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.