CMIR blazes trail of MI discovery

When Dr. Ralph Weissleder founded the Center for Molecular Imaging Research at Massachusetts General Hospital in 1994, he had a staff of only two people conducting research in a 200-square-foot space. Flash forward just over a decade, and the CMIR has expanded to one of the largest divisions of the hospital's vast department of radiology. The CMIR fills more than 12,000 square feet with a staff of 80 scientists and 40 postdoctoral fellows. Weissleder and colleagues have made discoveries responsible for defining the cardinal principles of molecular imaging and their revolutionary implications for radiologic practice.

"CMIR is a center with expertise in chemistry, biology, engineering, physics, and clinical medicine," Weissleder said. "We have postdoctoral fellows from all over the world."

Dr. James Thrall, chief of radiology at MGH, credits Weissleder's ability to build a diverse multidisciplinary staff as a prime factor for the CMIR's breakthrough research in nanoparticles, molecular biology, drug development, high-throughput screening, and novel optical imaging technologies.

"Dr. Weissleder has brought along some wonderful young investigators-sort of the second generation of molecular imaging researchers," Thrall said.

Weissleder's multidisciplinary approach has led to collaborative research in cancer, arteriosclerosis, and diabetes, expanding the universe of radiology.

"For years, research in radiology was aimed at building a better mousetrap, a better imaging device," Thrall said. "Now, we're not just trying to build a better CT scanner or better probes so that we can see lung cancer better; we're building devices and developing methods that allow people to do scientific work that they couldn't do otherwise."

Weissleder and his team have been leaders in recognizing the power of molecular imaging to tackle problems faced in other disciplines. Thrall cited their work with Dr. Judah Folkman, a professor of cell biology at Harvard University. Folkman discovered relationships between angiogenesis and oncogenesis, including the correlation between blood vessel and tumor growth. The CMIR is conducting clinical trials to calculate the vascularity of renal cell cancers and correlate that information with the tumor's histologic grade.

The CMIR's recent collaborations have also led to advances in gene therapy; specifically, imaging the expression of genes. Another application is labeling stem cells with both magnetopharmaceuticals and optical pharmaceuticals to track the cells' migration patterns in vivo.

"The therapeutic application of stem cells is going well beyond diagnostics to look at fundamental questions of general biomedical and bioscientific interest," Thrall said.

CANCER RESEARCH LEADER

The CMIR receives grants totaling more than $15 million annually, including a $2 million research center grant for in vivo cellular and molecular imaging centers from the National Institutes of Health and the National Cancer Institute. The CMIR is one of only eight centers in the country to receive such a grant because of its focus on cancer research.

"The CMIR was clearly one of the leaders in molecular imaging throughout the last decade. They have convinced people that molecular imaging is a very viable area of research that can actually deliver on the promise of revealing chemical information noninvasively. Their pioneering work has convinced people that the basic tools and technologies exist to make molecular imaging a worthwhile investment," said Dr. Daniel Sullivan, associate director of the Cancer Imaging Program at the NCI.

Sullivan specifically praised the CMIR for its work in developing optical probes for imaging cancers, including iron oxide MR agents and magnetic fluorescent nanoparticles (labeled with the near-infrared fluorochrome Cy5.5), which are effective for tumor margin delineation.

"When you remove a tumor, you want to make sure that the periphery of what you remove has no cancer in it," said Lee Josephson, Ph.D., a chemist on the CMIR team who has worked extensively with Weissleder in developing imaging agents. "We've been very interested in using these fluorescent probes for brain cancer, where the margin problem is particularly difficult."

Weissleder's interest in iron oxide imaging dates back to 1988 when he showed that an iron oxide agent he created could be used to characterize the metastatic contents of a rat lymph node. Working with Josephson and Dr. Mukesh Harisinghani, an assistant radiologist in the department of imaging and intervention, Weissleder has published research on monocrystalline iron oxides, which can improve detection of lymph node metastases in patients with prostate cancer and renal cancer. The method has also proven highly precise for measuring lymph node metastatic disease in the bladder and kidney, and the team is working to confirm its effectiveness in imaging breast lymph node metastases.

Harisinghani, who designed and conducted the clinical trials for the iron oxides, believes that the CMIR is unique in its ability to progressively take molecular imaging research from animal testing stages through clinical trials. Weissleder, a trained radiologist who still makes time to practice clinical radiology, is clearly a proponent of advancing research to the clinical stage, he said.

PERSONALIZED MEDICINE

"The future of radiology is personalized medicine," Harisinghani said. "Two decades from now, I don't think you'll hear people saying, 'I'm getting a CT scan or an MR scan"; you'll hear, 'I'm getting a scan for detecting a specific cancer or a scan to figure out if my treatment is working.'"

Once the patient begins the therapy, doctors can image the effects of treatment to make sure that it is working correctly.

"My work in imaging pharmacotherapy is very much tied to personal medicine," said Josephson, who is involved with imaging the early response to chemotherapy. "Even though imaging isn't the therapy, it makes imaging part of the therapy process."

A key step toward personalized medicine is development of a database of molecular imaging agents. Weissleder currently serves on an NIH advisory panel attempting to attain that goal and to eventually make the database accessible on the Web.

"When we identify targets that are overexpressed in a patient's tumor, we can go to our library of optical imaging probes and select the particular probe that has the highest likelihood of detecting the patient's tumor," Thrall said. "We then will administer that agent and track the spread of the tumor, or the method will help the surgeon determine that he or she has surgically removed the entire tumor. I think we'll see variations of this within three to five years."