With a $2.2 million grant from the National Institutes of Health, stem cell pioneer Dr. James Thomson, University of Wisconsin–Madison associate professor of biomedical engineering William Murphy and School of Medicine and Public Health medical informatics professor David Page will lead a team to derive and assemble the distinct cell types found in the human cerebral cortex.
The grant, one of 17 awarded nationwide on Tuesday, is part of a major initiative by the agency’s new National Center for Advancing Translational Sciences to improve the process for predicting whether drugs will be safe in humans. In recent years, more than 30 percent of promising medications have proven to be toxic to people despite favorable results in preclinical studies using animal models. The Thomson team intends to demonstrate how human pluripotent stem cells can be used to more effectively evaluate the safety of new drug candidates.
“Human pluripotent stem cells provide access to all the cells of the human body. This access means we can dramatically accelerate drug discovery and improve the speed and accuracy of drug toxicity testing while reducing the need for animal testing. To that end, we plan to develop a new tissue model for a particularly challenging area — developmental neural toxicity,” says Thomson, director of regenerative biology at the Morgridge Institute for Research.
Once the tissue models have been created, the team will expose them to a variety of known neural toxins as well as safe drugs and compare the changes in gene expression. In addition to providing insights into early brain development, the work is expected to result in computational formulas that can help predict the neural toxicity of promising new medicines.
Formulating the synthetic gels necessary to support the neural progenitor cells will be done in the lab of William Murphy, an associate professor of biomedical engineering with UW–Madison’s College of Engineering and orthopedics and rehabilitation with the School of Medicine and Public Health. Several different formulations of the gels will be needed to support the cells expected to contribute to capillary network formation (endothelial cells, pericytes and microglia) and the cells expected to form an outer lining known as the neural epithelium (neural and glial precursor cells).
“The hydrogels we are developing take into account the needs of the varying cell types, which arise at different times in early brain development,” says Murphy, who will be conducting the work in his lab at the Wisconsin Institutes for Medical Research. “The tricky thing is that we want the different layers of cells to connect with one another in a three-dimensional way, so the gels contain molecular-level scaffolding in the form of peptides to support the cells as they branch out.”
David Page, a professor of medical informatics with the School of Medicine and Public Health, will work to assess changes in the cells’ behavior after they have been exposed to the toxins. Using RNA sequencing, his team will identify differences in gene expression and develop complex mathematical formulas that can be programmed into high volume machines used to perform initial evaluations of new drugs.
“The benefits of these predictive mathematical formulas will be seen in several ways,” says Page, who specializes in machine learning and data mining. “We anticipate significant cost savings in drug development because in many cases, problems with neural toxicity only appear in late phases of testing and after considerable investment has already occurred. In addition, we hope that by programming these formulas into production equipment, developers will be able to identify promising drug candidates earlier and with greater certainty.”
Additional collaborators on the project include Ron Stewart, associate director of bioinformatics in regenerative biology at the Morgridge Institute for Research, and Michael Schwartz, an assistant scientist in biomedical engineering with the College of Engineering.
The initial two-year federal grant is expected to support the collaborative work of more than 10 scientists, postdoctoral researchers and graduate students. Full funding over the period is contingent upon achieving a series of technical milestones. If the project proceeds as planned, the team may qualify for additional funding over five years to continue further development and testing.
“This project brings together stem cell biologists at the Morgridge Institute with top researchers in UW–Madison’s departments of biomedical engineering and biostatistics and medical informatics to address an interdisciplinary problem that greatly impacts human health,” says Thomson, who also serves as the John D. MacArthur professor at the School of Medicine and Public Health. “This is precisely the type of interaction Morgridge was created to catalyze.”
About the National Center for Advancing Translational Sciences and National Institutes of Health
The National Center for Advancing Translational Sciences aims to catalyze the development, testing and implementation of diagnostics and therapeutics to address a wide range of human diseases and conditions. By improving the development process for diagnostics and therapeutics, the center strives to make translational science more efficient, less expensive and less risky. Visit ncats.nih.gov to learn more.
The National Institutes of Health, the nation’s medical research agency, includes 27 institutes and centers and is part of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical and translational medical research and is investigating the causes, treatments and cures for both common and rare diseases.
Note: The project announced Tuesday is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UH2TR000506. The above content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.