Modification of Germlines

An intervention in life itself?

December 06, 2019

When the genetic material of egg cells, sperm, their precursor cells or early-stage embryos is altered with the help of the tools of genetic engineering, scientists speak of germline interventions. According to a committee of experts, the German Ethics Council [https://www.ethikrat.org/filea...], germline interventions could be used in the future to 1) prevent hereditary diseases, 2) reduce the risk of disease or 3) improve the characteristics or abilities of future generations (enhancement).

Germline therapy to enable hearing?

A child that can hear – that’s one Russian couple’s biggest wish, as described in an article about them in the Science Magazine. Conceiving a healthy baby naturally is, however, not possible for the deaf woman and the half-deaf man. The only option that would enable a child of theirs to hear would be a so-called cochlear implant – an electronic hearing prosthesis. Because both the man and the woman have genetic anomalies in the genome of a gene called GJB2, they would pass on hearing problems to their offspring. Even with the help of preimplantation diagnostics, there is no way for them to conceive a child without the mutation. Russian scientist Denis Rebrikov, a researcher at the Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology in Moscow, is planning to help the couple with a germline therapy. Rebrikov would be only the second scientist – after the controversial Chinese scientist He Jiankui – to actively set out to create genetically modified babies. Here you can read more about how difficult it is for those affected to make a decision either in favour of or against the experiment: [https://www.sciencemag.org/new...].

1.) Germline interventions to prevent hereditary diseases

At the heart of research in this field lie the so-called monogenic diseases: these inherited diseases are caused by the failure or malfunction of a single gene. This is the case, for example, with cystic fibrosis, sickle cell anaemia or hereditary hearing impairment. By correcting this mutation, these diseases could certainly – or at least with high probability – be prevented. Such interventions could be particularly relevant in cases where both parents can only inherit defective gene copies and where the inheritance process is “autosomal recessive” – that is, where the disease will break out in the child if it inherits two mutated gene copies, one from the mother and one from the father. A current case in which such a germline intervention is discussed can incidentally be found in the info box.

2.) Germline interventions to reduce the risk of diseases

In the future, germline interventions could also be used for so-called multifactorial diseases, that is, diseases that are influenced by the effects of multiple genes together with, for example, environmental factors. Examples of multifactorial diseases are diabetes and cardiovascular diseases. Their complexity makes a possible germline intervention highly challenging. This kind of approach has not yet worked in humans.

3.) Germline interventions to optimise the human being

Smarter, sharper, nicer? Genetic interventions directed towards improving the physical, mental or character traits of a healthy person are called genetic enhancement. So far, however, little is known about the interaction of the genes responsible for such complex properties.

Immunity to HIV?

All three variants of germline intervention are permanent and may be inherited by future generations. Such interventions are risky – with consequences that are as yet unknown. And they entail any number of legal and ethical questions. Scientists, policy-makers and engaged citizens are therefore discussing whether researchers should be allowed to modify the human germline. In Germany, to date, this has been prohibited. In China, however, the genetic material of babies has already been altered. In 2018, the Chinese twins Lulu and Nana were born. Disregarding all scientific and legal standards, He Jiankui from the South University of Science and Technology in Shenzhen altered the genetic material of the babies with the CRISPR/Cas9 gene scissors.

The scientist claims to have performed the intervention to prevent the children from contracting HIV in the future. However, no evidence has been provided to substantiate this. According to the German Ethics Council, the question of whether this intervention should be categorised as enhancement or medical prevention is contentious. The scientist intervened in the twins’ germlines by removing a gene. With the help of this gene, the body normally produces a certain type of molecule (a so-called receptor), through which HIV attacks cells in the human body. A mutation of this gene causes some people to be protected against the virus. The germline intervention performed was also aimed at reducing the risk to Lulu and Nana’s offspring of contracting HIV. However, there is no such thing as 100 percent certainty. And it is by no means clear whether the deactivation of the gene might lead to negative consequences for the children. A study by the University of Berkeley, for example, has shown that people in whom a comparable gene mutation occurs naturally die earlier. [1]

What some researchers around the world are demanding

Should germline interventions be prohibited? Many legal and ethical aspects play a role when considering germline interventions. And the opportunities and risks of the interventions need to be explained and weighed up. In early 2019, a group of geneticists from seven countries called for a worldwide moratorium – that is, a legally authorised suspension – on germline interventions. They demanded that international rules need first to be established, and scientific, medical and ethical questions discussed, before germline modifications can be permitted worldwide. The group regards it as a prerequisite, however, that the general public be informed in advance before researchers are allowed to plan germline interventions. Additionally, the latter would have to be justified – and in the country affected there would have to be a societal consensus with regard to germline interventions. [2]

Among other issues, it remains an open question as to how such a consensus is to be established and measured. Other scientists believe that such moratoria are not effective. One of the sceptics, Jennifer Doudna, discoverer of the CRISPR/Cas9 gene scissors, told the Science Magazine [https://science.sciencemag.org...]: “I believe that moratoria no longer have the potential to function as countermeasures; instead, interest groups should advocate in favour of a well-thought-out regulation of this technology, without suppressing it.” In July 2019, the World Health Organization (WHO) published a declaration calling on the regulatory authorities of all countries to ban any and all clinical experiments involving human germline interventions. For the future, the WHO envisions an international register for this type of research, in which all studies would be recorded.

Not sacrosanct

The German Ethics Council has also called for a legal suspension. Although it doesn’t consider the human germline to be sacrosanct, it deems such interventions to be ethically irresponsible because of the risks they involve. [3] However, the potential that is offered by molecular biology when it comes to specifically modifying the genome of living beings has developed rapidly. Therefore, the likelihood of interventions in the human germline is constantly increasing. This raises the question whether the previous “categorical rejection” of germline modifications can be maintained. The Ethics Council recommends that the safety and effectiveness of such germline interventions be proven before they are carried out. The committee also proposes an international institution that can develop standards for germline interventions in humans, engage with the medical and societal conclusions in this field, and monitor further developments. Moreover, Germany’s Federal Government and parliament, the Bundestag, should work towards achieving an agreement that is binding at an international level. [4] [5]

Sources and bibliography

[1] https://www.nature.com/article...

[2] https://www.nature.com/article...

[3] https://www.ethikrat.org/mitte...

[4] https://www.ethikrat.org/filea...

[5] https://www.aerztezeitung.de/p...