Wednesday, August 02, 2006

Proteomic Mass Spectrometry--Advanced Tools for Bio-Research

The average cell is flooded with an ever-changing population of proteins. To understand what a cell is doing, it helps to be able to take a "snapshot" of all the proteins, examining them carefully for signs of dangerous mutations.

Brian Druker of the Oregon Health and Science University in Portland and Roberto Polakiewicz, chief scientific officer of Cell Signaling Technology in Danvers, MA, have extended the role of proteomic mass spectrometry in order to detect cell signalling protein mutations that may lead to cancer.

"There are potentially hundreds of mutations in a given patient," says Jeffrey Tyner, a postdoc in Druker's lab. Only some of those mutations actually contribute to the cancer -- and evaluating all of them is time-consuming.

In essence, DNA sequencing reveals only what the cell could do. Protein mass spectrometry, in contrast, provides a clearer picture of what the cell is doing. That's why Cell Signaling Technology believes its approach is more efficient. "Proteomic [mass spectrometry] gives you the true readout of what's going on in the cell," says Mark Cobbold, a clinician scientist at the University of Birmingham, U.K.

Druker's mass spectrometry study focused on acute myeloid leukemia, the most common form of the disease. And, while three common gene mutations are often to blame for it, in 30 to 50 percent of cases, the cause is unknown, says Tyner.

Druker hopes to duplicate his success in previous work on another form of leukemia, which led to the first successful molecularly targeted cancer drug, Gleevec (Imatinib). Approved for clinical use in 2001, the drug works by specifically binding to an abnormal tyrosine kinase protein and inhibiting it. The drug has worked wonders for some patients. "Druker is taking molecular medicine forward. Now he's looking for other [leukemia targets] using a proteomics approach," Cobbold says.

Looking at a cell's actual molecular activity using mass spectrometry lets Druker avoid much of the guesswork in searching for cancer mechanisms. Instead of years, it took his lab just weeks to uncover a mutation in a gene for a kinase called JAK3 that causes the signaling molecule to be abnormally active. They found the mutation in a cell line, then verified the result in patients.

In proteomic mass spectrometry the researchers first break up cancer cells, purify their proteins, and cut them up. They then further purify stretches of protein characteristic of active tyrosine kinases. This mixture is put into the mass spectrometry machine, which sequences the proteins. With this information, researchers know which proteins are abnormally active and why -- because of a mutation, for example -- and can search for a drug that acts against them.

Tyner hopes their work can be translated into clinical tests for determining the molecular cause of a patient's tumor. Protein mass spectrometry profiles of cells from a tumor biopsy could identify which protein is running amok and what drug would work best on it. "It's very attractive, the idea of looking at signaling in tumors and from that uncovering [genetic] profiles," says Cobbold.

Proteomics research is expanding almost exponentially, as its importance is sinking in. The Wikipedia link above provides several links to proteomics resources. Here is an animation that illustrates the use of mass spectrometry in protein sequencing. Here is a blog that specializes in mass spectrometry, and deals with proteomics occasionally.

This type of technology will become commonplace in the modern anti-aging clinical laboratory. Clients will be scheduled routinely for analysis of cell-signalling networks, both to formulate initial treatments, and to monitor ongoing treatment results. It is likely that many clients will learn initially about their cancers, or other serious diseases, from their anti-aging screening.

Because medical insurance companies are not likely to pay for these procedures for decades yet, early comprehensive anti-aging diagnosis and treatment will be quite expensive.


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