Applications in Human Disease
“We have been able to identify a number of processes or networks involved in pathogenic processes of the brain,” explained Dr. Galas. “These are complex; each network has 20 to 30 proteins, which are all connected. We’ve just begun the analysis, but this is leading to a way of understanding exactly how complex networks, fundamental to the functioning of organisms, are related to disease processes.”
Complex diagnostics will have to be developed in order to understand disease processes in clinical situations, noted Dr. Galas. An example of this is his group’s discovery that the prions produced proteins that appeared in the blood and corresponded to changes in the brain.
“We’re just beginning to figure out how to do all this. More sensitive and reliable methods to detect proteins in the blood are needed to move things forward. Other than mass spectrometry, the only major way to identify proteins experimentally is using antibodies, and that’s pretty crude and not really scalable,” said Dr. Galas.
Working in collaboration with Unilever, researchers at Entelos (www.entelos.com) developed a skin sensitization model, Entelos® Skin Sensitization PhysioLab®, to support a future change in how companies in the consumer-product industry will make safety assessments of products. This is based on a EU ruling, effective in 2013, that says new products will not be approved if they have any animal testing of ingredients.
“The idea was to put together an in silico approach to replace current animal tests,” explained Christina Friedrich, Ph.D., associate director, in silico R&D development.
The first generation of the model was based on replicating the current gold standard assay for skin sensitization, the LLNA (local lymph node assay). In this assay, the test product is applied to a mouse’s ear over three days, and on the fifth day, the mouse is sacrificed and the lymph nodes examined for proliferation of T cells.
“We were able to input certain chemical properties and reproduce downstream outcomes such as the number of T cells in the lymph nodes. Next, we looked at the individual pathways in biology to discover the key drivers for the sensitization response. The idea with this type of approach is the development of truly predictive assays at the earlier stages,” said Dr. Friedrich. Unilever now has this model in–house and is moving ahead with its own program to develop these assays.
What makes Entelos’ approach unique, according to Dr. Friedrich, is the company’s top-down method, which synthesizes quantitative data from thousands of peer-reviewed papers into a single framework. “Our model doesn’t contain every piece of biology ever known in a subject, but what it does do is get you to something usable much faster than a more standard bottom-up approach,” explained Dr. Friedrich. The company uses a mathematical method to quantitatively describe the relationship between various biological entities over time, making simulations and predictions possible.
Dr. Friedrich added that some current challenges include getting the right kinds of data to calibrate and validate models and explaining the modeling process. “What we’re proposing is a different way of doing business, and that can be a real challenge.”