The failure of the gene-edited babies experiment in China proves that we are not ready for gene-editing of human embryos

in the experiment editing human genes using the CRISPR system, but the experts say that there were many question marks, both ethical and scientific, and that it is not certain that they even succeeded in giving birth to girls immune to HIV 

By Dimitri Perrin, Senior Lecturer, Queensland University of Technology and Gatan Borgio, Geneticist and Group Leader, John Curtin School of Medical Research, Australian National University

More than a year ago, the world was stunned by Chinese biophysicist He Jiankui's attempt to use CRISPR technology to modify human embryos and make them resistant to HIV, leading to the birth of twins Lulu and Nana.

Now, crucial details have been revealed in a recent release of excerpts from the study, which have raised a series of concerns about how Lulu and Nana's genome was altered.

How CRISPR works

CRISPR is a technique that allows scientists to precisely edit any DNA by changing its sequence. When using CRISPR, a gene can be silenced by making it inactive, and specific changes can also be achieved, such as adding or removing a certain piece of DNA.

Gene editing using the CRISPR system relies on a connection between two molecules. One is a protein, called Cas9, which is responsible for "cutting" the DNA, the second molecule is a short RNA molecule (ribonucleic acid) that activates Cas9 to the state where it is supposed to cut.

The system also needs help from the compiled cells. DNA damage occurs frequently, so cells are required to repair DNA regularly. The repair mechanisms accompanying this are the ones that allow deleting and inserting changes when editing the genes.

How Lulu and Nana's genomes were modified

He Jiankui and his colleagues targeted the CCR5 gene, which allows the HIV virus to enter the white blood cells (lymphocytes) and infect the person.

One version of CCR5, known as CCR5 Δ32, is missing a particular string of 32 "letters" of the DNA code. This variant occurs naturally in the human population, and results in a high level of resistance to the most common type of HIV virus.

The team wanted to reproduce this mutation through activation CRISPR on human embryos, with the aim of making them resistant to HIV infection. But this did not happen as planned, and there are several ways that may cause failure.
First, although they claimed in the abstract of their unpublished paper that they were reproducing the human CCR5 mutation, in reality the team was trying to change CCR5 to the Δ32 mutation. As a result they created various mutations, the effects of which are unknown. Eventually, the twins' bodies may not have resistance toHIV And there may also be other consequences. Worryingly, they didn't check any of these things and went ahead with the embryos. This is not justified.

The mosaic effect

A second source of errors could have been that the editing was not completely efficient. This means that not necessarily all the cells in the embryos have indeed been edited. When an organism has a mixture of edited and unedited cells, this is called a "mosaic". Although the data is not available, it seems that Lulu and Nana are a mosaic. This makes it less likely that the babies whose genes have been edited will be resistant to HIV. The risk of mosaic should have been another reason not to implant the embryos. Furthermore, editing can have unintended effects elsewhere in the genome.

When designing a CRISPR experiment, the "guide" RNA should be chosen so that its sequence is unique to the gene you are targeting. However, "off-target" cuts can still occur elsewhere in the genome, at locations that have a similar sequence.
He Jiankui and his team tested cells from the edited embryos and reported only one off-target change. However, this test had to sample the cells that were no longer part of the embryos - that continued to develop. Therefore, the remaining cells in the embryos were not tested, and may have had off-target changes.

This is not the team's fault, as there will always be limitations in off-target and mosaic detection, and we can only get a partial image. However, that partial picture should have caused them to pause the experiment.

Bad idea to start with

We have described some Risks related to changes made to embryos, which can be passed on to future generations. Embryo editing is only morally justified in cases where the benefits clearly outweigh the risks. Aside from technical issues, the researchers did not even address unmet medical need.

While the father of the twins was HIV-positive and Amen was clean, there is already an established way to prevent an HIV-positive father from infecting fetuses. The staff members did also use the semen washing method. The only benefit of trying to change the genes, if proven, could have been a reduced risk of HIV infection in the twins later in life. But there are existing and safer ways to control the risk of infection, such as condoms and mandatory testing of blood donations.

Implications for gene editing as a scientific field

Gene editing has endless applications. For example, it is possible to produce in this way plants such as the Cavendish banana that are more resistant to destructive diseases. The use of garden editing can play an important role in the adaptation of plants to climate change. In the field of health, we are already seeing promising results with somatic cell editing (that is, changes that are not inherited in the patient's own cells): beta thalassemia and sickle cell anemia.

However, we are simply not ready for gene editing of human embryos. Our techniques are not mature enough and there are enough other methods, such as genetic testing before transplantation, that could provide an answer.

There is also still a lot of work to be done in the area of ​​regulation. There have been calls from individual scientists to ban embryo editing, including in expert panels from the World Health Organization to UNESCO. However, no consensus has emerged.
It is important that these discussions move to the second stage, where there is room for discussion and awareness of other stakeholders, such as patient groups and even the entire public.
For an article in The Conversation

More of the topic in Hayadan:

• Genetic engineering and animal-human hybrids: How China is leading a global divide in controversial research
• On the agenda - why fetuses should not be out of bounds
• Israeli researchers have developed a method that will enable the detection of thousands of genetic diseases in fetuses at the beginning of pregnancy through a blood test of the mother