2003 conference at Yale, and the 2003 European Science Foundation Workshop on Science and Human Values, where earlier versions of this paper were presented, and to two anonymous referees.
16 Statement on NIH Funding of Research Using Gene‐Editing Technologies in Human Embryos
Francis S. Collins
Genomic editing is an area of research seeking to modify genes of living organisms to improve our understanding of gene function and advance potential therapeutic applications to correct genetic abnormalities. Researchers in China have recently described their experiments in a nonviable human embryo to modify the gene responsible for a potentially fatal blood disorder using a gene‐editing technology called CRISPR/Cas9.
Genomic editing is already widely studied in a variety of organisms. For example, CRISPR/Cas9 has greatly shortened the time it takes to produce knockout mouse models of disease, enabling researchers to study more easily the underlying genetic causes of those diseases. This technology is also being used to develop the next generation of antimicrobials, which can specifically target harmful strains of bacteria and viruses. In the first clinical application of genomic editing, a related genome editing technique (using a zinc finger nuclease) was used to create HIV‐1 resistance in human immune cells, bringing HIV viral load down to undetectable levels in at least one individual. All of these examples of research using genomic editing technologies can and are being funded by NIH [National Institutes of Health].
However, NIH will not fund any use of gene‐editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed. Advances in technology have given us an elegant new way of carrying out genome editing, but the strong arguments against engaging in this activity remain. These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR/Cas9 in embryos.
Practically, there are multiple existing legislative and regulatory prohibitions against this kind of work. The Dickey‐Wicker amendment prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed (H.R. 2880, Sec. 128). Furthermore, the NIH Guidelines state that the Recombinant DNA Advisory Committee, “…will not at present entertain proposals for germ line alteration”. It is also important to note the role of the U.S. Food and Drug Administration (FDA) in this arena, which applies not only to federally funded research, but to any research in the U.S. The Public Health Service Act and the Federal Food, Drug, and Cosmetic Act give the FDA the authority to regulate cell and gene therapy products as biological products and/or drugs, which would include oversight of human germline modification. During development, biological products may be used in humans only if an investigational new drug application is in effect (21 CFR Part 312).
NIH will continue to support a wide range of innovations in biomedical research, but will do so in a fashion that reflects well‐established scientific and ethical principles.
17 Genome Editing and Assisted Reproduction: Curing Embryos, Society or Prospective Parents?
Giulia Cavaliere
Introduction: Genetic Diseases, Genome Editing and Existing Alternatives
Different reproductive options are available for couples or individuals at risk of transmitting genetic diseases to their offspring who wish to have children. In this paper, I explore ethical and social questions raised by the use of genome editing into the context of assisted reproduction and, in particular, as a potential alternative to preimplantation genetic diagnosis (PGD).
Some of the reproductive options available to this group of individuals include refraining from having genetically related children and/or using technologies to reduce or avoid the risk of transmission. The first set of options includes adopting existing children or turning to third‐party reproduction (i.e. relying on a gamete donor). Adoption is currently legal in many European countries, but eligibility criteria vary. For instance, in some countries, access to this practice is limited to married heterosexual couples (e.g. Italy), while other countries have wider access criteria and allow same‐sex couples (e.g. the Netherlands and the United Kingdom) and single parents (e.g. France and the United Kingdom) to adopt. In addition, other criteria such as marital status and age play a role in the decision to grant adoption.
Another possibility to avoid transmission of genetic diseases is for individuals to have partly genetically‐related children and to seek gamete donors. This is commonly referred to as third‐party reproduction, which allows couples to have children who are genetically related to a donor and to the unaffected individual in the couple. Third‐party reproduction is currently only legal in some countries (e.g. the United Kingdom, the Netherlands and Spain) and usually restricted to heterosexual couples. Moreover, the state only subsidises IVF with donor gametes in a few countries (Gianaroli et al. 2016).
Alternatively, prospective parents at risk of transmitting genetic conditions to their offspring can seek to procreate with the aid of assisted reproductive technologies (ARTs) and preimplantation screening technologies (such as PGD), which would allow them to have genetically related children free from the condition that affects them (or one of them). PGD allows the testing of embryos created with IVF for genetic abnormalities prior to their transfer in utero. This technology is currently legal in many European countries (Gianaroli et al. 2016), but in some countries it remains restricted to so‐called ‘serious’ conditions (e.g. in Italy and Germany), and in others is completely banned (e.g. in Poland and Switzerland; Biondi 2013; Gianaroli et al. 2016). Across Europe, eligibility criteria vary. In the United Kingdom, for instance, the Human Fertilisation and Embryology Authority (HFEA) periodically revises and updates the lists of conditions that are eligible for screening with PGD. Other countries, such as Germany and Italy, recently approved the use of PGD, but access to this practice remains restricted to a very limited number of severe, early onset conditions (Biondi 2013; Gianaroli et al. 2016).
PGD and Assisted Reproduction
Where PGD is legal, it is typically used in cases where both prospective parents are carriers of an autosomal recessive mutation. These mutations are responsible for the occurrence of autosomal recessive monogenic diseases (i.e. diseases caused by a mutation in a single gene) such as cystic fibrosis and sickle cells anaemia.1 When both prospective parents are carriers of such mutations, future offspring have a 1 in 4 chance of inheriting the mutated gene and developing an autosomal recessive disease, while they have a 1 in 2 chance of inheriting one abnormal gene and thus becoming healthy carriers. PGD allows the testing and selection of embryos created through IVF to transfer in utero those that are either free from the abnormal gene related to the prospective parents’ condition (or that are carriers of such mutated gene when no mutation‐free embryo is obtained). PGD is also effective in cases where one of the prospective parents is heterozygous for an autosomal dominant mutation, meaning that they carry two different variants of a gene. Autosomal dominant mutations are responsible for the occurrence of diseases such as Huntington’s and neurofibromatosis type 1. Future offspring have a 1 in 2 chance of developing autosomal dominant diseases even if only one of the prospective parents is affected, because it is possible that the embryo would carry the ‘good’ genetic variant from both parents. If the embryo inherited the disease‐causing variant from only one parent, however, the resulting child would be affected by the disease.
It could be the case that none of the embryos created through IVF is free from the undesirable genetic mutation. For instance, when one of the prospective parents is homozygous for a dominant genetic disorder, the risk of transmission to offspring is as high