# Syllabus

## Course Meeting Times

Lectures: 1 session / week, 2 hours / session

## Prerequisites

At least one of the following courses:

7.03 Genetics
7.05 General Biochemistry
7.06 Cell Biology
7.28 Molecular Biology

## Course Description

Where do new drugs and treatments come from? This class will take you from the test tubes and mice of the laboratory to the treatment of patients with deadly blood disorders. Students will learn how to think as a scientist through discussion of primary research papers describing the discoveries of several novel treatments. Topics such as gene therapy, the potential of drugs based on RNA interference and the reprogramming of somatic cells into stem cells for regenerative medicine will be discussed.

We will consider in depth the leukemia drug Gleevec, which is often hailed as a miracle drug or silver bullet. This drug is used to treat chronic myelogenous leukemia (CML) and kills leukemic cells while normal cells are left alone by targeting an oncogenic protein that exists in only the leukemic cells. The unprecedented success of this drug's achieving 90% efficacy in patients depended strongly on basic research. Firstly, an abnormal chromosome was discovered. Then the exact genetic defect — bcr-abl chromosomal translocation was identified. Importantly, the abnormal kinase activity encoded by the bcr-abl fusion genes was shown to be the cause of leukemia and finally a specific inhibitor of this kinase was developed.

This striking success increased the rationale for bringing 'bench' discoveries to the 'bedside.' We will discuss issues involved in drug development, such as lead compound discovery, modification through medicinal chemistry and efficacy and toxicity testing in vitro, in animal models and eventually in humans in large-scale clinical trials. Just as bacteria can develop resistance to antibiotics, leukemic cells similarly can evolve mechanisms to evade the therapeutic effects of Gleevec. Strategies will be discussed to attack Gleevec-resistant leukemic cells. Finally, we will explore the uses of Gleevec in diseases other than CML that constitutively express the oncogenic Abl kinase or other kinases that have proven also to be inhibited by Gleevec.

## Course Format and Goals

The course will involve a weekly analysis of two scientific papers. It is essential that everyone read the papers before coming to class so the papers can be fully dissected, figure-by-figure. The success of the class will depend on your participation in the discussions. The main goal of this course is to familiarize you with how to read and analyze primary scientific literature. You will practice critical reading and discussion of scientific papers and learn to evaluate data, experimental design and methods. You will also be introduced to a variety of classic and modern techniques in the area of hematology.

## Assignments

There are weekly reading assignments. In addition, each student will choose one of the papers presented during the course that they found particularly interesting and suggest either an experiment that they think was missing in this paper, or a follow up experiment that will help answer one of the questions relevant to this paper. Later in the term each student will give a short (10-15 min) oral presentation about the additional experiment they proposed.

Students should work on their papers starting in week #3 and plan to make their oral presentations prior to Week #11. (The last class is Week #13.)

## Grading

The course is graded pass/fail. A passing grade will be awarded to students who have satisfactory attendance, participate in discussions and have completed class assignments appropriately.

## Calendar

Course calendar.
WEEK # | TOPICS
--- | ---
1 | Introduction
2 | From Stem Cells to Blood
3 | Gene delivery vehicles engineered from viruses
4 | Treating genetic disorders by fixing the bad gene
5 | RNAi: Using an ancient defense against viral infection to turn off disease genes
6 | Future of personalized medicine using induced pluripotent stem (iPS) cells
7 | Field trip to the Whitehead Institute and to the Whitehead Flow Cytometry Facility
The journey of a 'wonder' drug, Gleevec
8 | Identification of bcr-abl translocation and its oncogenic properties
9 | Drug development for inhibiting kinase activity in the bcr-abl fusion
10 | Testing the efficacy of Gleevec in cell lines, mouse and human
11 | Evolving resistance to Gleevec
12 | Overcoming Gleevec resistance
13 | Use of Gleevec in other diseases