Lecture Summaries

1 Orientation Instructors and students will get to know each other, discuss the course objectives, review the syllabus, and introduce the topic for week 2.
2 History of stem cell biology and axis of research The mouse, Mus musculus, is one of the most used animal models for the study of basic biology and human disease. The ability to systematically alter the mouse genome is one of the core strengths of the mouse as an animal model which is entirely dependent on mouse embryonic stem cell technology. We will discuss two early papers that lay the groundwork for several Nobel Prize winning experiments performed in the mid-1980s. The first describes the ability to generate chimeras from embryonic carcinoma (EC) cells and the second describes the isolation of embryonic stem cells using conditioned medium from ECs.
3 What makes a stem cell a stem cell? Part 1 – Transcription Factors Each cell has a specific gene-expression program that determines the cell's potential and function. This program is largely controlled by transcription factors. Embryonic stem (ES) cells express a core group of transcription factors that maintain the unique ability of these cells to replicate indefinitely and give rise to all three germ layers. The first paper describes the cloning of a critical transcription factor for ES cells. The second describes how this transcription factor fits into the larger context of the transcriptional network.
4 What makes a stem cell a stem cell? Part 2 – Chromatin Structure The ability of a transcription factor to bind to its specific target DNA is regulated by many factors, including the dynamic 3D structure of packaged DNA. Accessibility of target genes by transcription factors is regulated by the changing composition of the chromatin proteins that coat the double helix of DNA. We will discuss the relationship between chromatin structure and gene activity and its role in the maintenance of a pluripotent cell state. In the first paper, the authors report using genome-wide technologies the observation that two opposing histone modifications, H3K4me3 and H3K27me3, sit at genes that are important for embryonic development. The second paper discusses how a single factor involved in regulating the chromatin state, histone deacetylase 1, regulate both proliferation and differentiation.
5 New Technologies ES cell research is a quickly evolving field. We will discuss recent technological advances applied to ES cell biology. The first paper utilizes RNAi screens to identify genes important for ES cells, while the second paper uses proteomic methodologies to identify how the transcription factor, Oct4, regulates key aspects of ES cell biology.
6 Field trip and 1st assignment

Field Trip: Stem Cells Seminar – MIT Biology Colloqium

Speaker: Judith Kimble, University of Wisconsin – "An RNA regulatory network controls C. elegans germline stem cells."



Kershncer, A.M., and J. Kimble. "Genome-wide Analysis of mRNA Targets for Caenorhabditis elegans FBF, a Conserved Stem Cell Regulator." Proc Natl Acad Sci USA 107, no. 8 (23 February 2010): 3936-41.

Morgan, C.T., M.H. Lee, J. Kimble. "Chemical Reprogramming of Caenorhabditis elegans germ fate." Nat Chem Biol. 6, no. 2 (February 2010): 102-4.

7 Cloning of mammalian cells

The production of the first cloned sheep (Dolly) over 10 years ago sparked much attention among the general public. Beyond producing a cloned animal, this paper was the culmination of many years of important biological research. The first paper is an example of some of the key work that was performed in the frog and that led to the landmark Dolly paper.

8 Reprogramming and Trans-differentiation - Transcription Factors, 2.0. The power of transcription factors to drive a specific cell state is so dominant that the expression of a small number can have a profound effect on cell. For years it has been well known that misexpression of transcription factors can alter normal cells to cause tumors. It is only recently, however, that we have learned to control this power for good. The first paper describes a technique to generate mouse ES cells from fibroblasts, cells that make up the skin, while the second describes the generation of heart muscle cells.
9 Are cancer-initiating cells stem cells? What gives rise to cancer? Is it a cell that has stem cell characteristics? Are tumor-initiating cells actually cancer stem cells? We will read and analyze two papers that claim the initiating cells should be termed cancer stem cells. We will discuss whether this terminology is justified.
10 Using lessons from stem cells to treat diabetes ES cells have the potential to generate any cell/tissue of a complex organism. Recent advances in the control of cell state allow for the differentiation of ES cells in vitro to many cell types. We will discuss how reprogramming and in vitro differentiation offer new avenues toward treatments of diabetes. The first paper describes the generation of insulin producing cells of the pancreas (beta-cells) in vivo from ES cell-derived tissue, while the second uses mouse genetics to generate these cells in vivo without transplantation of in vitro derived tissue.
11 Stem cell therapies The use of stem cells has been at the center of many debates, from their safety to ethical issues. Nonetheless, stem cells show great promise for the treatment of some diseases. We will explore current and future stem cell treatments. The first paper describes the original attempt, more than 50 years ago, at stem cell therapy, while the second uses stem cells to help neuronal regeneration.
12 The future of regenerative medicine One goal of stem cell research is to improve human health. We will discuss the latest ideas and the first clinical trial based on stem cell therapy. The first paper describes the generation of a prostate from adult stem cells, while the second paper reports animal model data that form the basis for the recently FDA-approved clinical trials of GRNOPC1, a drug developed by biotechnology company Geron™ Corporation.
13 Final assignment In-class debate concerning two research articles published in the last year. The students should include a summary of the key findings, a critical assessment of the scientific experiments, including controls, and an evaluation of the impact of the scientific discovery as well as present alternative experiments. Both papers expand on the concepts we have discussed to date, are related to the biology of "stemness" in specific tissues and may impact regenerative medicine in the future.