Stories from the far-side of research: a scientist’s view

Dolly the cloned sheep

BioPunk: Stories from the far side of research, is a newly published collection of short stories and commentaries exploring the human issues surrounding biomedical research.

In this extract, accompanying Adam Marek’s short story, Professor Bruce Whitelaw of The Roslin Institute, Edinburgh, reflects on the real science behind chimeric animals and inter-species breeding.

Animal biotechnology is still a relatively young area of biological science. With this status both excitement and what appear as large leaps forwards in our understanding and capability are possible. Perhaps this was best illustrated when in 1996 Dolly the cloned sheep was born at Roslin. But there have been other dramatic animals produced, for example the goat-sheep chimera or geep produced about a decade earlier.

Within an experimental context the production of chimeric animals, still predominantly rodents, is a powerful way to tease apart the factors that control how tissues, organs and body fluids are formed and function. Though the majority of chimeric animals that have been produced are intra-species, for example, a mouse that comprises cells from two different mouse strains, there are examples of inter-species chimeras. The geep and a recent study describing a mouse that has a pancreas derived from rat stem cells have stimulated much thought. Furthermore, there are also examples of chimeric animals that contain human derived cells. The vast majority of such studies utilise rodents and are proving valuable in rapidly advancing our understanding of biological function, most specifically within the context of blood formation. There are examples, however, of larger animals – goats – that have organs containing functioning human cells. It is expected that future cell-based therapies can be evaluated for their biological safety using these chimeric animals.

So, to make distinctions. Cloning produces a genetic copy of an animal. It can produce many such copies or clones, and this methodology has been applied to many species – laboratory, livestock, companion animals – and monkeys by the related method of embryo splitting. But in all of these studies, the species born was the same as that of the surrogate mother. In Adam Marek’s intriguing short story, a great ape is born from a human. This is science fiction but certainly thought provoking exposing the reader to a range of dilemmas; species conservation, deforestation, mans relationship with animals and in particular our interaction with the evolutionarily closely related great apes. Although studies are pushing the boundary, the ability for one species to give birth to another is still, so far, science fiction.

To achieve the orangutan birth from human female that underlies Adam Marek’s short story the developing ape foetus would need to be ‘hidden’ from the human womb. The womb would need to know that a foetus was developing but not sense the foetus as not-human. Otherwise the foetus would be aborted. This biological ‘trickery’ has not yet been achieved. If such methodology was to be developed the potential to apply it in a species conservation scenario could be attractive. There are, however, big biological barriers to be overcome; and even a scientific optimist would limit the imagination to methodology that would only work between closely related species. An example proposed by my colleague Dr Bill Ritchie would be the birth of a Scottish wild cat from a domestic cat.

The closest science has managed to get to this scenario are the chimeras I described above. In these animals, non-host cells are introduced either at a time when the host immune system is not yet fully functional or into animals that have an impaired immune system. The immune system is designed to recognise non-self cells and destroy them. The potential of utilising chimeric animals to accelerate the advance of scientific knowledge and the preclinical evaluation of new drugs and other strategies to treat disease is now an exciting area of biomedical research.

At Roslin, like many other research organisations, we have been generating chimeric mice for many years. This is a standard methodology. We are now exploring the formation of chimeric animals by introducing cells – usually stem cells – to the developing embryo. We are working with experimental animals including mice, rats, chickens and sheep. This is achieved by introducing stem cells into the preimplantation embryo which is an established methodology in mice and extensively used worldwide to produce transgenic mice. We are exploring this methodology in livestock. We aim to increase our understanding of the interaction between the placenta and the developing foetus, the role of specific immune cells in this process, and the role of cells in the early embryo. Our longer term goal is to characterise the network of interactions that enable the development of a healthy foetus. This is all purely academic research. The output of which is increased knowledge of biological processes.

The production of chimeric animals also offers potential biomedical applications. The possibility that animals could be used as bioreactors is being investigated. This opportunity has taken a step forward with the reporting of a rat pancreas in a mouse. In addition, there is considerable current optimism that stem cell therapies can be developed sufficiently to offer new surgical intervention strategies. Stem cells may be able to provide missing function, for example insulin production for those suffering from diabetes. But these stem cells possess characteristics which if not controlled resemble that of tumour cells. Therefore, if such cells are to be delivered to human patients a robust evaluation of their tumour forming capacity is required. We are exploring approaches that utilise chimeric animals to perform this assessment.

So, back to Adam Marek’s short story. Thought provoking, science fiction but a story that builds from what is currently an area of active scientific research.

Bruce Whitelaw

Professor Bruce Whitelaw is Professor of Animal Biotechnology at The Roslin Institute, Edinburgh.

This article was originally published in BioPunk: Stories from the Far Side of Research, a newly published collection of short stories and commentaries exploring the human issues surrounding biomedical research. Fourteen authors explore themes such as programmable memories, fatherless reproduction, nanotech implants, amphibian-powered scar treatment, full body modification and brain-scanning lie detectors, with accompanying commentary from scientists and ethicists actually working in these fields today. The book is supported by the Wellcome Trust and available now.