Source: NIH/National Institute of Allergy and Infectious Diseases
Posted: July 12, 2006
New Program Aims To Model Immune Responses And Key Infectious Diseases
A new program at the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH), aims to better understand the complex biochemical networks that regulate the interactions between infectious organisms and the human or animal cells they infect. The Program in Systems Immunology and Infectious Disease Modeling (PSIIM) will employ a powerful new approach called computational systems biology to develop a deeper understanding of how pathogens cause disease and how the immune system responds to them.
``Understanding the daunting complexity of biological systems is the greatest challenge and at the cutting-edge of science in the 21st century,'' says NIH Director Elias A. Zerhouni, M.D. ``The creation of this program will strengthen the intramural research program here on the NIH campus.''
The wealth of information gleaned about the human genome in recent years has identified many of the genes, proteins and other molecules involved in various biological systems. But understanding how these pieces work together to produce the complex physiological and pathological behavior of cells and organisms is not well understood. The goal of the PSIIM, which is a component of NIAID's Division of Intramural Research (DIR) under the leadership of immunologist Ronald N. Germain, M.D., Ph.D., is to create a way to ask how whole systems of molecules, cells and tissues interact during an immune response or when confronted with an infectious agent.
``The idea of the PSIIM,'' says NIAID Director Anthony S. Fauci, M.D., ``is to use systems biology to allow scientists to ask very big questions they may not have been able to fully address even a few years ago--such as how infectious organisms invade human cells, how the toxins they produce cause cell and tissue destruction and how these pathogens evade or manipulate the immune response.''
``Once we understand these interactions, we can make strategic decisions about how to interfere with infectious disease pathology or how to direct immune responses to better fight infections,'' says DIR Director Kathryn C. Zoon, Ph.D., adding that these new insights can serve as the starting point for the design of new drugs to treat diseases or the development of new vaccines.
By creating computer models of complex molecular interaction networks, PSIIM investigators will be able to simulate the biology of cells, tissues and, eventually, organisms. The program will also use state-of-the-art experimental approaches to determine how closely these simulations predict real behavior. As the models improve, scientists should gain the ability to predict how drugs and other interventions will affect a cell or organism and whether such treatments will be tolerated by the host while they fight the infectious agent. Although most of the studies will be conducted with less dangerous pathogens, special facilities in the new C. W. Bill Young Center for Biodefense and Emerging Infectious Diseases at NIH will enable PSIIM scientists to examine such questions with microbes that cause diseases such as anthrax, virulent forms of influenza, tularemia and plague. The program will encourage collaboration between NIAID researchers and other scientists from both inside and outside NIH in efforts to better understand infectious diseases and the immune system.
The cornerstone of the PSIIM research project is a software package called Simmune, which enables biologists to model many types of biological systems. Created by NIAID scientist Martin Meier-Schellersheim, Ph.D., and his colleagues, the software allows a scientist to use a simple graphical interface to easily define the interactions between individual molecules in a large network, or the behaviors of cells in response to external signals. Once a scientist inputs quantitative information obtained by laboratory measurements, Simmune can then simulate the behavior of the whole signaling network or of an entire cell. The software does this by automatically creating a mathematical model involving special equations and then solving these equations for the specific conditions the user entered into the program.
Before Simmune, making such mathematical models by hand often took months and required extensive expertise in applied mathematics. In addition, making changes to an existing model was very time-consuming, which limited the complexity of what could be modeled. ``With Simmune, we are trying to empower a broad range of biological experts, allowing them to easily make and modify detailed quantitative models of the biological systems they have studied in the lab for years. The hope is that these models will provide a deeper understanding of how complex behaviors arise, leading to new insights into disease,'' says Dr. Germain. ``One of the great advantages of Simmune is that it gives biologists a way to do the difficult mathematics needed for such modeling without having to actually be involved with the mathematics.''
In the first stringent test of the new software, Drs. Meier-Schellersheim, Germain and their colleagues demonstrated that Simmune can accurately predict cell function in both time and space. In an article to be published July 21 by the journal PLoS Computational Biology, they describe how they used the software to model a complicated cell-biological behavior known as chemosensing--a fundamental biological process whereby cells sense and respond to external signals, such as inflammatory chemicals involved in an immune response. Using Simmune, the NIAID team modeled what happens in a stimulated cell to the distribution of a membrane-associated molecule known as a phospholipid. The concentration of the phospholipid changes during chemosensing mainly due to the action of two enzymes that synthesize or break down this molecule. Scientists had thought that the destructive biochemical reaction that helps produce high and low concentrations of the phospholipid in different parts of the cell was regulated through some unknown mechanism acting throughout the cell. But a new model developed with Simmune predicted that the enhanced concentration of phospholipid at the ``front'' end of the cell (facing the source of chemical signals) resulted from a combination of two known mechanisms--a very rapid local inhibitory activity and the slower movement of another molecule to a distant part of the cell. The NIAID researchers, who tested their predictions in the laboratory, found that the experimental data matched very closely what they had predicted with Simmune.
The real power of the software, Dr. Meier-Schellersheim adds, is that it can do this same sort of modeling in nearly any cell-based biological system. ``This is a tool that can simulate signaling and cellular processes in general,'' he says, ``whatever system or process you are interested in.'' Because of the general utility of the approach, PSIIM is planning to collaborate extensively with scientists in other NIH institutes and centers, such as the National Cancer Institute's Center for Cancer Research, to help support research in areas such as cancer biology that are outside of the field of immunity and infectious diseases.
Posts: 559 | From Cary, NC | Registered: May 2006
| IP: Logged |
posted
Sounds very exciting. The questions I would have: can they really deal with biological complexity of polymicrobial diseases in computer modeling; can we trust NIH to get this right when they have failed in relatively simple questions of whether chronic lyme should be treated longterm?
Posts: 8430 | From Not available | Registered: Oct 2000
| IP: Logged |
posted
Lou, thanks for reading this. I agree that this has ENOURMOUS potential. Think of it! Biology becoming that much closer to legit hard science. We won't have to worry so much about theory anymore, because we can use math ( A perfect Science) to predict what happens, then we can see if it was right.
Here's the catch, We don't have to rely on the NIH. The program is free, and available online.
We need to get our experts up to date on this software, have them input our theories on Borrelia from experiemental data, and possibly we can begin to mathmatically predict how things happen within the body in a TRULY SCIENTIFIC WAY.
I don't know if this software can handle multiple infections at once, but who knows, maybe we can do them one at a time, and then use the mathmatical modeling software to combine these algorthims. Remember alegebra 2 and the substitution theory??
We combine all three, or four, or however many models into a mathamatical equation, and it gives us a model for how they would combine into one.
I think I'll find the link for Simmune and post it here very soon, just in case, the powers that be try to make sure that Simmune is only given to "licened" ie: NIH and Steere Camp people.
Seriously, if we can show that we are correct Mathamatically, I mean ****, argument over. There is no need for rebutal, its math for crying out loud. Equations are never wrong, people are.
Equations are only wrong if they are done incorrectly, but assuming we can design experiments and use that info quantitativly with this software, then, Lyme Wars Over.
Posts: 559 | From Cary, NC | Registered: May 2006
| IP: Logged |
II. Institute for Theoretical Physics Software What is SIMMUNE ? SIMMUNE is a computer program that can simulate collections of interacting cells. The cells are simulated as individual entities with individual positions in 3-dim. compartments. They can interact with each other via membrane receptors or by secreting molecules that diffuse within the compartment. The behavior of the cells and the properties of the molecules can be defined very flexibly. SIMMUNE was designed primarily to simulate immune system behavior, whence its name. How SIMMUNE works All cellular actions in a SIMMUNE simulation are controlled by stimulus-response mechanisms. A cellular stimulus response mechanism (cellular mechanism for short) consists of a description of a set of stimuli a cell needs to experience before it performs certain actions, and a description of those actions. Metaphorically, a mechanism thus may be considered to be a set of conditional actions: The cell checks whether certain conditions are fulfilled and if they are, it performs certain actions. In SIMMUNE, the condition part of a mechanism can consist of an arbitrary number of conditions that can be combined through logical AND or AND NOT. The action part may consist of one or more actions.
By defining the mechanisms they possess, the user of SIMMUNE defines the different celltypes that may be part of the simulation. Consider for example the mechanisms that describe the thymus dependent activation of a B-cell by a T-helper cell: A T-helper cell that senses a TCR:MHC2 complex on its surface reacts by expressing CD40-ligand and secretion of cytokines (like IL4 or IL5). A mature B-cell that finds a CD40:CD40-ligand complex on its surface and additionally receives cytokine IL-4 but not IFN-gamma switches isotype to IgG1 and gets activated to proliferate and differentiate. Reformulated as condition-action mechanisms:
mechanism 1 (agenttype: T-helper)
condition: TCR:MHC2 complex on surface
action: express CD40-ligand, secrete cytokines
mechanism 2 (agenttype: B-cell)
conditions: CD40:CD40-ligand on surface AND reception of IL-4 AND NO reception of IFN-gamma
actions: switch to isotype IgG1, proliferate, differentiate into antibody secreting plasmacell
So, if the user of SIMMUNE intends to investigate the behavior of an immune system simulation that includes this B-cell activation scheme he has to formulate and add the above mechanisms to the set of mechanisms of T-helper and B-cells respectively. The cellular actions that are possible include expression of membrane molecules, secretion of molecules, proliferation, movement along gradients of molecule concentrations, death. The cellular mechanisms in SIMMUNE have parameters that describe the timescales on which they happen. These parameters may describe the probability for the mechanism to occur or the amount of time needed by the cell to perform the actions of the mechanisms (if the conditions are fulfilled). The latter means that cellular processes which need a certain amount of time before they are completed can realistically be simulated with SIMMUNE, while in differential equation simulations such processes can only be modelled by describing them with a rate parameter. Some features of SIMMUNE SIMMUNE currently allows the simulation of up to 500.000 individual cells (this limit is imposed by computer power restrictions). Different spatial compartments with defineable transport of agents between them can be used. The status of simulations can be watched and manipulated with the help of a graphical user-interface.
Obtaining a copy of SIMMUNE To obtain a copy (binary) of the simulation software SIMMUNE together with a handbook please contact us via email. Supported platforms: Linux (Intel x86), LinuxPPC, IRIX (SGI) and Digital Unix.
Posts: 559 | From Cary, NC | Registered: May 2006
| IP: Logged |
That is a link to the scientific paper in a PDF which outlines Simmune.
Now, being that I'm not a theoretical physisict, I don't have a clue what many of these equations mean. I still need to read this thing through, but for those who have an sufficient grasp on higher mathamatics, perhaps you can explain what these equations mean to the rest of us.
Posts: 559 | From Cary, NC | Registered: May 2006
| IP: Logged |
posted
Did you read the book on the Jasons, which started out as a physics group of experts but has since included other scientists, including biologists? The point was made in the book that the physicists were always trying to simplify biology into nice neat packages that could become predictive, etc. in the way that physics was. But the biologists kept resisting because it was seldom as simple as the physicists wanted it to be.
Being a biologist by background, I am inclined to question people who come up with string theory and do thought experiments and never seem to come to the end of the particle types they can find. Of course, they do have that big success, Hiroshima. They need to be watched, in other words, when they leave their area of expertise.
However, it does look like there is beginning to be a base of immune system information re lyme, toll like receptors and all that stuff, to the point that someone who knows enough about it should explore the idea. There are certainly some big questions out there on lyme and autoimmune markers. Since autoimmunity is treated with steroids, and they make lyme and other infections worse, this is a giant question to answer.
Posts: 8430 | From Not available | Registered: Oct 2000
| IP: Logged |
posted
I see your point now that I've read a bit more. This program can't answer all our questions, it can only answer questions that we already know something about. So, since there is some info about Toll like receptors, that information can be programed into an equation, but if the program is missing any known or unknown variable, then the equation is not perfect.
Still, we could use this program with what we do know, and I still believe it can have an enormous bennifit to the Lyme Community if we can figure out questions like the one you just asked. That is something which truly puzzles me. How can Lyme Disease, which is both an autoimmune mediated disease, AND a active infection (though I believe the autoimmunity happens only with spirochetes, somewhere) not respond to steroids in a way that other autoimmune mediated diseases respond? It should make the killing of Borrelia easier, use steroids, and use antibiotics, take em both out, but it only seems to make the infection worse.
If we could use this program to figure something like that out, my friend, then we have accomplished quite a lot.
In the end, I understand your point about Biology and Physics. It takes an almost God like knowledge to be able to subject Biology to predictable equations, and since neither you, I, or the NIH have any diety in us, then my guess is that though this program will help a lot, it won't bring a truly physics paradigm to Biology. Thanks for making that point Lou, sometimes I get too excited about killing Lyme that I can loose my common sence.
Posts: 559 | From Cary, NC | Registered: May 2006
| IP: Logged |
posted
You absolutely do not need to apologize about getting excited about possible lyme research avenues. It really is rather touching to see someone who is looking ahead, trying to find new ways to apply existing tools to lyme to improve our situation. So what if this modeling is not ready yet for lyme, maybe it will get there if someone starts looking at where the blanks are, and gets that research done.
Posts: 8430 | From Not available | Registered: Oct 2000
| IP: Logged |
Truthfinder
Frequent Contributor (1K+ posts)
Member # 8512
posted
Wow. If this actually works, I can see where it could really speed up the process of finding some preliminary answers, which can then be tested on real microbes/ cells.
The development of this program must have taken quite a bit of $$ and time. Why in the world is it being offered for free?
Tracy
-------------------- Tracy .... Prayers for the Lyme Community - every day at 6 p.m. Pacific Time and 9 p.m. Eastern Time � just take a few moments to say a prayer wherever you are�. Posts: 2966 | From Colorado | Registered: Dec 2005
| IP: Logged |
posted
Thanks lou, I apprecaite that. I just want to end this disease so badly for all of us, and I know there are avenues we havn't tried yet.
Why are they offering it for free? Good Question.
Perhaps because they see this as a tool that will help mankind to such a degree that privateering this invention wasn't promoted.
It could also have to do with the fact that NIH scientists are no longer able to patent and make money off their inventions. They invented the software, and since they are now by law unable to make money off this invention, why not allow others to use it?
Posts: 559 | From Cary, NC | Registered: May 2006
| IP: Logged |
The Lyme Disease Network is a non-profit organization funded by individual donations. If you would like to support the Network and the LymeNet system of Web services, please send your donations to:
The
Lyme Disease Network of New Jersey 907 Pebble Creek Court,
Pennington,
NJ08534USA http://www.lymenet.org/
UBBFriend: Email this page to someone!
Printer-friendly view of this topic