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Aug 21, 2012

Silicon Peptide Chips Could Transform Diagnostics

  • Scientists have developed a silicon-based peptide chip that they claim could form the basis of a real-time, point-of-care diagnostic platform. The team, headed by researchers at Stanford School of Medicine and Intel, designed their prototype chip, which they’ve called the Intel array, for identifying proteins associated with severe forms of systemic lupus erthyematosus (SLE). However, they say the scalable platform could be applied to a broad range of proteomics studies, including epitope mapping and characterizing protein-protein interactions, as well as for personalized POC diagnostics.

    Stanford’s SLE researchers Paul Utz, M.D., Chih Long Liu, Ph.D., and colleagues hit on the idea of using photolithography to generate peptide arrays directly on a silicon surface that could potentially incorporate integrated semiconductor circuitry directly underneath each peptide to allow real-time measurement and analysis. The team had previously used a similar process to apply peptides onto other substrates as the format for a fluorescence-based proteomic platform.

    In partnership with their colleagues at Intel, the researchers have now evolved the technology to design and generate a microprocessor-grade silicon chip prototype in which the peptides are synthesized directly onto the chip, rather than being synthesized separately and then spotted onto the substrate. For their work on SLE, described in Nature Medicine, the investigators synthesized a chip that carried every possible overlapping peptide within the linear protein sequence of the N-terminal tail of human histone H2B, as well as peptides carrying post-translational modifications. They report on the chip’s construction and experimental results in a paper titled “On silico peptide microarrays for high-resolution mapping of antibody epitopes and diverse protein-protein interactions.”

    “Honestly, we thought it wouldn’t work,” Dr. Utz admits. In fact, the process not only worked, but the silicon arrays could have numerous advantages compared with arrays based on other substrates such as glass, circumventing the problems associated with nonspecific binding, making signal detection easier, and allowing the peptides to be arranged more closely together. “If we couple these Intel arrays with an electronic detection method, for example, we could have real-time sensing over a period of minutes,” Dr Utz adds.

    The 9,000-peptide H2B chip generated for the SLE research was used to identify epitopes within H2B that are associated with different forms of SLE, which could help in the stratification of patients enrolled into clinical trials of therapeutic candidates. “Our results corroborate reports showing that autoantibodies targeting post-translational modifications on histone proteins, notably acetylated and methylated epitopes, are associated with SLE pathogenesis,” the researchers state.

    “Companies developing therapies to block the pathway responsible for this binding are now accepting patients with lupus for clinical trials without knowing which subset of disease they are in,” Utz points out. “This method could potentially be used to identify only those patients likely to benefit, and aid in the identification of effective drugs.”

    But in a broader setting, combining the silicon array platform with other emerging technologies such as magnetic nanosensors could revolutionize the field of proteomics both in a research and clinical setting, the investigators claim. “By combining emerging nonfluorescence-based detection methods with an underlying integrated circuit, we are now poised to create a truly transformative proteomics platform with applications in bioscience, drug development, and clinical diagnostics.” 


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