In September, the Human Fertilisation and Embryology Authority (HFEA) will make a policy decision on whether research on animal-human chimeras should be allowed in the UK. The decision will be part of draft legislation to update the 1990 law on assisted reproduction and embryology and to establish a regulatory authority for tissue and embryos. As part of a period of public consultation, the UK Academy of Medical Sciences published a thorough, well-reasoned report over relevant issues. The public comment period ended 20 July, and the HFEA will make their policy decision in September.

Below is a summary of the report along with comparisons to relevant guidelines.

Human-animal hybrid research is complicated because it encompasses many combinations of biological entities: the introduction of human genetic material, cells, or tissues into animal cells, tissues or embryos, plus the converse experiments introducing animal DNA or cells into human cells or embryos. Additionally, different considerations apply to different animal species. Experiments also vary in aims, benefits and risks. Thus, the report concludes, research should be regulated on a case-by-case basis within a legislative framework that ensures consideration of both safety and efficacy.

The Academy working group who authored the report proposed that limits on human-animal hybrid research should be set out in primary legislation. More specifically, human embryos incorporating animal cells or DNA should not be implanted into a woman or an animal, nor should they be developed beyond 14 days in vitro. Even then, research should proceed only under license from the HFEA, mirroring the policy followed for human embryo research. Within this framework, an informed regulator should decide on individual research proposals, while considering the interfaces between the regulation of animal research, human embryo research and human embryonic stem (ES) cell lines.

The report then made recommendations specific to classes of experiments.

Introducing animal cells and genetic material into human cells and embryos

In interspecies somatic nuclear transfer, a human nucleus is inserted into an animal egg in hopes of creating human ES cells for research and for studying nuclear reprogramming. One such attempt has been published, and others are proposed.1,2 Concerns about such research center on whether animal genetic material would persist in human cells and whether it could introduce diseases into the human population. For instance, ES cells created from animal-human nuclear transfer (termed 'cybrids') could carry mitochondria of both human and animal origin. And in theory, mixing human and animal genetic material or exposing human nuclei to animal cells could allow retroviral contamination. The working group concluded that this risk was unlikely but should be monitored, and laboratory handling of such cells and tissues should be routine.

In contrast, introducing animal genes into human embryos for in vitro culture (of as long as 14 days) has not been proposed yet, but there may be reasons to do so. For instance, scientists could put the jellyfish gene for green fluorescent protein into human cells to study cell fate in developing embryos. Or by introducing mouse genes or gene-silencing constructs in human embryos, scientists could confirm their importance in early human development. Medical applications could also be envisioned, whereby animal genes could be temporarily expressed as markers of embryo quality in assisted reproduction.

The working group was not aware of any current scientific reasons to generate true hybrid embryos by mixing human and nonhuman gametes in vitro. However, the authors conclude, “given the speed of this field of research, the emergence of scientifically valid reasons in the future cannot be ruled out.”

The Academy working group argues that if a sound medical reason for introducing animal genes into human embryos exists, it should be allowed.

Several ethical concerns have been expressed over proposed research to introduce animal genes into human embryos. Some believe it undermines human dignity and human rights. The Academy working group argues that if a sound medical reason for introducing animal genes into human embryos exists, it should be allowed. After all, it concludes, animal materials such as pig heart valves have already been introduced into humans without compromising human dignity.

The report concludes that animal-human mixing does not redefine notions of human dignity: “If the concept of 'human dignity' has content, it is because there are factors of form, function or behaviour that confer such dignity or command respect. Either hybrid creatures would also possess these factors or they would not. If they do possess these factors, they would also have a specific type of dignity analogous or identical to human dignity that other creatures lack; if not, they would not. Either way, the distinction between creatures that possess dignity and those that do not remains as it is now.”

Another argument against such experiments is the so-called yuk factor, a negative gut reaction to procedures that are 'unnatural' and, to many, unfamiliar. The report argues that nearly all of modern medicine, such as vaccines, requires 'unnatural' interventions. Indeed, the first vaccines were condemned for introducing cow sores into humans. Likewise, the report dismisses the 'slippery slope' argument, saying it is not a good reason to prohibit valuable research but rather a reason to properly regulate it.

Introducing human genes and cells into animal and animal embryos

Many mice and other animals contain human DNA. This is already an active area of research with a long history and established regulations. However, transgenic animals are being made with ever-increasing amounts of human genetic material: mice have now been created that carry almost an entire copy of human chromosome 21, containing many hundreds of genes. The trend will continue with both mice and other animals, and an appropriate conceptual and regulatory framework for transgenic and chimeric animals containing significant amounts of human genetic material should be developed.

It is standard practice to introduce human cells (including ES and tissue-specific stem cells) into adult animals. For experiments using late-stage embryos, also called 'secondary embryos', the report refers to the International Society for Stem Cell Research (ISSCR) guidelines. Like the U.S. National Academy guidelines, these recommend particular scrutiny for experiments involving nonhuman primates. Experiments producing animals with human cerebral cortex or germ-line cells should also be subject to especially careful review.

More troublesome is injecting human ES cells into very early animal embryos to study their potency. The report describes just such an experiment by Ali Hammati-Brivanlou's group at Rockefeller University, where human ES cells were injected into mouse blastocysts3. The human cells did not appear to survive well in the mouse embryo, but even if they had, making sound conclusions would be difficult, and the report recommends that plans for such experiments be scrutinized carefully.

Guidelines released by the ISSCR and by the California Institute of Regenerative Medicine (CIRM), which funds stem cell research in California, both state that experiments introducing human ES cells into nonhuman animals at any stage of embryonic, fetal or postnatal development should be permissible after additional review by an ES cell research oversight committee, which should consider “the probable pattern and effects of differentiation and integration of the human cells into the non-human animal tissues.” Experiments in which human cells populated certain organs such as the animal gonads or brain, for instance, would be more ethically troublesome than those human cells populating the blood or liver4,5. The CIRM forbids introduction of human ES cells into primate blastocysts, as well as introduction of any ES cells into human blastocysts, and breeding of an animal in which human ES cells have been introduced at any stage of development.

The ISSCR guidelines propose that the proportion of human to animal cells and the time in development they are introduced is key: a small number of cells introduced at an early stage of development is equivalent to a large number of cells at a later stage. The earlier the cells are introduced or the larger the number, the more likely the cells are to integrate. The Academy working group supports this view, and recommends that agencies regulating human embryos, human stem cells and animal research establish a robust system to consult and communicate with each other to draw up sensible guidelines. It is still far from clear how to evaluate the safety and ethics of such experiments, which will be critical for the advancement of stem cell research and translational medicine, so at this point they should be regulated on a case-by-case basis until a consensus emerges.