The Initial Exposure to Subsystems

The initial exposure to subsystems should take approximately 5-7 weeks. The goals of this section will be

to understand one subsystem in depth,
to gain familiarity with SEED, KEGG, and other tools needed to explore the subsystem, and
to produce a detailed analysis of at least the SEED and KEGG assessments of which genes actually play each role in the sequenced genomes.

This can be summarized by thinking of the goal as having the student work with an existing subsystem and to write a detailed review of what is known of the subsystem. Obviously, the quality of the review is limited by the time available. It should lay the foundation for a more complete review (to be done over an entire semester), should thde student and professor select this project as a follow-on. The review itself should be an HTML document, although many of the detailed notes should also be included in the notes section of the updated subsystem.

I believe that the instructor should probably meet once per week for a lecture and be available for questions throughout the week. Students should sign up for the seed-users mailing list, and some advice can be gained via the subsystems forum. Students are encouraged to ask questions. If we get to many to handle properly, we will try some other mechanism.

Students need to compile a set of comments, criticisms, proposed alterations, and conjectures all relating to their subsystems. The final "product" of the course will be an enhanced subsystem with copious notes.

The First Week

During the first meeting, students must

learn how to access whatever version of the SEED they are to use,
pick or be assigned a subsystem to work on,
learn how to make a copy of the subsystem for themselves, and
begin an analysis of the subsystem.

The first three points need to be covered in a handout prepared by the instructor (and the handout should probably be a URL given to the students at the start of the first lecture).

The actual lecture should cover the overall goals of the course, assignments of subsystems, and then a period in which the instructor goes through the steps in an on-line demo.

I believe that the students should be given fairly substantial, but very well-known, metabolic subsystems that are not overly complex. Feel free to ask me for advice, and I urge instructors to let me know which they choose (so I can try to avoid having the same subsystem being reworked in multiple classes -- remember, the goal will be for the best efforts to be extended to full reviews).

I suggest that the instructor pick an existing subsystem and practice copying and deleting it. You might try one of mine, since I try to keep my latest copies published (so there is no chance that you can do anything too awful to them -- I can always just download a current version).

Once the students have seen how to copy a subsystem (to create their version with a distinct name), they should be given several specific goals to work on:

They should locate the section of the KEGG maps covered by the subsystem, and they should make drawings (or print copies of it) that can be used to make notes upon.
They should create an editable file showing the specific reactions, and each reeaction should be marked as either reversible or irreversible. I believe that this information is probably accessible via the EMP Database, but there may be many ways (including chatting with a good biochemist) to get the data.
They should begin compiling literature references to reviews and to papers in which enzymes of the pathway have been characterized.
They should learn how to access their copy, make a list of the variant codes, and attempt to figure out the meaning of each code. It is the responsibility of the author of the subsystem to assign meaningful codes, but this is often not done. The student needs to formulate what constitutes an operational variant of the subsystem.

This seems to me to be about what one might be able to accomplish in the first week.

The Second and Third Week

The goals of the second and third weeks are roughly as follows:

The student will need to learn how to access his subsystem and to understand the information that is included in it. The instructor will need to go through many of the fields and options. Gradually, the student will learn how to open up separate windows to keep track of distinct genes/proteins. A minimal introduction should be given, and then the instructor and students should move to specific questions (and let these drive the exploration).
I suggest that much of these two weeks be focused on cells of the spreadsheet that contain duplicate genes (if you find yourself with a subsystem that has few duplicates, so be it -- add more organisms to the spreadsheet). First ask the students to compile a list of spreadsheet cells that contain multiple gene IDs. Then, ask them to move through them seeing whether or not the duplicates make sense. Each duplicate warrants a discussion. Exploring the duplicates can consume an arbitrary amount of time, and in most cases the results will not be clear. However, this does offer a framework to explore the functionality of the SEED, and in many cases the analysis will reveal errors in the subsystems.

Perhaps the most valuable tool in analysis of duplicates will be the use of clustering on the chromosome. One might also consider introducing otrher techniques, but clustering is essential. The student should be asked to formulate a rough idea of which organisms show clustering. In cases with duplicates, the student should record which of the genes, if any, are in clusters.

The Fourth Week

The fourth week should be used to explore "missing genes"; that is, to focus on spreadsheet cells which probably should contain a gene, but do not. There are many possible explanations, and the student should move through the spreadsheet cells trying to determine what the most likely explanation is in each case.

The student will need to learn how to

determine whether or not the genome is missing pieces,
whether the missing gene occurs in a number or organisms,
whether it might be in the genome, but just not "called",
whether the pathway might not really be active in the organism, or
whether there is probably a new form of the enzyme that has not yet been characterized.

The Fifth and Sixth Week

The fifth and sixth week should be used to summarize results and polish the subsystem. The student should compose consistent variant codes and document them. A list of genes that should have been called, but were not, should be added to the notes. Outstanding issues requiring wet lab conformation should be summarized. If there exist genomes which should be added to the spreadsheet, the student should begin adding them.

Summary

These comments are intendced only as loose guidelines. Instructors are urged to keep detailed notes on how the overall structure of the class could be improved, what problems to watch out for, and so forth. As this component evolves we will try to update this all too brief discussion.