Simulation dramatizes immune cell response

Steven Schultz


Martin Weigert has been assisted in his work on ImmSim by, from his left, sophomore Zehra Nizami; Yoram Louzoun, a post-doctoral researcher in molecular biology; and Steven Kleinstein, a graduate student in computer science.

Princeton NJ -- Stealthy attackers slipping past a castle's sentinels. Nimble militias gathering at a moment's notice. Battles waging. Misguided troops turning on their own civilians.

It's not theater, or even history. It's immunology. Until now, however, it has been the sort of topic reserved for accomplished biology students, one of those junior/senior level courses with about four prerequisites.

Martin Weigert's freshman seminar "Why Immune Systems Fail: Autoimmunity, Influenza Pandemics and HIV" changes that. His trick is not so much a newfound eloquence in cutting through the usual scientific jargon, but rather a powerful computer simulation he helped develop.

The software, called ImmSim, bypasses the staid molecule-by-molecule descriptions in textbooks and allows students to see viruses and immune cells as players in a great drama. Sitting in front of a computer, students tinker with a virtual lab animal, directing ImmSim to "inject" doses of viruses and watching the reaction unfold as armies of immune cells emerge and fight the invader. Ultimately, they see whether the virtual animal lives or dies.

"It's very much a theatrical presentation of the cast of characters and the interactions between the characters," said Weigert, who is the Henry Hillman Professor of Life Sciences in the molecular biology department.

The software also promises to become a research tool that gives biologists unprecedented flexibility and precision in testing ideas -- with considerably less use of laboratory animals. Undergraduates using the software in previous incarnations of the class have developed novel ideas worthy of serious investigation and, in one case, published a paper proposing a possible new treatment strategy for rheumatoid arthritis.

For students who have taken the class, the approach succeeded not only in conveying information, but also in inspiring a passion for the subject.

"It was great, just great," said sophomore Robert Accordino, who took the seminar last year and then went on to a summer internship in immunology at the Yale Medical School. "My last summer at Yale was just spectacular and that would not have happened if it had not been for this course."

"His seminar was by far the greatest class I've taken at Princeton," said sophomore Alexandra Martin, who plans to take a conventional advanced-level course in immunology next year.

Martin used ImmSim to develop a more nuanced approach to an experimental treatment for diabetes, a disease in which the immune system mistakenly attacks the body's own insulin-producing cells. Calling her work "a brilliant insight," Weigert hopes students will continue to investigate it. "It was all her idea -- just phenomenal," he said.


ImmSim was conceived in 1989 by Phil Seiden, a physicist, now emeritus, at IBM's Thomas Watson Research Center in Hawthorne, N.Y. He developed it in collaboration with immunologist Franco Celada of New York University's Hospital for Joint Diseases, and soon after began collaborating with Weigert, who was then at the Institute for Cancer Research in Philadelphia.

When Weigert came to Princeton in 1993, he incorporated ImmSim into a graduate course, then began to think about it as a tool for introducing undergraduates to immunology. Seiden was skeptical of the idea because the subject seemed too complicated and the ImmSim software was not user-friendly. "I thought he was crazy, but it worked out fantastically well," said Seiden, who is now a visiting research collaborator at Princeton.

Seiden has since made the program more user-friendly, with a Windows-based interface, which has allowed Weigert to integrate it more fully into the class. Last year, students used ImmSim mainly for their final projects, but this year Weigert used it in the very first class.

The value of the simulation was apparent in a recent class session, which started with a relatively conventional discussion of textbook material, then moved to the computer lab. In the classroom portion, Weigert spent an hour longer than he had intended explaining several key features of the immune system as illustrated by its interactions with the flu virus. Later, in the computer lab, it took students only about 20 minutes to run through a simulated experiment that would have taken months for highly trained scientists to perform with real animals. They exposed a virtual mouse to a virus and immediately saw the classroom material demonstrated in dramatic form as they watched for attacks by one type of immune cell after another, like infantry following artillery.

That day's experiment had not been prepared by Weigert or even a graduate student; it was set up by sophomore Zehra Nizami, who took the class last year and was hired by Weigert to assist with this year's class.

Touch of drama

Even though ImmSim shows students charts and graphs of the immune system's performance, it avoids mathematical formulas. Instead, it relies on a more life-like concept in which the body is defined as a big grid and each square contains one of the many cells or molecules of the immune system or invading pathogen. Each entity is assigned rules for how it interacts with its nearest neighbors, whatever they happen to be.

In a typical simulation, the user describes some sort of attacker, such as a virus, and the computer ascribes the properties of that invader to some of the squares. The computer proceeds to calculate the interactions between all the squares and their neighbors. The outcome of each interaction is partly a matter of chance, which reflects the way real molecules react in the body. The computer repeats this process over and over, each step representing the passage of a small amount of time. The element of chance in each calculation gives the overall result a touch of drama because no two outcomes are the same.

This approach is referred to as a "cellular automata" method because the outcome is the net result of many entities acting independently, just as in the real immune system. The accuracy of the answers depends on whether all the players are accounted for and if the "rules of engagement" are defined correctly.

So far, it seems that the model is rather accurate. Indeed in some cases, the researchers have struggled to match ImmSim's results with those shown in textbooks, only to find that the textbooks were not accurate -- or at least oversimplified the richness and dynamics of actual immune responses.

Steven Kleinstein, a graduate student in computer science who is working with Weigert, said one of his research interests is checking ImmSim against actual experimental results, but that work is still in its earliest stages. The researchers have begun to interest colleagues in conducting experiments specifically designed to test observations made from ImmSim simulations.

Weigert and colleagues believe the software offers two major benefits for researchers. First, it allows scientists to use the "shotgun" method of testing a broad range of ideas with little concern about wasting money, time or animal life. Second, it lets users track the fates of individual cells or specific classes of cells in a way that is nearly impossible in an actual animal.

Seiden, for example, recalled a time when his collaborator Celada came to him and wanted to test the effects of 25 different vaccine dosing regimens. Seiden suggested running the simulation 25 times for each regimen, the equivalent of using 625 mice. Celada wanted to repeat the experiment only five times. "I realized he was trying to save mice," Seiden said. "I said, 'My mice are cheap.' So we did all 625 combinations."

Weigert, Seiden and colleagues continue to add refinements and immune system components, making ImmSim more attractive both as a research and teaching tool. "We hope and anticipate that this will be a living textbook that is changing according to how student projects and scientific research evolve," said Weigert.

For more information about ImmSim, visit this Web site:


[an error occurred while processing this directive]