Designing Preclinical Studies in Germline Gene Editing: Scientific and Ethical Aspects

Anders Nordgren

doi:10.1007/s11673-019-09947-9

Abstract

Human germline gene editing is often debated in hypothetical terms: if it were safe and efficient, on what further conditions would it then be ethically acceptable? This paper takes another course. The key question is: how can scientists reduce uncertainty about safety and efficiency to a level that may justify initiation of first-time clinical trials? The only way to proceed is by well-designed preclinical studies. However, what kinds of investigation should preclinical studies include and what specific conditions should they satisfy in order to be considered well-designed? It is argued that multispecies and multigenerational animal studies are needed as well as human embryo editing without implantation. In order to be possible to translate to first-time clinical trials, animal studies need to satisfy strict conditions of validity. Moreover, embryo studies intended for translation to first-time clinical trials need to correspond to the animal studies in experimental design (with exception of implantation). Only in this way can uncertainty about risk for harm (safety) and prospect of benefit (efficiency) in first-time clinical trials be reduced to a modest level. If uncertainty is not reduced to such a level, first-time clinical trials in germline gene editing should not be initiated.

Highlights

Gene editing has emerged as a promising approach in many areas of bioscience, especially with the development of the CRISPR/Cas9 technology
Gene editing in humans may in principle be carried out on somatic cells as well as on the germline (Nuffield Council on Bioethics 2016; National Academies of Sciences, Engineering, and Medicine 2017)
Preclinical research on germline gene editing without implantation is an important step in reducing uncertainty, but not necessarily a step toward genetic modification of future generations

Summary

Introduction

Gene editing has emerged as a promising approach in many areas of bioscience, especially with the development of the CRISPR/Cas technology. What is the proper response to uncertainty about risk for harm (safety) and prospect of benefit (efficiency) in first-time clinical trials on germline gene editing? This proposal is very much in line with the well-known recommendation by Orkin and Motulsky in their 1995 report to the U.S National Institutes of Health (NIH) They stressed the necessity of focusing more on preclinical research before initiating first-time clinical trials in somatic gene therapy (Orkin and Motulsky 1995). If this potential benefit is very high, could it be justified to continue to firsttime clinical studies despite some remaining uncertainty about risk

A Four-Part Framework

Conclusion