Interview with Fredrik Lanner who is CRISPR’ing healthy human embryos

In the past year there has been a great deal of attention given to the potential use of CRISPR-Cas9 for gene editing in human embryos. An important recent development, described in a new NPR article by Rob Stein, is the use of CRISPR-Cas9 in healthy human embryos for developmental biology research by assistant professor Fredrik Lanner of The Karolinska Institute. Dr. Lanner, who invited Stein into his lab to observe the work, kindly agreed to do a Q&A interview with me (below) on his team’s use of CRISPR-Cas9 gene editing for research in healthy human embryos.
ssistant Professor Fredrik Lanner

Assistant Professor Fredrik Lanner. Picture by Rob Stein

PK: What got you interested in doing gene editing in healthy human embryos?

FL: I studied mouse preimplantation development during my postdoc in Janet Rossant’s lab and one of the discoveries we made was the importance of fgf-erk signaling in EPI-PE segregation (Yamanaka, Lanner and Rossant Development 2010). A couple of years later two papers showed that the same mechanism is not controlling the same segregation in human embryos. Since then it has become widely appreciated that the mouse probably is not such a great model system for the human and we really need to start studying human embryos to understand human preimplantation development. I therefore moved back to Sweden, Karolinska Institutet to start my own lab with that specific focus. As a first start we have built a transcriptional single cell roadmap of how the first cell types emerge during the first week of human development (Petropoulos et al Cell 2016). We now want to move from descriptive to functional studies. For this we are of course using pharmacological inhibitors for various signaling pathways but to be able to elucidate which transcription factors are important for how the first cell types are established and how pluripotency is controlled we need other approaches. CRISPR is therefore an obvious next step to evaluate.

PK: Did you have to get some kind of official approvals from your own Karolinska Institute? Did you also need some kind of approval from the Swedish government?

FL: We applied for and got ethical permits from the Swedish regional ethics board (EPN.SE) last spring, 2015. We have also lifted these experiments in KI’s internal ethics board, to inform the KI leadership of our plans and to make sure we had their support.

The Swedish law is clear that genome editing is only allowed within the first 14 day as long as the embryo is not transferred back for a continued pregnancy. This means that heritable genome editing for clinical purposes would not be allowed in Sweden. The clear legislation has been key in us moving ahead with these plans.

PK: What is the source of funding for this work?

FL: Towards the functional gene studies I have internal funding from KI and external funding from the Knut and Alice Wallenberg foundation and through Lau fellowship. For our embryo research I also have funding from the Swedish Research Council, Ragnar Söderberg fellowship and the Swedish Strategic Research Foundation.

PK: Did you receive any kind of bioethics training related to CRISPR’ing human embryos or discuss it with a bioethicist before beginning?

FL:  We have discussed it within the KI ethics council consisting of people with legal, ethics and research expertise. I have further presented and discussed at the symposium organized by National Academies of Sciences in Paris http://www.nationalacademies.org/gene-editing, and a Scandinavian meeting organized by The Norwegian Biotechnology Advisory Board. Early October I will discuss this further with The Swedish Gene Technology Advisory Board. We have followed these discussions closely during the last two years.

PK: I realize you declined to say to Rob Stein what gene(s) you are targeting, but can you name them now? My own view is that with gene editing of human embryos that transparency is needed combined with a strong base rationale, which together make for good reasons to be open publicly about the genes being targeted. If you can’t say the genes is it because you’re concerned about competition from other researchers?

FL:  We are targeting genes that we think will be involved in lineage specification and establishing pluripotency. We want to be open but I’m still not ready to disclose exactly which genes we will focus on.

PK: Are you aware of other teams in your own or other countries doing gene editing in healthy human embryos? I’m trying to get a sense of how much of this kind of work is ongoing around the world.

FL:  No I only know of Kathy Niakans’ plans to look at similar questions.

PK: Is one of your ultimate goals to aid in fertility treatments? Would this involve in the future germline gene editing of human embryos then used to make people if all went well? Or would it rather be based on the knowledge you gain, but applied in a non-gene editing approach during reproduction? How are you seeing this play out in the future?

FL:  We are trying to generate fundamental knowledge and we don’t have any ambition to move in that direction. I’m actually pretty skeptical that the technology will be used for genome editing in the early embryo anytime soon. My questions concerns efficiency, safety and competitiveness compared to preimplantation genetic diagnosis. Targeting somatic cells is already leading the development of this technology.

PK: What is the source of the human embryos being used in your research?

FL:  The embryos are from infertility treatments where the couples mostly have gotten their children. In Sweden you can only store the embryos frozen up to 5 years after which they will be destroyed. At that point they can instead donate the embryos to research. These embryos are frozen at embryonic day 2 at which time the embryo consists of 4 cells.

PK: How did you decide to invite a journalist into you lab to observe the work?

FL:  Since NPR has a good reputation I did not hesitate to let Rob Stein come and visit if he could come the date we were planning to perform the experiment and as long as it did not impact on the practical work.  However, it is clear that we can not have reporters in the lab while we perform experiments on a regular basis.

PK: Anything else you feel is important to know?

FL: I would like to emphasize that we have not rushed into this but spent extensive time evaluating targeting strategy in human ES cells. We got the ethical permit during the spring of 2015 after which we have followed and participated in national and international discussions surrounding this technology over a year. This discussion has led to several organizations recommending that the fundamental research in cultured embryos is acceptable and important whereas the clinical translation of the technology with intention to generate a person is not. This in accordance to our Swedish legislation and has encouraged us to initiate these studies to evaluate the feasibility to study gene function in early human embryos using CRISPR-Cas9. I would also like to emphasize that I strongly think these experiments should be performed in genetically normal embryos if we are to learn anything about normal human preimplantation development.

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Where are all the new CRISPR human embryo papers?

Last year I heard from several sources that there somewhere between 3-5 unpublished manuscripts reporting the use of CRISPR gene targeting in human embryos being shopped around at various journals in addition to the one that had been published. Since that time we’ve seen a grand total of one additional paper reporting on CRISPR of human embryos.

So what gives?

Were the sources wrong?

I don’t think so and I believe there are additional labs pursuing research on the use of CRISPR in human embryos.

Depending on the context, the oversight, and the training of those involved, there may be nothing wrong with these studies at all. In fact, they could be positive and teach us a lot if the teams are careful. However, CRISPR’ing human embryos without a good rationale and appropriate oversight is unwise. I also cannot imagine supporting use of CRISPR with the intent to make a modified new human being for many years to come if ever. You can learn more about the history of genetic modification and my views as well as those of CRISPR leaders in my new book, GMO Sapiens.

So where are all the CRISPR human embryo papers? I can think of a few main reasons why we haven’t seen more so far.

embryo human

Wikimedia Photo

Editors as gatekeepers? One possible reason we haven’t seen more CRISPR’d human embryo papers is that journal editors are reluctant to publish them and are acting as essentially gatekeepers for this kind of work. If true, what are the potential risks or benefits of such a de facto filtering system and what is the basis by which the editors are making such decisions?

Outcomes of first 2 pubs discouraged more? Another possibility is that other research teams have been discouraged by the first two papers reporting CRISPR use in human embryos. I can see at least two levels at which those considering working and publishing in this area might be reluctant to proceed because of the first two papers. On the one hand, both papers reported technical challenges with this research, which was discouraging. On the other hand, both papers were heavily criticized by some.

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