Healthcare – Molecular Diagnostics
The Sooner, the Better—with Molecular Diagnostics
The sooner an illness is recognized, the better the chance of recovery. New imaging techniques and biochips from Siemens are helping detect the very first signs of illness on a molecular level.
Siemens' Biograph uses a combination of two imaging processes—PET and CT—to reveal pathological metabolic changes. The result is improved diagnostics
There's no such thing as a perfectly healthy person. That said, there's a world of difference between the minor ailments that most of us have and life-threatening conditions such as cancer or a stroke. And yet, many serious illnesses can be healed or avoided if they are recognized in time. While imaging technology (see article Before Illness Strikes) and laboratory diagnostics already play an important role in the early detection of illness, such methods are generally only applied once a patient has developed symptoms such as constricted arteries or abnormal blood readings. In the future, however, diagnostic procedures will be able to detect a disease much earlier. For example, doctors armed with the ability to determine metabolic changes at the molecular level will be able to diagnose cancer much sooner than they can today.
Molecular diagnostics includes both in vitro procedures, which are conducted outside the body using DNA and protein chips, and in vivo imaging, which takes place within the body. "Siemens is involved in both areas," explains biochemist Dr. Ralph Gareus, project manager at the department of New Business Development at Siemens Medical Solutions in Erlangen, Germany. "I believe molecular imaging represents one of the most promising technologies of the future. This combines conventional imaging techniques with special contrast agents so as to make metabolic changes visible," Gareus says. "That means diseases can be diagnosed long before the patient begins to manifest any anatomical changes or abnormal blood readings."
Reasearch and development engineers at Siemens have already achieved spectacular results with molecular imaging, including the development of the Biograph, the world's first combined positron emission tomography (PET) and computed tomography (CT) scanner. Before examination, the patient receives an injection of a sugar solution tagged with a radioactive isotope, which is absorbed by cells throughout the patient's body. Because of their uncontrolled growth, cancerous cells consume an enormous amount of nutrients. As a result, they accumulate up to ten times as much tagged sugar as normal tissue does, which produces a bright spot on PET images. But the images produced by stand-alone PET scanners are tough to place because anatomical detail is missing. That's where CT comes in. Once the PET data is combined with the data generated by the CT, physicians not only see the cancer, but can tell where it's located.
Tomorrow's mini lab
Diagnostics in 2005: A drop of blood placed in the cartridge is initially separated into its components in the first chamber (1). The genetic material to be detected (either bacterial DNA or—where the human genome is the issue—the patient's own) is extracted and transported to the second chamber (2), where it is amplified. The third chamber (3) contains a biochip to detect DNA sequences. Finally, the cartridge is inserted into a small Siemens device that automatically analyzes the data
The Biograph is not the only molecular imaging system developed by Siemens. Researchers in Erlangen are also working on an optical imaging technique based on fluorescent contrast agents that use light from the near-infrared region. "This works without x-rays, and offers a highly selective and sensitive technique for imaging cancer cells. It's therefore a very attractive option for human applications," says Gareus. The secret behind the new technology is the use of so-called smart contrast agents. On their own, these are inactive and only fluoresce under radiation after they have come into contact with particular target molecules such as tumor-specific enzymes.
At present, smart contrast agents are being tested on animals (see insert Detecting cancer at the cellular level and Pictures of the Future, Fall 2001, article The Transparent Patient). Licensing for human use is not expected until 2007 at the earliest. "Scientists at Massachusetts General Hospital have successfully tested the new contrast agents on mice," says Gareus. "For the imaging itself, they use a prototype we developed." Because infrared light penetrates only to a maximum of five centimeters beneath the skin, medical applications would be restricted to conditions such as skin cancer or lymph node abnormalities in the neck area. "That's why we're also working on a special fluorescent-optical imaging camera for use inside the human body," explains Gareus, who adds. "That will take the surgeon right up to a tumor so that it can be closely examined."
Detecting cancer at the cellular level
Optical imaging with fluorescent contrast agents uses light from the near-infrared wavelength band. The so-called smart contrast agents used in the process are currently being tested on animals. While inactive on their own, these agents fluoresce under illumination as soon as they come into contact with tumor-specific enzymes. Licensing for human use is not expected until 2007 at the earliest.
This image was made available by Prof. Ralph Weissleder, Massachusetts General Hospital
How aggressive are tumors? Molecular imaging can tell researchers how invasively—how quickly and to what extent—cancer cells are spreading into neighboring tissues. Here, two human breast tumors with different levels of tissue invasiveness were implanted in a mouse. The mouse was injected with a fluorescent contrast agent that is activated by a tumor-specific enzyme that facilitates tumor growth through the breakdown of surrounding, healthy tissue. The tumor on the right fluoresces much more strongly and is therefore considerably more invasive than the one on the left.
This image was made available by Prof. Ralph Weissleder, Massachusetts General Hospital
Is the cancer treatment working? Smart contrast agents are also used to monitor therapy. The image on the left shows the tumor before treatment with a specific protease inhibitor, which prevents the tumor from spreading. The impact of this specific inhibitor is clearly recognizable after two days as indicated by the substantially weaker signal (right).
According to Gareus, molecular imaging holds enormous potential. "By 2007, it will be a key tool in the early detection of cancer, arthritis, neurological conditions such as Alzheimer's, and, in particular, coronary artery disease," he say. For instance, molecular imaging will help diagnose the minuscule areas of plaque that appear on arterial walls long before blood vessels actually become constricted and the chances of a heart attack increase. Molecular imaging will also play an increasingly important role in the planning and monitoring of therapy. In this way, it will help physicians determine the extent to which a tumor has responded to therapy. Furthermore, molecular imaging could provide an alternative to biopsies in gene and stem cell therapy, where it would be possible to test, in vivo, whether genes introduced into the body produced the desired proteins and whether stem cells colonize the body as expected.
One Card Does It All. Siemens has also come up with a number of highly promising innovations for in vitro diagnosis. In cooperation with biotech startup pes Diagnosesysteme GmbH, Siemens has developed a sensor with an integrated chip that can analyze a blood sample much faster than a fully equipped laboratory, yet do so with exactly the same degree of accuracy. (see Pictures of the Future, Spring 2002, Intelligent Blood Sensors).
Many DNA and protein tests still have to be performed by research laboratories at considerable expense. "Until now, the complexity of genetic information and its interpretation has required both specialized personnel and sensitive and expensive optical detection equipment. Thanks to new developments in biotechnology, however, it is now possible to miniaturize the technology to such an extent that it will all fit on a single microchip," says Dr. Emil Wirsz, director of New Business Development at Siemens Medical Solutions in Erlangen.
The lab-on-a-chip not only controls entire laboratory processes, but also comes with all the requisite substances and reagents. "We'll see a breakthrough in molecular diagnostics at the beginning of 2005," predicts Wirsz. "It's then that we're likely to see the market launch of a DNA cartridge the size of a credit card." Developed by Siemens and biotech company november AG, the cartridge will have many applications, including the diagnosis of infections, tumors, and hereditary diseases; tests on the tolerance to, and efficacy of, medication; and the detection of a genetic predisposition to certain conditions.
At the heart of this mini lab will be a DNA chip produced by november that contains around 100 electrodes. A single chip can simultaneously distinguish between 12 different target molecules on the basis of their DNA. Analysis of this data is conducted fully automatically by a unit developed by Siemens. "We have already successfully tested the first prototypes," says Wirsz, a specialist in IT and electrical engineering. "Acute and life-threatening infections require immediate treatment. Bacterial or viral pathogens can be specifically identified using the catridge."
The revolutionary—and to date unique—feature of the cartridge is that it unites three different procedures in a highly compact format: sample preparation, amplification of the pathogen's DNA—necessary to ensure a sufficiently strong and measurable signal—and DNA identification. "Lab-based diagnostics are still relatively expensive. For example, the polymerase chain reaction required to amplify the DNA costs at least 80 €," says Wirsz. "That's more than the cost of our complete mini laboratory."
Ulrike Zechbauer