Germline Editing: Made in Germany?
Note: This article was originally published in February 2024 in issue 268 of the German-language journal Der Gen-ethische Informationsdienst (GID). It is also part of an English-language dossier on Heritable Human Genome Editing published at the same time. Minor edits have been made.
Calls for German embryo research
Pressure on the German Embryo Protection Act is growing. The scientific community is launching a renewed attack on the controversial law and demands access to embryos for so-called high-ranking research objectives. "Germline therapies" are among the boastful promises of the proponents.
The German Embryo Protection Act (ESchG) prohibits not only controversial reproductive technologies such as oocyte transfer and surrogacy, but also research on human embryos. It became effective in 1991 as a criminal law passed on the grounds of “pro-life” arguments. The legislators referred to Article 2 Para. 2 Sentence 1 of German Basic Law: "Everyone has the right to life and physical integrity." Human life must "not be made an object for the benefit of others" and this must "also apply to human life at the stage of its earliest embryonic development."
Since its adoption, the ESchG has attracted the displeasure of some German scientists who disagree with its moral-theological justification and seemingly irrational unequal treatment of embryos before the law. After all, although abortion is prohibited, it can - unlike embryo research - be carried out by those involved under certain circumstances with impunity. And as researchers have not tired of pointing out for more than three decades, embryos produced by in vitro fertilization (IVF), which is now carried out tens of thousands of times a year, are regularly discarded if they are not used, effectively "killed."
Around the turn of the millennium, the pressure on legislators grew due to the international stem cell hype. In 1997, the cloned sheep Dolly was born and research promised the development of therapies for all kinds of diseases from embryonic stem cells. Scientists imagined a gloomy scenario in which Germany would not be able to keep up with the international research competition and German patients would be left empty-handed if research could not use embryos. As a compromise, the Stem Cell Act was passed in 2002, allowing the import of embryonic stem cells that were produced abroad before a certain date in the past (currently May 1, 2007). This may only happen if a research question can only be resolved using embryonic cells and if it serves "high-ranking research objectives" - which the responsible authorities decide on the basis of an individual assessment by the Central Ethics Committee for Stem Cell Research set up for this purpose.
A new attempt
Making use of the current public and political debate on the legalization of some reproductive technologies, proponents have engaged in a renewed push for embryo research in Germany. In October last year, the Federal Ministry of Education and Research (BMBF), currently led by the German Free Democratic Party (FDP) organized an ELSA (Ethical, Legal, Social Aspects) conference entitled Human embryos in medical research: Taboo? - Justifiable? - Opportunity? The introductory speech by Federal Minister of Education and Research Bettina Stark-Watzinger emphasized the latter: "We should seize opportunities that we can seize." She promised that stem cell research would make it possible to understand and cure diseases.
The statements from the scientific community were clear, she said, and it was an issue of freedom of research. If we limit it, we would have to justify it well. However, her announcement that "we will not sweep risks under the carpet, no argument should go unheard" was barely fulfilled. With few exceptions, the invited speakers were all in support of embryo research. These included members of the German science lobby organization Academy of Sciences Leopoldina, which has long advocated for the legalization of embryo research, as it would "help to better identify and treat infertility, improve the survival and healthy development of embryos and fetuses during pregnancy and prevent miscarriages and premature births." At the BMBF conference, the speakers repeatedly mentioned the statistic that approximately 30 percent of natural pregnancies end in premature miscarriage and referred to the unexplained failure of IVF in many cases, suggesting that these could be prevented through research. The finding that many early miscarriages are caused by lethal chromosomal aberrations in the embryo was not mentioned, but makes the fulfillment of this promise questionable.
Surplus embryos and old promises
Physician and Leopoldina member Claudia Wiesemann cited the development of elective single embryo transfer (eSET) as an example of the successful improvement of reproductive medicine through embryo research. In this method, a larger number of egg cells are fertilized and the embryo with the highest chance of development is transferred. The selection criteria are morphological characteristics. In Germany, this method is prohibited; the ESchG makes it illegal to fertilize more eggs from one person within an IVF cycle than planned embryo transfers. The medical advantage: eSET can reduce the rate of multiple pregnancies, which are dangerous for pregnant people and developing children. The method also has a beneficial side effect for research, as many surplus embryos are produced which would then be available for experiments. As Leopoldina President Gerald H. Haug reported at the BMBF conference, the government has planned to legalize eSET, meaning that more embryos than are needed for IVF would soon be intentionally produced, which could then be used for research. Law expert and Leopoldina member Jochen Taupitz also referred to the fact that currently around 50,000 surplus frozen embryos exist, a number that would increase when using eSET.
Proponents also keep the several decade old promise of a therapeutic use of human embryonic stem cells (hES) alive. Due to their ability to mature into all possible tissue types, hES would hold "great potential for regenerative and personalized medicine," writes Leopoldina on its website. What remains unmentioned is that this potential has not yet been realized, although a great deal of money has been invested in this field of research in other countries such as the USA in recent decades. Many clinical studies have been carried out, but no treatment has yet been successful enough to be established as a routine therapy. At the BMBF conference, stem cell researcher Fredrik Lanner from the Swedish Karolinska Institute was only able to present his research group's plans for future clinical trials using hES-based therapies for age-related macular degeneration.
Genome editing as a new opportunity
Proponents of embryo research are now putting forward a new argument, claiming a need to further develop new genome editing technologies such as CRISPR-Cas for reproductive applications. In 2017, Leopoldina members published a discussion paper in which they spoke out in favor of a general acceptance of "germline therapy." Although the content of the paper is only intended to reflect the opinion of the authors and not Leopoldina, the editor is then Leopoldina president Jörg Hacker. According to the authors, the new technology enables "interventions of such unprecedented precision and efficiency that a reappraisal of the situation is required." Why germline interventions are ethically justifiable was not even discussed. Co-author Jochen Taupitz even argued in a talk at an event organized by the German Ethics Council in 2016 that from an ethical and moral point of view there is a requirement to approve the technology in order to prevent serious diseases and disabilities. According to the discussion paper, the only decisive factor is technical safety: an "acceptably low risk" of a germline intervention "in comparison to the hereditary disease it seeks to prevent" must be achieved. And in order to gain "the empirical bases for such a risk assessment and the subsequent normative evaluation of the risks and opportunities," it is necessary to allow conducting research with human embryos in Germany.
Subsequently, the Leopoldina advocated the legalization of embryo research for "high-ranking research objectives" in a 2021 statement. For the authors, this means, among other things, being able to "critically review and evaluate the opportunities and risks of this form of gene therapy," referring to heritable genome editing. Although they note both insufficient justification of the need for germline interventions and the risk of "enhancement of biological traits," they still conclude that this research should be carried out.
The description of germline interventions as "genome surgery," "germline therapy," and "gene therapy" in the Leopoldina's publications is astonishingly imprecise for scientists. No existing humans are being treated, rather, embryos are being created in the laboratory specifically for this purpose. This rhetorical trick was also used at the BMBF conference. In a discussion about germline interventions, Jan Ellenberg, co-author of the statement, claimed that the life of a patient with sickle cell anemia was saved by the technology. Being a biologist, Ellenberg is probably aware that the patient’s treatment with a CRISPR-based somatic gene therapy had nothing to do with germline interventions, as it was applied in adulthood.
The Leopoldina authors refer to a report of the German Ethics Council in which a majority of members affirmed the ethical permissibility of research on early human embryos in vitro. At the BMBF conference, the Chair of the German Ethics Council, Alena Buyx, also pointed out that in its statement on heritable human genome editing the council had spoken out in favor of embryo research for the first time, as it is needed for the further development of germline interventions to prevent monogenetic diseases. According to Buyx, this research is not only permissible, but also necessary.
Ignoring the consequences
Thus, technological possibilities alone are proposed to guide legislation on research with human embryos. However, instead of reducing the debate - as seen at the BMBF conference - to opposing poles of "dignity of the embryo vs. supposed scientific rationality," we could apply a nuanced consideration of possible consequences. This approach, voiced by feminists for decades, views research as embedded within a commercialized science and healthcare system and social inequalities, in which germ cells and embryos could become a commodity. This argument could underline the necessity of maintaining the ESchG, without resorting to moral-theological "pro-life" arguments. From a very practical point of view: How would the surplus embryos make their way from medical practice to research? Would fertility clinics receive financial compensation for the "production" of the supplied research resource? Would there be incentives to remove as many eggs as possible from patients so that some remain for research?
Egg retrievals always carry a medical risk, and the more hormonal stimulation is used, the greater the risk. Even if there are no direct financial conflicts of interest, research interests and the associated pressure to obtain research funding could also create conflicts of interest between patient welfare and the scientific goals of reproductive medicine researchers. And what happens if the "surplus" embryos are not enough? Will advocates then call for further changes to reproductive medicine legislation to allow egg "donations" purely for research purposes? Would a market emerge in which economically disadvantaged people "donate" eggs, e.g. in order to be able to afford their own reproductive medical treatment?
In addition, the unrealistic promises described above with regard to research results for therapeutic purposes could be critically analyzed. Not to mention the many arguments against further research into germline interventions that arise when social consequences are included in the considerations. Unfortunately, all these aspects represent a gaping hole in the public debate.
Dr. Isabelle Bartram is a molecular biologist at the University of Freiburg’s Institute of Sociology and Program Director at Gen-ethisches Netzwerk (Gen-ethical Network), a Berlin-based nonprofit organization advocating for the responsible use and governance of human genetics. In collaboration with feminist and ecological movements, GeN enables nuanced debates that focus on the social impacts of these technologies.