During its first century, radiology focused on anatomy. Diseases, however, are essentially biochemical, and many important questions cannot be answered by examination of anatomy alone. For example, a solitary lung nodule is a clear anatomic finding, but what is important usually is not visible, namely, whether it is benign or malignant. Similarly, the mass remaining after treatment might be unresponsive tumor, or it might be fibrosis. To solve diagnostic problems such as these, biological (also called molecular) imaging is being developed.
The basic technical requirements for a biological imaging method are high spatial and temporal resolution and the ability to detect nanomolar to picomolar concentrations of target molecules. Some techniques are already used clinically. Magnetic resonance is a standard analysis tool of chemists, and the chemical information that can be obtained from the signals is increasingly appreciated by clinicians.1 Positron emission tomography (PET) measures the appetite of cells for glucose. The hungriest cells are nearly always malignant. With the help of PET, it is possible to determine the nature of a solitary lung nodule, to stage non-small-cell lung cancer and lymphoma, and to evaluate recurrence of colorectal cancer or lymphoma.2 Technetium Tc 99m sestamibi and technetium Tc 99m tetrofosmin are substrates for the membrane P-glycoprotein transporter that is responsible for multidrug resistance in cancer cells. A sestamibi or tetrofosmin nuclear scan thus can identify cancer patients in whom certain drugs are unlikely to be effective. The radiolabeled monoclonal antibodies against cancer antigens are yet another familiar form of biological imaging. But some of the most interesting applications are still in development, many at centers established to advance the field of biological imaging.
Centers Dedicated to Biological Imaging
Established centers devoted to biological imaging are beginning to proliferate on university campuses nationwide. The following centers are based in the radiology department and have extensive collaborative relationships.
The Center for Molecular Imaging Research at Massachusetts General Hospital-Harvard Medical School, Boston, has several research emphases, especially imaging gene expression, including imaging of angiogenesis and gene delivery to tumors. Umar Mahmood, MD, PhD, describes its breadth of research by saying that “we collaborate with people who have interesting biological questions we can answer using novel imaging approaches.”
The Center for Biomedical Imaging & Informatics at the University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School was founded by the departments of radiology, pathology, and pharmacology. It has collaborations with the Department of Computer Science and the Center for Computer Aids to Industrial Production at Rutgers University. Among the particular interests at the center are data mining and computer-assisted diagnosis.
The Biological Imaging Center at the Beckman Institute, California Institute of Technology, Pasadena, Calif, specializes in developmental biology and has a three-dimensional atlas of mouse anatomy based on magnetic resonance microscopy, as well as high-field MR images of murine models of human diseases.
Special Interest at the NCI
Because of the huge impact of cancer on the population and the many deficiencies in our ability to diagnose and treat it, the US National Cancer Institute (NCI) has identified biological imaging as an area of “extraordinary opportunity” and is soliciting applications for research funding. The NCI is particularly interested in new methods for early diagnosis, disease characterization, and outcome assessment. The agency also hopes to foster the research collaborations that are essential to work in biological imaging and to develop infrastructure to hasten the discovery and validation of new imaging methods.
A research team at the Center for Molecular Imaging Research at Massachusetts General Hospital, Boston, is trying to exploit cathepsins to detect breast cancer. These proteolytic lysosomal enzymes attracted scientific attention when it was found that some of them are significantly overexpressed in breast cancer, particularly lesions with greater invasive and metastatic potential. The team developed probes consisting of a delivery vehicle and a fluorochrome joined by a peptide sequence on which a cathepsin can act. The fluorochrome is quenched when it is attached to the probe, which enters the cancer cells thanks to the leakiness of tumor blood vessels. After the fluorochrome is liberated by cathepsin action, it fluoresces in the near-infrared range and is detectable by an optical imaging system. A proof of concept trial in cell culture has been successful,3 and in mice bearing human breast cancer, tumors as small as 1 mm could be identified with this method.4
Searching for Blood Vessels
Another feature of cancer that is being exploited for imaging is its abnormal vascularity. Noninvasive measurements of the number of blood vessels could be valuable, not only to identify tumors, but also to monitor clinical trials of antiangiogenesis agents for cancer or of proangiogenesis agents for vascular disease. Bredow and associates at the Center for Molecular Imaging Research demonstrated the potential of a monoclonal antibody against endoglin, a receptor for transforming growth factor-b and a marker of endothelial proliferation.5 Sipkins and colleagues from the Lucas MRS Imaging Center at Stanford University School of Medicine, Stanford, Calif, linked a paramagnetic contrast agent to a monoclonal antibody directed against endothelial aVb3 to obtain detailed MR images of tumor blood vessels in rabbits.6
Imaging tumors in mice and rabbits is not the goal, of course, but clinical applications of similar techniques might not be far off.
“There is a natural progression with any new imaging modality over 5 to 10 years,” says Umar Mahmood, MD, PhD, a member of the research team studying cathepsins as an imaging tool. “First, it works in cell culture, then in animals, then in patients in research centers, and then, finally, in community hospitals. First it is a curiosity; then people say, ‘We could never get along without it.’ For years, people wondered whether MR spectroscopy had any clinical utility. Now, it is a reimbursable examination.”
Turn Up the Volume
On September 27, by voice vote, the US House of Representatives passed the National Institute of Biomedical Imaging and Bioengineering Establishment Act. The Academy of Radiology Research and more than 40 other professional organizations supporting the new Institute are now working with Senate Majority Leader Trent Lott toward consideration of Senate passage before Congress adjourns for the year.
Although the National Institutes of Health (NIH) has several imaging projects, notable the American College of Radiology Imaging Network (ACRIN), funded by the National Cancer Institute, which conducts clinical trials of medical imaging, the present structure of the NIH is not well suited to supporting the developments in imaging that are so important to the continued growth of noninvasive medicine. First, each agency is focused on a single disease or organ system, whereas imaging takes in the entire body. Second, imaging research deals with physics and mathematics, whereas the institutes within the NIH focus on biology. Partly as a result, there has been considerable duplication of effort and wasted resources. (Recently, more than 35 federal organizations in nine departments were involved in telemedicine.) Some observers believe the absence of a coordinated strategy for imaging research largely accounts for the fact that CT and MRI were developed largely outside the United States.
In his testimony on September 13 before the House Subcommittee on Health and Environment, Bruce J. Hillman, MD, chair of the Department of Radiology at the University of Virginia School of Medicine, a chancellor of the American College of Radiology, and chair of ACRIN, explained why imaging has become so critical:
“Medical imaging is the ‘non-invasive biopsy,’ the method of disease quantitation, the guidance for new treatments still to be developed that will form the underpinnings of molecular medicine. [N]ew medical imaging technologies will detect alterations in the genetic or molecular makeup of cells that have the potential to progress to disease. We then will employ imaging technologies to precisely determine what fraction of cells are so affected. Finally, medical imaging technologies will be integrated with new therapeutic methods to either guide or monitor treatment, so that we can much more precisely…ensure that only diseased cells are treated while preserving normal tissue.”
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Examining Gene Activity
Cancer, and many other diseases, have numerous chemical abnormalities that might be exploited for imaging. Yang and coworkers at the University of Pittsburgh have found that spectral imaging can detect melanoma in situ. Their study also revealed that some of the genes and antigens thought to be characteristics of the vertical growth phase and metastases are expressed in the in situ stage.7 Radiochemists have produced labeled antisense and peptidomimetic compounds that detect active oncogenes. Such techniques might identify cancers in their earliest stages or reveal the extent of their aggressiveness.8 Bell and Taylor-Robinson of the Robert Steiner MR Unit at Hammersmith Hospital in London described smart MRI contrast agents that become detectable in the presence of an active transferred gene.9 Researchers at the Center for Molecular Imaging Research have described ways to persuade cells of interest to take up supermagnetic nanoparticles to permit MRI detection.10,11 They think that it will be possible to further develop such MR marker genes to noninvasively track where transgenes are delivered during gene therapy. For example, this could potentially help neurosurgeons determine where they need to redeliver vectors into brain tumors. For some cancers, dynamic contrast MRI correlates well with traditional outcome measures and may be able to predict the response to treatment.12
Getting More from Computed tomography
The Center for Biological Imaging & Informatics at the University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School is trying to obtain more and better biological information from anatomic images such as CT scans. Its prototype clinical decision support (CDS) system is intended to characterize, track, and assess morphometric changes in metastatic tumors in the liver.
“As new treatments have become available for liver metastases, each targeting a specific type of tumor, it has become increasingly important to distinguish among the biological subclasses of the disease,” says David J. Foran, MD, director of the center.
The CDS system consists of a computer vision module and an intelligent image archive, both developed using Java. The computer gathers data and performs an objective preliminary analysis, after which the human radiologist takes over.
“The advantage of this division of labor is that by exploiting the aptitudes of both computers and humans, one can devise a system that enables physicians to work more efficiently and improve their capacity to assimilate subtleties and complexities,” Foran explains. In a preliminary feasibility trial, the CDS system was able to identify all of the lesions on a set of CT scans and automatically compute the volume and spatial and spectral signatures of each one. Given scans of the same lesion over time, the CDS system was able to provide information on the net change in tumor volume and objective, reproducible measures of changes in lesion shape. The center is now using a database of 300 clinical cases to evaluate the potential of CDS for surgical planning, disease management, and outcome assessment.
Explicating the Brain
When the brain is working, the busy areas consume more oxygen and glucose, and blood flow increases. Functional MR (fMRI) and PET, which measure these changes, therefore are valuable tools in our efforts to understand the brain.13 John L. Nosher, MD, chair of the radiology department at the University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, describes a new research project using fMRI.
|Tumors as small as 1 mm were identified in mice bearing human breast cancer by use of specially devised probes and a fluorochrome joined by a peptide sequence on which a cathepsin can act. Images are provided courtesy of Umar Mahmood, MD, PhD, The Center for Molecular Imaging Research at Massachusetts General Hospital-Harvard Medical School, Boston.|
“A psychologist here is interested in the brain development of children who have suffered neonatal hemorrhage or were born to drug-abusing mothers. He saw fMRI as a useful tool for this research and approached us with the idea. We have just started a study in which teenagers with a history of either of these problems will look at visual patterns while we are obtaining fMRI scans.” The findings will then be compared with those in persons of the same age without such a medical history.
fMRI also is being employed in combination with other techniques for study of the brain, such as EEG. In this way, it is possible to compensate for the deficiencies of each method. fMRI has high spatial resolution but is relatively slow, whereas EEG is fast but has poor spatial resolution.
What Lies Ahead? A Warning
At the Center for Molecular Imaging Research, the Radiology Department is the driving force in biological imaging “because we have all the tools,” Mahmood notes. But he cautions that radiology could lose this exciting new field as it has others.
“For the first 20 years, cardiac catheterization was done by radiologists,” he points out. “Now, it is almost exclusively the realm of cardiologists. Obstetricians do ultrasonography, neurologists read brain MR films, and orthopedic surgeons read plain films and MR scans of the spine.
“Radiologists traditionally have been trained in anatomy and less in the underlying molecular basis of disease,” he says. “But when imaging looks at physiology, radiologists who are not trained in that field will lose the work to someone who is. Interventional radiologists have focused primarily on the mechanical aspects of vascular disease, whereas cardiologists have also applied pharmacologic tools and are expanding into peripheral as well as coronary vascular disease. As the field of biological imaging grows, the younger generation of radiologists will have to know much more about the pathophysiology of disease.”
Judith Gunn Bronson, MS, is a contributing writer for Decisions in Axis Imaging News.
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- Tung C-H, Bredow S, Mahmood U, Weissleder R. Preparation of a cathepsin D sensitive near-infrared fluorescence probe for imaging. Bioconjug Chem. 1999;10:892?896.
- Mahmood U, Tung C-H, Bogdanov A Jr, Weissleder R. Near-infrared optical imaging of protease activity for tumor detection. Radiology. 1999;213:866?870.
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