Focus: Bioethics
Monsters or Research Tools? The Use of Chimeras in Biomedical Research
In Madison, WI, approximately 300 scientists, clergy, educators and members of the general public met for The 5th Annual International Bioethics Forum: Clones and Chimeras. At this Forum, scientists and nonscientists engaged in a dialog to understand the science behind the research and debated the promises and pitfalls of such research. Here we present some of the ethical issues discussed at the forum and current guidelines proposed by the National Academies for the conduct of such research. The Annual International Bioethics Forum was founded and first sponsored in 2002 by the BioPharmaceutical Technology Center Institute, Promega Corporation, the University of Wisconsin-Madison and the Wisconsin Alumni Research Foundation. Since the inaugural event, the International Bioethics Forum has been held annually in April, drawing participation from clergy, educators, journalists, ethicists and scientists from around the world.
By Michele Arduengo, Ph.D.
Promega Corporation
Published in May 2006
Chimeras in Literature and Science
For some, the word “chimera” evokes a picture of the monstrous offspring of Echidna, the Greek mythological “Mother of All Monsters”. Chimera is one of her offspring described as having a lion’s head, a goat’s body and a serpent’s tail. And, actually, Echidna is a chimera herself, a woman with a serpent’s tail. But chimeras aren’t only the stuff of ancient myths. At the Bioethics Forum, Justine Burley, D.Phil., M.Sc., Adjunct Associate Professor at the National University of Singapore, pointed out that modern day fiction and fairy tales are full of chimeras, many of them presented in a more positive light than they were in ancient Greece. For instance, in The Lion, the Witch and the Wardrobe, C.S. Lewis creates protagonists that are chimeras, including Mr. Tumus, a combination of goat and man. In the Harry Potter books, J.K. Rowling describes a variety of chimeras including Hippogrifs, Centaurs and Merpeople.
Ask a scientist about chimeras though, and she probably won’t turn to myth or even modern fiction. Today in research circles, “chimera” elicits a different picture: sheep with mostly human livers that could be used for organ transplants, pigs with human blood coursing through their veins, mice with human neural cells to model human diseases, and people who have received replacement heart valves from a pig. A chimera is an organism that has cells contributed by two different individuals. Those individuals can be of the same or different species.
The Biology of Chimeras
Chimeras are not always unnatural; most twins carry a few cells from the brother or sister who shared the womb with them, and most mothers have a few cells circulating in their blood from each child to whom they have given birth. Many people celebrate the promise of research chimeras. For instance, organ transplant research may benefit through creating organs that would reduce tissue rejection. Human-animal chimeras that model human diseases may well be more reliable for preclinical testing of new therapeutics, making the introduction of new pharmaceuticals a little safer. However, researchers and ethicists are also urging caution and discussion of how human-animal chimeras are used in research.
Research using chimeras continues to be a powerful tool for understanding biology and disease. The SCID (severe combined immunodeficiency) mouse was created by transferring human immune stem cells into a mouse to model human immune disorders. But it’s the creation of a chimera that involves the transfer of human neural tissue into an animal host that causes many people to pause. Several scientists have proposed transplanting human neural stem cells into mice to model therapies for diseases such as Parkinson disease. Indeed, researchers in California have transplanted human neural cells into mouse brain, creating a mouse that has approximately 1% human cells. So far the mice have shown no human characteristics. Still, how far should science go? To get an answer to this question, Irving Weissman, Director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University, asked the review board at Stanford to consider an experiment in which a mouse with 100% human neural cells would be created. The National Academies of Sciences also convened a panel to draw up guidelines for embryonic stem cell research, which includes guidelines for creating human-animal chimeras. These guidelines were published in 2005, and as of May 2006, the National Academies have created the Human Embryonic Stem Cell Research Advisory Committee. This committee will continue to review scientific developments and the changing issues related to these developments as well as determine the need to revise and update the existing guidelines.
The guidelines proposed by the National Academies formed the basis of much discussion at the Bioethics Forum. Derek van der Kooy, Ph.D., Professor in the Department of Medical Biophysics at the University of Toronto and Cynthia B. Cohen, Ph.D., J.D., from the Kenedy Institute of Ethics at Georgetown University, led a session that included many audience questions about the National Academies guidelines and their potential impact on biological research. The final panel at the Forum, which included Timothy Caulfied, LLB, LL.M., from the University of Alberta, Cynthia Cohen, and Robert Streiffer , Ph.D., and Clive Svendsen, Ph.D., from the University of Wisconsin-Madison, also revisited the 2005 guidelines and the continued work of the National Academies to review and revise the guidelines.
Guidelines Proposed by the National Academies (USA)
The National Academies' guidelines focus on research that involves transplanting embryonic human stem cells into another animal at the blastocyst. The blastocyst is the ball of cells formed approximately three to five days after fertilization that implants into the wall of the uterus, usually on day five, in human pregnancy. Embryonic stem cells are harvested from blastocysts.
With regard to chimeras, the National Academies guidelines say that no animal embryonic stem cells should be transplanted into a human blastocyst. Also, in addition to the traditional oversight by an internal review board, a second oversight committee (Embryonic Stem Cell Research Oversight—ESCRO committee) should approve any research that involves putting human embryonic stem cells into a non-human animal. Any animal that has received human embryonic stem cells must not be allowed to breed, and that no human ES cells should be transplanted into nonhuman primate blastocysts. Furthermore, the National Academies guidelines say that human embryonic stem cells should only be introduced into nonhuman animals when no other experiment can provide the needed information. Any experiment in which human neural cells are introduced into a nonhuman animal, if they might contribute significant structural components to the brain of the host animal, requires strong scientific justification.
These guidelines, address the concerns of many people who feel that ethical problems could arise if human-animal chimera research is not thoroughly vetted before it is conducted. If followed, the guidelines should prevent possibilities such as animals with human gametes breeding and potentially producing a fertilized “human” zygote, and they will allow research to proceed at a metered pace so that society can realize the potential good of such technology while minimizing the harm. Although these guidelines are not mandatory, funding agencies will probably require adherence to them when funding is awarded.
Summary
The 5th International Bioethics Forum: Clones and Chimeras in Madison, WI, discussed the potential for understanding disease and developing more effective therapeutics as a result of research involving embryonic stem cells, cloning and the creation of human-animal chimeras. However the discussions at the Forum also recognized that this research raises many important ethical and moral questions and underscored the importance of maintaining dialog between scientists and nonscientists at all times.