DISEASE DIAGNOSTICS: Third-harmonic generation reveals malarial infection

Canadian researchers have developed a technique that relies on nonlinear optical effects to detect the existence and extent of the malaria parasite in human blood. The advance offers the promise of low-cost, self-contained, field-portable kits to diagnose the disease effectively in regions where it is endemic and qualified technicians are rare.

Injected into humans through the bite of the anopheles mosquito, the malaria parasite induces successive periods of shivering, fever, and sweating. Some 350 million to 500 million new cases are reported each year, and the disease kills up to three million people annually, most in sub-Saharan Africa.

Identifying malaria in its early stages requires qualified technicians to obtain microscopic evidence of the parasite’s DNA on stained slides containing a patient’s blood. To determine the progress and severity of the disease, factors relevant to the choice of treatment, technicians count the number of infected cells in the blood sample.

A team led by Paul Wiseman, associate professor of chemistry and physics at McGill University (Montreal, Quebec, Canada), has proposed a far less labor-intensive method to achieve the same result. It relies on the nonlinear optical effect known as third-harmonic generation.

“It’s the optical equivalent of harmonics in acoustics but much harder to produce,” Wiseman says. Just as an organ pipe produces notes that are harmonics of the basic frequency, certain crystals can produce optical harmonics of light that strikes them. However, Wiseman notes, the effect is produced only by femtosecond or picosecond pulsed laser sources with very high photon densities, and only in certain substances. One such substance is hemozoin, a crystalline substance secreted by the malaria parasite.

“Hemozoin has a huge nonlinear response for the third harmonic,” Wiseman says. Zapped with infrared laser pulses at 1180 nm, the substance produces a blue glow at a wavelength of about 393 nm (see figure). “So strong was the effect the first time a graduate student applied the process to hemozoin that we were worried that we had damaged the sample,” Wiseman says. “The signal from the hemozoin was greater than we have observed in any cell type, with signal/noise ratios that reach 1000:1.1 This method allows rapid and robust detection of early stage infections of blood cells.”

Using two-photon fluorescence (red, left) and third-harmonic generation (blue, left), researchers at McGill University have been able to more quickly and accurately image plasmodium falciparum-infected red blood cells (indicators of malaria). Images on the right are normal microscope images of the same area.
Click here to enlarge image

Now, Wiseman says, “we’re imagining a self-contained unit that could be used in clinics in endemic countries. The operator would inject the cell sample directly into the device. It would then come up with a count of the total number of existing infected cells without manual intervention.”

For starters, the team must find a light source to replace the expensive optical-parametric-oscillation laser used for the preliminary studies. “Maybe we could build a device around a cell sorter with a fiber laser centered on a specific wavelength as the light source,” Wiseman says. “We need to see how cost-effective we can be on the fiber-laser side. The scale of the photonics industry may bring down the price.”



1. J.M. Bélisle et al., Biophysical J. 94, L26 (2008).

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