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Interviewee: Richard Caprioli, Vanderbilt University
The pathologist looking at your tissue biopsy will soon be able to see the levels of actual molecules involved in diseases like cancer and its spread.
Biochemist Richard Caprioli and his team at Vanderbilt University are developing ways to combine an instrument that analyzes chemicals, with microscopy and other medical imaging tools to improve diagnosis and treatment
“The advantage of this technology is that it allows you to look at the molecular disposition, the placement of molecules, and that’s critical in disease,” Caprioli explains. “For example, if you wanted to look at the edge of a tumor, one of the things that you want to know is that edge rapidly growing, is it an aggressive edge, or is it somewhat dormant or is the tumor not going to grow?”
Caprioli, along with Erin Seeley and others, call the new technique “molecular imaging.” It uses an instrument called a mass spectrometer, long used by chemists in their basic research. Mass spectrometry is the “gold standard” of chemical identification in forensic, environmental and pharmaceutical labs, and compact versions of the instrument travel to hazmat scenes and fly to Mars. It detects the types and amounts of the various molecules in a sample, and in the new science of proteomics, it can even analyze the large, complex protein molecules that build our cells.
“The effort here has been, how do we get these kinds of fantastic discoveries at the molecular level, that occur at the basic science research labs, now into the clinical arena, and eventually to the bedside,” Caprioli says.
As they write in the Proceedings of the National Academy of Sciences, instead of destroying samples by pulverizing and dissolving them, they incorporate lasers to analyze intact tissue samples from biopsies. That lets them see not only the levels of telltale molecules but their location-like those important edges.
“The lasers bounce energy into the tissues to bounce molecules out, and that’s how we measure these,” says Caprioli. “It’s an exciting new technology, but it’s not just for gear heads. This will make a major difference in how we diagnose and prognose disease.”
When a pathologist examines a tumor biopsy, they have stains that reveal some features and properties of the tissue that help them decide on the diagnosis, prognosis and treatment. But, explains Caprioli, “the disposition of molecules varies greatly, and it’s very difficult to see this, if not impossible to see this, in some of the normal histological tests that are done.”
“The challenge, then, is to work with the clinicians and the pathologists who will look at that piece of tissue and say, ‘Look, I think this area of the tissue looks compromised in some way,’ but from a microscope that’s all you can really say. The technology that we’re developing then goes into these areas, uses the art and practice of the pathologist to now look at the molecular makeup of those areas of the tissue. And now we’re able to say yes, that is a very aggressive molecular pattern, or not.”
Caprioli explains that the ability to screen a tumor’s genes is not enough information in the “new era of personalized medicine.”
“You can look at the genomic information as a type of blueprint for cells, but what is actually built, what actually makes us up as human beings, is different in every single person,” he says. “And so that genetic component directs molecules to be made, but we really need to know what actually is made, because not all of them are made at any one given time. They change in time and they change in space.”
Cancer is just one example of the technique’s usefulness. The team has also demonstrated methods for analyzing other types of tissues, from Alzheimer’s Disease plaques to developing sperm. They even showed how they could diagnose disease in a spleen sample preserved in formalin for over 100 years. “We were working with the University of Tennessee and there were some collaborators there who got a sample from Sweden from a lady who died of a disease and the biopsy was taken 109 years go, and it was sitting in a preservative for this 109 years, and we were able, then, to use our technology to discover what the disease was,” says Caprioli. “It shows you the robustness of the molecular makeup of tissue and how modern technology can pull these mysteries apart and lead us to understanding what the disease of a particular patient is.”
He says studying archival tissue is of “enormous value” to biomedical researchers. “They go back many, many years, biopsies that were taken many years ago, and most importantly the outcome of the patient is known. So this gives us the opportunity, then, to look at the molecular makeup of that disease and that biopsy and then know what happened to the patient.”
In addition to microscopes, the researchers are also working to combine mass spectrometry with medical imaging technologies like MRI. “The value that this multiplexed imaging brings is that each imaging modality brings a new view, and when you put them together then you get a whole leap in understanding,” he says. “For example, the technology that we’re developing can take molecular pictures and insert them into MRI images. And so where there’s an aberration in am MRI image, it may not be clear what the molecular counterpart of it is. We can then put that in the image, and so it really brings a whole new dimension to imaging to mix these different modalities.”
The researchers are already helping to usher the new technology into some hospitals, and he emphasizes that its routine use is not a long way off.
“Many years ago, for example, lasers were research tools, and now we have them in our players at home, we have them in almost every electronic device that we buy,’ says Caprioli. “these things become routine, and I think instruments like this will be routine in clinical analysis in a very short period of time.”
This research was published in PNAS Advance online edition the week of August 4, 2008, and funded by the US Public Health Service, the National Cancer Institute, the Aslan Foundation, the National Institutes of Health and the US Department of Defense.
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