Pictures of the Future      Spring 2005

Tiny Terminators

By 2020 many major illnesses, including cancer and heart disease, may be managed to the extent that the threat they pose is substantially reduced. Genetic testing and a new group of molecular-based sciences being developed by Siemens and the Center for Molecular Imaging Research in Boston could make this possible.

Tomorrow’s health care system will begin with a pin prick. A technician at your general practitioner’s office will deposit a drop of your blood on a tiny card, which will be placed in an analyzer about the size of a laptop. Within minutes the analyzer’s organic LEDs will tell your doctor whether you are likely to develop—or have started to develop—anything from breast or bladder cancer to atherosclerosis or even Alzheimer’s. Known as quicklab, the card, which is now being developed by Siemens, is equivalent to an entire laboratory on a chip (see (Pictures of the Future, Fall 2004, article Biosensors). Using micro channels, chambers and pumps that rely on capillary forces, the chip extracts DNA or proteins from blood or other bodily fluids, compares them with an array of synthetic bio molecules, and pinpoints anomalies.

Used on a regular basis, quicklab promises to become the first line of defense in a new spectrum of healthcare practices that will stress prevention and holistic, personalized treatment. Cheaper, quicker, easier to administer, and more accurate than current tissue- and blood-based tests, quicklab technology will screen the population for the earliest hints of illness, help to eliminate vast numbers of needless tests—43 % of all prostate, ovarian, colorectal and lung cancer tests produce at least one false positive result, costing over $1,000 in additional medical care expenditures per tested patient, according to the American Association for Cancer Research—and allow the healthcare system to concentrate on treating those who actually need treatment.

Detecting Delinquent Cells. Over the next ten to twenty years, many illnesses, including cancer and heart disease, may be diagnosed and treated so early that they could cease to be a threat. For instance, suppose that fifteen years from now a routine quicklab test shows that you have prostate cancer-related proteins in your blood. If you’ve had regular tests for the last few years, chances are this test will have detected the very first stage in cancer development. What would happen next?

The answer is taking shape at the Center for Molecular Imaging Research, (CMIR) at Massachusetts General Hospital (MGH) and Harvard University in Boston. There, researchers led by Harvard Medical School Professor Ralph Weissleder, Director of the CMIR, are zeroing in on ways of spotting and exterminating cancer cells (and many other kinds of delinquent cells, such as those involved in arterial "vulnerable plaque") years before any of today’s technologies can even detect them.

To detect prostate cancer—and a range of other potential killers—Weissleder’s team has developed biodegradable nanoparticles that fit into the cells’ receptors as precisely as a key fits into a cylinder. Thus, any cell that absorbs them is, by definition, cancerous. Furthermore, since they disturb magnetic fields, the particles will be visible to the next generation of high-field magnetic resonance (MR) imaging machines now being developed by Siemens. Indeed, work in this area, which is called molecular imaging, is already at an advanced stage. "15 clinical trials are currently underway here at MGH to determine the efficacy of these nanomaterials and other molecularly targeted agents," says Weissleder. (Siemens’ commitment to molecular imaging was highlighted by its announced intention to purchase Knoxville, Tennessee-based CTI Molecular Imaging in March, 2005 for about 1 bn. US-$.)

Getting Cells to Glow. At this point your doctors will know almost exactly where the cancer is located. The only problem is that, from a surgeon’s point of view, pre-cancerous cells look exactly the same as normal cells. Naturally, the images developed using nano particles and MR could be used during surgery (augmented reality), but the visualization process would be simpler and more intuitive if the cancer cells would, for instance, glow. With this in mind, Weiss­leder and Siemens Medical Solutions are collaborating on development of new medical devices and technologies that could take advantage of nano "labels" that fluoresce in the near infrared when absorbed by cancer cells. Under their direction, CMIR scientists have identified proteins unique to cancer cells and designed substances that are attracted to the cells’ surface structures. When injected, the labels, which are made of fluorescent molecules, are "quenched"—in other words, like two flashlights facing each other in close proximity, no light escapes. But in this case, the "flashlights" are tethered to one another by a "linker" that is made of a peptide sequence that can be broken only by a protein or enzyme found inside cancer cells. Once the linker is broken, the label can fluoresce. In short, if the labels find cancer cells, they are first absorbed. Then, as the target protein that signals cancer goes to work, the linker holding the "flashlights" together is dissolved, and the cancer cells begin to glow.

Given an injection of fluorescent labels before prostate surgery, cancer cells would now be visible using a CCD (charge coupled device) imaging system. "This is something very new in medicine because it means that surgeons will be able to see cancer cells and remove them before they have begun to do any damage," explains Dr. Christian P. Schultz, who is Director of Molecular Imaging at Siemens.

Cellular Surgery. The operation itself would involve an as-yet-to-be-finalized combination of micro-endoscopy using a fiber optic confocal microscope (endoscopic versions of such microscopes, which visualize fluorescent objects three-dimensionally, are already available), and treatment using radio-frequency heating of the cancer cells or cryoblation (freezing). Infrared structures (cancer cells) would have to be spatially overlapped on the visual images to allow the surgeon to distinguish between normal and abnormal tissues. With a view to eventually making such procedures possible, Siemens is working with Weissleder’s team in developing catheter-based, as well as hand-held imaging devices that will function in both the visible optical and near infrared ranges. "Taken together, these technologies open the door to seeing individual cancer cells and removing them," says Weissleder. "It adds up to a phenomenal advance," adds Schultz.

New Medical Knowledge. Regular, comprehensive gene- and protein-based screening, early detection of illness, whole-body imaging when disease is found, pin-point identification of dangerous cells, precision surgery based on the removal of only those cells that pose a threat, and regular monitoring to ensure that new disease has not developed—that’s the vision that Siemens and CMIR are working to fulfill. With few exceptions, the pieces of this immensely complex technology puzzle are being developed, with some having entered, and others approaching clinical trials.

"In all of this, we must not forget the crucial role of information technology and the software that will drive it," Says Mohammad Naraghi, M.D., head of Busi­ness Development at Siemens Medical Solutions, "The development of holistic, integrated healthcare that goes from predisposition testing to screening for specific illnesses, all the way to early diagnosis and personalized treatment will rely on—and spur—the development of new IT solutions that will refine our understanding of diseases and how to manage them."

Indeed, CMIR and Siemens are on the road to creating a new software platform called MI Portal that will be designed to function as a comprehensive information clearinghouse for all medical modalities, and will integrate knowledge from genomics and proteomics. "The question is," asks Schultz, "If we screen all the information from all the diagnostic and therapeutic tools at our disposal – and we will have much more as quicklab and molecular imaging gain momentum – will we be able to create new medical knowledge that can be translated into clinical practice?"

What seems certain is that a process has been set in motion in which growing quantities of medical and molecular information will be refined into ever more precise knowledge that will in turn be focused on solving individual health needs.
                                                                                                                 Arthur F. Pease