Saturday, December 1, 2018

Genetic modification of embryos. Regulations must be updated to reflect current realities

Last week the news broke that a Chinese scientist, He Jiankui, had edited the genome of an embryo that was carried through a normal pregnancy to birth. This is another first from China. Three years ago a Chinese scientist had reported the first use of the CRISPR technology to modify embryos that would and could not continue through a normal pregnancy. That experiment, although controversial, was well within accepted scientific practice. It nevertheless created a firestorm of responses in the Western media, painting China as a lawless country where “anything goes”. A very similar experiment was later carried out in the US, this time with much praise in many media reports.

Unlike the experiment three years ago the new research was not announced through the publication of a scientific paper, but through a YouTube video, released at the start of the Second International Summit on Human Genome Editing in Hong Kong, China. There Dr. He presented some of the details of what he had done and answered questions, but the full details and verification of the experiment are still not available. Dr. He himself claimed that the news of the experiment was leaked prematurely, and the plan apparently had been to publicize it after proper peer review and publication in a scientific journal. What is known is that Dr. He altered a gene responsible for resistance to HIV infection.

There was an immediate criticism of the experiment both from within China and from international experts. The Ministry of Health and the Ministry of Science and Technology in China announced that the experiment was illegal, that they would launch an investigation and that they would suspend his permission to do research. Although Dr. He was on leave from his regular job at his University, and did the experiments in a private capacity, they also distanced themselves from the research. A large group of Chinese scientists published open letters in the Lancet criticizing the experiment.

When evaluating what was done it is important to be clear about what the basis is for the criticism. There are those who condemn it because they believe that any modification of the human genome should be prohibited, or because no research on human embryos should ever be permitted. Given the advances in somatic gene therapy, and acceptance of IVF, relatively few people hold these opinions today. Then there are some who believe that any germline genetic modification should not be permitted. That also is increasingly a minority opinion. The first international summit on Human Genome Editing explicitly permitted some types of such research, as do countries such as the UK, China, the US and Sweden. In 2017 the Dutch Health Council recommended that the current legal restriction on creating embryos specifically for research purposes should be lifted. Finally, there are those who believe that any attempt to bring a genetically altered embryo to birth should be prohibited. Many countries have such prohibitions, including the UK and China. This position is also increasingly being rejected by influential bodies. The UK Nuffield Council has recommended that there should be a path towards clinical use of germline modification, and the consensus statement of the Second Summit in Hong Kong also affirmed that this could be permitted under the right circumstances.

The widespread criticism of Dr. He’s experiment is therefore not necessarily because he did anything that was in principle wrong, but that he had not followed proper procedures and that the technology is not mature enough at this time for a clinical trial. Procedural requirements would include proper review by research ethics review committees and regulatory authorities. The claim about the immaturity of the technology is based on expert views that not enough is known about germline modification in general and the function of the altered gene in particular to justify the experiment at this time. It is difficult to assess the strength of these arguments without access to all the details of the experiment.

The recent developments demonstrate that all countries need to consider how to regulate this new technology appropriately, but blanket prohibition of germline modification or embryo research is not the solution. Although one may reasonably hold that germline modifications of viable embryos is currently premature, it is going to be impossible to get consensus for a view that research that can reliably correct disease causing genes in embryos should remain prohibited. In fact, the consensus statement of the Second Summit rejected such a blanket moratorium or prohibition. Although they concluded that “the scientific understanding and technical requirements for clinical practice remain too uncertain and the risks too great to permit clinical trials of germline editing at this time”, they also urge “that it is time to define a rigorous, responsible translational pathway toward such trials.”
Specifically, this means that countries should move towards implementing national laws and regulations that will facilitate such a pathway. Unfortunately, very few countries seem prepared to do so.

Paradoxically, perhaps, even for the USA this may prove to be difficult. It is one of the few countries where there is no formal legal, nationwide, prohibition against germ line modification for clinical purposes, although in practice there is. This is partly because of limitations on what federal authorities can regulate and partly because of the political nature of the issues raised by these technologies. In the US there is a prohibition against federal funding of research on embryos. Such funding can, however, be done with private or state funding. FDA regulates clinical trials and has regulatory authority over somatic gene therapy, and would presumably also have regulatory authority over germline gene therapy. FDA, however, regulates market authorizations of the medicinal products, and can deny such authorization if the rules, including those that prohibit germline modification, have not been followed during research and development. Privately funded research where no such authorization is sought would fall outside the scope of FDA’s regulatory authority. This small opening is largely theoretical. More important is the fact that the strict rules governing federal funding and FDA regulations against germline modification, largely for political reasons, makes it difficult to implement more sensible rules in the US, that would allow some types of germ cell modifications to move forward towards clinical use, but prohibit others.

The other extreme are countries that have ratified the Oviedo Convention which is legally binding in many European countries, both within and outside of the EU. (Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine from 1997). The convention is legally binding in those countries that have signed and ratified it, and they include countries such as Denmark, France and the Czech Republic within the EU, and Norway and Turkey outside the EU. There are notable countries that have neither signed nor ratified the convention, such as Germany and the United Kingdom, and some countries that have signed, but not ratified the convention, such as the Netherlands and Sweden. There are two articles that taken together basically prohibit any research that modifies the human germline modification. Article 13 states that

An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants.

Article 18 prohibits the creation of human embryos for research purposes. Research can therefore only be done on leftover embryos from IVF, which makes most basic research difficult.  Germany, which has not ratified the Oviedo convention, has an even stricter national prohibition both against germ line modification and most research on embryos in general, in the Embryonenschutzgesetz from 1990 (Act for the protection of embryos). Paragraph 2 of this Act makes it a criminal offense to produce and manipulate embryos that will not be maintained through a normal pregnancy. Paragraph 5 prohibits any germline modification.

This leaves only a few countries where it may be possible to develop an appropriate regulatory framework. They include countries that already have an accepted legal framework for embryo research and germline modification, such as Sweden and the UK. Although both of these countries are in the EU, they have not ratified the Oviedo convention, and they allow certain types of embryo research that involves germ line modification. Although in both countries it is currently prohibited to do germline modification of viable embryos, their regulatory structure makes it possible to relatively easily develop appropriate regulations for a pathway towards clinical use of the new tecniques.

In the UK, genetic editing of germ cells is regulated by the Human Fertilisation and Embryology Act of 1990. It basically prohibits any actions that create or manipulate human embryos except those that are approved by a licensing authority, the Human Fertilisation and Embryology Authority (HFEA). This is the independent national regulator of any treatment or research that involves the use of human embryos. Some activities are expressly forbidden by the Act itself, others are permitted under certain conditions. For example, embryos whose genome has been altered cannot be used for treatment purposes. Research on human embryos can only be carried out during the first 14 days. Research on human embryos, including genetic modification, can only be done for certain purposes. This regulatory framework is both strong enough to effectively prohibit certain types of research or clinical use, at the same time that it is flexible enough to be changed to allow appropriate modifications when that is warranted by scientific developments.

China is in many ways in a similar situation to the UK. There is currently a ban on genetic modification of viable embryos in the 2003 Guidelines. This prohibition was appropriate in 2003, but such a blanket prohibition needs now to be modified and clarified. The other problem is the absence in this Guideline of any effective oversight mechanism for such research and any sanctions for violations. China has, however, other regulations that can be used if suitably modified. First, there is the 2003 regulations for Assisted Reproductive Technologies (ART), issued by the Ministry of Health These include oversight and licensing of ART clinics, and have been used to close such clinics that are not in compliance with the rules. These could be strengthened and modified to apply to gene editing of embryos, similar to what is done in the UK. Second, there is the 2016 Ethics Review Measures for Biomedical Research Involving Human Beings. These require review by an approved research ethics committee for all health research, which does include embryo modification. These rules should also be strengthened. For example, one could explicitly require that certain types of research, such as modification of the embryo genome, should be reviewed by the provincial level or national committee of ethics experts. There is already a mechanism for such review in these regulations. And one could introduce a licensing and sanction system where only certain institutions are allowed to carry out such research, and/or only some ethics review committees can review such research. Sanctions for violations are already present in the rules. In addition, one would have to include basic principles and procedures for the review of such proposals.

There is a certain urgency to this task. China is now one of the leading countries for frontline genetic research. Fortunately, in China, there is available both a regulatory infrastructure and a vibrant community of scholars willing to have an open debate about these issues, which this latest case has demonstrated.