Three questions for Martina Ralle
Martina Ralle, Ph.D., is assistant professor of molecular and medical genetics, OHSU School of Medicine. She’s also a faculty member in the Graduate Program in Molecular and Cellular Biosciences.September 11, 2015
What's been the most interesting development in your area in the last two years?
Our lab is interested in the role of copper in cellular processes, particularly those that lead to neurodegenerative diseases and/or determine a cell's fate towards differentiation or proliferation. One of our main tools to determine the distribution and concentration of copper in cells and tissue is X-ray fluorescence microscopy (XFM), a technique that requires highly brilliant X-rays that only third and fourth generation synchrotron sources can provide. Over the past two years, improvements and method development of XFM have greatly simplified our experimental requirements and at the same time now allow us to scan samples at a resolution approaching that of electron microscopy.
What projects are you currently working on and are there opportunities for fellow faculty to participate?
We discovered highly-concentrated copper foci in the ventricular regions of mice brains. The average concentration of copper, an essential nutrient but also highly toxic to cells if not properly bound or stored is around 100 –200 µM in mammalian tissue. In Wilson's disease, where copper accumulates to high concentrations in the livers and brains of patients, the levels go up by about 5 –10-fold. As a consequence of these high copper levels, Wilson's disease patients experience liver disease. If the copper is not chelated properly, eventually the patient requires a liver transplant. The copper foci in mice brains exhibit concentrations of more than 1,000-fold that of the surrounding tissue, yet they are not toxic to the cells. We found similar, albeit less concentrated copper foci in maturing mice livers. Fractionation experiments showed that this copper is predominantly in the membrane fraction i.e. in organelles. The copper foci disappear after P30-P40 when the mouse livers have fully matured. Because of the location of these foci in the brain as well as the developmental stage when they appear in livers of mice we suggest that they are resident to stem or actively proliferating cells. We are currently testing this hypothesis in livers but also in cultured crypts and mouse intestines where cells throughout all stages of the cell lineage are present and their location is known. The nature of our work as well as the uniqueness of our expertise invites collaborations from faculty with different backgrounds, and we welcome collaborations from anybody who is interested in studying the role of metals in disease or other processes. Besides our research, we are also managing the Elemental Analysis Core with a user base spanning clinical, basic and industry research, as well as clients who want to know how much arsenic is in their wine or mercury in their salmon!
A hypothetical: If you could have one tool that would solve a seemingly impenetrable problem in your work, what would it do? You have unlimited resources to design this tool, so think big.
The limiting factor, besides funding, for many of our projects is the scarce availability of beamtime at suitable synchrotrons. Unlike other microscopic techniques, XFM is very time consuming, and obtaining data from enough replicates is difficult. Given an infinite amount of money, I would purchase a microprobe beamline at the Argonne National Lab and sufficient computational resources to allow for higher sample throughput. This would also enable me to pursue my dream project to create a 'metallomic map' of the brain where investigators would be able to look up metal concentrations and/or metal binding proteins at maximum resolution by simply clicking on a map of a brain section.
About Three Questions
This Q&A series features OHSU School of Medicine faculty members talking about their work with the goal of getting to know them and different areas across the school. View more