Where We Are At, Part I

Taken from a sharktank digest

I talked to a friend of mine from the list, the other night, who was not afraid to ask questions. He made me realize that some of you, many of you, do not have a handle on the basics of this research. There is no shame in that. You lead busy lives. You have CF. Or you simply think that you are too stupid to understand (this is NEVER true). So,I am going to take some of my time, to get those of you who are not up to date on the basics, up to date.

This is important for several reasons (or I would not do it): (1) You will be able to convince your docs of the efficacy of the treatments that we are now advocating, and will in the future, advocate, if you can understand it yourself. (2) You will cut my work, and produce better search material, more precise search material, if you understand these concepts.(3) Your questions will help us to more clearly delineate our own search for the truth of this disease, and you can form these questions better if you understand more. (4) You will feel more comfortable attempting the use of the new compounds, and therapies that we generate here on this list, if you understand the properties behind their use.

So here we go: The reason that you or your child has CF is because you are missing the FUNCTION of a protein: the CFTR. The FUNCTION, not the protein, itself. It depends upon your mutation as to whether you are missing the protein (as in stop mutations) or not, but that is not relevant to what we are attempting here on this list. Now, this protein sits in the MEMBRANE of the cells that line your lungs, and other organs whose lining has these cells (epithelial) in them. These organs are called exocrine organs. They secrete. They put out fluid. Some tissues, or compositions of cells that line them secrete, and some absorb. The ones that we are concerned with secrete. Keep that in mind.

When this protein is in the membrane of these types of cells, it acts like a door, letting things OUT ONLY. It doesn't let things in very much at all. It's main job is to let things out--to secrete. The protein that is missing, once again, is the CFTR, but there IS another protein that is a lot like it, and that is the MRP (or the multi-drug-resistance associated protein).

Now, what is a protein? It is very simple. A protein is a chain of amino acids. Don't worry about what "amino acids" means right now. It is not important. Just remember the chain, okay? So, a protein is a chain, and just like you drop a chain on a table, it will make certain figures, depending on how you drop it. The thing about a protein, as a chain, is that it always makes the same figure, when it is dropped. It always has the same structure, if it is the same protein.

I like to think of the CFTR protein as kind of a butterfly shape. Or a "W". The middle of the "w"; the point that is lower than the side points, sticks up, along with the side points, outside of the cell. It receives a chemical called phosphate, from adenosinetriphoshate (and turns that chemical into adenosine DI phosphate--see the "tri" and the "di"--three turns to two, when it loses it's phosphate). This is how it is activated; how it starts to do it's job: transport, or secrete.

There are other proteins, like the CFTR, that sit in the membrane of a cell, and act as a door to the outside of the cell. These proteins also have that structure, or one similar: they have that middle part of the "W" that is able to be activated by the phosphate from adenosinetriphosphate. One of these is the MRP protein. It is this protein that CURED CF patients, in France, for two years. This is why we look at it all of the time. Because it cured CF in patients for two years at a time, and because it has been studied for 25 years, which is a much longer time than the CFTR protein has been studied.

Those are the good things about this protein, the MRP. Let me tell you the bad thing, the catch to it all: it is made by the cell, in large quantities, only when there is some kind of toxic metal put into the system, in the form of cancer drugs (which is what caused it to be made in the cancer patients with CF that it cured, in the first place). If we tried to get this protein to be made in the people that we are dealing with, with our limited knowledge, we would probably kill them.

So, we do the next best thing: we study it, and we look at what it causes to be secreted. And now, we come to what we are doing here. There are certain things that the MRP secretes. GSH is one of them (or rather, GSSG, the oxygenated form of GSH). Metallothionein, or a form of it, is another. Sulfates, glucuronides. All of these things. But GSH and MT are the most important ones, and these are the things that can be traced back, very readily, to some of the "misworkings" of the system, both in terms of inflammation and of infection, that we see in CF.

Melanie Childers
29 June 1999