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Proteomics Being Used to Probe For Answers On Why WTC Firefighters Are Still Sick

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Proteomic pattern profiling is not necessarily only for cancer: According to two members of the NCI’s Early Detection Research Network for biomarker research (see PM 10-3-03), it may also help solve one of the health mysteries that emerged in the wake of the 9/11 terrorist attacks.

John Semmes, an associate professor at the Eastern Virginia Medical School in Norfolk, Va., is working with collaborator Bill Rom, professor of environmental medicine at New York University, to discover whether differences in protein expression patterns could help explain why some firefighter veterans of the World Trade Center rescue effort developed a chronic respiratory condition — commonly called “World Trade Center cough” — while others recovered from more temporary conditions.

“These firefighters go in and they breathe in all these terrible elements, and most of them recover from these upper respiratory things, but about a hundred or so have not recovered. And the big medical question is ‘what is it and why,’” Semmes said.

So far he is not ruling out more traditional environmental factors as the sole explanation for differences in firefighters’ reactions. That’s why he is first waiting for the firefighters’ New York-based physicians to gather complete histories on each of the patients for which Semmes’ group is receiving a serum sample, before he plunges into serum pattern profiling. “You want to determine the biological phenomenon that’s occurring,” Semmes said. “Is this a separate biological entity, or are you going to be able to explain it because they have a lot of other mitigating circumstances. Maybe they smoke a lot — maybe we’ll find that everyone who has the chronic ailments also are heavy smokers.”

If the mitigating factors, how-ever, can’t explain everything, that’s when Semmes will be ready to step in with the pattern analysis of serum samples.

Semmes’ group plans to use a combination of approaches to find differentially expressed protein patterns and to identify the proteins involved. In the first run, the sera samples will be run through what Semmes called “the tried and true path using the SELDI type of profiling approach,” but with one change: the scientists will first use Bruker Biosciences’ automated magnetic bead front-end affinity separation kit before depositing the samples on the SELDI chips, “so we can get eventual deposition onto the desorption surface to be more uniform,” Semmes said.

Once he finds peaks of interest, Semmes said he will then run the serum through a second run in which affinity beads are again used to isolate the proteins, before running the sample on a multidimensional separation system and then through Bruker’s new Ultraflex TOF/TOF tandem mass spec analysis to identify the proteins.

Finally, the TOF/TOF identifications will be verified through immunoassay-type traditional experiments. “If indeed they are the proteins that we think they are, then we have a hit,” he said. “If it’s an interesting protein that might have some relationship to how the disease might develop, then you’re golden. If it’s not, then you go and look for another one.”

Semmes said he hopes to have some preliminary results from the experiments by the middle to later part of this year.

Semmes has plenty of experience looking for proteins in differentially expressed patterns: his group published work on the application of SELDI protein profiling to prostate cancer, which predated Petricoin and Liotta’s February 2002 Lancet paper on the application of such techniques to a disease state, Semmes said.

Petricoin’s group, however, was the first to apply an algorithm to automate the process, Semmes noted. As Semmes continues his prostate cancer work, he said his and Petricoin’s group are often “neck-to-neck on a lot of things, although fortunately we each have our own niche.” Although the basic concepts are the same, some differences between Semmes’ and Petricoin’s methods, according to Semmes, are that they each use different algorithms, and while Petricoin uses the Applied Biosystems Q-STAR for analysis now, Semmes is using the Bruker TOF/TOF.

Unlike cancer, where there is a recognized path between biomarker patterns and a diagnostic, the results from the comparison of proteins in firefighters with WTC cough and those without would not really be directly applicable to a diagnostic, Semmes said. But “it would be nice to discover whether there are certain proteins that are being expressed or secreted in the sera of these individuals that are not present in the ones that have recovered.”

The ultimate goal of all this work would be an understanding of the mechanisms to the point of possibly developing a therapeutic. Semmes said that all the information would be “freely exchanged” with anyone else around the country doing research on a similar group of people.

— KAM

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