Three people diagnosed with liver cancer on the same day in the same hospital are likely to have different prognoses, tumor growth rates, and responses to a given cancer drug. In many respects, they have three different diseases. Now a tool that is a mainstay in chemistry and physics labs may help doctors characterize each patient’s cancer in great detail and ensure that the entire tumor can be removed during surgery.
The tool is mass spectrometry, which can quickly identify any molecule in a sample by measuring its mass and charge. The technique has great potential for molecular biology and personalized medicine, because the ability to identify a broad spectrum of molecules in a tissue or even inside a cell would give an intimately detailed picture of its activities and disease state. But traditional mass spectrometry isn’t practical in the clinic, since it involves intensive sample preparation and must be done inside a vacuum. During a reading, the sample breaks apart, destroying spatial information about where each molecule was in the sample.
In a few months, Purdue and Vanderbilt researchers expect to begin experimental use of mass spectrometry in the operating room. They will use a sample collector that works in open air and leaves tissue intact. Called DESI, the collector was developed by Purdue chemistry professor R. Graham Cooks in 2003, and can be used with commercial MS machines. Along with Vanderbilt biochemist Richard Caprioli, Cooks is testing the device on human tumor biopsies to characterize the chemical differences between tumor and normal tissue and between aggressive and slow-growing tumors.
[Click here for images of the DESI collector.]
Pathologists often examine a biopsy under a microscope during surgery to help doctors remove the entire tumor. In DESI’s initial clinical tests, it will be used to scan biopsies alongside the pathologist, to verify and refine its ability to delineate tumor borders.
Cooks and Caprioli can make a crude map of a tissue biopsy surface by performing a DESI reading at multiple spots, each about 500 micrometers in area. First, a hose sprays the tissue surface with a mist of charged solvent particles. The solvent picks up molecules from the surface, imparting them with an electrical charge, and is then sucked up by another hose into the vacuum chamber of a mass spectrometer, where it is analyzed.
[Click here for examples of mass spectrometry images.]
“In the cases we’ve looked at, which include different grades of tumor, as well as tumor and nontumor regions, you have a very characteristic molecular fingerprint,” Cooks says.
During surgery, DESI could be used to create molecular profiles of tumors that would allow doctors to personalize their patients’ post-operative care. Caprioli believes mass spectrometry can play an important role in such personalized medicine. DESI can be used to perform rapid, extensive analyses of not only biopsies but also urine and blood samples and the surface of human skin, and it could detect molecular markers of diseases such as cancer much earlier on.
Genomics and proteomics – personalized medical tools that examine a person’s genome and what proteins his or her cells produce – are important, but are limited because they get at only a few kinds of molecules. Using mass spectrometry, a doctor could look for non-protein, non-DNA markers of disease in urine, blood, or biopsy to determine how aggressive a patient’s cancer is. “We want to look at all classes of molecules together,” Caprioli explains, which mass spectrometry does well.
Caprioli and Cooks have focused on lipids, the oily molecules that make up cell membranes and that can be abnormal in cancer cells. Using DESI to examine the areas where normal tissue abuts cancer tissue, the researchers saw different distributions of many kinds of lipids on either side of the tumor border, demonstrating that mass spectrometry can detect chemical differences between normal and cancerous tissue. “We don’t know what it does on proteins yet. We might have to play around with conditions to get it to work,” Caprioli says, pointing out that the method is young.
Caprioli and Cooks want a doctor to be able to look at a tumor’s mass spectrometry profile, and, if the patient “only has a prognosis of six months, as with some brain tumors, my God, you throw everything you can at them,” says Caprioli. But because cancer treatment can be harrowing for patients, “In another case you might say, no, the molecules for aggressive disease are not here, so we don’t have to treat them aggressively,” he adds.
The DESI method, if refined, could be used to perform what’s called mass spectrometry imaging. So far, the technique has not been done in the open air; now the DESI technique could expand its reach to the human body. Mass spectrometry imaging does more than straightforward mass spectrometry: in addition to gathering chemical information, it pinpoints where in a tissue the molecules under study are located. A mass spectrometry image is “a picture that has information like a TV picture, except it has mass information instead of color information,” explains Nick Winograd, a Pennsylvania State University chemistry professor and mass spectrometry imaging pioneer. The advantage of the technique over, for example, tagging molecules with fluorescent proteins, is that one doesn’t have to design a tag for each molecule to be studied.
Winograd uses a mass spectrometry imaging method called SIMS, which has 500 times the resolution of DESI, to examine the activity of individual neurons. And Caprioli also does imaging work. Using a matrix of protective molecules to shield tissues from the havoc in the mass spectrometry chamber, he has imaged tumors at 10 times the resolution of DESI. But as Winograd points out, with DESI, Cooks “has the tremendous advantage of being able to do [his studies] in the air,” without extensive sample preparation.
Using mass spectrometry imaging, Winograd explains, “all of us would like to be able to take a tissue slice and, for example, map the chemistry of drug molecules applied in a critical environment, or do fundamental science and determine in a blue-sky fashion what molecules are in the tissue, and where they’re located.”
All the major mass spectrometry manufacturers are working on commercializing imaging devices, according to Caprioli. He and Winograd say biologists would jump at the chance to use mass spectrometry devices. “I think it will be in the mainstream very quickly, within the next few years,” Caprioli says.
But having a high-resolution image isn’t necessary to generate the kind of molecular profiles of cancer that Cooks and Caprioli hope to. “What’s important is not so much the spot size as the kinds of molecules that you get out,” says Caprioli. If all goes well, Cook says, DESI mass spectrometry could be used to scan a patient’s tissue directly during surgery, with no biopsy necessary.
Home page image courtesy of Richard Caprioli, Vanderbilt University. Caption: Each color in this image of a section of rat brain represents a different protein.