There is a lot involved in the discovery of new drugs to fight disease. What's important to remember is the immense amount of fundamental research that is vital to ultimately paving the way to new types of therapeutics.
Starting from the beginning means identifying how a protein structure is built, how it moves, and how it communicates with other proteins and cells in the body. In a recently funded project involving Boston Children's Hospital and Northeastern University, chemistry Professors John R. Engen and Roxana Iacob have teamed up with Prof. Timothy A. Springer–a renowned immunologist and structural biologist from Harvard Medical School (HMS) and Boston Children's Hospital–to uncover the inner-workings of an extremely complex class of proteins. Understanding these proteins could eventually lead to the development of drugs designed to treat diseases such as cancer, heart disease, and diabetes.
Transforming Growth Factor (TGF) beta is a member of the TGF-β superfamily of cytokines, which is made up of proteins that bind to receptors on certain certain cells and cause messages inside those cells to be sent. TGF-β contributes to many cellular functions, such as cell growth, but there is not enough known about this protein family. "It's hard to solve the structure and understand how they all work because TGF-β and it's relatives are very complicated," said Engen.
Despite the intricacies, understanding the inner workings of TGF-β is critical due to its role in many diseases, including cancer.
Similar to behaviors observed with integrins, also a protein Springer studies, TGF-β transmits information from the outside that will instruct the cell to grow, divide, or kill itself. TGF-β is related to many cancers because it's susceptible to misinforming cells to proliferate even when they shouldn't, and it's those misfires that cause disease.
With Springer's expertise in signal transduction across membranes and Engen and Iacob's experience in Hydrogen/Deuterium Exchange Mass Spectrometry (HDX MS)–a method championed by Prof. Engen–the team hopes to better understand the structural and dynamic aspects of TGF-β superfamily.
Early in 2014, through another collaborator from HMS, Prof. Springer and Profs. Engen and Iacob met to start a collaboration on the TGF-β superfamily. "Basically, we met and he described the complexity and the challenges of this project and we were intrigued by the opportunities that this research could lead to, especially using HDX MS. So we agreed to start working on the project right away" Iacob said.
Iacob has now worked on 10 family members in the 33-member TGF-β superfamily. Amongst those, a very interesting protein Bone Morphogenic Protein (BMP) was studied – a protein used during procedures such as hip replacements to promote bone growth. The Springer lab has been performing electron microscopy on some of these family members, and the technique used by Engen and Iacob will be able to uncover additional information needed to learn about the inner workings of the TGF-β superfamily.
The objective of the recently funded grant that supports this project is to work around the family tree for these proteins. "The goal of the project is to understand, structurally, what happens with this protein (TGF-β) and other family members," said Iacob. "It's fundamental research for now, but it's very important because, based on our findings, it will be easier to create therapies."
"All of (the proteins) are drug targets," said Engen. "You can name many diseases, and these proteins are likely connected somehow. Some of the proteins are involved in the immune system, some of them are involved in bone growth, others in embryonic development."