Editing the human germline
Gene editing of human embryos raises ethical questions of its own: why editing a somatic cell and editing an embryo are different kinds of act, how the debate over research on human embryos ran, what rules the United States and other countries set on editing them, where the line on enhancement was drawn, how safe a first trial would have to be and who should decide, what such a change might do to people and to society, and what the first gene-edited babies showed.
Somatic cells and embryos
Somatic cells, sometimes called adult cells, are any body cells other than the gametes. They are usually differentiated and do not differentiate further in vitro, and when used therapeutically they die when the patient dies, so they pose little ethical risk beyond the usual efficacy and safety concerns that apply to any individual patient. An embryo produced by fertilising an egg in vitro proliferates without differentiating for months to years, and its cells contain the complete genetic blueprint of a unique human being. Genetic manipulation of such an embryo raises several ethical concerns, particularly because a baby developed from it would pass the modified genome on to all subsequent generations, changing the gene pool. Editing the germline would affect not only the individual but also their offspring , and so future generations.
Beyond potential complications such as limited on-target editing efficiency, off-target editing and mosaicism, the most significant moral and ethical issue CRISPR-Cas9 raises is that the corrected gene integrates into the genome and so passes to the progeny. Because there is uncertainty even in the organisms in which CRISPR-Cas9 is used, it is unclear how the gene might react in the new genetic milieu of the offspring. A gene is also very complex and interacts with other genes and proteins in the organism and with the environment to produce a phenotype, in ways not yet fully understood. So modifying a gene without clear knowledge of all the variables is a moral and ethical conundrum.
The long-term hope is that gene editing could be used to fix disease-causing mutations before they are passed on.
The debate over research on human embryos
Whether scientists should be permitted to modify the genes of human embryos, or be limited to adult cells and non-human embryos, has long been argued in public and in private: in churches, synagogues and mosques, at academic conferences and in government. Whether to approve the use of human embryos in research remains an intensely personal decision. Some see the embryo as endowed with the sanctity of life, a potential unique human being, and its use as tantamount to murder. Others argue that the scientific information gained is of greater value than the cells, and may point out that most embryos used in research are left over from in vitro fertilisation, where a number are usually selected for implantation, others preserved for future use and the rest discarded or used in research. Like most ethical questions, this one has no correct answer, but compromises were reached and decisions made.
Rules on editing human embryos
Gene editing research had mostly focused on mutations in somatic cells, and editing germline mutations had generally been considered completely unacceptable. Most clinical applications of gene editing target somatic cells, and most researchers have stayed clear of germline editing, though the field is moving toward editing germline cells. Gene therapy research in general had avoided changes to germline genes, with their inherent ethical and long-term safety questions.
In the United States, technical and ethical concerns led to a 2005 policy that permitted scientists to use CRISPR on adult cells and non-human embryos and forbade experimentation on or destruction of human embryos. The policy was enforced, more or less, by denying taxpayer funding to scientists who worked with human embryos. Pharmaceutical companies, often a source of funding, had little interest in a one-time curative procedure. The National Institutes of Health ban was an impediment to many laboratories, though some scientists got around it with private funds.
In 2015 Chinese researchers announced that they had edited human zygotes that were not intended for pregnancy, drawing concern from the research community worldwide. The zygotes were triploid and would never have been viable, but the research community felt an ethical line had been crossed. Later that year the first International Summit on Human Genome Editing, held in Washington, DC, reached a consensus that editing should not be used to modify embryos intended to establish a pregnancy and that many technical and ethical issues should be settled before anyone attempted germline editing or used it clinically. The summit did not call for a ban on germline editing for research purposes.
In February 2017 a report by the US National Academy of Sciences was widely seen as a green light for genetic modification of human embryos, and shortly afterwards Shoukhrat Mitalipov of Oregon Health and Science University became the first researcher to report creating genetically modified human embryos in the United States. Three Chinese researchers had published before him and concluded, because of editing errors and incomplete take-up of the modified gene, that CRISPR modification was not yet safe for clinical use. Mitalipov did not encounter those problems, but he never intended to implant the modified blastocysts and destroyed them at the eight-cell stage. In response to Mitalipov's report, Congress instructed the FDA to withhold approval of any study intended to produce a baby from a modified embryo. That did not preclude a baby being produced from a modified embryo in another country without such a ban.
In August 2017 a research group in Oregon reported using CRISPR to edit the genome of a human embryo, and the announcement drew immediate concern from many scientists because it was a move to change germline genes, affecting future generations. That month the American Society of Human Genetics published a position paper recommending against germline genome editing. In the words of the society's director of science policy, germline editing could in theory prevent a child being born with a genetic disease, but its potential use raises a multitude of scientific, ethical and policy questions that cannot all be answered by scientists alone and also need to be debated by society.
By 2019 several countries had also issued their own guidelines on germline editing. In the European Union germline editing and eugenics were banned , although some member states permitted editing of embryos for basic research under strict regulations, with embryos that could not be implanted or allowed to develop into a human being. In the United States, a National Academies report concluded that germline editing might be permitted in future, but only under strict oversight, and the National Institutes of Health would not review proposals or research grants involving germline editing. In the United Kingdom and Sweden, editing of human embryos was permitted for research purposes only. Japan's draft guidelines of September 2018 permit editing of human embryos with restrictions: they allow it for research into early human development, restrict manipulation of embryos for reproduction, though not in a legally binding way, and do not permit it for genetic enhancement.
The line on enhancement
Most researchers worldwide agreed that, for the time being, genetic modification of the human embryo should be limited to correcting severe diseases for which there is no alternative treatment. The National Academy of Sciences' advisory committee, which had global representation, drew a red line at genetic enhancement. In the words of the committee's co-chair, editing to enhance traits or abilities beyond ordinary health raises concerns about whether the benefits can outweigh the risks, and about fairness if it is available only to some people. So genetic enhancement was not available, though its use would likely become an issue. Height shows how little is understood: scientists have identified 697 small genetic variations on 4 loci that affect it, and the genes for athleticism or intelligence have not been found. Helping patients with genetically complex, poorly understood diseases such as diabetes is likely to take most of the field's energy in the near future.
Safety, and who decides
The greatest peril to scientists in the field would be to introduce CRISPR clinically before they fully understand it. CRISPR intervention is not 100% safe and never will be, which leaves the question of how safe is safe enough. For all CRISPR's scalpel-like precision, changes at off-target loci make its results unpredictable. A single death would validate the scientists and citizens opposed to the work and move them to demand a moratorium on further CRISPR research. Unforeseen results short of death could also be judged intolerable and stop or slow progress. Selectively bred tomatoes, for example, are large, uniformly red and long-lasting, but have no flavour, an unintended result. A child born with the intended red hair and an unintended third arm would likely bring an outcry. Review boards will have to examine all available safety data and determine what level of risk is acceptable, and the data would ideally include long-term observation of modified mammals and their offspring. Scientists would do best to remember the case of Jesse Gelsinger, the first person to die while enrolled in a genetic trial.
Engineering an embryo for implantation and creating a modified baby is a very serious business with the potential to change humans as a species, and the decision to go ahead is a grave one. It should take into consideration every piece of data and every red flag raised by any laboratory anywhere. It should ideally be made with complete transparency by a globally representative body of scientific experts, ethicists, lawyers, religious leaders and ordinary citizens, ideally through several levels of review with unanimous decisions. The body's members should be prudent, demanding, free of conflicting interests and unimpressed by the science.
Understanding of genetic manipulation is at a very early stage. Studies on human embryos have been done and will likely become the accepted form of experimentation. Some of the ethical questions are already present and others are not yet, and the issues should be approached transparently, with input from a variety of sources and a global view.
Effects on people and society
Germline modification appears to be on its way, which raises the question of what exactly it creates: whether genetically modified children are still human, or whether the loss of randomness has changed them in some fundamental way. Although a change in the genome is rather dramatic, people are always changing in small ways. All the body's cells, including those of the brain, heart and bones, are continually replaced, and people are themselves only at this exact moment, so perhaps the adjustment will not be too difficult.
The social question can be pictured through two children on a swing set, one genetically modified and one natural. The first has perfect hair, health and physique and attends a private school for intellectually gifted modified children, and the second is pudgy, runny-nosed and tentative and attends a public school. The picture asks how the mothers will feel about their choices, and how the mother of the natural child might act when planning her next pregnancy. Modification would almost certainly come at a cost, and it could widen the separation between haves and have-nots: modified children would likely find doors opened to better schools, jobs and wealth, and perhaps even defy death. At the extreme, society might divide into near-identical privileged elites and commoners modified for loyalty and a strong work ethic.
CRISPR has raised a host of new ethical questions that have left ethicists scrambling to catch up. Genetic modification of people raises further questions:
- Who will take responsibility for ensuring that payers, legislators and citizens are genetically literate? Studies have shown that people understand more genetics than previously assumed, and that they learned it seldom from biology lectures and more often from documentaries, blogs and other media about the impact on particular patients and families.
- How much should be charged for a modification that prevents a serious disease? It is a one-time treatment, but it cures completely and prevents a lifetime of resources spent on care and a great deal of suffering.
- Will insurers pay, and should they then have access to the patient's DNA? Do scientists hold copyrights on genetic modifications?
- Does a person born of a modified embryo own their own genome, or does someone else?
- Is modification at its core a kinder, gentler eugenics? What forces will shape the vision of perfection, and will that vision change over time?
- Will the loss of variation cost gifts such as the creativity that often accompanies some forms of mental illness?
- Will pairings between modified and unmodified people, or between people with different modifications, need study?
- How do future generations sign consent?
- Could a fascist government euthanise citizens who are genetically flawed, and who would pass the screening? Could it order an army optimised for aggressiveness and bravery?
The first gene-edited births
The report in November 2018 of the birth of two babies with CRISPR-edited DNA amplified the discussion of gene editing and its place among therapeutics , and highlighted the urgent need to address the ethical concerns of germline editing. At the second International Summit on Human Genome Editing, in November 2018, He Jiankui of the Southern University of Science and Technology in Shenzhen reported that he had created the first gene-edited babies, twin girls, and he posted a video announcement. Scientists at the summit and elsewhere condemned the news strongly. Critics noted that at least one of the babies was a mosaic of cells edited in different ways. They also argued that the chosen gene, CCR5, whose editing disables the CCR5 protein and so protects against HIV infection, addressed no unmet medical need, which is the usual standard for gene editing, and that HIV infection is preventable and manageable by other, less expensive methods. Informed consent was obtained by He himself rather than by a trained, uninvolved professional, and prospective participants were told the experiment was for an AIDS vaccine, with no mention of gene editing. As of 2019 the results had not been published in a peer-reviewed journal.