Genetic Engineering of Human Embryos- for discussion

Commentary by Ernst-Martin Füchtbauer

The new and accelerating technical development of the CRISPR/Cas9 system opens up for the possibility of targeted genetic modifications in germline competent human embryos. This is an avenue, which until very recently has been regarded as absolutely off limits. To cross the border between genetic modifications of somatic cells and germline cells was simply not conceivable, at least in most Western countries. Indeed, the border has not yet been crossed, but we are getting closer.

In two recent papers Chinese scientists used triploid human embryos as a ‘model’ to either treat ß-thalassemia [1] or to recapitulate a spontaneous mutation in the CCR5 gene [2], which results in resistance against HIV infections. Both targets are clearly chosen due to their potential for future therapeutic application.

Shortly after the first of the two papers was published, the Board of Directors of the ISTT posted a statement [3], which among other arguments contains the following sentence:

Uses of genetic engineering in human embryos should be limited to disease mitigation for those diseases where no other option is available; we reject the idea of “designer babies”.

This raises the question whether there are at all diseases where there are no other options (now or in the future). Hereditary diseases are rarely transmitted by homozygous parents, which makes preimplantation diagnostics (PID) an obvious safer and ethically far less disputed alternative. The example, ß-thalassemia reaches in very limited populations, like the Maldives, a frequency that puts about 1% of couples at risk to be double homozygous. But still, is not a CRISPR/Cas9 based hematopoietic stem cell therapy the obvious and much easier developed therapy?

However, the case of targeting CCR5 is fundamentally different. As no one can claim that being wild type for CCR5 is a disease, this is a clear designer approach. Given that we know relatively little about the function of CCR5, one might wonder how we can be sure that it is beneficial to mutate it in a world of ever changing microbial threats. It seems that developing a CCR5 blocking drug or somatic mutations of CCR5 in HIV patients is the obvious way forward.

It is my feeling that many colleagues, some of whom I greatly admire, are beginning to accept experiments with the obvious goal to modify the human germline ‘if it is the only cure for severe diseases’. However, I have not heard one convincing example of such disease that is not in principle “treatable” or “avoidable”. Finally we should keep in mind that the Hardy-Weinberg equation ridicules all eugenic attempts to clean the population from ‘disease’ alleles.

I am increasingly concerned because the discussion in our community has, within a few months, taken an almost purely technical turn about off target risks and efficiency. We neglect many decades of thorough philosophical and ethical literature on the issue. There is more at stake than the possible treatment of a few rare diseases.

These questions are too important to just wait and see. We as ISTT members are so close to the topic that we need to have an honest and open discussion about our opinions. This blog could be a starting point and I invite/encourage you to add to this discussion.

[1] Liang, P. et al. Protein Cell (2015)

[2] Kang, X. et al. J. Assist. Reprod. Genet. (2016)


TT2016 – President’s Synopsis

The opening night of TT2016 was momentous promising subsequent days filled with good friends and good science. We welcomed more than 700 delegates who attended, and then proceeded to hear a wonderful talk from Andras Nagy (2005 ISTT Prize winner). Andras’ talk was followed by a delicious buffet with wine, friends, colleagues and music. The opening proved to be an excellent portent of what was to come. Over the next three days, we heard many excellent talks—talks that encompassed the use of transgenic technologies, and especially CRISPR/Cas9 technology.

Charles Gersbach presents CRISPR/Cas9 modification of the dystrophin gene
Charles Gersbach presents CRISPR/Cas9 modification of the dystrophin gene

We heard about methods to ameliorate muscular dystrophy, to humanize large animals for xenotransplantation, to make swine resistant to an endemic disease, and to examine infertility in humans. We discussed technologies that would use epigenome to target the “regulome”, that would examine non-coding areas of the genome, that would recapitulate immune syndromes in ES cells, and that would allow us to assess phenotypic changes in embryonic lethal mutant mice using imaging. We learned both the history behind the CRISPR/Cas9 system, and newer CRISPR systems that are in development. We discussed ethics, gene drive, non-injection technologies, new injection technologies, and methods of generating many more oocytes in mice. There were seventeen abstracts chosen for full presentation, examining technological developments, large CRISPR/Cas9 initiatives, and transposon-mediated transgenesis. The remainder of the more than 125 abstract submssions were displayed throughout the meeting in the spacious poster room. Three were chosen as Poster Award winners, including Vera Jansen (Optogenetic tools to study cAMP signaling in cilia and flagella), Charles-Etienne Dumeau (Efficient method for the isolation of functional single cell from the ICM of mouse blastocyst), and Hiromi Miura (Generation of knockdown mice by CRISPR/Cas9-based targeted insertion of artificial miRNA sequence). On the last day, the ISTT Young Investigator Award (sponsored by inGenious Targeting Laboratory) was given to Pablo Ross based on his work developing ES cells in farm animals.

Charles River Representative, Iva Morse, and Jan Parker-Thornburg and Elizabeth Williams (ISTT, Inc.) present the Best Poster Awards to Vera Jansen (absent), Charlie
Iva Morse (Charles River), and Jan Parker-Thornburg and Elizabeth Williams (ISTT, Inc.) present the Best Poster Awards to Vera Jansen (absent), Charles-Etienne Dumeau, and Hiromi Miura (represented by Masato Ohtsuka).
Thomas Zeyda (inGenious Targeting Laboratory) and Jan Parker-Thornburg (ISTT President) present the Young Investigator Award to Dr. Pablo Ross, UC Davis.
Thomas Zeyda (inGenious Targeting Laboratory) and Jan Parker-Thornburg (ISTT President) present the Young Investigator Award to Dr. Pablo Ross, UC Davis.
TT2016 - Cryopreservation Workshop presentation by Lluis Montoliu.
TT2016 – Cryopreservation Workshop presentation by Lluis Montoliu.

The meeting was preceded by two workshops—one on programmable nucleases (headed by Radislav Sedlacek) and one on cryopreservation (led by Martin Fray, INFRAFRONTIER). Those who attended the workshops were very pleased with the learning opportunities that were afforded them. In addition, immediately following the meeting was one additional workshop on zebrafish transgenesis (Leads: Petr Bartunek, Zbynek Kozmik, Christian Mosimann and Graham Lieschke). All of the workshops were well-attended and greatly appreciated!

First Orbis pictus lecture given by Richard Behringer.
First Orbis pictus lecture given by Richard Behringer.

There were a number of new initiatives at TT2016. We had Orbis pictus lectures—lectures designed to use pictures and clear descriptions to demonstrate answers to a problem. Richard Behringer gave an excellent, encyclopedic presentation of methods of producing genetically modified animals in a vast variety of species. Later, Thomas Boehm described how lymphoid organs developed throughout evolution to the point where vertebrates now have a thymus. Also, for the first time, we had concurrent sessions. Delegates needed to choose whether to hear about ethics in animal use, or new injection and superovulation technologies. Overall, the scientific program was exceptional!

Departing Board members
Presentation of thank-you gifts to departing ISTT Board members – Wojtek Auerbach (absent), Boris Jerchow, and Tom Fielder.

The ISTT, Inc. held its third General Assembly just prior to the Gala Dinner. During that meeting, we sadly said goodbye to three departing Board members: Tom Fielder, Boris Jerchow and Wojtek Auerbach. We also reviewed ISTT finances, membership, committee activities, and interactions with our affiliated organizations. One new ISTT initiative that was presented was an outreach committee to our members (and non-members) who perform transgenic technologies in non-rodent (generally large-animal) species. The ISTT large animal group will be headed by Martina Crispo and Bruce Whitelaw. The meeting ended with a presentation inviting membership to attend TT2017 in Salt Lake City, Utah, USA, hosted by Susan Tamowski.

A wonderful time at the Zofin Palace.
A wonderful time at the Zofin Palace.

The social program prepared by our Czech colleagues was also amazing. Delegates enjoyed the opening buffet with traditional Czech music. However, it was the Gala Dinner that proved to be the high point of the social program. The Zofin Palace was full with partygoers. The wine flowed freely, the food was wonderful, and the string quartet (plus clarinet) fantastic as well. Overall, TT2016 can be considered as one of the best TT meetings ever, and I am proud, as ISTT President, that we helped to host such a wonderful meeting. Thanks so very much to the organizers—Radislav Sedlacek, Inken Beck and Nicole Chambers. Due to their amazing work, the ISTT has again had a successful TT meeting!