Teaching Responsible Conduct of Research (RCR): A Resource Guide for Professional Science Master’s Degree Programs Case Studies from Biology and Biotechnology Case: ‘Humanizing’ Animals Discipline: Biology and Biotechnology Ethics Topic: Animal Studies Case Subject Matter: Chimeric Animal Studies Controversy: ‘Humanizing’ Animals Authors: Michele Hom, Sara Wingate Jenny, a molecular biology doctoral student, is contemplating instructions her PI gave her that morning. The approval and executive decision finally come through – begin inserting human stem cells into the developing brain cortex of fetal murine embryos in utero and continue inserting human stem cells into embryonic cortex of multiple generations of the same murine progeny. It had been a long decision proposal caught in the middle of multiple discussions, debates and concerns over the past several months. Substantial research concluded that creating a new murine animal model to emulate human-like brain physiology and function would greatly enhance pre-clinical in vivo research efforts to discover and develop new potential drug therapies to treat Alzheimer’s disease. Current Alzheimer’s animal model have proven inadequate for this debilitating disease and have not yet been fully analyzed. Much research is being conducted on the possibility of utilizing chimeric animal models to increase the correlation of pre-clinical animal model research to results that could be predicted in clinical trials in human research subjects. Jenny’s PI is one of the leaders in this research. It is generally accepted that certain animal models may not produce the same outcomes when the same experimental drugs are tested in human subjects and fuels the controversy that challenges the validity of animal models and their biological systems compared to human physiology when pharmaceuticals are tested in preclinical trials, therefore these results should be disregarded. There is no guarantee that any results obtained when tested on animals would have the same result in humans. Understanding this discussion and with the advent of biotechnology, the decision to produce murine models with a significant percentage of human neurons would present more Page 1 Teaching Responsible Conduct of Research (RCR): A Resource Guide for Professional Science Master’s Degree Programs realistic data when assessing pharmaceutical therapeutics and the impact on the human (mouse) brain. Jenny’s PI proposed to develop a chimeric murine model for Alzheimers would include murine and human DNA. Jenny is a conscientious doctoral student who has done a substantial amount of animal studies but recognizes her obligatory responsibilities of her academic status and the possible consequences of objecting to research directives give to her by her PI. She is concerned with the possible effects of combining human stem cells with murine developmental fetal brain matter that, as has been contemplated in the literature, could conceivable produce animal subjects not only with the desired human neurological characteristics but also with unintended human developmental conscious characteristics. Such a development would call into question the very meaning of human vs. animal as it is understood and defined today. Jenny, however, being concerned about her pending doctoral dissertation and graduation, decided to forgo her intrinsic morality concern and develop the murine models as instructed knowing full will that these mice and their future progeny could have fully humanized brains. Though concerned, she presumed the project would be OK and assumed her supervisors and PI had a thorough understanding of the significance and possible risks this study entailed. She also speculated that even if a mouse had a humanized brain, the weight at 0.4 grams would be inconsequential compared to the 1400 grams that a human brain is composed of. One issue she did not consider was the consequences of creating a mouse with neurological function that might impart an unintended consequence of producing a murine species with consciousness that was more human than mouse. A couple years passed and Jenny, now a Ph.D., moved to a post-doc position at a leading medical center. Amy, who replaced Jenny, is conducting a study that involved the use of the progeny of the murine models Jenny produced using human stem cells. As she prepared to euthanize one of the mice observed the mouse lie down in a “fetal-like” position and appeared to look directly at her. Amy, who had no prior knowledge of the previous experiments, had never before observed such human-like behavior and became concerned that these murine subjects were curiously unique – and in fact too unique based on the literature. She contacted the local papers with her observation their capabilities of almost human-like behavior. She created quite a controversy stimulated by the media, that resulted in the entire laboratory and the research being produced being discontinued. This not only affected the researchers but also the Alzheimer’s research that, through the use of these human- Page 2 Teaching Responsible Conduct of Research (RCR): A Resource Guide for Professional Science Master’s Degree Programs like animal models, had become the standard for Alzheimer’s in vivo drug testing and have produced two novel therapeutics about to enter first-in-human clinical studies. Teaching Questions: Does this research violate second-order moral questions regarding the very nature and purpose of Morality itself? Should the research to develop an animal model with a humanized brain for Alzheimers research been allowed to continue? Should it have been a concern that human consciousness produced in a non-human species could be an unintended consequence of the research? Now that immutable human-like characteristics have been observed and confirmed what should be done with the research, with the progeny, and with the experimental data, processes and know-how? Page 3