Getting into a sticky situation
By Deborah Inkpen
Dr. Valerie Booth and the NMR spectrometer. (Photo by Chris Hammond)
Dr. Valerie Booth, professor of Biochemistry at Memorial, found herself in a “sticky” situation when she began studying proteins, quite literally. That’s because she is studying proteins that are not soluble in water, but the kind associated with human cell membranes.
“Hydrophobic is a technical word for sticky,” said Dr. Booth with a laugh. “They are proteins designed to be embedded in your cell membranes, they don’t wander around lose, so that’s why they are sticky.”
She said that it’s important to study these proteins because if they are not functioning properly then you can develop a disease. “Genetic diseases occur because you have a protein that’s either not there or not functioning properly.”
Dr. Booth says that proteins are the body’s “molecular machines” and are central in the countless processes that maintain all living organisms. “A protein’s function comes about as a direct result of the particular features of its three-dimensional structure,” she said. “We need to know this structure in order to properly understand how a protein works, as well as to design drugs to modify the protein’s function to treat a disease. The details of this structure are too small to be seen directly, even in the most highly magnified images, and so we use techniques such as nuclear magnetic resonance (NMR) to determine the structure.”
Dr. Booth recently received funding from the Canada Foundation for Innovation for a NMR Spectrometer for High Resolution Structural Studies of Membrane Proteins to assist with her research.
“It’s labour-intensive doing the high resolution structures but it’s the only way to get information that you need to rationally design a drug. Without rational design you are into screening millions of molecules for the activity you want, which also takes a lot of time,” she said. “Proteins that are embedded in the cell’s membrane constitute about one-third of all proteins and are especially important in health and disease. These membrane-associated proteins pose unique technical challenges and relatively little is currently known about their structures. However, recent advances in both making the protein samples and using NMR to determine their structures mean that many membrane proteins are now amenable to structure determination for the very first time. In order to make the most of the NMR data, we combine this data with computer simulation. We use NMR and computational approaches to reveal the underlying mechanisms behind the function of several membrane-associated proteins.”
Dr. Booth has also been working in collaboration with a local company, NewLab Clinical Research, which looks at identifying genes associated with human disease. Currently Dr. Booth and NewLab are working on two proteins whose genes were found to be associated with psoriasis by NewLab in collaboration with Dr. Wayne Gulliver, Clinical Professor of Dermatology at Memorial University. “I work with the protein that the gene codes for, to understand how it works and then to use the knowledge of the structure to help design a therapeutic to treat that the disease,” she said. “There’s something very special about Newfoundland our possibilities for genetic research. We can identify a gene and say it’s associated with this disease but what do we do with that? You can inform people that they are likely to get this disease and that may be of some help but what we are doing is providing a connection between identifying a gene that’s important in a disease and actually coming up with a drug that will treat a disease.”
Dr. Booth and her team study proteins that are found in lung surfactants. “If you are born without the protein we study which is called SP-B you don’t survive, you can’t breath,” she explained. She said that about fifteen years ago, hospitals began giving lung surfactants isolated from animals to premature babies with trouble breathing. It helped improve mortality. However, she hopes her research will result in the development of artificial therapeutics which will stay active longer and work more effectively.
“First, we are looking to understand how the proteins work and second, we can use the knowledge so that we can design therapeutics. The drugs designed based on this knowledge can either act to replace a missing protein or to modify the function of a protein that’s not doing what it’s supposed to, thereby treating the disease.”