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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CRISPR embryo OK signals ongoing liberal UK trend on human modification

Kathy Niakan

Dr. Kathy Niakan, Francis Crick Institute Photo

With the approval today of the use of CRISPR in human embryos, the UK continues its recent trend toward a more permissive regulatory policy on human genetic modification. There are both risks and scientific benefits that come along with this trend.

Last year the UK approved an experimental technology with the goal of preventing the transmission of mitochondrial disease. The approach would try to prevent this terrible genetic disease but in the process would also create genetically modified babies. I lobbied the UK Parliament to not approve this technology (variously called 3-person IVF, mitochondrial transfer, and more controversially “3-parent babies”) at this time.

My view was that there wasn’t even close to enough data to support its safety and efficacy at present, but in the future we might know more that tells us it is wise to proceed. I still feel that way today and I’ve heard rumors that the UK scientists even now with the 3-person IVF approval are taking a relatively slow-go approach on its implementation. If correct, I think that’s wise of them. The 3-person IVF technology could do more harm than good. We just don’t know.

With a green light now for CRISPR’ing human embryos at the request of Kathy Niakan, a biologist at Francis Crick Institute, the UK continues its broader trend toward being more open to genetic modification on the human front. The stated goal of the UK CRISPR research on human embryos is not to make designer babies, but rather to advance our understanding of human development, which remains poorly understood:

“I promise you she has no intention of the embryos ever being put back into a woman for development,” Robin Lovell-Badge, group leader at the Crick Institute, told TIME. “That wouldn’t be the point. The point is to understand things about basic human biology.”

Dr. Lovell-Badge is right on this research potentially teaching us very important things about human biology and I can’t imagine that Dr. Niakan has any interest in designer baby research. I’m not worried about that and I’m excited about the research potential here.

It’s frustrating for us biologists that we still know more about the development of other animals (e.g. mice or fruit flies) than that of our own species. CRISPR could change that and I believe it could do it in a big way. So with the appropriate oversight, bioethics training, and transparency, I could support this CRISPR work in the UK. I need time to read up on what exactly they have planned. Also, see my ABCD plan on human germline modification.

However, at the same time we have to be clear that thing aren’t so simple in terms of keeping control of technologies and there are big risks here at a more global level. Collectively we are walking a fine line in this area. All it would take is someone going rogue by taking the same CRISPR’d embryos and implanting them in a surrogate for the field to find itself in a very dangerous situation.

The UK is heading in a more permissive direction on human modification. That may be appropriate to some extent and worth some risk, but how far should it go? What about the US, China, and other countries? We need more talk (meaning dialogue, debate, etc.) to go along with the increasing action (research) in this area.

UK Biologist Asks to Make GM Human Embryos For Research

Earlier this year, a research team in China crossed a scientific line for the first time in history by using gene editing technology called CRISPR-Cas9 to make genetically modified (GM) human embryos. Other researchers around the world including now one in the UK according to Reuters have expressed interest in creating GM human embryos too as a means to learn more about early human development.

Kathy Niakan

Dr. Kathy Niakan, Francis Crick Institute Photo

In many countries around the world the creation of human embryos for any research purpose is not permitted, but the use of embryos left over from IVF procedures is in some cases allowed. However, in the UK genetic modification of any human embryos (even such left over human embryos) is not currently permitted with the exception of three-person IVF (aka mitochondrial transfer) for the purpose of trying to prevent mitochondrial disease.

Now Dr. Kathy Niakan of the Francis Crick Institute has asked the UK government for permission to make and study the development of GM human embryos.

Although us biologists know a great deal about the development of many organisms including other mammals, surprisingly little is known directly about human embryonic development. That gap is a problem and a roadblock to prevention and treatment of human diseases, particularly developmental disorders. Dr. Niakan has done some impressive, very important research and her studies of gene edited human embryos could in theory prove equally valuable.

Gene editing to produce GM human embryos even solely for laboratory studies is nonetheless very controversial so from a societal perspective there are complexities here beyond the scientific challenges. An international gathering of scientists organized by the US National Academy of Sciences (NAS) will meet in Washington, D.C. on December 1-3. On the agenda is a healthy discussion of these issues with the goal being to come up with policy recommendations for how best to navigate the road ahead related to human genetic modification. One possible outcome is a consensus for a moratorium on clinical use of human gene editing technology. I favor that, but with specific allowance for some embryo editing research in the lab.

This NAS meeting was organized in an impressively short period of time made all the more important by the sense that there will be an increasing number of researchers such as Professor Niakan seeking to making gene edited human embryos for research purposes. It also seems probable that others may aim to go much further to relatively quickly try to deploy genetic modification technology in the clinic such as for reproductive purposes, which would be a big mistake.

For more on the request by Dr. Niakan and background, I recommend this excellent Science piece by Gretchen Vogel.