a bioethicist at Tufts University, said the main uncertainty about the new technique was whether reasonable alternatives to gene editing already exist.

As the authors themselves noted, many couples use pre-implantation genetic diagnosis to screen embryos at fertility clinics, allowing only healthy ones to be implanted. For these parents, gene editing could help by repairing mutant embryos so that more disease-free embryos would be available for implantation.

Hank Greely, director of the Center for Law and the Biosciences at Stanford, said creating fewer defective embryos also would reduce the number discarded by fertility clinics, which some people oppose.

The larger issue is so-called germline engineering, which refers to changes made to embryo that are inheritable.

If youre in one camp, its a horror to be avoided, and if youre in the other camp, its desirable, Dr. Greely said. Thats going to continue to be the fight, whether its a feature or a bug.

For now, the fight is theoretical. Congress has barred the Food and Drug Administration from considering clinical trials involving germline engineering. And the National Institutes of Health is prohibited from funding gene-editing research in human embryos. (The new study was funded by Oregon Health and Science University, the Institute for Basic Science in South Korea, and several foundations.)

The authors say they hope that once the method is optimized and studied with other mutations, officials in the United States or another country will allow regulated clinical trials.

I think it could be widely used, if its proven safe, said Dr. Paula Amato, a co-author of the study and reproductive endocrinologist at O.H.S.U. Besides creating more healthy embryos for in vitro fertilization, she said, it could be used when screening embryos is not an option or to reduce arduous IVF cycles for women.

Dr. Mitalipov has pushed the scientific envelope before, generating ethical controversy with a so-called three-parent baby procedure that would place the nucleus of the egg of a woman with defective cellular mitochondria into the egg from a healthy woman. The F.D.A. has not approved trials of the method, but Britain may begin one soon.

The new study involves hypertrophic cardiomyopathy, a disease affecting about one in 500 people, which can cause sudden heart failure, often in young athletes.

It is caused by a mutation in a gene called MYBPC3. If one parent has a mutated copy, there is a 50 percent chance of passing the disease to children.

Using sperm from a man with hypertrophic cardiomyopathy and eggs from 12 healthy women, the researchers created fertilized eggs. Injecting CRISPR-Cas9, which works as a genetic scissors, they snipped out the mutated DNA sequence on the male MYBPC3 gene.

They injected a synthetic healthy DNA sequence into the fertilized egg, expecting that the male genome would copy that sequence into the cut portion. That is how this gene-editing process works in other cells in the body, and in mouse embryos, Dr. Mitalipov said.

Instead, the male gene copied the healthy sequence from the female gene. The authors dont know why it happened.

Maybe human sex cells or gametes evolved to repair themselves because they are the only cells that transmit genes to offspring and need special protection, said Juan Carlos Izpisua Belmonte, a co-author and geneticist at the Salk Institute.

Out of 54 embryos, 36 emerged mutation-free, a significant improvement over natural circumstances in which about half would not have the mutation. Another 13 embryos also emerged without the mutation, but not in every cell.

The researchers tried to eliminate the problem by acting at an earlier stage, injecting the egg with the sperm and CRISPR-Cas9 simultaneously, instead of waiting to inject CRISPR-Cas9 into the already fertilized egg.

That resulted in 42 of 58 embryos, 72 percent, with two mutation-free copies of the gene in every cell. They also found no unwanted mutations in the embryos, which were destroyed after about three days.

The method was not perfect. The remaining 16 embryos had unwanted additions or deletions of DNA. Dr. Mitalipov said he believed fine-tuning the process would make at least 90 percent of embryos mutation-free.

And for disease-causing mutations on maternal genes, the same process should occur, with the fathers healthy genetic sequence being copied, he said.

But the technique will not work if both parents have two defective copies. Then, scientists would have to determine how to coax one gene to copy a synthetic DNA sequence, Dr. Mitalipov said.

Otherwise, he said, it should work with many diseases, a variety of different heritable mutations.

R. Alta Charo, a bioethicist at University of Wisconsin at Madison, who led the committee with Dr. Hynes, said the new discovery could also yield more information about causes of infertility and miscarriages.

She doubts a flood of couples will have edited children.

Nobodys going to do this for trivial reasons, Dr. Charo said. Sex is cheaper and its more fun than IVF, so unless youve got a real need, youre not going to use it.

A version of this article appears in print on August 3, 2017, on Page A1 of the New York edition with the headline: Scientists Repair A Risky Mutation In Human Embryo.

Original post:
In Breakthrough, Scientists Edit a Dangerous Mutation From Genes in Human Embryos - New York Times

A landmark study suggests that scientists could soon edit out genetic mutations to prevent babies being born with diseases. The technique could eventually let doctors remove inherited conditions from embryos before they go on to become a child.

That, in turn, opens the possibility for inherited diseases to be wiped out entirely, according to doctors. But experts have warned that urgent work is needed to answer the ethical and legal questions surrounding the work.

Though the scientists only edited out mutations that could cause diseases, it modified the nuclear DNA that sits right at the heart of the cell, which also influences personal characteristics such as intelligence, height, facial appearance and eye colour.

The breakthrough means that the possibility of germline genome editing has moved from future fantasy to the world of possibility, and the debate about its use, outside of fears about the safety of the technology, needs to run to catch up, said Professor Peter Braude from Kings College London. Scientists warned that soon the public could demand such treatment and that the world might not be ready.

Families with genetic diseases have a strong drive to find cures, said Yalda Jamshidi, reader in genomic medicine atSt Georges, University of London.Whilst we are just beginning to understand the complexity of genetic disease, gene-editing will likely become acceptable when its potential benefits, both to individuals and to the broader society, exceeds its risks.

The new research, published in Nature, marks the first time the powerful Crispr-Cas9 tool has been used to fix mutations. The US study destroyed the embryos after just a few days and the work remains at an experimental stage.

In the study, scientists fertilised donor eggs with sperm that included a gene that causes a type of heart failure. As the eggs were fertilised, they also applied the gene-editing tool, which works like a pair of specific scissors and cuts away the defective parts of the gene.

When those problematic parts are cut away, the cells can repair themselves with the healthy versions and so get rid of the mutation that causes the disease. Some 42 out of 58 embryos were fixed so that they didnt carry the mutation stopping a disease that usually has a 50 per cent chance of being passed on.

If those embryos had been allowed to develop into children, then they would no longer have carried the disease. That would stop them from being vulnerable to hypertrophic cardiomyopathy and would save their children, too.

Every generation on would carry this repair because weve removed the disease-causing gene variant from that familys lineage, said Dr Shoukhrat Mitalipov, from Oregon Health and Science University, who led the study.

By using this technique, its possible to reduce the burden of this inheritable disease on the family and eventually the human population.

The heart problem is just one of more than 10,000 conditions that are caused by an error in the gene. The same tool could be used to cut out those faults for all of those, and eventually could be used to target cancer mutations.

The work could lead to treatments that would be given to patients, once it becomes more efficient and safe. Using such a treatment on humans is illegal in both the US and the UK but some experts expect that law will soon be changed, and that the legal and ethical frameworks need to catch up with the technology.

There is some suggestion that the editing work could take place in the UK. Though using the research as treatment is illegal there as well as the US, the regulatory barriers are much higher in America and look unlikely to be changed.

In the US, there are various regulations and restrictions on how embryos can be edited, including stipulations that such work cant be carried out with taxpayers money. UK regulators are more relaxed and liberal about those restrictions, leading to suggestions that it could eventually become the home of such work in the west.

The UK has become the first country that allows mitochondrial replacement therapy, another treatment that opponents warn could allow for the creation of designer babies.

Individual cells days after injection (PA)

UK researchers can apply for a licence to edit human embryos in research, but offering it as a treatment is currently illegal, said a spokesperson for the Human Fertilisation and Embryology Authority (HEFA), which would regulate any such experiments.

Introducing new, controversial techniques is not just about developing the science gene editing would need to offer new options to couples at risk of having a child with a genetic disease, beyond current treatments like embryo testing.

Our experience of introducing mitochondrial donation in the UK shows that high-quality public discussion about the ethics of new treatments, expert scientific advice and a robust regulatory system are crucial when considering new treatments of this kind.

Doctors said that any change in the law would have to strictly keep such treatment to being used for medical reasons, and not for designer babies that have other characteristics edited out.

It may be that some countries never permit germline genome editing because of moral and ethical concerns, said Professor Joyce Harper from University College London. If the law in the UK was changed to allow genome editing, it would be highly regulated by the Human Fertilisation and Embryology Authority, as is PGD, to ensure it is only used for medical reasons.

But that work has already received significant opposition.

Dr David King, director of the Human Genetics Alert, which opposes all tampering with the human genome, said: If irresponsible scientists are not stopped, the world may soon be presented with a fait accompli of the first GM baby.

We call on governments and international organisations to wake up and pass an immediate global ban on creating cloned or GM babies, before it is too late.

Professor Robin Lovell-Badge from the Francis Crick Institute said the research only appears to work when the father is carrying the defective gene, and that it would not work for more sophisticated alterations. The possibility of producing designer babies, which is unjustified in any case, is now even further away, he said.

Read more here:
Human embryo editing breakthrough is a 'major advance' towards controversial treatments for babies - The Independent