Tuesday, September 11th, 2012
Central Park East - 7:10am

Another beautiful Fall-ish feeling morning today!  As promised, welcome to Part III of What does Jen do at grad school? 

Part III:  What does this have to do with computational modelling, mathematics, and why would any governmental agency (i.e. the NIH or NSF) ever give you money to do something so esoteric?


Well, let's review first.  It's been a few days after all. 

We had established that Interleukin 2 is a "cytokine" or a messenger that goes between T cells to tell them to become activated because there is something dangerous around.  T cells, if you recall, are immune cells distinct from B cells that either kill virus-infected human cells or help B cells make antibodies to fight off pathogens. 

T cells express low levels of Interleukin 2 receptor and are surrounded by Regulatory T cells, which express higher numbers of the Interleukin 2 receptor.  This is to protect you from T cell activation when there's only low levels of Interleukin 2 around. 

When a T cell Interleukin 2 receptor senses a molecule of Interleukin 2, inside it's cell membrane it phosphorylates STAT5, which then goes to the nucleus and changes gene expression in 2 ways:
1.  Tells the T cell to make more Interleukin 2 receptor
2.  Tells the T cell to divide and make more of itself. 

Now, STAT5 is phosphorylated predictably in response to Interleukin 2 connecting with the interleukin 2 receptor.  

So, it's a little more complicated than this, but for simplicity's sake we'll say:

1.  For every molecule of Interleukin 2 that interacts with the Interleukin 2 receptor, 1 molecule of STAT5 gets phosphorylated.  Additionally, we'll represent it like this:

This is the part where most people take one look at an equation and say "NO WAY, José!"  You're not MOST people, though, right?  The fact that there are 2 arrows refers to the fact that nature isn't perfect.  Sometimes, Interleukin 2 and the Interleukin 2 receptor fall apart before they get the chance to make a molecule of phosphorylated STAT5.  Most of the time they stick together well and succeed in making a molecule of pSTAT5.  "K" is a way that we refer to "rate" in science.  Rate, like the RATE at which your car is going is measured in Miles per hour.  The K represents the "RATE" at which a molecule of pSTAT5 is either made (on) or falls apart (off).  So, a molecule of STAT5 may be phosphorylated at a rate or "k on" of 1 molecule per second and may fall apart at a rate or "k off" of 1 molecule every 5 seconds. 

So now, experimentally, we can measure how much pSTAT5 is in a cell and how much Interleukin 2 receptor it has on it's surface.  As I mentioned in earlier posts, we have trouble measuring the amount of Interleukin 2 that is in the lymph node at any given time.  It's technically difficult, which means that we haven't figured out an accurate way to do it yet. 

So, if we know how much pSTAT5 is in a cell, and the rate at which pSTAT5 either is made or falls apart, AND we know how much Interleukin 2 receptor is on the cell, we can calculate the amount of Interleukin 2 that the cell must be "seeing." 

Why would we want to do that?  Why would we want to know how much Interleukin 2 is in a lymph node at any given time? 

Well there's something else about this system that we only know from testing it "in vitro" or in a plastic plate where we put T cells and pathogenic stuff and see what happens. 

We know that the amount of pathogen (i.e. virus or bacteria or venom, etc...) is proportional to the amount of Interleukin 2 that T cells make (we can measure Interleukin 2 in vitro, but it's hard to measure it in a living animal).  That is, as amount of pathogen increases, the amount of Interleukin 2 that gets made also increases.  You can represent this with the graph below.

 

So, as I mentioned above, if we can calculate the amount of Interleukin 2 from the amount of pSTAT5 and Interleukin 2 receptor that are in the cell, we can also calculate the amount of Pathogen that was initially present.  

Cool.  

"But!!!!"....(you may say)....

"But can't you just count how much pathogen was in a body in the first place?  Can't you culture bacteria and viruses and stuff like that? Why do you need such a roundabout way to do something that can already be done?"

"YES!  You can." (I'll respond)  

What about autoimmunity?  What about Graft Versus Host Disease (GVHD) following bone marrow transplants?  What about Lupus?  What about Rheumatoid Arthritis?  What about Crohn's Disease?  What about Psorasis?  What about Rheumatic Fever following Streptococcus infection?  

There isn't really any measurable bad stuff from those types of diseases, but we have a LOT of T cell activation.  We have so much T cell activation that your body's own T cells are attacking your kidneys, skin, intestines, heart, and joints.  But if you culture an affected person's blood there's no bacteria and no viruses.  There's no parasites and no allergens.  But if the T cells are activated, there must be bad stuff there....

and we can measure it....by NOT measuring it.  

Just by knowing how much pSTAT5 and Interleukin 2 receptor is on the surface of T cells.  

Cool.  

I'll conclude tomorrow.  I hope this was clear.  It got a little more complicated today so if anyone has any questions don't hesitate to email me or text me!  

Have a great day!