A Clearer Picture of Cancer

A new, high-resolution imaging system captures “early” photons.

The list of genes and proteins associated with cancer and other diseases is growing rapidly: earlier this month, for instance, scientists reported sequencing the whole genome of a cancer cell for the first time. A field called molecular imaging puts this information in context by letting scientists watch biological molecules in action inside diseased cells and tissues. Now researchers have found a way to let molecular imaging that uses near-infrared light peer deeper into the body.

Sharper image: Laser light that passes directly through animal tissue (A) is less diffuse than light that the tissue scatters (B). Images made using unscattered light (C) show the localization (red) of a tumor in a mouse more clearly than those made with scattered light (D). They also show the tumor’s extent in the other side of the lung.

Fluorescent-protein tags can be made to target just about any biological protein, be it an enzyme that helps cancer cells advance through surrounding tissue or a marker of arthritic inflammation. But their use has been limited to shallow tissues in humans or to small animals. The markers are activated by, and emit, near-infrared or infrared light, which scatters in tissue; the more tissue the light has to penetrate, the blurrier the images. A new 3-D near-infrared imaging system uses ultrafast cameras to capture light that hasn’t scattered. It’s been used to create richer, higher-resolution images of the molecular workings of lung cancer in mice, and with further development, it might be used to study disease in thicker tissues and in people. The research was led by Vasilis Ntziachristos, director of the Institute for Biological and Medical Imaging at the Helmholtz Center, in Munich, and Mark Niedre, assistant professor of electrical and computer engineering at Northeastern University, in Boston.

You can see how tissue scatters light by holding a laser pointer to your fingertip, says Niedre: the light spreads out and your finger glows. By the time most of the photons emerge, they “have bounced numerous times in the tissue and contain little image information,” says Changhuei Yang, a professor of electrical engineering and bioengineering at Caltech, who is not involved in the project.

Niedre and Ntziachristos’s imaging technique records photons that have taken a relatively straight path through the body and thus contain better imaging information. But the photons also pass through the tissue much more quickly, which is why previous imaging techniques haven’t been able to exploit them. The Munich and Boston researchers used a combination of an ultrafast light source called a femtosecond laser and an ultrafast camera to capture these so-called early-arriving photons. Light that bounces around inside the tissue before emerging doesn’t get recorded by the new imaging setup. “We’re preferentially choosing photons with more spatial information,” says Niedre. The group also created better models of how these photons travel, which help sharpen the images even further.

Capturing early-arriving photons makes for much better pictures of the biological activity of deeper tissue. In images of mice with lung cancer, Niedre says, “we resolved features that you couldn’t see” with a conventional infrared-imaging setup. Not only were the images sharper, Niedre says, but they also revealed molecular markers of inflammation and other problems throughout the lungs. The slower imaging setup showed only the tumors themselves.

The images were also three-dimensional, an effect that the researchers achieved by moving the laser up and down and back and forth while spinning the mouse. A similar principle is used in clinical computed tomography (CT) scans, which use x-rays instead of infrared light and an imaging system that moves around the patient.

Improving image resolution by catching early-arriving photons isn’t a new idea, but it took some technical finesse to make it happen. Bruce Tromberg, director of the Laser Microbeam and Medical Program at the University of California, Irvine’s Beckman Laser Institute, says that the new work is “retro cool.” When researchers like Tromberg first started working on imaging with infrared light, they hoped to look at the early-arriving photons but didn’t have good enough fluorescent markers or hardware. Now that better markers and cameras are available, Tromberg says, it’s logical to revisit the idea.

Arjun Yodh, a professor of physics and astronomy at the University of Pennsylvania and another optical-imaging pioneer, is skeptical that the new approach will work in thick tissues in people, where the scattering is greater than it is in a mouse’s chest cavity. Niedre himself cautions that the work is still in its early stages, and that the instrumentation and image processing will need substantial improvement before the technique can be applied to larger animals and humans.

Until that time, the technique will allow researchers to study the progression of cancer in greater detail in animal models. Much of the basic biology of cancer is still a mystery–in particular, the molecular processes that allow it to spread from the initial tumor site to others throughout the body–and the new technique will give biologists a better look.

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