The use of model organisms has greatly benefited the study of many human diseases including cancer, diabetes, congenital heart disease and multiple neurodegenerative disorders. For example, we witnessed the decade-long quest to construct increasingly sophisticated and reliable mouse models of the human cancer syndrome type 1 neurofibromatosis (NF1) (Jacks et al., 1994; Silva et al., 1997; Cichowski et al., 1999; Vogel et al., 1999; Zhu et al., 2001; Zhu et al., 2002). Novel chromosome engineering technology was pioneered in the race to elucidate the DiGeorge syndrome gene, which is responsible for cardiovascular and craniofacial defects in children harboring deletions of a portion of chromosome 22 (Lindsay et al., 1999; Lindsay et al., 2001; Merscher et al., 2001). Seemingly simple organisms like the fruit fly, the nematode worm, and even baker’s yeast unexpectedly emerged as powerful new model systems to study the most complicated of neurodegenerative diseases, including Parkinson’s, Alzheimer’s and Huntington’s diseases (Link, 1995; Krobitsch and Lindquist, 2000; Auluck et al., 2002; Outeiro and Lindquist, 2003). Thus, the power of diverse experimental model systems is being brought to bear on many devastating human diseases. Over the past decade these new model systems have provided key insights into disease mechanisms and have led to the development of novel therapeutic strategies. One such success story is the emergence of histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington’s disease. HDAC inhibitors were first discovered to be efficacious in a fly Huntington’s disease model (Steffan et al., 2001). These results were replicated in mouse models and clinical trials are currently underway in human Huntington’s disease patients.
In recognition of the important role experimental model systems play in biomedical research, at the University of Pennsylvania (PENN), we devote an entire graduate-level course to the study of human disease models: Seminar on Current Genetic Research: Modeling Human Disease in Diverse Genetic Systems. We survey a diverse group of diseases, ranging from neurodegenerative disorders such as Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis and the polyglutamine diseases (for example Huntington’s disease) to childhood genetic diseases such as fragile X mental retardation, NF1 and Rett syndrome. We also cover digestive diseases, diabetes, congenital heart disease, muscular dystrophy, deafness and even some human sleep disorders that have a genetic component. This course is open to first- and second-year graduate students in all biological research programs at PENN. The range of topics and the diverse backgrounds of the students are major strengths of the course. For example, neuroscience students get the chance to learn about heart development and cancer biology, whereas developmental biology students are exposed to animal behavior and electrophysiology experiments. Moreover, students working in mouse labs get to learn about the potential usefulness of other systems, such as fruit flies or zebrafish, and how those systems might be able to complement their current research project.
The weekly class is run in a seminar-style format and each week we focus on a different human disease (Table 1). During each class, a student is selected to lead the discussion. This student gives a brief introduction to the particular disease that we are covering that week. The introduction includes essential background information on the disease, such as clinical features, rate of incidence and genetics, as well as gaps in our current understanding of disease mechanisms. The discussion leader also provides background information on new techniques used in the papers that we are covering that week. This might include an explanation of the Cre-loxP system in the mouse, how to make mosaic clones in Drosophila, temperature-sensitive mutations in C. elegans, high-throughput genetic screens in yeast, or the experimental advantages of zebrafish.
Following this introduction, the entire class participates in a roundtable discussion of two primary research papers that involve the use of genetic model systems to study the disease being covered that week. We take turns walking through each figure of the papers, discussing the positive and negative aspects of the experimental approaches. These discussions are usually lively, as we rigorously evaluate whether or not the authors’ conclusions are supported by the presented data and what additional data and/or control experiments would be useful to strengthen their conclusions. Following our 1.5–2-hour discussion of the papers, the student leader presents a summary of the papers and we discuss future directions for this research and ways to improve existing disease models. Each week, PENN faculty members with particular expertise in a given model system and/or disease area join the discussion and often provide insight into where the field is currently heading.
At the end of the semester, for their final assignment, pairs of students select a recent or in-press article related to human disease modeling and write a ‘Journal Club’ type article on that paper. These ~800-word articles include an introduction of the disease and open questions in the field. This is followed by a summary of the paper, including details about novel experimental approaches and significant results. The student authors finish the article with a forward-looking discussion of how this work is likely to influence the field and lead to new treatment and/or diagnostic strategies, as well as additional issues that remain unresolved and suggestions on how they could be addressed by constructing next generation disease models or by additional experimentation in other model systems. Finally, the students will have the opportunity to submit these articles for potential publication in the Journal Club section of a future issue of DMM.
The completion of the human genome sequence witnessed the birth of new graduate level programs and courses devoted to genomics and bioinformatics. Now that the genomes of various model systems have been sequenced and it is clear that many human disease genes are well conserved in these systems (Rubin et al., 2000), intense research efforts have been focused on harnessing the power of model organisms to explore the function of human disease genes and on defining how they contribute to disease pathogenesis. Although there are benefits to each model system, there are also limitations. Relying on multiple systems mitigates the potential pitfalls associated with relying on any one of them. For new diseases, we do not know which model system will pay off in the long run. More likely, each of these models will offer a unique advantage and it will be the synthesis of multiple approaches that will be the most productive. Thus, disease modeling in the classroom, at PENN, as well as in university classrooms around the world, will help equip the next generation of scientists with the tools and ideas that are necessary to explore and tackle even the most daunting human diseases.
Aaron Gitler is an Assistant Professor in the Department of Cell and Developmental Biology at the University of Pennsylvania.