In Depth Report from April 29th Paris Human Gene Edit Meeting

Editor’s note. Caroline Simons attended both the April 28th (see her report on that here) and 29th Paris meetings on human gene editing/genetic modification. Today, we have her in depth report on the April 29th meeting. I have posted her piece in full with only minor edits. If you are in a rush you can skip to the last page for Caroline’s top 10 takeaways from the meeting.

By Caroline Simons

The meeting of NAS and NAM which took place in Paris on 29 April was webcast live. A recording of the presentations will be posted in the coming weeks. This blog post is my record of the presentations and an attempt to give an overall impression of the discussions.

Paris Gene Editing Meeting

Credit, Caroline Simons

This meeting is one of a series which has been organized by the Committee to assist in its examination of the ‘scientific underpinnings as well as the clinical, ethical, legal and social implications of the use of human genome editing technologies in biomedical research and medicine.’ The Committee is examining both somatic and germline genome editing. It focuses on 7 areas in particular. These relate to the current state of the science, future directions and challenges, potential clinical applications, alternative approaches, and the efficacy and risks of gene editing in humans. The Committee asks if explicit scientific standards should be established to quantify off-target genome alterations, if current ethical and legal standards for human subjects research adequately address human gene editing technologies and what are the ethical, legal and social implications of the use of these technologies in humans. The Committee seeks to identify what principles or frameworks might provide appropriate oversight for these technologies and to assess the prospect of international harmonization of policies.

The Committee will prepare a report and make recommendations later this year. This report will ‘include a focus on advice for the United States’, and will ‘provide a framework based on fundamental, underlying principles that may be adapted and adopted by any nation’.

This 3rd Consensus Study Meeting was a larger gathering than the meeting of FEAM, the UK Academy of Medical Sciences and the Académie Nationale de Médecine France which was held the previous day. Attendees included European Commission representation, prominent scientists, philosophers, ethicists and lawyers from Europe, the US, Canada, China, Singapore and Malaysia. Three panels of speakers addressed the principles underlying governance, international governance perspectives and potential applications for germline editing. The meeting wrapped up with a moderated discussion among all of the attendees.

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Meeting summary of Paris human gene editing workshop

Editors note: This is a guest post from Caroline Simons who is attending the two Paris meetings on human gene editing. For more background on those meetings see here.

By Caroline Simons

There were just over a hundred participants at the workshop organized by the Federation of European Academies of Medicine, the UK Academy of Medical Sciences and the Académie Nationale de Médicine France. That number included experts in the fields of science, medicine, law and bioethics. They came from Europe, the US and China (and, I think I may have heard, one French politician).Caroline Simons

Some were engaged in active research, others represented national academies, policy making bodies, patients, research funders and industry. I noted one participant from the US represented DARPA, a reminder that gene-editing technologies may have harmful as well as therapeutic applications. There were about a dozen journalists, of whom two may cover this event in English – Anna McKie of Research Fortnight and Oliver Moody of The Times.

Académie Nationale de Médicine

Académie Nationale de Médicine, Credit Caroline Simons

The aim of the workshop was to consider current scientific activities in the European Union (EU) regarding genome editing and the regulatory landscape across the EU member states for this research and its clinical application in humans. The stated intention was to foster discussion between experts, provide information to the public and stakeholders and to consider whether an EU regulatory framework to govern the safe and acceptable use of human genome editing is desirable, and how it could be achieved. There were no agreed conclusions or recommendations from this workshop, but many interesting presentations and observations. A paper which will draw on the workshop discussions is to be published.

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Scoop on this week’s Paris human gene editing/genetic modification meetings

This week there will be two meetings in Paris as part of the ongoing international dialogue on human genetic modification/human gene editing, CRISPR, and figuring out a wise path forward.

Paris CRISPR Meeting

A one-day workshop will be held on April 28th “jointly organised by the Federation of European Academies of Medicine (FEAM), the UK Academy of Medical Sciences and the French Academy of Medicine; with kind support from the InterAcademy Partnership for Health and the French Academy Foundation. It will be held at the French Academy of Medicine in Paris.”

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New Paper on CRISPR of Human Embryos Highlights Serious Tech Problems

A new paper was recently published on CRISPR of human embryos for genetic modification. I’ve got to read this publication more carefully, but here’s a quick initial take on this human CRISPR 2.0 study.

The paper is Kang, et al. and is entitled “Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas-mediated genome editing”. This is only the second paper reporting genetic modification of human embryos. The first paper, also from China, created quite a stir last year and reported a lot of technical problems with the genetic modification of the human embryos.

Human embryo CRISPR

Part of Figure 1 from Kang, et al.

This new paper comes from a team led by Yong Fan from Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. The researchers focused on using CRISPR to try to create a specific form of the CCR5 gene allele called CCR5Δ32 that reduces human susceptibility to HIV. As in the first human embryo CRISPR paper, these scientists also used so-called 3PN human embryos that are generally believed to be non-viable. The point of the use of 3PN embryos is to reduce ethical concerns.

How did the CRISPR’ing of human embryos turn out this time?

In rare cases the team were able to create the CCR5Δ32 mutation within the human embryos (5-15%) and they did not observe in a limited screen any so-called off-target effects (i.e. CRISPR making edits in other genomic spots such as other genes where it might go). These are positive outcomes from the study. At the same time, however, they ran into trouble with another serious issue and that is that their approach more often than not led to the creation of other CCR5 mutations besides CCR5Δ32.

These other mutations called Indels were observed 36-63% of the time and could lead to complete inactivation of CCR5 or production of abnormal forms of the protein. CRISPR can lead to Indels instead of precise point mutations due to cells utilizing a specific type of DNA repair in response to cutting by Cas9 called non-homologous end joining.

In order for an attempt to make human embryos that bear CCR5Δ32 to be successful even in an in vitro experiment with no intent to produce a genetically modified person, you could not have the embryos have CCR5 Indels. It is also important to point out that the authors did not do whole genome sequencing to look for off-target effects, but only looked at a couple dozen or so predicted off-target sites. Furthermore, a successful production of CCR5Δ32 human embryos would need to have both CCR5 alleles get changed to have the CCR5Δ32 mutation. The authors did not find such homozygous CCR5Δ32 embryos had been created in their studies. Another problematic issue was that they observed evidence of mosaicism in these embryos as well.

Thinking about this in the big picture and longer term, the idea to change the CCR5 allele to make humans resist HIV infection would most likely invoke creation of a genetically modified person, but I suppose could also involve modifying blood cells ex vivo for subsequent infusion in more of a gene therapy approach.

Overall my quick first take on this paper is that more than anything it shows the many problems with hoping for success with this kind of research. The paper does not in my opinion strengthen the case that CRISPR’ing of human embryos with reproductive intent is ever something that could work well enough to be done clinically.

The authors seem to realize that and they write, “We believe that any attempt to generate genetically modified humans through the modification of early embryos needs to be strictly prohibited until we can resolve both ethical and scientific issues.”

The key word there seems to be “until”, which seems to leave the door open at least a crack.

I expect we will see many more papers like this one and frankly I’m not quite sure how I feel about that.

For my take on human genetic modification using CRISPR more broadly including the targeting of CCR5, check out my new book, GMO Sapiens.

You can’t retract a designer baby: #CRISPR, social justice, & risks

CRISPR baby retraction

You couldn’t just retract a genetically modified designer baby should something go wrong. Retraction stamp part of image from Medscape

There’s a questionable notion floating around out there in the numerous discussions over heritable human genetic modification.

This idea goes that if germline human gene editing goes awry for any number of reasons, scientists could simply reverse it by applying genetics again.

The reversal notion does not fit with the reality of science as we know them today and could be harmful in giving false reassurance of the safety of genome modification.

To put it another way, you can’t retract a designer baby or its genetic modifications if they are later proven to be problematic.

If human modification were done in the germline (sperm and eggs or in a 1-cell embryo), then for better or worse every one, barring chimerism, of the trillions of cells of the resulting genetically modified (GM) baby would have that genetic modification. How would you effectively reverse an unexpectedly deleterious hard-wired change in all of those cells? The reality is that it would be impossible. Trying to do so would also raise the very real possibility of introducing yet more problems as well.

If the reversibility notion of human genetic modification is meant instead in a broader population sense such that within the larger human population that accidentally harmful genetic changes could be reversed or at least their transmission stopped, what would that entail? Forcing people who carry such unexpectedly “bad” genetic changes not to reproduce? We need to consider social justice issues.

Or is reversibility only implied in the context of gene drive-based genetic modification introduced into organisms in a natural ecosystem rather than humans? Even there I’m doubtful reversal attempts would work and others are also skeptical.

Overall, scientists and others should use greater caution in discussing the notion of reversibility of genetic modification. It would not be as simple as portrayed sometimes. Other notions such as genetic “off switches” for modifications in organisms (while elegant systems in the laboratory setting) could also prove in the real world to be impractical amongst heterogeneous cells in an organism within a population of organisms.

This doesn’t mean that people should stop working on or thinking about reversal strategies or conditional approaches to genetic modification. Quite the opposite as that work is important and should continue, but the notion that one could “simply” reverse an introduced genetic problem is misleading and downplays legitimate concerns over safety. It also potentially exaggerates human control of genetics in the real world.

As some of you readers know, I’ve written a new book on human genetic modification including on possible use of CRISPR in people. In the book I discuss the potential upsides and risks of CRISPR’ing people. The book is called GMO Sapiens. In it I discuss something called “reproductive quarantine” where humans with unexpectedly negative genetic outcomes from modification attempts are prevented by governments from reproducing.

While CRISPR’ing people would be an experiment, if something goes wrong with it then unlike a bad experimental outcome in a test tube or in a dish, or even a profoundly flawed paper that can be retracted, I don’t see how you undo the harm at the very least to individuals.

More broadly this raises the point that in these kinds of hypothetical human genetic experiments, the person becomes the experiment, necessitating a higher level of discussion that includes bioethical and social justice considerations.