In this study, the researchers got the data they needed to develop their computational model by treating normal mice with TNF, then determining whether the cells proliferated or died. They found that cell fate depended on the cells' location in the intestine cells in the ileum proliferated, while those in the duodenum died.
The multi-faceted result would likely not have been seen in a lab dish. "In cell culture, you would have gotten one or the other," Lauffenburger says.
They also correlated the diverse outcomes with the activities of more than a dozen proteins found in the cells, allowing them to determine how the outcomes depended on quantitative combination of key signaling pathways, and furthermore, to predict how the outcomes would be affected by drug treatment. The researchers then tested the model's predictions in an additional cohort of mice, and found that they were accurate.
The researchers are now trying to figure out in more detail what factors in the intestinal cells' environment influence the cells to behave the way they do. They are also studying how genetic mutations might alter the cells' responses.
They also plan to begin a study of neurological diseases such as Alzheimer's disease. Cancer is another disease that lends itself to this kind of modeling, says Jacks, who was not part of this study. Cancer is an extremely complicated disease that usually involves derangement of many cell signaling pathways involved in cell division, DNA repair and stress response.
"We expect that our ability to predict which targets, which drugs and which patients to bring together in the context of cancer treatment will require a deeper understanding of the complex signaling pathways that exist in cancer," says Jacks. "This approach will help us get there."
|Contact: Caroline McCall|
Massachusetts Institute of Technology