What is the meaning of the word "visualization"? Rudolf Arnheim, Harvard University Professor, researched and wrote books about visualization and the role of visualization in guiding human thought. Short of reading these books, here is a nice, simple visuallization example: I am sitting atop a red blood cell, with a mock malaria parasite inside of it. Hemoglobin, the major protein inside the red blood cell, has a strong, red color. Through time, the malaria parasite feeds on the hemoglobin, so the hemoglobin disappears from the cell. In this visualization, the parasite is not growing, is not moving and is not reproducing. Only the hemoglobin is disappearing from the red blood cells. The top frame has less hemo than the bottom...hence I call it a reversed time sequence, because time is flowing from bottom to top frames). My avatar is about 2 microns tall, relative to the actual size of the red blood cell.
This is a very simple visualization, all done within SL. It took me less than five minutes to make this. Visualization is easier to some and harder to others, but SL is very easy, simple and fast when it comes to visuallzation work. There are no 1CellPk scripts controlling this visualization..just me manually changing the colors. So, it is just a simple illustration of visualization, meant for my graduate students to begin to understand how to use SL for 1CellPK visualizaiton purposes. In the future, I would be looking forward to my graduate students experimenting with visualizing changes occurring within the parasite inside the red blood cell. I would like to be able tosee us "treat" the red blood cell with drug (chloroquine, falcipain-2 inhibitors, etc) and visualize what happens to the drug as it distributes inside the red blood cell and then inside the parasite, and then see what it would happen inside the parasite as it is affected by the drug. Eventually, drug distributions should be controlled by mathematical models. We should be able to make simulations (5-D movies) of drugs with different chemical properties as they distribute inside the parasite. Then, we should be able to sort and analyze the dynamics observed in the movies based on drug's chemical structures. That is, Cheminformatic Assisted Image Arrays. The 5-D movies would be comprised of x,y,z spatial coordinates, signal and time. Linking the movies to chemical structures would make it 6D. Each chemical structure can be described as a multidimensional object, so in fact, a CAIA can have many, many dimensions.
7 comments:
That's a great point that visualization is not necessarily a lot of information - just enough represented in the right way to communicate effectively. In terms of checking the validity of your models, are you set up experimentally to work with Plasmodium falciparum?
To maximize our chances of success, it is best to have all experimental and computational methods firmly extablished first. So, we will start performing preliminary studies in my lab: testing drug accumulation in (healthy) red blood cells exposed to a homogenous extracellular drug concentration. If our prediction of drug accumulation in red blood cells is good, then we will seek a collaborator (expert in malaria) to test predictions of drug accumulation in red blood cells infected with Plasmodium. By then, we should have much of the basic experimental methodology figured out, as well as identifying potential pitfalls, so as to avoid them.
How are you going to measure the concentration in the RBC? Are you relying on an intrinsic property of our products to show up under microscopy?
There are equations/established methods out there to do such experimetnal measurements of drug mass and concentration, but here is a quick description of the general methodology:
While in suspension, one can incubate the RBCs with drug, then centrifuge them down into a pellet, then assay the mass of drug in the pellet. One can get the RBC volume in the pellet by measuring the hemoglobin mass of the pellet (the concentration of hemoglobin in an RBC tends to be constant). In addition, one can get the non-cell drug mass in the pellet by measuring the concentration of some extracellular marker that does not bind to the cells (say, spiking the blood with Trypan Blue, and measuring the amount of Trypan Blue in the pellet)...the extracellullar ratio of Trypan Blue/Drug mass ratio should be constant.
PS.. for detecting drug we would use an LC/MS instrument. We have one such instrument here. Hopefully your molecules will be detectable and measurable...let's find out!
Definitely - this makes a lot of sense. We can ship you some of the compounds that were active against Plasmodium. But if you have been following some of my recent posts, I have some doubts about the actual concentrations achieved during testing. We should be able to get some solubility data shortly to know what we are measuring. Also I think we have a decent plan for getting good library sizes with water soluble ammonium salts, using boc-protected amino acids in the Ugi syntheses.
JC,
For us, establishing good experimental methods for cellPk measurement is a top priority. It is going to take us some time, because Jason (2nd year graduate student in charge of this project) is also taking classes... We will develop the methods with positive control compounds first (i.e. chloroquine). Then we should be able to tackle your compounds. Having said that, please take your time to figure out how to make the compounds water soluble...many compounds fail in clinical trials just because they are not water soluble enough. They need to be sufficiently water soluble that the will enter the body when taken orally. So, one should really aim for a BCS class I clinical candidate early on in the drug development process. It is well worth the effort to have a BCS class I drug candidate, if the ultimate aim is for it to be successful in the clinic.
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