Rhesus Monkeys Genetically Modified to Study Human Brain Development

A team of scientists at the Kunming Institute of Zoology, China, have created 11 transgenic rhesus monkeys with human versions of the MCPH1 gene, which is important for the development of the brain, in particular for brain size. Lentivirus was used for delivering the human gene into the monkey genome, which, unlike methods like CRISPR, does not replace the original gene. The original, or endogenous, MCPH1 gene was still active in the transgenic monkeys. Against expectation, the transgenic monkeys did not have larger brains, suggesting that more genes are involved in affecting brain size. Their brain development was, however, delayed, as it is in humans, and there were some signs of cognitive improvement, such as better short-term memory and shorter reaction time.

The research paper has been accepted for publication in the Chinese journal National Science Review and is available here. The study was first reported in China Daily, and then picked up by MIT Technology Review.

In an article on the CNN website, Su Bing, one of the lead authors, responds to criticism and accuses Western critics of

hypocrisy and recklessness, saying that the project was being unfairly judged by Chinese research “stereotypes.”

“Exploring the genetic mechanism of human brain evolution is a major issue in the natural sciences, and we will continue our exploration,” he said.

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Gene-Edited Primates in China: Latest Developments

According to a news article in the latest issue of Nature, scientists at the Institute of Neuroscience (ION) in Shanghai have produced five clones of a gene-edited macaque monkey. The gene-edited monkey had a gene disabled that has a role in sleep-wake cycles. Mu-ming Poo, neuroscientist and director of ION, says he “is planning to first create models of brain diseases, such as Alzheimer’s disease, Parkinson’s disease, a severe genetic intellectual disability called Angelman syndrome and several genetic eye disorders.”

In Europe and the US, non-human-primate research increasingly faces regulatory hurdles, costs and bioethical opposition. This stands in contrast to China; the country’s 2011 five-year plan set primate disease models as a national goal. The science ministry followed up by investing 25 million yuan (US$3.9 million) into the endeavour in 2014.

The article notes some ethical concerns, one of which is that gene-edited monkeys might be used for research when mice would be scientifically just as appropriate. There is a common assumption that during the same procedure or in the same situation, mice suffer less than nonhuman primates because of their lower cognitive capacities. Peta’s objection is that the practice of gene-editing animals and then cloning them is “monstrous” and causes them to suffer. Poo suggests that the practice might actually reduce animal suffering, as it may help reduce the number of animals needed for developing and testing therapies.

Gene-Editing and Nonhuman Primates in China

A recent article by Sarah Zhang in The Atlantic discusses the possibilities of using gene-editing technologies in order to create better primate models for neurological and psychiatric diseases. New gene-editing technologies, in particular CRISPR, have increased the interest in primate research and China appears to be taking the lead in this area of research.

Read more here: “China Is Genetically Engineering Monkeys With Brain Disorders” The Atlantic, June 8th, 2018.

SCHEER Preliminary Opinion on NHP Research: No Phase-Out

The European Commission’s Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) has released a preliminary opinion on “The need for non-human primates in biomedical research, production and testing of products and devices” [PDF]. This is an update on the 2009 opinion.

SCHEER does not foresee that research on non-human primates (NHPs) can be completely phased out, but recommends further advancement of the 3Rs (Replacement, Reduction, Refinement) in NHP research. A total ban on the use of NHPs would force NHP research out of Europe to countries with lower standards. This is likely to result in a decrease of animal welfare.

In the EU, non-human primates are mostly used for development and safety testing of pharmaceuticals and medical devices, usually to meet regulatory requirements. NHPs are also used for research in the areas of treatment and prevention of infectious diseases, neuroscience, ophthalmology and xeno-transplantation.

The opinion’s summary notes:

There is an urgent need to conduct systematic reviews and meta-analysis of all areas of NHP use. This would potentially significantly reduce the number of NHPs used and the resources required by identifying where they are unsuitable models or where they have contributed very little to current knowledge. Additionally, it may provide evidence for more targeted use of NHPs, which is important for ethics committees and funders of research. Emphasis should also be given to ensuring proper reporting of NHP studies and effective knowledge transfer, focusing NHP research in centres of excellence and the development of suitable, harmonised training courses. Continued work is necessary to develop improved means of assessing pain, suffering and distress in NHPs, including the psychological impact of their use in research. Scientific knowledge about the welfare impact of husbandry and procedures, even after refinement measures have been applied, needs to be factored into harm-benefit assessments.

SCHEER is planning a public hearing in Luxembourg on March 14th to discuss the Preliminary Opinion.

 

NIH Report on NHP Oversight: Did the NIH Overlook the Ethics?

The US National Institutes of Health (NIH) held a workshop on September 7th, 2016, on “Ensuring the Continued Responsible Oversight of Research with Non-Human Primates.” The workshop led immediately to controversy about its approach and selection of speakers (see article in Science). Recently the NIH published its report on the workshop [PDF].

Psychologist Stacy Lopresti-Goodman and ethicist Adam Shriver, writing for the Hastings Center blog, criticised the NIH for failing to consider properly the ethical issues involved. They argue that it is not sufficient to consider utilitarian arguments regarding benefits, we should also consider such issues as autonomy and dissent, upper limits on harm, and the ethics of captivity. They also complain about the lack of ethicists in the discussion and the absence of critical views.

This appears to be a case of conflicting expectations stemming from different understanding of ethics. The NIH seems to consider ethics primarily as an issue of regulation and oversight, and perhaps utilitarian cost-benefit analyses, while philosophical ethicists usually understand ethics, at least in significant part, as the critical study of moral justification. The NIH workshop was clearly concerned with the former and not the latter.

NHP Model a Success in Research on Pediatric Anesthesia

A new editorial (unfortunately behind a paywall, but the first page is available in free preview) in the journal Anesthesiology discusses the use of a nonhuman primate model in research on pediatric anesthesia. According to the editorial, rhesus macaques provide a “highly translationally relevant model,” which “makes unique contributions to understanding the phenomena and potential mechanisms of long-term cognitive and behavioral changes after general anesthesia early in life.” The editorial corresponds to an article published in the same issue, by Coleman et al.: “Isoflurane Anesthesia Has Long-term Consequences on Motor and Behavioral Development in Infant Rhesus Macaques.”

The editorial explains the usefulness of the model, especially in comparison with rat models:

There are a number of important advantages to studying this question in nonhuman primate models, not the least of which is the ability to study the effects of general anesthesia in the absence of surgery. Physiologic monitoring and support is much more feasible in an infant monkey than in an infant rodent. Thus, long-term effects of anesthesia exposure cannot easily be attributed to hypoxia, hypercapnia, and so forth. The stage of brain development at birth of a rhesus monkey is similar to that of a 6-month-old human infant, whereas based on many neurobiologic markers, postnatal day 7 rats that are at peak vulnerability to anesthetic neurotoxicity may more closely match the stage of brain development of a third-trimester human fetus. Nonhuman primates also have the capacity to perform more complex tasks and have a sophisticated social structure, like that of humans, allowing more translationally relevant tests of cognition and socioemotional behavior. (Anesthesiology, 126(1), January 2017: 6-8; references omitted).

The editorial also discusses the advantage of using behavioral tests that have been validated for both human and nonhuman primates. This further strengthens the translational relevance of this nonhuman primate model.

Rhesus monkeys a successful model for Huntington’s disease

From BrainFacts.org:

Nonhuman primate models offer greater promise for understanding and treating neurodegenerative diseases like HD because they are more similar to humans. The brains of rhesus macaque monkeys, for example, share anatomy and developmental trajectory with human brains. And unlike rodents, rhesus monkeys possess fine motor control and complete complex cognitive tasks, abilities that are progressively impaired in HD.

Read the full story here.

Australia’s NHMRC Issues New Guidelines on NHP Research

Australia’s National Health and Medical Research Council (NHMRC) has issued new Principles and guidelines for the care and use of non-human primates for scientific purposes. The document includes principles for the care and use of non-human primates in research, guidelines for the care of non-human primates and checklists for institutional animal ethics committees and inspectors.

According to the document, two necessary but not sufficient conditions must be met for NHP research to be justified:

1. no alternative to the use of non-human primates is suitable to achieve the stated aims of the project, and
2. the potential effects on the non-human primates are justified by the potential benefits.

The document also stresses the application of the 3Rs (Replacement, Reduction, Refinement) at all stages, as well as the role of animal ethics committees (AEC). An AEC can only approve an NHP research proposal if the proposal shows sufficiently that there is no alternative to the use of NHPs and that the potential benefits justify the potential burden on the animals.

New Brochure on the Benefits of Primate Research

The Foundation for Biomedical Research, based in Washington D.C., has published a brochure describing the life-saving benefits of non-human primate research. Check it out here.

The brochure appears to be based on a somewhat more informative white-paper, The Critical Role of Nonhuman Primates in Medical Research, published by the Foundation last August.

More on NHP Research in China

A recent Nature editorial on NHP research in China notes the advantages that China has in the field, in particular the availability of primates and the absence of opposition to NHP research. On that second point, the editorial concludes:

Chinese researchers’ freedom from animal-rights pressures will probably continue for the foreseeable future, but it is not a given. To maintain that support, and to make it easier for researchers elsewhere to form collaborations, they will have to show that they are abiding by principles that guide the international scientific community — that monkeys should be used only when necessary and in as small a number as possible.

See: “Monkeying around” Nature 532, 281 (21 April 2016) doi:10.1038/532281a

The motivation for the editorial is an article on the topic in the same issue: David Cyranoski: “Monkey kingdom: China is positioning itself as a world leader in primate research” Nature 532, 300–302 (21 April 2016) doi:10.1038/532300a