Acceptance and Access to Gene Editing: Science and Our Obligations to Mankind
Authors: Yuman Fong, Perry B. Hackett
Journal: Molecular Therapy (2016)

It has been six decades since the elucidation of the structure of DNA,1Watson J.D. Crick F.H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid.Nature. 1953; 171: 737-738Crossref PubMed Scopus (8367) Google Scholar four decades since the introduction of restriction endonucleases opened up recombinant DNA technology, and a decade and a half since the sequencing of the human genome.2International Human Genome Sequencing ConsortiumFinishing the euchromatic sequence of the human genome.Nature. 2004; 431: 931-945Crossref PubMed Scopus (3498) Google Scholar We are on the verge of therapies that could permanently remedy genetic diseases. Gene editing using cellular, viral, and synthetic nucleotide templates, accompanied by engineered site-specific nucleases (zinc finger nucleases [ZFNs], clustered regularly interspaced short palindromic repeats [CRISPR]/Cas, transcription activator-like effector nucleases [TALENs]) now offer possibilities of treatment for diseases such as hemophilia, thalassemia, or cancers related to genetic mutations.3Kohn D.B. Porteus M.H. Scharenberg A.M. Ethical and regulatory aspects of genome editing.Blood. 2016; 127: 2553-2560Crossref PubMed Scopus (35) Google Scholar Decisions on which diseases as well as how to regulate and pay for treatments are increasingly debated.4The National Academies of Sciences, Engineering, and Medicine. Academies’ consensus study on human gene editing begins; first data-gathering meeting February 11–12, 2016. http://www.nationalacademies.org/newsroom/.Google Scholar Much of the debate on gene engineering involves the ethics of genetically altering germ cells and embryos.5Cyranoski D. Ethics of embryo editing divides scientists.Nature. 2015; 519: 272Crossref PubMed Scopus (36) Google Scholar In this Editorial, we wish to discuss other pertinent issues on the application of precision genetic technologies to encourage open discussion, debate, and planning. There are some diseases that essentially everyone would agree should be treated with somatic cell gene editing. These include adenosine deaminase deficiency, hemophilia, β-thalassemia, cystic fibrosis, and many others, where targeted gene correction of cells to produce structural or secretory proteins would alleviate or abrogate devastating effects of the disease. The potential savings in human suffering, societal expense, and gain in human life and productivity would justify gene-editing therapy. However, we will need to reduce costs in order to allow wide access. The first gene therapy approved in Europe, a treatment of lipoprotein lipase deficiency, has a projected cost of 1.4 million US dollars.6Ylä-Herttuala, S. Glybera’s second act: the curtain rises on the high cost of therapy. Mol Ther. 23, 217–218.Google Scholar Part of the reason for this high cost is the expense of viral vector production. The NIH currently funds basic research and some clinical trials in selected diseases. We should increase funding for vector production optimization and find other strategies for decreasing the real cost of gene therapy. Such efforts should also allow potentially lifesaving treatments to be available to patients in developing nations. In contrast, correcting genomes in gametes, germline gene therapy, has been off-limits due to uncertainties of insertional mutagenesis.7Smithies O. Gregg R.G. Boggs S.S. Koralewski M.A. Kucherlapati R.S. Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination.Nature. 1985; 317: 230-234Crossref PubMed Scopus (670) Google Scholar However, precision genome engineering in animal cells has improved nearly 10 million-fold to an efficiency of approximately 40%,8Tan W. Carlson D.F. Lancto C.A. Garbe J.R. Webster D.A. Hackett P.B. Fahrenkrug S.C. Efficient nonmeiotic allele introgression in livestock using custom endonucleases.Proc. Natl. Acad. Sci. USA. 2013; 110: 16526-16531Crossref PubMed Scopus (225) Google Scholar with few accompanying off-target events.9Carlson D.F. Lancto C.A. Zang B. Kim E.S. Walton M. Oldeschulte D. Seabury C. Sonstegard T.S. Fahrenkrug S.C. Production of hornless dairy cattle from genome-edited cell lines.Nat. Biotechnol. 2016; 34: 479-481Crossref PubMed Scopus (186) Google Scholar Objections to genome editing in germ cells continues to focus on these possible off-target effects and concerns of creating adverse genomic mutations that could enter the human gene pool. Also debated is specifically whether and which individuals should be allowed decide which genes to alter or eliminate in the human gene pool. Effective treatments for genetic diseases will allow affected individuals to live into child-bearing age. Currently, parents have the right to request prenatal genetic screening and embryo selection for some diseases, e.g., cystic fibrosis, Fanconi anemia, and retinoblastoma. Discussion of embryo selection should be part of counseling for individuals undergoing somatic cell gene-editing therapy. We will also need to encourage health insurance plans to pay for this service, because it is being performed for individuals who may be without disease phenotype. Such embryo selection programs should decrease the cost of medical care by reducing the incidence of disease phenotype. Now that whole genome sequencing is widely available and at increasingly lower cost, we might consider screening for genes responsible for major diseases in early adulthood as part of a preventative medicine program. A key question is which genes and diseases do we target for screening and whether we include genes responsible for conditions such as hypertension or obesity. For good reasons, children are usually not subjects for “first-in-man” trials. In morbid childhood diseases, as soon as the safety of the approach is documented, we should rapidly transition to testing the efficacy in children. They are necessary subjects and often informed and willing subjects of such trials.10Gene Transfer and Rare Diseases Workshop - Webcast. https://auth.osp.od.nih.gov/office-biotechnology-activities/biomedical-technology-assessment-oversight-human-gene-transfer-research/september-13-2012-gene-transfer-and-rare-diseases-workshop-webcast.Google Scholar Decisions on trial design and pace should not only reside with scientists and bureaucrats and needs to include voices from patients, families, care givers, and advocates. Women are now being ruled out as participants for trials targeting mtDNA.11Kyriakouli D.S. Boesch P. Taylor R.W. Lightowlers R.N. Progress and prospects: gene therapy for mitochondrial DNA disease.Gene Ther. 2008; 15: 1017-1023Crossref PubMed Scopus (68) Google Scholar Because such gene manipulation can result in alteration of germ cell mitochondria in the eggs and can therefore be passed to progeny, all such trials planned in the US involve only men. However, we need to consider women beyond child-bearing age or who have agreed not to have children. Furthermore, long-term follow up of treated individuals will be key to enabling debate and policy based on experience and data. The offspring of individuals who have been subject to gene therapy or gene therapy trials should also be encouraged to participate in long-term genetic and phenotypic follow-up studies. Most importantly, the debate and dialog on the editing of germ cells should continue. The current ban on germ cell gene editing (GCGE) is both justified and understandable, given concerns for off-target and on-target intended and unintended consequences. However, having a well-defined mechanism for vetting and studying such GCGE is important. As our methodology for gene editing becomes more precise and our mapping and understanding of silent areas of the human genome improves, it is likely that highly specific editing of genes encoding defects responsible for human suffering and mortality will be possible. Only if all constituencies and stakeholders are heard can we come to rational guidelines and decisions as to the format for study and approval of these new therapies. Only then can science meet the needs of human suffering.