Pictures of the Future      Fall 2008

From Molecules to Man

From genes and proteins to cells, tissues and our entire organism, scientists are in the process of piecing together a systems view of how we work. As they do so, they are linking the results of laboratory tests to diagnostic images, injecting the resulting knowledge into advanced decision-support systems, and devising strategies for early detection and targeted treatments.

An immense puzzle is being assembled. It begins with the genes and proteins that activate, accelerate, brake and shut down cascades of processes through­out our bodies. It goes on to include entire cells and the complex communities that form individual tissues. And it embraces the more familiar world of organs and organisms, attempting to differentiate, in each of its countless pieces, what is normal from what is not. In short, the "puzzle" is what scientists call systems biology. It is an integrated vision of everything from molecules to man, and it is—through our growing understanding of fundamental biological mechanisms—the key to the early detection of diseases.

Like the holistic vision driving systems biology itself, Siemens Healthcare is moving steadily toward a form of informational integration that is designed to eventually bring all the pieces of the puzzle together. As it does so, it is riding the crests of fast-moving waves of change in medical imaging technologies (see Imaging) in vitro diagnostics (see Biomarkers and Vista) medical informatics (see Epidemology) and a vast range of applications, including early detection of breast and metastatic cancers (see Breast Diagnostics and Breast Cancer Prognosis Test), prostate cancer, and disease-associated biomarkers (see Biomarkers).

Says Bernd Montag, CEO of Siemens Healthcare’s Imaging and IT Division, "Our unique advantage is embodied in the combination of molecular diagnostics and imaging, together with our advanced information and workflow-enabled systems. These systems integrate the information from different in vitro and in vivo modalities, and, together with patient-specific data, transform information into knowledge that the clinician can leverage for optimized care. The true potential of this knowledge is that it will help to enable personalized medicine."

By acquiring Diagnostic Products Corporation, Bayer Diagnostics, and, most recently, Dade Behring, Siemens Healthcare has not only become "the world leader in the $32 billion (€20 billion) in vitro diagnostics (IVD) industry," says Donal Quinn, CEO of Siemens Healthcare’s Diagnostics Division, but has magnified the power of its spectrum of imaging modalities.

To understand what the synergistic potential of in vitro and in vivo diagnostics is in combination with advanced IT, consider the fact that an increasing number of blood tests may soon be linked to imaging information. For instance, most major illnesses, ranging from cancers to cardiovascular and neurological diseases can—at least in principle—be detected through blood tests. That’s because diseased cells produce proteins that are substantially different from those manufactured by physiologically normal cells. These proteins migrate to the surfaces of cells, where they are eventually washed away into the blood.

"If you can detect these proteins—also known as biomarkers—with blood tests, then the next step is to figure out how to localize the source of that biomarker with imaging—and evaluate it with IT," explains Walter P. Carney, PhD, Head of Oncogene Diagnostics, Inc. of Cambridge, Massachusetts, a part of Siemens Healthcare Diagnostics. "What we want to do is to combine circulating biomarkers with imaging biomarkers to be able to visualize pathologies sooner and understand them in vivo. This will lead to uniting early detection technologies with personalized, targeted therapies—in short, connecting the dots between the worlds of in vitro and in vivo information."

And that’s what’s happening. At Siemens’ Biomarker Research facility in Los Angeles, for instance, researchers are beginning to redefine healthcare by developing imaging biomarkers that may be able to zero in on specific atherosclerotic lesions known as "vulnerable plaques"—those most likely to rupture, thus causing a stroke or heart attack. Such lesions are thought to be one of the major underlying causes of emergency room admissions worldwide.

Expected to enter human trials in coming months at a major medical center in Los Angeles, the new imaging biomarkers hold great promise because, says Hartmuth Kolb, PhD, Vice President of Siemens Molecular Imaging Biomarker Research, "what we see as physical stenoses with angiography aren’t necessarily the vulnerable plaques. The vulnerable ones are essentially hidden. But with this new technology we hope to learn how to see them."

In this case, the imaging biomarkers, which are designed to bind specifically to proteins produced by vulnerable plaques, are being imaged with Siemens’ new HD (high definition) PET-CT (positron emission tomography / computed tomography) scanner. Once vulnerable plaques can be pinpointed with these technologies, the resulting information might be mapped onto future angiography exams, allowing cardiologists to stent dangerous areas, thus preventing potentially unstable atherosclerotic lesions from rupturing and occluding arteries..

An even more advanced treatment scenario is offered by Dr. Mukesh G. Harisinghani (see interview), director of the Clinical Discovery Program at the Center for Molecular Imaging Research at Massachusetts General Hospital (MGH). He points out that magnetic nanoparticles developed at MGH "can be tagged to identify specific types of receptors on the cells that form vulnerable plaques." With this in mind, he foresees the evolution of angiography to include "a small catheter that Siemens is already developing that would be inserted into high-risk vessels to release targeted nanoparticles that would zero in on vulnerable plaques and be visualized by means of optical infrared imaging," he says. Treatment might then involve an injection of nanoparticles carrying a therapeutic agent that would specifically target the cells in vulnerable atherosclerotic tissues.

Worlds of Information. Nowhere is the complexity of the healthcare puzzle or the scope of the molecules-to-man vision more evident than in its information technology dimension. It is here that the results of billions of increasingly automated in vitro tests are merging with patient data and being mined for knowledge creation. It is here that established modalities such as CT, MR, and PET are merging with each other (PET-CT, PET-MR) and with new technologies such as optical imaging to create even more exact information. And it is here that the intersection of biomarkers and an expanding universe of magnetic nanoparticles, radioactive tracer materials, and fluorescent molecules is set to unleash a revolution in early disease detection.

How will organizations ultimately be able to focus all of this information in ways designed to intuitively support a physician’s decision-making process at the point of care? Probably the most advanced infrastructure now available in this area is Soarian, Siemens’ healthcare workflow engine. Across the board, from administration to clinical management, Soarian integrates information and presents it logically to clinicians. "It brings a patient’s longitudinal clinical information, such as past illnesses and history, and most current data, such as vital signs, meds, and test results to the physician’s fingertips in the form of a Web-based electronic patient record," says Workflow and Solutions CEO Tom Miller (see Rhön Klinikum). "What’s more," he says, "as we enter the era of personalized and predictive medicine, such systems will also include genetic predisposition and other information that will alert and guide physicians in determining preventive measures, watchful observation, earlier diagnosis and the most appropriate treatments."

Many Soarian functions will eventually be powered by Siemens’ patented Remind platform (see Pictures of the Future, Spring, 2008, Remind and Digital Assistants).

Designed to dynamically integrate a patient’s imaging, lab and genetic results with those from patients with similar conditions, Remind is expected to aid physician decision making and help in the early detection of diseases.

Like rivers pouring into a reservoir, data from many sources will flow together in tomorrow’s Soarian-Remind environments. For instance, in the context of a European Union-funded program called Health-e-Child (Pictures of the Future, Spring 2007) Siemens researchers are using commercially-available gene chips "to search for DNA changes that are associated with childhood brain cancers," says Dan Fasulo of the Integrated Data Systems Department at Siemens Corporate Research (SCR) in Princeton, New Jersey. "Eventually," he says, "the results will lead to development of a chip designed to detect genetic predispositions to many childhood diseases." As researchers learn to detect such mutations and begin to develop strategies for visualizing and treating associated diseases, the resulting knowledge will be transformed into algorithms and will flow into the decision-support environment, where all children will benefit from the results.

"Health-e-Child is about assembling the knowledge base for early detection of a range of pediatric diseases," says Paul Camuti, President of SCR. "It is one of many systems that are helping us to put different pieces of a complex puzzle together to discover what combinations of diagnostics and therapeutics result in the best outcomes. This represents a fundamental transition from the trial-and-error treatments of the past to the knowledge-based diagnostics of the future."
                                                                                                             Arthur F. Pease