Scientists around the world rely on liquid chromatography (LC) and mass spectrometry (MS) systems to separate, identify, and quantify the compounds present in samples for analysis that can be dissolved in a liquid. Over the past 40 years, LC and MS have become indispensable tools in the quest to cure diseases, develop new drugs, and ensure the safety of foods and beverages.
But what about the many compounds that are insoluble, or for other reasons difficult to analyze by mass spectrometry? That question has long driven the research of Sarah Trimpin, Associate Professor of Analytical Chemistry at Wayne State University. It's not a mere academic question. Many biological constituents, such as membrane proteins, are hydrophobic and difficult to dissolve, making analysis by traditional solvent-based means problematic.
That poses a problem for disease research and treatment. For example, the most important protein class for drug action is membrane proteins which serve as targets for approximately 70% of all drugs.
“It is difficult to analyze membrane proteins really well,” said Prof. Trimpin. “If you look at the x-ray crystallography data bank, there are only a few membrane proteins. Because they are difficult to solubilize, they’re also difficult to crystallize. Nuclear magnetic resonance (NMR) is challenged. Mass spec is challenged. The tools that are available for membrane proteins are not all that satisfactory.”
Prof. Trimpin has spent four years working to develop a new approach, that she calls “inlet ionization” and “vacuum ionization”, which developed out of her solvent-free MALDI studies, a subject she has written about a number of times in Molecular & Cellular Proteomics, an academic journal focusing on structural and functional properties of proteins and their expression, but that also welcomes Technological Innovation and Resources, the category this work was published under.
Trimpin's quest began when the Swiss-born scientist was working on her Master's degree at the University of Konstanz in Germany.
“I was working initially on Alzheimer's Disease,” she explained. “And I liked that research, because I thought I was making an impact. But then I realized how little of an impact I was having because the amyloid plaques are insoluble. That was the first time I realized the limitation of our present day analytical technology for these kinds of problems.”
Prof. Trimpin went on to the Max Planck Institute for Polymer Research, where she earned her Ph.D. in 2002 (from the University of Mainz). Her thesis Methodological Developments of MALDI-TOF Mass Spectrometry for Frontiers of Macromolecular Analytics successfully ionized insoluble nonvolatile compounds and was awarded the best Ph.D. thesis from the German Society for Mass Spectrometry in 2003.
Trimpin's “ah-hah” moment came during her time as a joint postdoctoral fellow at Oregon State University and Oregon Health & Science University, where she studied the alkylation of the highly phosphorylated neurofilament protein complex that again was challenged by the formation of insoluble particulates.
“While I was in Oregon working on a solvent-free ionization method,” she said, “I learned about David Clemmer’s work with ion mobility at Indiana University. And then I decided, 'Ooh, this is the solution.' The problem is that you can’t take advantage of ultraperformance liquid chromatography (UPLC) if you can’t solubilize the sample in a mobile phase suitable for MS. Ion mobility separations gave me the ability to ionize and then separate the ions by size, shape, and charge before MS.”
“It was fortunate that in Professor Clemmer’s lab, vacuum matrix assisted laser desorption time-of-flight (MALDI) was not available with IMS-MS,” she recalled. “And that’s when I decided, 'Okay. Let’s rethink things and re-examine how ions are formed and how we can better ionize insoluble and even soluble analytes.’”
Prof. Trimpin dedicated herself to developing the optimum ionization method and discovered a new ionization process for use in mass spectrometry perhaps described best in her most recent Molecular & Cellular Proteomics article. “The initial experiment that took me down the path of a new ionization technology was basically an alternative way to perform atmospheric pressure MALDI, and has led to ionization processes that with a matrix or solvent require only heat or vacuum,” she explained. “That’s where we use, for example, the Waters SYNAPT G2 MALDI source that operates from vacuum, where we can produce ESI-like ions using a solid state matrix - just like MALDI - but without a laser. We also work from AP using the same mass spectrometer; the sample containing the matrix and analyte is deposited onto a strip of paper or put into a pipette tip, and then exposed to the vacuum produced at the skimmer cone. Spontaneously, ESI-like results are created from analytes like bovine serum albumins and protein complexes and then by separating them with ion mobility, we achieve better separation and mass resolution than we’ve seen before using ESI with these analytes. The simplicity of this method is an added advantage.”
The technique, though it is still a research project, has intriguing possibilities with far-reaching implications for protein chemists, biochemists, biologists and other scientists who may not be experts in mass spectrometry. For example, field- portable and clinical mass spectrometers are potential application areas.
Prof. Trimpin's latest innovation is just the latest in a history of accomplishments. The daughter of a successful builder, Sarah grew up in the Rhine Valley of Germany. As a young girl, she was a serious gymnast, eventually working her way up to the state level. “I think that's where I got my competitiveness,” she said.
She did not plan on a career in science. “I actually wanted to study history,” she said. “It was my counselor at the University of Freiburg who talked me into studying chemistry, because I was good in chemistry and math in high school.”
Prof. Trimpin's research interests are wide-ranging. In addition to the research articles in Molecular & Cellular Proteomics, she has published 32 others since joining the faculty at Wayne State University in 2008. She has also written six reviews and five book chapters, and has co-edited a book, Ion Mobility Spectrometry-Mass Spectrometry: Theory and Applications, with Prof. Charles L. Wilkins of the University of Arkansas.
Prof. Trimpin has received numerous awards in a variety of areas including the National Science Foundation CAREER Award in 2010. Others are the 2010 American Society for Mass Spectrometry Research Award; the 2010 DuPont Company Young Investigator Award; the 2011 Eli Lilly and Company Young Investigator Award in Analytical Chemistry; the 2012 Wayne State University Schaap Faculty Scholar Award; the 2013 Pittsburgh Conference Achievement Award; the 2013 Journal of the American Society of Mass Spectrometry Best Reviewer recognition, and the 2013 Wayne State University College of Liberal Arts and Sciences Teaching Award. She was also named a Top Young Investigator of 2007 by Genome Technology magazine. And in 2011, the Trimpin Laboratory joined elite company as a Waters Center of Innovation.
However, Prof. Trimpin's favorite form of recognition does not involve awards. “To see that you can influence a student’s life, that’s quite rewarding, too,” she said. “In the beginning they come into your lab with more curiosity than knowledge, but then after a while a light goes on. And then they begin to see the purpose and potential of the science we do and really contribute to it. And you know you've influenced somebody’s life for the better.”
Whether doing research or teaching, Prof. Trimpin believes success is all about how you approach the subject. “To have a real impact, you have to actually think outside the box,” she said. “You have to, well, let your brain play with possibilities beyond the standard beliefs.”
By letting her brain play, Prof. Trimpin is hoping to move science forward. “I'm interested in enabling anything that is analytically challenged,” she concluded. “I don’t want to invent another ionization method just for the fun of it, but to solve problems that haven’t been solved before. If I can solve one or two of those issues with our technologies, that would be wonderful.”
To commercialize some of their ideas, Professors Trimpin and Charles McEwen founded a university spin-off company, MSTM, in 2013.