The publication of the draft sequence of the common chimpanzee genome in September 2005 was heralded as an advance that confirmed the proposals of Darwin1 and Huxley2 more than a century ago: that humans share common ances-tors with African great apes3,4. In addition to highlighting vast homologies between human and chimpanzee DNA sequences, primate comparative genomics is providing insights into the question of what makes members of Homo sapiens different from their nearest evolutionary relatives. There is great interest in identifying the genetic factors that underlie the traits that are traditionally taken to be the hallmarks of our species: higher cognition5, complex language and vocalization systems6, skin phenotypes7, immune and reproduction system functions8,9, sensory perception10,11, self and social awareness12 and other idi-osyncrasies of our physiology, anatomy and behaviour13. Although computational predictions of function can be made from large data sets, determining which sequences are functionally related to com-plex, lineage-specific phenotypes can likely be accomplished only by experimental investigation.

One potentially appealing experimen-tal strategy is to investigate the functional effects of human-lineage specific (HLS) sequences in transgenic non-human pri-mates (NHPs). Ideally, the species chosen for this research should be those that share the greatest genetic similarity with H. sapiens to increase the likelihood that they will express the HLS sequences in ways that give a clear indication of their function in humans. Although the long generation times of apes makes them less than ideal for genetic studies, the high level of similarity between their genetic background and that of humans makes them an attractive host species for transgenic studies of the function of HLS sequences. However, we argue that the scientific insights that can potentially be gained by this approach are outweighed by ethical concerns regarding the generation of such ‘humanized’ apes. The same evolu-tionary proximity that makes this research strategy attractive renders it ethically unac-ceptable in apes, including greater apes (chimpanzees, orangutans, bonobos and gorillas) and lesser apes (gibbons), because apes have the greatest potential to produce human-like phenotypes and, as such, carry a unique potential for harm.

Human lineage-specific sequencesIn addition to the human genome sequence14, we now have the complete draft genome sequences of chimpanzee4 and rhesus macaque15. Draft assemblies are currently available for the gorilla, oran-gutan, marmoset and lemur (see Further information for a link to the Ensembl database), and a draft Neanderthal genome sequence has recently been published16. Draft sequences of the bonobo and baboon are also underway (see Further information for a link to the National Human Genome Research Institute’s Approved Sequencing Targets Information). These data sets pro-vide a rich and unprecedented resource for mining lineage-specific genomic changes among humans and NHPs. Evolutionary genomics has already uncovered a wide range of HLS sequences. Genes affected include those that show striking HLS increases or decreases in copy number17–19, genes that have changed dramatically at the sequence level specifically in humans20 and genes that show altered brain expression between human and chimpanzee21,22. These genes span a range of functional character-istics, from those with no known function to those implicated in various anatomical and physiological processes5, including several genes linked to higher cognitive functions21–23. We can expect that, as more primate genomes are completed, the list of HLS genomic changes will substantially expand and further stimulate interest in understanding the functional consequences of such changes. This in turn can be expected to generate an increased interest in using transgenic animals as a means of studying HLS gene function.

Transgenic research using NHPsFor uniquely human sequences or genes, transgenic research using NHPs could likely be accomplished with existing techniques, through exchange of an HLS sequence with a homologous sequence of the transgenic host species or through addition of HLS sequences to the host genome24–27. However, new advances will be required to study the functional conse-quences of differences in gene expression, as precisely altering expression levels in

S C I E N C E A N D S O C I E T Y

The ethics of using transgenic non-human primates to study what makes us humanMarilyn E. Coors, Jacqueline J. Glover, Eric T. Juengst and James M. Sikela

Abstract | A flood of comparative genomic data is resulting in the identification of human lineage-specific (HLS) sequences. As apes are our closest evolutionary relatives, transgenic introduction of HLS sequences into these species has the greatest potential to produce ‘humanized’ phenotypes and also to illuminate the functions of these sequences. We argue that such transgenic apes would also be more likely than other species to experience harm from such research, which renders such studies ethically unacceptable in apes and justifies regulatory barriers between these species and other non-human primates for HLS transgenic research.

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transgenic research by increasing copy number or modifying the regulatory region of a gene remains technically challenging. Nevertheless, improving our abilities to control the number and genomic location of copies of integrated transgenes and levels of temporal and spatial expression is a high priority in human gene transfer research, owing to the crucial implications for the safety and efficacy of human gene therapy and other treatments.

Transgenic technology has commonly been applied to generate mouse models to study several human disorders, including neurodegenerative disorders28, auto-immune diseases29,30 and cancer31. There are also National Institutes of Health (NIH)-supported efforts aimed at human-izing mice by developing transgenic strains that contain human-specific alleles (see Further information for a link to the NIH Requests For Applications (number RFA-mH-08-050)), and a recent study has examined the function of human alleles of the forkhead box P2 (FOXP2) gene in transgenic mice32. However, there are limits to what scientists can learn about the func-tion of human genetic sequences in mice because of the substantially different genetic backgrounds of the two species and their considerable anatomical and physiological differences. In particular, there are large dif-ferences between rodents and humans in the relative size and composition of the areas of the brain associated with higher cogni-tion. Thus, the possibility that anything near human cognition would result from HLS sequences transferred to a mouse using con-ventional transgenic approaches is remote.

Recently, there has been a shift towards using transgenic NHP models for disease research. The first transgenic NHP was produced in 2001 (Ref. 26) and, in 2008, a rhesus macaque that showed hallmark features of Huntington’s disease became the first transgenic monkey model of human disease, raising the hope of ultimately developing new therapies27,33. Another experimental approach is the recently reported generation of transgenic NHPs to study mitochondrial gene replacement in primate offspring24. The goal of developing new therapeutic approaches using these methods is an admirable one, yet it raises important ethical questions about the pos-sible extension of studies using transgenic apes for studying the function of HLS sequences. We argue that there is a need to distinguish between the use of apes and all other NHPs (which we refer to as ‘monkeys’ hereafter) for such research.

The basic rationale for pursuing trans-genic research on HLS sequences is that it could provide important information regarding the basic scientific question of what makes members of H. sapiens differ-ent from their nearest evolutionary rela-tives. The results of such research may also produce clinical benefits, especially given that HLS gene variants have been found to be disproportionately enriched in genomic locations implicated in human diseases19,21, and that rapid genomic changes in the human lineage are often thought to pro-duce human disease as a by-product25. It is possible that HLS variants that affect human phenotype could provide important insights into disorders and clinically rel-evant phenotypes that are difficult to study by other means — including cognitive disease25, neurodegenerative disorders34, social behaviour disorders such as autism35, dementia36 and speech articulation defects37,21 — and gene delivery systems34 for therapeutic use. As this research is still in its early stages and its benefits are still theoretical, it is appropriate to proactively examine the ethical concerns related to NHP transgenic research.

Animal welfare regulationsThe prospect of conducting transgenic NHP research differs according to country; no international animal welfare regula-tions exist at present, although recently the OIE World Assembly of National Delegates approved a fifth strategic plan for implementing the OIE global objectives in animal health and welfare38. Currently, transgenic research involving any NHP could be approved in some countries, including the united States and China, which have no specific bans on this type of research39–43. The use of great apes for most research is effectively banned in the united Kingdom, New Zealand, the Netherlands, Austria and Sweden44–46, and the ban in Austria and Sweden also includes the lesser apes47. The European

union is now considering updates to their animal welfare laws that would mirror requirements in the united Kingdom48. Although monkeys are used for research in the united Kingdom, regulations require additional oversight, including a special license for the individual researcher, project and institution43,49.

Animal welfare regulations and guide-lines vary around the world, but all share a commitment to the ‘Three Rs’: replacement, reduction and refinement. The Three Rs state that animals should only be used if there is no alternative and, when animals are neces-sary, only the most humane methods should be used on the smallest number of animals required for scientific validity39,41,45,50–52. However, the Three Rs are criticized by some for not providing a way to give special con-sideration to certain species such as NHPs42.

The ethical issuesThe ethical concerns raised by the produc-tion of human–non-human chimaeras that could result from the transplantation of human brain or retinal stem cells to non-human embryos or fetuses are addressed in the literature53–56. Stem cell chimaera research differs from transgenic research in that chimaeras are produced by combin-ing cells (full genomes) of one species with those of another, in contrast to adding or deleting one or several genomic sequences in a host animal through transgenics. Thus, ethical oversight of transgenic research will differ in some aspects from the framework developed for chimaera research owing to differences in scientific procedures. For these reasons, the factors and concerns sur-rounding the oversight of HLS sequences in transgenic research merit a detailed ethical analysis particular to this research. This article anticipates that discussion by focusing on the ethical concerns regarding the likely harm to humanized apes and the ambiguities inherent in determining our ethical obligations to them.

Predictive and diagnostic uncertainty in transgenic NHP research. The transfer of an HLS gene or genomic variant into a NHP could have a specific, discrete effect that has a more or less dramatic impact on a phenotype of relevance to human function. However, biomolecular systems are inter-dependent and most genes seem to have multiple functions that can be apparently unrelated. So, such a gene transfer could equally have a wide array of unexpected and/or deleterious effects. For example, even if gene targeting could be carried

…even if gene targeting could be carried out specifically, the pleiotropic nature of most genes would often make the phenotypic impact of a transgenic intervention extremely difficult to predict or interpret.

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out specifically, the pleiotropic nature of most genes would often make the pheno-typic impact of a transgenic intervention extremely difficult to predict or interpret. Furthermore, the effect might not emerge immediately but only as offspring are produced, even if the transgene is studied first in other animals21,57. This uncertainty raises the risk of producing unanticipated harm to transgenic NHPs. moreover, if HLS gene transfer accomplishes its intended aim and produces a measurable change in a ‘human-like’ NHP phenotype, this would raise another set of ethical concerns. Even if a transgenic NHP displayed phenotypic traits that made it only slightly more similar to a human there would be further ethical questions concerning the vulnerability of the animal to harm.

Ethical obligations towards NHPs in transgenic research. Animal welfare in general, and the use of primates in par-ticular, is often debated in the literature in terms of ‘moral status’, a term meant to describe what entities are owed in their own right rather than their instrumental value to others58,59. moral status is not an all-or-nothing assessment as ethically justified regulations allow research on humans and prohibit capricious animal use. Additionally, consideration of our ethical obligations to humans and animals is not dependent on inherent capacities alone but also includes relationship ele-ments. For example, this consideration is applied to humans who lack many human capacities and to companion animals, such as cats, dogs and horses, which lack higher order capacities. merely labelling an entity as having or lacking moral status cannot do the ethical work of sorting out our particular obligations. Rather, ethical obligations should be determined by care-fully assessing the answers to at least five questions. What are the goals of research? What is the probability of success? Which animals are to be used? What effect will there be on the animals used? Are there any alternatives? These questions repre-sent a moderate approach to the ethics of animal research: they assume that some animal research is warranted and can be ethically justified, and also recognize that not every scientific finding automatically outweighs the interests and welfare of the animals that demonstrating that finding might require60.

The literature is growing on ethical issues in the creation and research use of transgenic animals in general and primates

in particular. Some analysts try to articulate the unique concerns in transgenic research in terms of the ‘unnaturalness’ of ‘cross-ing species boundaries’, citing unspecified downstream evolutionary and ecological risks61,62. Others turn to notions of ‘animal integrity’ or ‘species-specific dignity’ to try to focus their critiques on the effect of transgenic manipulations on the ani-mals54,63–65. This approach is headed in the right direction, but it usually remains at a relatively abstract level that is hard to apply to the conduct of animal research.

It can be both strengthened and sharpened by considering the purely biological chal-lenges that would be faced by any trans-genic ape that expressed a humanized phenotype. At the far end of the spectrum are cognitive changes that might give trans-genic apes enough self-awareness to appre-ciate the ways their lives are circumscribed and to suffer, albeit immeasurably, in the full psychological sense of that term. but it is not necessary to go that far. Imagine the life of the transgenic chimpanzee that, although no more self-aware than other chimpanzees, is hairless, walks erect, lacks long canine teeth or vocalizes like a human. There may be no question of a ‘normal’ primate life in the wild for this chimpanzee: it is likely to be condemned by its engineering to live in an artificial environment and to depend on humans for its welfare. Outside the laboratory, this chimpanzee could be considered a gro-tesque curiosity and unusually susceptible to exploitation and inappropriate treatment for commercial gain. In the laboratory colony, moreover, the transgenic chimpan-zee is unlikely to be able to be socially suc-cessful with its own species and might be potentially viewed as strange and an outcast by those without its differences. Ill-suited for both the animal and human worlds, the humanized chimpanzee is likely to sustain more injuries and encounter more pri-vations than non-engineered members of either species.

Apes share many capacities with humans, such as the capacity for attachment and empathy, communication, internalization of social rules, giving, trading, revenge, social maintenance and attending to group bound-aries. Altering such capacities could exacer-bate harm to these animals. Even if the only effect of humanizing expressions of HLS sequences served to inhibit or destroy the characteristics that these apes already share with us, we have harmed them, even from a human ‘speciesist’ point of view. It is hard to imagine a case in which apes transgenic for HLS sequences would not experience these social harms and the physical welfare con-cerns they would generate. Therefore, it is reasonable to conclude that this research will almost never be ethically acceptable. With respect to policy, this conclusion supports higher regulatory barriers, in terms of safe-guards and review, against any such trans-genic HLS sequence research with apes.

Of course, monkeys also display many of these same social and behavioural char-acteristics. To that extent, should they enjoy the same protections as apes when it comes to transgenic research with HLS sequences? Clearly there is an evolutionary spectrum among NHP species and any line drawing that occurs across it will be to some extent arbitrary. The evolutionary and genomic distance between monkeys and humans is great enough to diminish the prospect that one or a few HLS sequence insertions in a monkey genome will produce human-like phenotypes, or that those phe-notypes will be as socially challenging for monkeys as they would be for apes. For the same reason, humanized apes would be at greater risk of exploitation. From the ethical point of view, the more social and cognitive capacities primates possess, the weightier our obligations to them become. However, if a line is needed for policy and regulatory purposes, the line between the ape and mon-keys is relatively clear. This reduced risk of harm of a human-like phenotype suggests that transgenic HLS sequence research with monkeys may not always be ethically objec-tionable and could be regulated on a case-by-case basis by institutional animal care and use committees, including public representa-tion in the form of community members.

ConclusionsA few conclusions can be drawn from this discussion. First, because apes have the greatest potential to functionally express HLS sequences as they are expressed in H. sapiens, they are most at risk of expe-riencing harm and exploitation following

Imagine the life of the transgenic chimpanzee that, although no more self-aware than other chimpanzees, is hairless, walks erect, lacks long canine teeth or vocalizes like a human.

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such transgenic research. Second, the chal-lenge of assessing our ethical obligations to humanized apes is profound. The ethical concerns raised by the generation and use of apes as transgenic hosts to study HLS sequence function render this research ethically unacceptable, justifying regula-tory barriers between these species and monkeys. Concurrently, we recommend that the possible use of monkeys in trans-genic HLS research should be examined on a case-by-case basis by animal welfare review boards, with special attention paid to the unique transgenic issues in care-ful application of the Three Rs in primate research. Some information regarding HLS gene function can potentially be obtained using HLS transgenic mice. Another alter-native would be to use the clues given to us by comparative identification of HLS sequences in further studies of members of our own species. Although the NHP genome is similar to ours, there are also substantial differences. Thus, there are lim-its to what we can learn about the function of HLS variants until we study them in the human genome in which they may exist as naturally occurring variations. by this more direct means, we can potentially identify deficiencies or mutations in HLS sequences and phenotypes that seem to accompany these changes. Human HLS research is also laden with serious ethical questions about what it might mean for a human to lack the hallmarks of ‘humanness’, and how that research might be used and potential harms and abuses avoided. These ethical questions deserve their own further analysis.

Marilyn E. Coors is at the Department of Psychiatry and Center for Bioethics and Humanities, School of Medicine, University of Colorado Denver Anschutz

Medical Campus, Mail Stop B137, 13120 East 19th Avenue, Aurora, Colorado 80045, USA.

Jacqueline J. Glover is at the Department of Pediatrics and Center for Bioethics and Humanities,

School of Medicine, University of Colorado Denver Anschutz Medical Campus, Mail Stop B137,

13120 East 19th Avenue, Aurora, Colorado 80045, USA.

Eric T. Juengst is at the Center for Bioethics, School of Medicine, 314 A McNider Hall, University of North

Carolina, School of Medicine, Chapel Hill, North Carolina 27599, USA.

James M. Sikela is at the Department of Pharmacology and Human Medical Genetics and Neuroscience

Programs, School of Medicine, University of Colorado Denver Anschutz Medical Campus,

Mail Stop 8303, RC1 North Tower P18‑6117, 12800 East 19th Avenue, PO Box 6511,

Aurora, Colorado 80045, USA.

Correspondence to M.E.C. email: Marilyn.Coors@ucdenver.edu

doi:10.1038/nrg2864

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AcknowledgementsThe authors acknowledge the assistance of C.J. McCormick, M. O’Bleness, L. Dumas, J. Dang, J. Keeney and M. Douse for critical reading and preparation of the manuscript. J.M.S. is supported by National Institutes of Health (NIH) grants R01-MH081203 and RO1-AA11853. M.E.C. is supported by NIH grants 5P60DA011015 and RO1-DA029258. E.T.J. is supported by NIH grant P50-HG03390.

Competing interests statementThe authors declare no competing financial interests.

FURTHER INFORMATIONensembl: http://www.ensembl.org/index.htmlNational Human Genome research institute’s Approved sequencing targets information: http://www.genome.gov/10002154National institutes of Health requests for Applications: http://grants.nih.gov/grants/oer.htm

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