Investigação genética

Genetics in medicine—progress and pitfalls

Last week, the White House decreed that human germline gene editing in biomedical research is discontinued in the USA until ethical and safety concerns are resolved. This technology involves modification of the genome in germ cells, which can then be inherited and passed on to future generations. “The administration believes that altering the human germline for clinical purposes is a line that should not be crossed at this time”, said John P Holdren, Director of the White House Office of Science and Technology Policy.

In recent years, genome engineering technology has developed the ability to edit DNA more precisely than before. The new technology is based on an enzyme complex that binds and splices DNA at precise locations, and can target a dysfunctional gene by first deleting, then repairing or replacing the target sequence with another molecule. One such technique, CRISPR/Cas—short for clustered regularly interspaced short palindromic repeats—has received attention after a study from China used the technique for the first time to edit nonviable human embryos to disable the gene for β-thalassaemia. However, the study did not go to plan. The procedure worked only in a fraction of embryos, and, worryingly, mutations were introduced into other parts of the genome. Mosaics in which the embryo only had the desired change in some of its cells were also created. Clearly, the technology is still in its infancy and has many hurdles to overcome before it can be used clinically.

Nevertheless, the study caused a public outcry and has divided scientists worldwide. Those supporting CRISPR germline engineering believe the technology could prevent severe genetic diseases, but that research in viable embryos should be postponed. Those against CRISPR germline engineering cite the unquantifiable safety issues and ethical minefield of imposing unpredictable effects on future generations who cannot provide consent. There is also no compelling medical use for this technology at present, since other approaches exist to prevent genetic diseases, for example, embryo screening. Concerns that this technology would represent eugenics (enhancing the genome to create desirable traits rather than preventing disease) have also been raised. But whether for or against, there is agreement on the need to have an open debate on the pros and cons of this technology. A similar situation arose on the safety of mitochondrial donation, which was approved in the UK earlier this year. Arguably a less invasive approach than germline editing, this method is likely to involve some risk but was felt to be justified by the gravity of the mitochondrial diseases it could prevent, which are otherwise difficult or impossible to treat.

A welcome response  has come from the US National Academy of Sciences and National Academy of Medicine, who are launching an initiative to formulate guidelines on human gene-editing research that will serve researchers, clinicians, policy makers, and the public, in the USA and globally. Researchers and other experts will convene at an international summit later this year, to weigh up the benefits and risks, and ethics and safety concerns around this research, as well as to explore the potential of alternative approaches that do not alter the germline.

Putting contentious technologies aside, this week's Lancet features two studies into how applications of genomic research can improve patient outcomes by helping to predict treatment responses in individuals. Jessica L Mega and colleagues use a genetic risk score to identify individuals at risk of incident and recurrent coronary heart disease, and report that higher-risk groups have a greater benefit from statin therapy. In another paper, Mega and coworkers report the largest ever study of warfarin pharmacogenetics undertaken as part of the ENGAGE AF-TIMI 48 trial, comparing warfarin with edoxaban as an anticoagulant. Patients were classified by genotyping. Those who were sensitive and highly sensitive responders were at higher risk of bleeding with warfarin than were normal responders and had lower bleeding rates with edoxaban compared with warfarin, making edoxaban the preferred treatment.

As the precision medicine movement gathers pace, advances in genome sequencing, analysis, and engineering will need to continue. Huge amounts of new genetic information will become available through initiatives such as the UK's 100 000 Genomes Project, which will provide comprehensive genomic information for NHS patients by 2017—with the aim of delivering an ethical and transparent genomic medicine service for the NHS. Yet careful progress and debate, bringing in all stakeholders, will be needed to craft appropriate use of genomic information in the evolving landscape of clinical practice, and to set appropriate boundaries for high-risk, high-reward methods for genome engineering.

The Lancet, 06 June 2015