To mark its 10th anniversary, Drug Discovery & Development magazine invited industry vendors to reflect on the history and made predictions about future of the industry. Featured here are verbatim comments from this company.
FEI Company
Headquarters
Hillsboro, Ore.
Location(s)
Eindhoven, The Netherlands
Years in Drug Research
5 Years
Spokesperson
Matt Harris, vice president and general manager of FEI’s Life Science Division
Web site
About the company
FEI is the premier provider of 3D ultrastructural imaging solutions for the life sciences. FEI develops and manufactures electron and ion beam systems for high-resolution imaging and analysis, including scanning electron microscopy (SEM), transmission electron microscopy (TEM), and focused ion beam (FIB). TEM is used extensively in life science applications to explore structural biology down to the molecular scale with significant current emphasis on determining the three dimensional structure of proteins and viruses using cryogenic sample preparation techniques.
FEI focuses innovation on the creation of complete high-resolution imaging solutions for life scientists – from sample preparation to automated imaging to 3D reconstructions of biological samples in their native hydrated state. These solutions empower life science research in Structural Biology, Cellular Biology and the emerging Systems Biology.
The company’s line of business as it was 10 years ago. Changes in life science/drug research that influenced business.
TEM has long been used to look at biological materials. Ten years ago, the primary emphasis was on two-dimensional imaging and resolving structures too small for imaging with optical microscopy, less than a few hundred nanometers, but not yet at the molecular level. The primary limitation in imaging biological materials has been the vulnerability of the specimen to damage from the electron beam, and sensitivity of cellular components to induced conformational changes during sample preparation procedures. Early procedures focused on removing water from the sample and then staining and “fixing” with chemical or physical methods that made it compatible with the microscope vacuum and selectively enhanced contrast for features of interest. Although they worked well to a certain extent, these techniques were often disruptive of molecular structure and prevented imaging at that level.
Scientific challenges in the next 10 years.
The primary challenge in biological materials remains the vulnerability to electron beam damage and inherent low contrast of the sample material. Significant progress has been made in overcoming this limitation through cryogenic sample preparation, new detector technologies and computational techniques. Of these, foreseeable advances in detector technology offer the greatest potential for further improvements in TEM capability through the reduction of noise and consequent improvements in image quality, i.e., contrast, signal-to-noise ratio and resolution. We expect the next 10 years will bring greater improvements in image quality with a lower dose of radiation and, therefore, less damage. Another area of expected improvement is the use of automation to improve consistency and throughput. It is conceivable that the entire TEM process flow will be automated to the extent that it becomes practical to set up whole farms of systems for high content/high throughput screening, much like the approaches during the genomic revolution.
Factor(s) that drove the development of technologies during the last 10 years and greatest area of growths.
Three areas have seen the greatest progress and had dramatic impact on the way TEM is used in life sciences:
- cryogenic sample preparation (in particular, vitrification, which freezes the sample so quickly that water does not crystallize) preserves the specimen in its native, hydrated state, unperturbed by conventional staining and fixing techniques;
- high-sensitivity, low-noise, electronic detectors gather the image information more efficiently, increasing the amount of information that can be derived per unit dose of irradiation;
- computational techniques permit the combination of many images into a single higher contrast, lower noise image.
Equally important has been the development of computational techniques that combine multiple images into a three-dimensional representation of the structure.
On the application side, the dramatic advances in genomics have fueled increased interest and progress in structural biology at the molecular level. TEM is now accepted on an equal footing with X-ray diffraction and nuclear magnetic resonance in the determination of macromolecular structure (though not yet atomic). The complementary nature of the techniques provides a powerful means of cross validation, with each adding to the refinement of a particular model or analysis.
Bold Prediction: Where will drug research technology be in 10 years?
With technological advances, TEM will be able to provide fast, flexible imaging of biological structures down to the molecular scale. Advances in signal detection and image processing will enable this molecular level performance in biological materials. This may have significant implications for the way drugs are discovered and developed. It should increase the rational component of drug design by allowing the designer to directly visualize the target structure and assemble a therapeutic agent with the desired structural characteristics. As direct TEM data becomes more accepted, it should accelerate the drug approval process by offering intuitive visual confirmation of structural information deduced from other means, and the development of manufacturing processes (especially biologically based processes) by monitoring performance and improving process efficiency. Correlative techniques with light microscopy should provide high resolution imaging of structures localized by fluorescent labeling. High speed, time resolved imaging should be capable of analyzing the dynamics of flexible proteins and protein-protein interactions.
