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September

September 26: Scientists Develop New Type of Biosensor: Device Accurately Measures the Interactions Between Biological Molecules

Darryl Bornhop, the chemist who invented back-scattering interferometry.

Researchers supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) have developed a new method to study the behavior of molecules, particularly how they interact with each other.

In a study appearing in the September 21 issue of Science, chemists at Vanderbuilt University report that a new and deceptively simple technique – shining a red laser like those used in barcode scanners into a microscopic, liquid-filled chamber where two kinds of molecules are mixed -- can measure the interactions between free-floating biological molecules including proteins, sugars, antibodies, DNA, and RNA. In fact, the researchers have demonstrated that it is sensitive enough to detect the process of protein folding. 

The method represents an entirely new application of interferometry, a powerful technique that combines light from multiple sources to make precise measurements. Interferometry is used in everything from astronomy to holography to geodetic surveys to inertial navigation. The researchers call the new method back-scattering interferometry or BSI.

The equipment required for the new biosensor is surprisingly modest: a helium-neon laser like those used in grocery store scanners, a mirror, a charge-coupled device or CCD detector like those used in digital cameras, and a special glass microfluidic chip. The chip contains a channel about one fiftieth the size of a human hair. There is a “Y” at one end that allows the researchers to inject two solutions simultaneously, each containing a different kind of molecule. It is followed by a serpentine section that mixes the two.

Finally, there is a straight observation section where the interactions are measured. An unfocused laser beam is directed through the channel at this point. The beam is reflected back and forth inside the channel about 100 times. Each time the light beam strikes the channel some of the light is transmitted back up to the mirror where it is directed to the detector. There it forms a line of alternating light and dark spots called an interference pattern.

It turns out that the interference pattern is very sensitive to what the molecules are doing. If the molecules begin sticking together, for example, the pattern begins to shift. The stronger the binding force between the molecules, the larger the shift. This allows the system to measure interaction forces that vary a million-fold. That includes the entire range of binding forces found in living systems.

The underlying physics of this highly sensitive measurement technique are still being worked out. The researchers know that it responds to minute changes in the index of refraction, which is a measure of how fast the light travels through the liquid in the chamber compared to its speed in a vacuum. They hypothesize that it has to do with the rearrangement in the water molecules that cover the surface of the proteins: When two proteins react they squeeze the water molecules out of the area where they bind together. This displacement changes the density of the liquid slightly which, in turn, alters its index of refraction.

Vanderbilt has applied for and received two patents on the process and has several other patents pending. The university has issued an exclusive license to develop the technology to Molecular Sensing, Inc. Bornhop is one of the founders of the start-up and serves as its chief scientist. The company plans on completing a prototype system this fall.

Additional information including images can be found at: http://www.vanderbilt.edu/exploration/stories/backscatter.html.

Reference:
Bornhop DJ, Latham JC, Kussrow A, Markov DA, Jones RD, Sørensen HS. Free-Solution, Label-Free Molecular Interactions Studied by Back-Scattering Interferometry. Science 21 September 2007 317: 1732-1736 [DOI: 10.1126/science.1146559].

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August

August 30: Funding Opportunity for the Armed Forces Institute of Regenerative Medicine

The U.S. Army Medical Research and Material Command (USAMRMC), with the Office of Naval Research (ONR) and the NIH are establishing the Armed Forces Institute of Regenerative Medicine (AFIRM) dedicated to the repair and regeneration of battlefied injuires through the use of tissue engineering and regenerative medicine. Therapies developed by the AFIRM will also serve trauma and burn patients in the public at large. The closing date for applications is October 19, 2007. The full announcement of this Funding Opportunity can be found at http://www.grants.gov/search/search.do?oppId=15133&mode=VIEW or at http://www.usamraa.army.mil/pages/index.cfm (click on PAA).

August 1: Novel Optical Techniques Show Promise in Predicting the Presence of Pancreatic Cancer

Researchers at Northwestern University and Evanston-Northwestern Healthcare have developed two new complementary optical technologies that discriminate between normal and cancerous pancreatic tissue. The methods are minimally invasive and may avoid complications often associated with pancreatic biopsies. The research is supported by the National Institute of Biomedical Imaging and Bioengineering, the National Cancer Institute, and the National Science Foundation.

Pancreatic cancer carries a 5-year survival rate of less than 5%, mainly as a result of the advanced stage most cancers exhibit when discovered. Direct probing of the pancreas also carries a high risk of complications including pancreatitis, an inflammation of the organ. In this new approach, the Northwestern team led by Vadim Backman, a professor in Northwestern’s Biomedical Engineering Department, samples tissue adjacent to the pancreas for signs of early cancer. They surmise that the genetic/environmental factors that result in a cancerous lesion in a particular tissue site should also be detectable outside this location.

In a pilot study of the new approach, the researchers used four-dimensional elastic light-scattering spectroscopy (4D-ELF) and low-coherence enhanced backscattering spectroscopy (LEBS) to assess biopsies taken from the lining of the nearby upper small intestine (the periampullary duodenal mucosa). The optical techniques enable the researchers to probe tissue from macromolecules to whole cells using light-scattering signals from the tissue. The patterns or fingerprints that result from these techniques provide comprehensive, depth-sensitive information about the tissue. For each biopsy, light-scattering data were recorded from seven different tissue sites spanning the entire surface.

Although the pilot study was small, involving 51 individuals, the 4D-ELF and LEBS techniques demonstrated a high sensitivity (95%) and specificity (91%) when identifying pancreatic cancer versus normal tissue. The techniques had an even greater sensitivity and specificity (100% and 94%, respectively) when differentiating tumors that had the potential for surgical removal, which the researchers defined as stage 1 or 2 lesions.

Multiple optical markers were used to assess the epithelial tissue structures in the biopsies. Using these markers, researchers found that the duodenal mucosa of pancreatic cancer patients exhibits a series of architectural changes, including more densely packed cellular structures and a possible increased concentration of intracellular macromolecular complex. Statistical analyses confirmed that the 4D-ELF and LEBS optical markers were detecting cancer and not differences in smoking history or age. In addition, a pathologist performed confirmatory histological analysis of biopsies after 4D-ELF and LEBS measurements were taken.

Future studies will evaluate benign pancreatic and biliary disease to improve the specificity of the optical markers used in the current study and may examine additional markers to improve performance. These additional markers would take advantage of the collected but unused information from the light-scattering fingerprints. Backman’s team anticipates large-scale clinical trials to test the technique, which they say will benefit from advances in ultra-thin endoscopes that reduce patient discomfort and need for anesthesia.

Additional information on this important research can be found at: http://www.nsf.gov/news/news_summ.jsp?cntn_id=109781&org=NSF&from=news

Reference:
Liu Y, Brand RE, Kim YL, Turzhitsky V, Roy HK, Hasabou N, Shah D, Backman V. Optical markers in duodenal mucosa predict the presence of pancreatic cancer. Clin Cancer Res., accepted (2007).

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