Guest Post: Carolyn Neuhaus, Ph.D.
Paper: Ethical issues when modelling brain disorders in non-human primates
In early 2016, Nature published a letter from a group of Chinese researchers reporting that they had created rhesus macaques with “autism-like” behaviours. The macaque was bred with a mutation in the MeCP2 gene. Overexpression of MeCP2 occurs in MeCP2 Duplication Syndrome, a disorder that shares many of its core symptoms with autism spectrum disorders. This would not be newsworthy, except that their macaques’ mutation was also heritable: at least some future offspring inherited the mutation, making it possible to create a sustainable colony of primates with the same mutation. The monkeys they created exhibited typical behaviors of humans with autism: increased stress response, repetitive behaviour, and less social interaction than their wild-type peers. This was interpreted as evidence that the genetically modified monkeys would provide a valuable model to study autism. The authors concluded, “These results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.” Among those on the list: autism spectrum disorders, Alzheimer’s disease, bipolar disorder, and schizophrenia.
The publication of these results was heralded by some as a great advance in neuroscience. Leaders of the China Brain Initiative stated, “It is likely that, through more extensive use of macaque monkeys as an animal model, Chinese teams will obtain new insights into the neural mechanisms underlying higher cognitive functions and generate monkey models for brain disorders that could be used for developing new therapeutic treatment.” Walter Koroshetz, Director of the U.S. National Institute of Neurological Disorders and Stroke, has also called out the Chinese efforts to “develop nonhuman primate models of brain disease using the macaque, an old-world primate that may have more relevance for humans [than other animal models of brain disease].” The imperative to understand the brain and brain disorders, and discover new therapies so desperately needed by suffering patients, has been taken by some to justify, if not require, creating primate models of brain disorders.
Such is the rationale for creating primate models: The brain disorders under investigation cannot be accurately modelled in other non-human organisms, because of differences in genetics, brain structure, and behaviours. But research involving humans with brain disorders is also morally fraught. Some people with brain disorders experience impairments to decision-making capacity as a component or symptom of disease, and therefore are unable to provide truly informed consent to research participation. Some of the research is too invasive, and would be grossly unethical to carry out with human subjects. So, non-human primates, and macaques in particular, occupy a “sweet spot.” Their genetic code and brain structure are sufficiently similar to humans’ so as to provide a valid and accurate model of human brain disorders. But, they are not conferred protections from research that apply to humans and to some non-human primates, notably chimpanzees and great apes. In the United States, for example, chimpanzees are protected from invasive research, but other primates are not. Some have suggested, including in a recent article in Journal of Medical Ethics, that protections like those afforded to chimpanzees ought to be extended to other primates and other animals, such as dogs, as evidence mounts that they also have complex cognitive, social, and emotional lives. For now, macaques and other primates remain in use.
Prior to the discovery of genome-editing tools like ZFNs, TALENs, and most recently, CRISPR, it was extremely challenging, almost to the point of prohibitive, to create non-human primates with precise, heritable genome modifications. But CRISPR (Clustered Randomized Interspersed Palindromic Repeat) presents a technological advance that brings genome engineering of non-human primates well within reach.
This new paper in the Journal of Medical Ethics is novel in asking: Insofar as NHPs are being considered for use as model organisms for brain disorders, can this be done ethically? I argue that it cannot. Bracketing for the purpose of the paper the important, if gridlocked, debate over the moral status of non-human primates, I argue that we nonetheless have three reasons to put a stop on the creation of NHP model organisms to study brain disorders: (1) animal welfare concerns, (2) the availability of alternative methods of studying brain disorders, and (3) unmet expectations of benefit.
The lure of using new genetic technologies combined with the promise of novel therapeutics present a formidable challenge to those who call for slow, careful, and only necessary research involving NHPs. But researchers should not create macaques with social deficits or capuchin monkeys with memory deficits just because they can.
Updated on 26/ 9 to correct information on MeCP2 Duplication Syndrome