Pictures of the Future    Spring 2007

Headline of first Content

Imagine traveling down a moonless highway with no way of knowing what was on either side of the road. Out there, in the distance, would be some three billion towns and roadside crossings; yet only a few of them would have names. The rest would be too silent and faceless to even notice. If your job was to find all the nameless towns and figure out what was going on in each of them, you would be confronting an information challenge equivalent to understanding the human genome—the comprehensive genetic instruction manual found in each cell of our bodies.

The "towns" in such a journey might be the base pairs of adenine and thymine, or guanine and cytosine, for instance, that connect the sugar phosphate backbones of the double helix out of which our 46 chromosomes are made. Or they could be "cities"—groups of base pairs otherwise known as genes—capable of forming proteins. Today, most of the towns and cities that have been identified look like rough neighborhoods—places where tough guys like cystic fibrosis and sickle cell anemia hang out. Yet they are the ones we can see as we drive along. The rest are yet to be discovered.

"Understanding the human genome—finding out the names of all of those towns and what they mean for us—will open the door to personalized medicine," says Tony Bihl, Chief Executive Officer of Siemens Medical Solutions Diagnostics in Tarrytown, New York. "It will mean early detection of disease, treatment with drugs that match a patient’s individual needs, follow-up with imaging systems that track—and help to adjust—treatment response over time, and advanced information technology that optimizes in vitro and in vivo technologies every step of the way.

Assembling a Vision. And that’s exactly what Siemens has. As of January 1, Diagnostic Products Corporation (DPC), based in Los Angeles, California, and Bayer Diagnostics, based in Tarrytown, New York, merged into a vast new, 5.7-billion-euro vision called Siemens Medical Solutions Diagnostics that employs about 8,000 people. As this happened, Siemens became, according to Bihl, "The first company anywhere to bring in vitro laboratory diagnostics together with in vivo medical imaging." (For more, see In Vitro Diagnostics). Since then, General Electric, with its purchase of Abbott Laboratories' Diagnostics Business, has endorsed this vision as well.

Coming on the heels of the $1 billion, 2005 purchase of Knoxville, Tennessee-based CTI Molecular Imaging, Inc. (see In Vivo Diagnostics), the formation of the Diagnostics unit marks a turning point for Siemens toward becoming what Prof. Dr. Erich R. Reinhardt, President and CEO of Siemens Medical Solutions Group, calls "the world’s first full-service diagnostics company." Indeed, Siemens now combines a vast value chain that stretches from molecular diagnostics and immunoassays, to blood, urine and tissue tests, to imaging modalities ranging from pre-clinical research systems (see Molecular Therapy) to clinical ultrasound CT, MR and positron emission tomography (PET) scanning. Furthermore, through its Soarian integrated hospital software platform, syngo universal interface, and collective idea machine populated by thousands of scientists and software specialists, Siemens offers the IT capabilities to merge the in vitro world of lab tests with the in vivo world of imaging in medically meaningful and synergistic ways that are set to improve workflows and cut healthcare costs.

Fundamental to Siemens’ vision of a full spectrum of synergistic diagnostic services is a focus on the biology of disease. "Understanding what is happening on a molecular level, how disease actually starts, how genes commence a mutation process, express certain proteins, influence other cells, and initiate a tumor or trigger another disease will allow us to develop in vitro diagnostic tests and molecular imaging procedures to manage these processes," says Michael Reitermann, President of Siemens Medical Solutions’ Molecular Imaging (MI) Division, in Hoffman Estates, Illinois. Like Bihl, Reinhardt and others, he shares the view that what is most exciting about this process is the promise of earlier and earlier disease detection "The sooner we detect disease, the easier and less costly it is to treat," he says.

Blood-Based Cancer Tests. For experts in molecular imaging like Reitermann, the process of early disease detection begins in places such as Med MI’s recently expanded R&D facility in Los Angeles, which has received FDA approval to start clinical trials on a new imaging biomarker for Alzheimer’s disease. A biomarker is a protein found in blood, urine or tissue samples that can be used to develop diagnostic tests for specific diseases. The biomarker’s location and activity can be tracked using PET scanning. Developments in early disease detection are also in full swing at the new Diagnostics unit’s Oncogene Science Biomarker Group, in Cambridge, Massachusetts, where researchers are zeroing in on a biomarker called Serum HER-2/neu, which is excreted into the blood by breast tumor cells. "The marker is present at extremely low levels in normal female blood," explains Diagnostics unit Vice President for Global Molecular R&D Dr. Norbert Piel. "But when breast cancer arises, it reaches higher levels than normal, and we have developed an FDA-approved test that detects these." The Oncogene Science Group has also developed tests to measure three other cancer-related proteins, making Siemens Medical Solutions Diagnostics the only company to have a panel of four oncoproteins. Several pharmaceutical companies are developing targeted therapies to address these oncoproteins, thus opening the door to personalized medicine for cancer patients.

Such tests exemplify the promise of molecular medicine. Although still lacking the sensitivity to detect early-stage breast tumors—a development that is now in the pipeline—the HER-2 test provides a simple, painless way of detecting whether therapy is working. "This is very important, both from a medical as well as an economic point of view, because until recently, the best feedback came from biopsies," says David Hickey, Diagnostics unit Vice President for Global Strategic Marketing. "Using simple blood-based biomarkers to help clinicians guide expensive therapy can make a real difference in optimizing the economics of healthcare."

The direct result of our knowledge of what a normal human genome looks like—and the proteins its 30,000 to 40,000 genes express and do not express—the HER-2 test is one of the first of a new class of products that will help to avoid expensive biopsies while providing feedback as to whether medical treatment—which can run to tens of thousands of dollars per year per patient—is working or not.

What’s more, the HER-2 biomarker is on the cusp of the nascent connection between in vivo and in vitro molecular diagnostics. At Massachusetts General Hospital (MGH) in Boston, for instance, researchers are working with Siemens to image HER-2 levels in mice by labeling Herceptin—the medication often used in treating HER-2-related breast cancer—with a fluorochrome label. The labeled Herceptin binds to the HER-2, allowing its level and location to be visually tracked in vivo since it is produced by the tumor and is therefore found at its highest concentration there. "The technology is potentially transferable to humans and could be valuable in monitoring the adequacy of therapy," says Dr. Umar Mahmood, associate professor of radiology at Harvard Medical School and director of the Mouse Imaging Program at MGH’s Center for Molecular Imaging.

Other molecular tests that join in vitro with in vivo technologies are also on the horizon. For instance, Diagnostics unit researchers are excited about the potential for a revolutionary convergence between the company’s in vitro biomarkers that assess the status of the liver with regard to the hepatitis B and C viruses (HBV and HCV) and the use of ultrasound. Worldwide, hundreds of millions of people are infected with HBV and HCV, which can be life threatening because chronic infection can lead to liver fibrosis and cancer.

Furthermore, fatty liver disease, an increasingly common diet-related illness, has many of the same disease characteristics. Yet today, the only way of monitoring these conditions is by means of biopsies. "But," says David Okrongly, PhD, Global Head of the Diagnostics unit’s Molecular Diagnostics Business, "we’ve developed three tests that measure different markers of liver fibrosis. We’ve found that ultrasound techniques can be useful in evaluating liver elasticity, which changes as liver disease progresses. Our initial studies have shown that in the near future, physicians may be able to use a combination of ultrasound and biochemical staging to monitor patients with liver disease, and thereby decrease or eliminate the need for a biopsy." Okrongly adds that the liver fibrosis markers, which are now being clinically evaluated, are not yet commercially available.

Disease monitoring and staging are also advancing rapidly through the use of magnetic resonance (MR) imaging, positron emission tomography (PET), and single photon emission computed tomography (SPECT), all of which are being used to visualize molecular processes through the use of agents that zero in on disease mechanisms. In MR, scientists are concentrating on the development of iron oxide nanoparticles—and are opening up remarkable new areas of medicine in the process. For instance, researchers have capitalized on the fact that iron oxide molecules (which return a signal in a magnetic field) are naturally absorbed by monocytes—white blood cells that are part of the immune system.

With this in mind, the researchers have determined that in some cases of narrowing of the arteries, the major problem is an inflammation. "We can see this with MR because magnetically labeled monocytes are clearly homing in on these areas," says Dr. Robert Krieg, director of molecular magnetic imaging at Siemens Med. "This is a huge new area that could have tremendous importance in terms of the selection of medications used in the treatment of cardiovascular disease."

Magnetic nanoparticles are also being used to determine if cancers have spread beyond an initial site—one of the primary questions doctors want to answer before deciding on a course of treatment. For instance, in breast and prostate cancers, metastases first occur in nearby lymph nodes. Because macrophages in normal nodes clear impurities from the blood efficiently, any circulating magnetic nano particles wind up inside these nodes.

Cancerous nodes, on the other hand, absorb few if any of the particles. The result, thanks to close collaboration between Krieg’s team, researchers at Massachusetts General Hospital, and imaging and data integration specialists from Siemens Corporate Research in Princeton, New Jersey, is a new MR imaging technology that simplifies identification and classification of lymph nodes by producing a color-coded map showing those nodes that are healthy (green), questionable (yellow), and cancerous (red) in a 3D anatomical image. The technology, according to MGH’s Dr. Mahmood, is now being tested in a clinical trial. "Because of its ease of use," says Mahmood, "this will help to accelerate the introduction of nanoparticle imaging into community practice once the agent is approved by the FDA."

Working with a completely different class of biomarkers, Siemens scientists involved in positron emission tomography research have added a fluorine-18 label to a subtly altered thymidine molecule (a close relation to thymine, which is one of the four structural units of DNA) as a fundamental vehicle for studying the mechanism of cell growth in cancer. Since the substance—now known as FLT—is nearly a perfect copy of the naturally-occurring molecule "it is absorbed by cells—particularly cancer cells because of their higher growth rates—in proportion to normal thymidine, but doesn’t actually get incorporated into the cells’ DNA," explains Ward Digby, PhD, Director of Biomarker Product Manage­ment at Siemens’ Molecular Imaging Division in Knoxville, Tennessee. "FLT has become a powerful pre-clinical research tool in determining how cancer cells grow, and could be used in monitoring therapies in humans," he adds.

IT: Putting the Picture Together.If there is one challenge that towers above all others in creating a full service diagnostics company, it is how to integrate the vast and growing bodies of data from the worlds of in vivo and in vitro diagnostics—two fields that have historically been miles apart. Already, how­ever, a practical solution is taking shape at Massachusetts General Hospital, where a major Siemens-MGH project called the Molecular Imaging Portal is being developed (see Knowledge-Based IT). Designed to provide a platform for the integration of pre-clinical, clinical, genetic, proteomic and medical imaging data, the Portal represents the first step toward what may eventually become a universal decision support tool for everyone in the medical sciences. "It’s a fantastic, new research tool," says Digby. Adds MGH’s Mahmood, "The long-range idea behind the project is that as genetic information on patients becomes more affordable, doctors will be able to combine it with lab tests and imaging data to optimize and personalize therapy and make better predictions as to outcome."

Working along similar lines, researchers from Siemens Corporate Technology and Siemens Medical Solutions are researching analytical tools for a 16.7 million euros, four-year, EU-sponsored program called Health-e-Child (see Health-e-Child Takes Shape). The project will integrate genetic, clinical and epidemiological information on a number of pediatric diseases with a view to developing clinical decision support systems (CDSS).

Meanwhile, Siemens is also expanding its REMIND (Reliable Extraction and Meaningful Inference from Nonstructured Data) medical decision support system. The system develops personalized knowledge models by mining large amounts of patient data, including imaging, clinical, and genetic information, and combining these with medical knowledge. These models can then be used to develop personalized therapy plans at the point of care. Furthermore, Siemens continues to improve its GeneSim genetic knowledge, physician-support portal (Knowledge-Based IT).

The outlines of where such systems—as well as the broader trends in molecular medicine—will take us are gradually taking shape. Like a vast funnel, information from countless sources will gradually be distilled into decision support tools that will be available wherever and whenever they are needed through integrated hospital software platforms such as Soarian, and with key information and decision documentation being recorded in an electronic patient file. Furthermore, just as imaging modalities such as PET and CT have been integrated, the information from such systems will be combined with a torrent of data generated from armies of yet-to-be-developed molecular tests that will, in turn, be derived from our exploration of the human genome—a drive down a moonless highway where many, many towns are yet to be named.
                                                                                                              Arthur F. Pease