In First, Scientists Edit Gene in Human Embryo, Reviving Debate Over 'Designer Babies'

Using genetic editing technique, team repairs mutated heart-disease gene in human embryos, but clinical trials, let alone 'cured' babies, will have to wait for lawmakers to come round

Embryologist Ric Ross places human embryos onto a petri dish at the La Jolla IVF Lab in La Jolla, California, U.S., on Tuesday, March 24, 2009. President Barack Obama earlier this month lifted restrictions on federal funding for embryonic stem-cell research and called on Congress to provide more money for such study to make the U.S. a leader in the field. Photographer: Sandy Huffaker/Bloomberg News
Embryologist Ric Ross places human embryos onto a petri dish at the La Jolla IVF Lab in La Jolla, California, U.S., on Tuesday, March 24, 2009. President Barack Obama earlier this month lifted restric SANDY HUFFAKER/Bloomberg

Human babies cannot technically be engineered yet and in many countries, "genetic editing" of embryos has been banned anyway. But the techniques are advancing faster than the legislation, and now scientists have shown they can fix a certain mutation in very early-stage human embryos using a low-cost, cutting-edge genetic editing technique.

Crucially, the team stressed in a phone press conference with reporters that it was not doing genetic editing or embryo engineering: it was fixing a mutation.

"The goal was to cure a disease caused by a genetic mutation using the CRISPR–Cas9 editing tool," explained team member Paula Amato of the Oregon Health and Science University Hospital.

Actually, curing babies remains many years down the line. But significant progress was achieved.

The team worked with a gene called MYBC3, that normally codes for a crucial heart protein. Mutation in this gene is one of most common causes of hereditary, and deadly, hypertrophic cardiomyopathy, which affects about 1 person in 500 and is especially prevalent in certain groups, such as in the center-east of France.

Cardiomyopathy can be treated. But the genetic cause cannot be addressed – at least, not now. In the future, in theory, one could create test-tube embryos, test them for harmful mutations and either pick ones without any, or if mutations are found, edit them out. Indeed, the whole idea of the team is to prevent the disease in the first place by ridding the baby of the mutation back in the test-tube.

Reversion to wild-type

For their experiment, they took one sperm donor with a mutation in a gene called MYBC3 and 12 non-mutant (normal, or wild-type) egg donors. They then created embryos that were heterozygous for the mutation.

DNA is double stranded. We all have two copies of each gene, one from out mother and one from our father, also called the "alleles" of a gene. Homozygous mutations are when both alleles, from father and mother, have the mutation. Heterozygous mutations are when one allele is mutated but the other is normal. (The normal type is called "wild type").

The embryos had one mutant MYBPC3 allele and one normal one.

CRISPR is a cutting-edge, low-cost method humans borrowed from bacteria (which use it to cut the DNA of viruses that attack them). It enables scientists to accurately cut DNA where they want to, for instance to remove existing genes or add new ones. In this case, it was used to target the mutated MYBC3 gene and cut the DNA there only, ignoring the normal gene.

Once DNA is damaged, the team figured, the cell's natural mechanisms would kick in and fix the damage using the wild-type gene as its template. The desired result is for both alleles to become wild-type. That seems to be what indeed happened in two-thirds (72%) of the embryos.

While the maternal allele served as the template, there is no reason to think the result would be different if the male allele had been wild-type, Shoukhrat Mitalipov of Oregon Health & Science University explained.

By the way, the CRISPR system was used when adding the sperm to the egg. Doing it that early apparently eliminated the problem of mosaicism, which is when different cells in the body have different DNA.  All the cells in the corrected embryos had two normal alleles.

This husky is an example of mosaicism
Karen Knowlton/AP

One day, too soon?

There is however controversy over whether editing people, especially using CRISPR, is a boon or a bone-headed idea.

The risk of this happening soon is real. Unlike every other gene editing technique invented so far, CRISPR is relatively simple and cheap to use, and with every other geneticist using it, some wonder whether stray, potentially risky genome edits are already running around. Some fret about edited super-organisms disrupting entire ecosystems. Just look at what ordinary invasive species do.

"Clinical trials" in the case of research into curing hereditary diseases using gene-editing techniques (the team's caveat that they're not editing anything duly noted) means allowing the repaired embryo to develop, implanting it, and allowing it to develop to term, after which it's supposed to grow up, go to university and so on. Under the present regulatory environment in the West, it’s unthinkable, the scientists explain.

Barriers to American research, for instance, include regulations constraining federal funds for embryo research, says the team: the NIH does not currently support it, and the Food and Drug Administration is prohibited from considering any clinical trials related to germline genetic modification. Brexit legislation would be a walk in the park compared with this.

There's also more science to do before even contemplating clinical trials.

"We would definitely want to replicate this study with other mutations and other donors," Amato clarifies.  Crucially, though, they first have to improve the technique they already invented, Mitalipov noted: they have done some groundwork, he said, but have achieve efficiency of 90 percent to 100 percent, and find out exactly how the embryos are repairing the mutations they cut.

They hope their method can be perfected and used to prevent a range (if not all) of diseases caused by heterozygous mutation, such as cystic fibrosis, or breast cancer caused by the BRCA genes. One day.

Moreover, though keen to pursue research in a more embracing regulatory environment, the team, with Sanjiv Kaul and Jin-Soo Kim, stresses the importance of regulation in this incredibly sensitive area of "editing" humans.

They actually don't like the word editing: they didn't edit anything or modify anything. What they did is modify an existing mutated gene, using technology to lead the cell to correct itself based on existing wild-type maternal genes. And having stressed that, again, they emphasize that as speculation about germline modification and "designer babies" swirls, lines have to be drawn, and they have to be drawn by the authorities. The agencies have to decide what we have to treat. Where to draw that line.Cardiomyopathy can be treated. But the genetic cause cannot be addressed – at least, not now. In the future, in theory, one could create test-tube embryos, test them for harmful mutations and either pick ones without any, or if mutations are found, edit them out. Indeed, the whole idea of the team is to prevent the disease in the first place by ridding the baby of the mutation back in the test-tube.

Reversion to wild-type

For their experiment, they took one sperm donor with a mutation in a gene called MYBC3 and 12 non-mutant (normal, or wild-type) egg donors. They then created embryos that were heterozygous for the mutation.

DNA is double stranded. We all have two copies of each gene, one from out mother and one from our father, also called the "alleles" of a gene. Homozygous mutations are when both alleles, from father and mother, have the mutation. Heterozygous mutations are when one allele is mutated but the other is normal. (The normal type is called "wild type").

The embryos had one mutant MYBPC3 allele and one normal one.

CRISPR is a cutting-edge, low-cost method humans borrowed from bacteria (which use it to cut the DNA of viruses that attack them). It enables scientists to accurately cut DNA where they want to, for instance to remove existing genes or add new ones. In this case, it was used to target the mutated MYBC3 gene and cut the DNA there only, ignoring the normal gene.

Once DNA is damaged, the team figured, the cell's natural mechanisms would kick in and fix the damage using the wild-type gene as its template. The desired result is for both alleles to become wild-type. That seems to be what indeed happened in two-thirds (72%) of the embryos.

While the maternal allele served as the template, there is no reason to think the result would be different if the male allele had been wild-type, Shoukhrat Mitalipov of Oregon Health & Science University explained.

By the way, the CRISPR system was used when adding the sperm to the egg. Doing it that early apparently eliminated the problem of mosaicism, which is when different cells in the body have different DNA.  All the cells in the corrected embryos had two normal alleles.

One day, too soon?

There is however controversy over whether editing people, especially using CRISPR, is a boon or a bone-headed idea.

The risk of this happening soon is real. Unlike every other gene editing technique invented so far, CRISPR is relatively simple and cheap to use, and with every other geneticist using it, some wonder whether stray, potentially risky genome edits are already running around. Some fret about edited super-organisms disrupting entire ecosystems. Just look at what ordinary invasive species do.

"Clinical trials" in the case of research into curing hereditary diseases using gene-editing techniques (the team's caveat that they're not editing anything duly noted) means allowing the repaired embryo to develop, implanting it, and allowing it to develop to term, after which it's supposed to grow up, go to university and so on. Under the present regulatory environment in the West, it’s unthinkable, the scientists explain.

Barriers to American research, for instance, include regulations constraining federal funds for embryo research, says the team: the NIH does not currently support it, and the Food and Drug Administration is prohibited from considering any clinical trials related to germline genetic modification. Brexit legislation would be a walk in the park compared with this.

There's also more science to do before even contemplating clinical trials.

"We would definitely want to replicate this study with other mutations and other donors," Amato clarifies.  Crucially, though, they first have to improve the technique they already invented, Mitalipov noted: they have done some groundwork, he said, but have achieve efficiency of 90 percent to 100 percent, and find out exactly how the embryos are repairing the mutations they cut.

They hope their method can be perfected and used to prevent a range (if not all) of diseases caused by heterozygous mutation, such as cystic fibrosis, or breast cancer caused by the BRCA genes. One day.

Moreover, though keen to pursue research in a more embracing regulatory environment, the team, with Sanjiv Kaul and Jin-Soo Kim, stresses the importance of regulation in this incredibly sensitive area of "editing" humans.

They actually don't like the word editing: they didn't edit anything or modify anything. What they did is modify an existing mutated gene, using technology to lead the cell to correct itself based on existing wild-type maternal genes. And having stressed that, again, they emphasize that as speculation about germline modification and "designer babies" swirls, lines have to be drawn, and they have to be drawn by the authorities. The agencies have to decide what we have to treat. Where to draw that line.