Michael Washburn on the Development and Applications of MudPIT
Scientist Interview: July 2011
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It was appealing to me at the time to go into a non-traditional kind of place like this. I had interviews and opportunities at other universities, a more traditional assistant professorship path. But here's a place where they wanted us to bring this really powerful proteomics technology to bear on biological problems off the bat. We had the opportunity for extraordinary collaborations and amazing resources and support from senior colleagues, from the president of the institute and the scientific director on down. Everything about it seemed like the right decision. Think about how often institutes like this are built and how infrequently these opportunities come along.
My wife, Laurence Florens, and I work together and we thought we should do this and see what happens. And then we got the opportunity to work with Ron and Joan Conaway, Jerry Workman from Penn State, who came here at the same time we did. And then Ali Shilatifard came here in 2007 and we've been working with his group too. With all of their groups we contribute to the study of transcriptional regulation and chromatin remodeling. Our group's real interest has been in developing new ways to analyze transcription and chromatin remodeling complexes, and generating quantitative data on how they interact and assemble. There's just a great team of scientists here at the Institute.
What is the most interesting thing you've done or learned with MudPIT since you go to the Stowers Institute?
What I think is the most interesting is our ability to look at protein complexes and interaction networks in a novel way and to add a level of organization that we never had before. The question we're trying to answer is how proteins interact with each other inside a cell; how do these protein complexes change, and what do the complexes look like—which proteins are interacting with which other proteins, and what happens to these protein complexes when they are subjected to a drug, for instance, or when one protein in the complex has been deleted through genetic manipulation?
Proposed architecture of the Rpd3 Small and Large
complexes from a quantitative proteomics analysis of a deletion network.
(Reprinted with modifications from Sardiu
et al.,
PLoS One. 2009 Oct
6;4(10):e7310.
We're now able to ask these types of questions because of these new technologies and their applications. We're getting completely new insights into how these complexes are shaped, how they look, how they interact, and how they change upon some sort of stimulation or disruption. That's what gets me excited about this research.
What do you think is the biggest challenge to doing your research?
The biggest challenge is probably always going to be good sample preparation. With mass spectrometry, the phrase "garbage in, garbage out" always holds. What's necessary is careful, conscientious, meticulous sample preparation, something we've all gotten better at as the years go on. But that's still the biggest challenge. The technology is there. We can do a lot of really cool stuff. A lot depends on how creative we are, the way we design the experiment, and then how good we are at preparing the cell lines, the strains, getting really good samples prepared so we can take advantage of all this.
For me, personally, the other biggest challenge is to someday crack the NIH nut. Stowers provides a great deal of resources, but there is a limit. Laurence and I have a group of 12 people and they're what the funding pays for. To expand the quantitative analysis of protein complexes—what happens to these complexes upon stimulation, deletion, or disruption—we need funding. Then we could do this more aggressively with a high-throughput approach, and we could do it in human tissue cultures.
I think we're at a point now that we have demonstrated what we can do really well in yeast and also in human tissue culture. We'd like to expand our use of these techniques in tissue culture models and begin to apply these technologies to disease-related tissue culture models. We can now ask some questions that are directly related to human diseases, but for that we need more funding still and I've never been able to crack the NIH and get funding from them for our research.
That may be the first time I've heard such a highly cited researcher voice that particular problem. Why do you think it is?
Well, I'm probably not a good enough grant writer. Although it may also be that there's just not a study section that really fits what we're doing. There are study sections that have funded some brilliant mass spectrometry and protein mass spectrometry method development. And then there are biochemistry and molecular biology study sections, but none are doing any medium-scale, so-called systems biology projects, which is kind of how I categorize us. So part of the problem is that it's hard for us to find a home at NIH and the other part is that I'm just not good at writing grants. A final part is probably that it's just a terrible funding environment right now.
Michael Washburn, Ph.D.
Stowers Institute for Medical Research
Kansas City, MO, USA
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MICHAEL WASHBURN'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Washburn MP, Wolters D, Yates JR, "Large-scale analysis of the yeast proteome by multidimensional protein identification technology," Nat. Biotechnol. 19(3): 242-7, March 2001 with 2,112 cites. Source: Essential Science Indicators from Clarivate.
KEYWORDS: PROTEIN MASS SPECTROMETRY, PROTEOMICS, MULTIDIMENSIONAL PROTEIN IDENTIFICATION TECHNOLOGY, MUDPIT, CHROMATOGRAPHY, PROTEIN COMPLEXES, YEAST, COLLABORATIONS, TRANSCRIPTION REGULATION, CHROMATIN REMODELING, INTERACTION NETWORKS, SAMPLE PREPARATION, HUMAN TISSUE CULTURE, DISEASE-RELATED TISSUE CULTURE MODELS, FUNDING.
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