Scientific Research Questions
The range of reproductive options investigated by the URPP H2R includes the potential future scenarios that rely on CRISPR-based technologies. The opportunities and risks of human germline editing using the CRISPR technology are being discussed extensively worldwide. Genetic modification of the germline with CRISPR might represent a promising approach for curing monogenetic disorders (e.g. cystic fibrosis), and for reducing genetic risk factors associated with common chronic diseases in which multiple genes interact with environmental factors (e.g. obesity, coronary heart disease, diabetes, Alzheimer’s disease, and multiple cancers). However, the consequences of such modifications for future generations are still unclear; indications are ambiguous, and technical feasibility is challenging. Here, we intend to evaluate opportunities, risks, and limitations specific to the CRISPR technology for germline editing. We will address these specific questions:
- Can we improve the precision, reliability, and safety of CRISPR to a point where we can consider its use in human embryos?
- Do we understand enough about complex genetic diseases to be able to delay or suppress their onset?
- Can modifying the human germline ever be ethically defensible?
This high-risk sub-project unites competencies in biology, reproductive medicine, Artificial intelligence/machine learning, embryology, genetics, philosophy, theology, sociology, and law.
Our first goal is to assess the efficiency and precision of available CRISPR technologies and to develop improved variants.
Our second goal is therefore to evaluate the technical feasibility of introducing multiple precise genetic changes in a single cell or zygote.
Our third goal is to systematically introduce and study disease-associated allele variants in mouse models and ex vivo organoid models. Potential target diseases include cardiovascular diseases, obesity, and cancer.
In the first four years, we will mainly focus on testing the efficacy and safety of CRIPSR technologies, and in years 5 to 8 we will put an emphasis on the development of improved tools. Likewise, in the first four years, we will mainly try to understand why risk alleles are associated with certain genetic diseases, and in the years 5 to 8, we will attempt to develop CRISPR approaches that can correct mouse models carrying these risk alleles. Concurrent with this cutting-edge medical-technological research, we will conduct an interdisciplinary legal, ethical-
philosophical, psychological, and social investigation whose findings will inform the evaluation of CRISPR.