Scientists at The University of Manchester have developed a new and fast method for making biological ‘chips’ – technology that could lead to quick testing for serious diseases, fast detection of MRSA infections and rapid discovery of new drugs. They are aiming to develop ‘nanoarrays’. These would be much smaller than existing ‘micro arrays’ and would allow thousands more protein samples to be placed on a single ‘chip’, reducing cost and vastly increasing the volume of data that could be simultaneously collected.
Researchers working at the Manchester Interdisciplinary Biocentre (MIB) and The School of Chemistry have unveiled a new technique for producing functional ‘protein chips’ in a paper in the Journal of the American Chemical Society (JACS), published 22 August 2008. The paper is “Direct Site-Selective Covalent Protein Immobilization Catalyzed by a Phosphopantetheinyl Transferase”.
Functional protein arrays could give scientists the ability to run tests on tens of thousands of different proteins simultaneously, observing how they interact with cells, other proteins, DNA and drugs.
As proteins can be placed and located precisely on a ‘chip’, it would be possible to scan large numbers of them at the same time but then isolate the data relating to individual proteins.
The Manchester team of Dr Lu Shin Wong, Dr Jenny Thirlway and Prof Jason Micklefield say the technical challenges of attaching proteins in a reliable way have previously held back the widespread application and development of protein chips.
Current methods also require proteins to be purified first – and this means that creating large and powerful protein arrays would be hugely costly in terms of time, manpower and money.
Now researchers at The University of Manchester say they have found a reliable new way of attaching active proteins to a chip. Biological chemists have engineered modified proteins with a special tag, which makes the protein attach to a surface in a highly specified way and ensures it remains functional.
The attachment occurs in a single step in just a few hours – unlike with existing techniques – and requires no prior chemical modification of the protein of interest or additional chemical steps.
Immobilization of proteins onto solid supports is important in the preparation of functional protein microarrays and in the development of bead-based bioassays, biosensors, and industrial biocatalysts. In order to generate the stable, functional, and homogeneous materials required for these applications, attention has focused on methods that enable the efficient and site-specific covalent immobilization of recombinant proteins onto a wide range of platforms. To this end, the phosphopantetheinyl transferase Sfp was employed to catalyze the direct immobilization of recombinant proteins bearing the small, genetically encoded ybbR tag onto surfaces functionalized with CoA. Using mass spectrometry, it was shown that the Sfp catalyzes immobilization of a model acyl carrier protein (ACP) onto CoA-derivatized PEGA resin beads through specific covalent bond formation. Luciferase (Luc) and glutathione-S-transferase (GST) ybbR-fusion proteins were similarly immobilized onto PEGA resin retaining high levels of enzyme activity. This strategy was also successfully applied for the immobilization of the ACP, as well as ybbR-Luc, -GST, and -thioredoxin fusion proteins, on hydrogel microarray slides. Overall, the Sfp-catalyzed surface ligation is mild, quantitative, and rapid, occurring in a single step without prior chemical modification of the target protein. Immobilization of the target proteins directly from a cell lysate mixture was also demonstrated.
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