Pluripotent stem cells and genome engineering for modeling human diseases

Lectures: 1 session / week, 2 hours / session

At least one of the following prerequisites is required:

7.03 Genetics

7.05 General Biochemistry

7.06 Cell Biology

7.28 Molecular Biology

One of the major priorities in biomedical research is understanding the molecular events that establish the complex processes involved in human development and the relationships of these processes to human disease and disease progression. The role of stem cells as a tool to help reveal these processes has long been appreciated. During the 20th century, Mario Capecchi, Martin Evans, and Olivier Smithies made ground-breaking discoveries using mouse embryonic stem cells for gene targeting in mammals. Their efforts made it possible to modify DNA of specific genes within the genomes of living and fertile mice, allowing scientists to determine the roles of individual genes in health and disease. This approach of genome engineering has produced numerous non-human vertebrate models of human disorders, including diabetes, cancer, cardiovascular and neurodegenerative diseases. For their discoveries, Capecchi, Evans, and Smithies shared the 2007 Nobel Prize in Physiology and Medicine. In 2012, the Nobel Prize in Physiology and Medicine was received by Shinya Yamanaka and John Gurdon for their discovery that cells of mature humans and other animals can be reprogrammed to an early embryonic stage, known as pluripotency, which can then lead to various cell types of the adult organism.

This work and many other studies have stimulated the stem cell field into generating these pluripotent stem cells from human patients, and these patient-specific stem cells have been used to better model human diseases by reflecting the disorder in a culture system. Scientists can now cause the patient-specific stem cells to become the cell type that is affected by the disease, to study the diseased cells and understand the mechanisms underlying disease progression, and to use these cells to test potential treatment options. In this class, we will explore stem cell biology and the way in which it has developed and shaped our ability to study complex human disease.

We will introduce the field of stem cell biology and genome engineering through critical reading of both the classical and newest primary research literature. This course will focus on the methods behind embryonic and induced pluripotent stem cells, genome editing to create transgenic animal models of human diseases, regenerative medicine such as the transplantation of stem cell- derived cell types to replace diseased tissues, and current hot topics in genome engineering such as CRISPR/Cas9; a novel method that can be used within a live organism or cells to delete or insert genes of interest. In addition, this course will discuss specific disease model systems and their benefits / limitations for understanding the disease and treating human patients. Students will obtain a deep understanding of the main concepts and questions concerning stem cell biology, become familiar with current research techniques to model complex human diseases, and learn to critically evaluate the experimental design and claims in this field.

Each week, two scientific manuscripts will be assigned as required reading for the following week. The class session will begin with students summarizing the manuscripts, discussing each figure and table, the experimental methods, the key experiments and the key control experiments, the author's conclusions, potential future experiments and the meaning of this research work in regards to the specific research field. In the final ten minutes of the class period, the instructors will introduce the upcoming topic for the following week to provide any information necessary for students to understand the upcoming required reading.

The main goal of this course is to teach students how to read and critique the primary biomedical scientific literature. Students are encouraged to voice their viewpoints, ask questions, and describe their interests to drive the course of discussion. Students are expected to come to class each week prepared to discuss the manuscripts. Students will be expected to be able to summarize the assigned manuscripts and discuss the figures and tables in each.

The class is graded on a pass / fail basis, and grades will be determined by student participation and engagement in the course topics, as well as by attendance at each class session and completion of the oral and written assignments.

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