Future perfect? The possible ethical issues of genetic technology *H&H Plus*

The development of new genetic technologies is simultaneously one of the most scientifically extraordinary and most ethically challenging aspects of modern veterinary medicine. Over recent years, we have developed the ability not only to test adult horses for genetically heritable traits, but also to screen equine embryos prior to transfer into a mare. With the advent of genetic editing, we stand poised at the beginning of an era in which humans can manipulate the equine genome in ways that can affect both current and future generations of horses. However, while this offers us wonderful opportunities to improve equine health and welfare, it also opens up some fascinating ethical questions. [subscriber-content]The sequencing of the equine genome in 2010 facilitated understanding of how diseases are inherited. As of last year, 237 equine traits or disorders with a genetic basis had been catalogued by the University of Sydney. This knowledge enables breeders to avoid breeding from animals carrying the genes for diseases, particularly where the method of inheritance is “autosomal recessive” – meaning that horses will show symptoms of this type of disease if they have two copies of the defective gene (one inherited from each parent). A horse that inherits only one copy of the defective gene will not show signs of the disease. If he is crossed with another horse also carrying one copy, there is a 1:4 chance that the foal will inherit two copies and show symptoms. Genetic testing enables us to identify so-called “carrier” animals, to avoid crossing them. Examples of diseases that can be tested for in this way include warmblood fragile foal syndrome; naked foal syndrome in the Akhal-Teke, first described by scientists in 2017; and foal immunodeficiency syndrome affecting Fell and Dales ponies. Other genetic diseases are inherited by a mechanism known as “autosomal dominant”, where an animal that inherits just one copy of the defective gene (from either parent) will show signs. Since the severity of these signs may vary, it is not always easy to physically identify a gene carrier. Genetic testing is, again, useful to prevent these diseases, such as malignant hyperthermia disorder in quarter horses, paint horses and Appaloosas. Many breed societies, including the World Arabian Horse Organisation and various warmblood studbooks, now encourage voluntary genetic testing of breeding animals. The American Quarter Horse Association insists that stallions are tested for five heritable diseases and will no longer register foals with specified genetic abnormalities. Moral questions Such uses of genetic technologies are ethically uncomplicated. The “harm” caused to the animal being tested involves taking either a blood test or a hair sample, and is clearly outweighed by the benefit of avoiding breeding foals with debilitating, painful and sometimes fatal health problems. The ethics become more complicated when we consider that equine embryos can now be flushed out of a mare’s uterus and biopsied to test the embryonic cells for genetic disease. The intention is the same as that behind testing adult animals – to avoid foals being born which will suffer from disease. An embryo found to be carrying the disease gene is discarded. Some people consider the killing of embryos morally problematic. Others believe it is a lesser harm than allowing foals to be born which will suffer and may die from genetic disease, particularly since embryos are considered incapable of suffering. We can also carry out genetic testing for susceptibility to sport-related injury and disease, a controversial practice in humans that is not yet well developed in the horse. We do know that there is genetic variation in the risk of fracture in thoroughbred racehorses, and that there is a genetic basis of equine exertional rhabdomyolosis (sometimes termed azoturia, or tying up). If our overall aim is to improve equine welfare, then testing to avoid breeding from animals carrying these genes must be an ethically “good thing”. Yet should we test for other traits, which have no direct impact on the future horse’s wellbeing but will affect the foal’s usefulness to humans? The obvious example is testing for the “speed gene” in thoroughbreds, which can be used to inform decisions about breeding and whether horses are better suited to speed or stamina events. Genetic testing can also identify the sex of an embryo before transferring it, in order to produce only foals of the “desired” sex. Rewriting the code The ethical debate becomes even more complex when one considers the possibility of genetic editing – a process that involves using an enzyme known as an endonuclease (typically the Cas-9 endonuclease) to “cut” the equine genome. Scientists can then replace an unwanted gene with one that is desirable, or turn a gene on or off. Where gene editing is used in embryos, rather than in existing animals (which has been carried out experimentally in dogs), the changes will probably be heritable and will thus affect all future generations. By genetically editing embryos, we could remove disease genes or those that predispose to injury for good. To some people, such fundamental human interference with nature is never justifiable. Others may believe that it is justifiable, and indeed ought to be done on welfare grounds. The same techniques can be used to alter the equine genome to enhance performance. This has already been reported by a group in Argentina, who have genetically edited polo pony embryos to influence muscle mass. Is this ethically justifiable? All of the arguments mentioned so far about indirect, positive effects on welfare apply, but there is an additional aspect. In the current state of science, gene-editing can involve “off-target effects”. These are unpredictable, harmful side effects, such as those that cause cancers. Currently, they are poorly understood. Use of genetic editing is therefore slightly scary, in the sense that we don’t know exactly what is going to happen – we might make adverse changes to the equine genome which are heritable and cause problems in many generations. We must consider such risks if we are aiming to improve equine health and welfare. If the reason for genetic editing is to remove a disease gene, we may decide that the potential harms of off-target effects are outweighed by the benefits to future generations of avoiding disease. But if we’re aiming simply to “enhance performance”, these risks may not be justified purely for our own benefit as humans. The conundrum is that our ability to avoid off-target effects will never improve unless genetic editing is allowed. Given its huge positive potential, we should continue to explore its possibilities – provided that the equine community works together to gather data and regulate use, protecting animal welfare. Engineering an athlete Some liken equine genetic selection for performance to the production of human “designer babies”, deeming the practice morally unacceptable because it represents an unjustifiable human interference with nature. The argument is not that simple. Being able to identify correlations between genetic traits and athletic ability (as Swedish researchers have done for several equine breeds) allows us to breed and train a horse for the discipline for which he has the most natural aptitude. This may have a positive welfare impact, as he is then more likely to be better treated, and it may also reduce “wastage” of unsuccessful, unwanted horses. This reasoning is predicated upon a true correlation between the identification of “desirable genes” and athletic performance, however, which is not guaranteed. Some famous thoroughbreds were retrospectively discovered to be of the “wrong” genotype for the races they won, suggesting it is not so clearly predictable. Ref Horse & Hound; 23 July 2020 [/subscriber-content]