Photo by Dan Addison
Edward Botchwey, assistant professor of biomedical engineering at the University of Virginia
Photo by Melissa Maki
Jason Papin, assistant professor of biomedical engineering at the University of Virginia
At first glance, it seems an innocent enough question: How does it work? But for two assistant professors at the University of Virginia Department of Biomedical Engineering, this question launched the discovery of an innovative new research method that could forever change the way scientists think about drugs and medical therapies.
It all began when Edward A. Botchwey III and his students began investigating a small molecule called Phthalimide Neovascular Factor 1 (PNF1) — a new drug developed by Dr. Milton Brown, former U.Va. chemistry professor and current director of the Drug Discovery Program at the Georgetown University Medical Center. Botchwey’s lab has shown that PNF1 stimulates angiogenesis, or the formation of new blood vessels — but it is not known how.
“Angiogenesis plays a critical role in tissue repair. If we could figure out how these therapeutic small molecules are creating new blood vessels, it would be a great advancement for tissue engineering and regenerative medicine,” Botchwey says. “In order to move this project to the next level, we needed to understand how the drug (PNF1) worked.”
Enter Jason A. Papin, whose research centers on the development of computational tools to analyze large biological networks. Through computational modeling, Papin seeks to describe the body and its cells’ responses to medical therapies from a systems perspective — holistically, rather than looking at the behavior of individual genes.
“Most biological research goes by: ‘Here’s my problem. Let’s find a related gene, isolate it and see how it works.’ If you have thousands of different genes with many different responses, you’d pick the one gene that has the greatest single response and characterize it,” Papin says. “But that’s not the way a cell works. These genes are affecting each other.”
In evaluating the behavior elicited by PNF1, Botchwey and Papin gathered tens of thousands of data points on genes that were turned “on” or “off” by the drug over several points of time. After inputting the data into specialized software, they compared them against a library of known gene associations. By finding consistencies with known interactions, Botchwey and Papin were able to hypothesize the regulatory pathways — or networks — of PNF1 stimulation, which will in turn help them predict the behavior of cells affected by the drug and design optimal methods for its delivery.
“The process of evaluating the data in this way is, itself, novel,” Papin says. “This is an opportunity to show how this type of application can have a real impact.”
The researchers believe that their computational approach to evaluating the body’s reactions from a systems perspective can be used to elucidate the mechanism of other small molecules that have advantages over traditional therapies, such as large proteins. Small molecules are usually cheaper and simpler to manufacture, and with Botchwey and Papin’s systems approach to drug development, they could potentially lead to more effective treatments with fewer unwanted side effects.
“The possibilities are truly exciting,” Botchwey says. “Now, with the understanding of how this small molecule is working, we can apply it to other therapies. Along the way, we’ve developed this new method of research that could be applied to a number of other research problems.”
Botchwey and Papin’s research concerning PNF1, titled “Mechanistic Exploration of Phthalimide Neovascular Factor 1 Using Network Analysis Tools,” was recently dubbed a “Hot Paper” by Tissue Engineering (Volume 13, Number 10). Read the paper online at: http://www.liebertonline.com/doi/pdfplus/10.1089/ten.2007.0023
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