By Luke Liem
Optical imaging involves the use of highly sensitive cooled CCD cameras for detecting low levels of visible light emitted from bioluminescent probes in smaller animals. A company called Xenogen, based in Alameda, CA, is marketing one such optical imaging system. Xenogen’s IVIS system is designed specifically to image mice and is targeted at researchers who want to visualize biological and disease processes in live animals, or in vivo. Many academic institutions and biotech/pharmaceutical research labs are purchasing these optical imaging systems for both clinical and pre-clinical studies because they are quick and relatively easy to use. In vivo small animal imaging systems can help researchers substantially speed up the drug development process by allowing them to run quick tests of biological hypothesis and obtain proofs of principles in live animal models.
(Image courtesy of Xenogen Corporation)
Impact on Drug Development – Understanding Biology
New drug development is a long and expensive process, requiring up to 15 years of committed resources and $300-$500 million in costs per approved drug. As a result, pharmaceutical and biotechnology companies are constantly seeking new technologies that will accelerate the development of new drugs.
Most drugs fail because researchers develop drugs around disease targets without fully understanding the biological processes involved in a disease. During initial drug screening, researchers often use testing methods that involve cells or molecules on laboratory dishes (in vitro) outside the context of physiology of living animals. Many drugs end up failing the drug metabolism and toxicity screening when tested in animal models, before even reaching human trial.
Xenogen’s in vivo optical imaging systems can be used by researchers to run quick tests to investigate how diseases progress and how experimental drugs work on diseases or infections in live animal models. Because the animals do not need to be sacrificed to measure the biological activities, the researchers gain better quality data on the same live animal over time. In addition, there is substantial cost saving because genetically engineered mice can cost up to $300 per mouse.
To best illustrate the cost saving, Xenogen provided the following example; if an experiment runs for eight hours and calls for data every two hours, and each data set requires six mice, the old method requires 24 mice to be sacrificed, costing $7200 per experiment. Using Xenogen’s in vivo optical imaging system, the same six mice can be monitored through the entire eight hours, costing only $1800 and representing a 75 percent reduction in cost. In many drug metabolism and toxicity screening tests, over 200 mice need to be sacrificed, so the cost saving is even more significant.
Image courtesy of Xenogen Corporation
How The Science Works – Firefly and Gene-Splicing
Luciferase is an enzyme that occurs naturally in firefly, jellyfish and some bacteria. Scientists from Xenogen have figured out a way to take the gene for Luciferase, cut it out of the chromosome of a firefly, then paste it onto either living animals (e.g. a transgenic mice) or cell lines (e.g. cancer cells). These genetically engineered living animals and cell lines can be configured to either emit light continuously or in response to specific stimuli.
In experiments conducted to study cancer, “tagged” cancer tumor cells are introduced into a mouse, and researchers can track the progress of the metastasis of the cancer tumor using the sensitive IVIS imaging system manufactured by Xenogen. The researchers may experiment with various drug treatments and observe their effect on the mice in real time without the need of sacrificing them.
To detect the very low level of light emitted from a live animal, the IVIS system features a cryogenically cooled CCD camera, a dark imaging chamber to minimize incident light, and specialized software to quantify and analyze the results. The animal is anesthetized and placed in the dark imaging chamber. Two images are typical taken: one black-and-white (or grayscale) background photo of the mouse and one color overlay of the emitted photon data. The emitted-photon image is generated by detecting photons accumulated during the exposure time — from a few seconds to a few minutes — resulting in a two-dimensional array of data. The visual representation of this data appears as a “pseudocolor” image, representing the relative numbers of detected photons, overlaid on the black-and-white background image of the animal.
(Image courtesy of Xenogen Corporation)
Michael Sterns, Xenogen’s VP and Chief Business Officer, estimated that the company would have an installed base of over 150 systems worldwide by the end of 2003. The company has licensed its real-time in vivo imaging technology to such firms as Pfizer, Novartis, Millennium Pharmaceutical, Bristol-Myers Squibb, Merck, Chiron and AstraZeneca. In addition to imaging systems, Xenogen is also marketing a line of light producing cancer cell lines, bacteria and fungi as well as transgenic mice under the Bioware™ and LPTA® brand name. Xenogen is a private company with revenue exceeding $20 million in 2003. The Company has raised around $100 million in private funding from a diverse range of investors based both in Europe and the US.
Commenting on Xenogen’s unique business model of generating revenue from both instruments and reagents, "Xenogen is a instrument/reagents company that can provide very specialized services for our pharmaceutical customers. Our technology is a tool for researchers to better understand the disease processes in both preclinical and in clinical studies," said Dr. Pamela Contag, Founder and President of Xenogen. "We also see our business model evolving into that space where an increasing share of revenue will come from the reagents that we develop."
"In the next five years, optical imaging will be a significant translational technology from animal into human and it will contribute significantly to our understanding of human diseases," said Dr. Contag. "Our vision for Xenogen is to be a leader in the field of optical imaging developing the instrumentation as well as the biology and the reagents required for the understanding of human disease."