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Lab-on-a-Bead Deciphers Biomolecules
by Mingyong HAN

anobiotechnology has emerged as an exciting field that combines the innovative potential of nanotechnology with biotechnology. To fully address its interdisciplinary nature, the Institute of Materials Research and Engineering (IMRE) and the National University of Singapore have come together to assemble a diverse and multifaceted research team.

One dominant trend in bio-technology is the development of ultra-sensitive and multiplexed technologies for the rapid detection and measurement of genes, proteins and cells. Recent advances in microfabrication have led to the creation of miniaturised devices such as DNA or protein microarrays or biochips for high-throughput bioanalysis. The IMRE-NUS researchers have worked towards a nanotechnological platform, or lab-on-a-bead, for multiplexed analysis of biomolecules. They have already demonstrated some concepts in their previous research.

Existing ways of labelling and visualising DNA and protein molecules rely on the light-emitting properties of a limited group of radioactive elements, chemical dyes, and protein molecules. Biological research needs a broader range of more reliable, more robust and safer labelling molecules so as to enable high-throughput bioanalysis and determination of multiple-molecule types present in a cell.

The multidisciplinary team has managed to "bar-code" DNA and proteins, using tiny light-emitting crystals known as quantum dots. By embedding quantum dots in microbeads bearing short strands of DNA, the researchers have created labels that can recognise particular DNA molecules of interest and tag them with a unique identification code. These crystals can be tailored to give off light when certain disease-causing genes or proteins are detected.

Alternative labelling techniques, which often rely on radioactivity or organic dyes, have several drawbacks; radioactive markers can have short life-spans and are toxic, while organic dyes come in a limited number of colours and may quickly lose their glow.

Quantum dots are superior in several ways. Compared with organic dyes, they are brighter and more stable, give sharper signals, and have the ability to change colour. Moreover, differently coloured dots can be activated by a single wavelength of light - an approach not possible with other labelling systems.

A quantum dot emits light of a specific colour or wavelength, depending on its size. The intensity of the light given out also varies with dot quantity. The basic concept for multiplexed bioanalysis relies on finding a way to develop a large number of differently coloured smart nanostructures that have molecular-recognition abilities and built-in codes for rapid target identification.

For example, the surface of a polymer bead can be bonded to biomolecular probes such as oligonucleotides (short nucleotide chains) and antibodies, and identification codes are embedded in the bead's interior. By integrating molecular recognition and optical coding, each bead could be considered a tiny "chemical lab" (lab-on-a-bead) that detects and analyses a unique sequence or compound in a complex mixture.

Twenty-four-bit true-colour displays like computer monitors require over one million colours created by combining the three primary colours - red, green and blue. In the lab-on-a-bead project, the plastic beads used are coded by controlling the size and number of dots in the beads. For instance, a system that uses three dot colours, each with ten intensity levels, would theoretically have beads of about 1,000 (103) different combinations of colour and intensity. With five dot colours, the number of combinations increases to 100,000.

These beads are attached to short strands of DNA or protein mixed with the target DNA or protein. Strands matching the target will attach to it. By reading the light codes of the beads attached to a matched strand, the scientist would be able to determine the make-up of the target DNA or protein. With 30,000 to 40,000 discriminated colour beads, the possibility theoretically exists for encoding the human genome in a single test. Thus, instead of dealing with individual trees, scientists can look at the entire forest.

To demonstrate the use of quantum dot-tagged beads for biological assays, the research team designed a model DNA hybridisation system using oligonucleotide probes and triple-colour-encoded beads. Target DNA molecules are labelled with a fluorescent dye or quantum dot. Optical spectroscopy at the single-bead level yields both the coding and the target signal. The coding signals identify the DNA sequence, and the target signal indicates the presence and the abundance of that sequence.

The lab-on-a-bead technology allows more flexibility in target selection (for example, adding new genes or single-nucleotide mutations), faster binding kinetics (similar to those in a homogeneous solution) and cheaper production. It will provide high sensitivity and high-reaction speeds for many types of multiplexed assays, ranging from immunoassays to single nucleotide polymorphism (SNP) detection. It also allows easy-to-use, high-throughput and low-cost assays. This multiplexing technology could combine the advantages of quantum dots with those of microfluidics and microarrays. The team aims to initially use the technology in biomedical devices for practical applications.

Competing technologies include lab-on-a-chip (biochip) in which miniature DNA-decoding troughs are etched onto flat surfaces. Lab-on-a-chip represents one of the hottest new approaches to multiplexed genetic analysis. The researchers expect lab-on-a-bead to be the next step, providing an easier way to screen and identify a large number of gene sequences, and dispensing with the need for inconvenient gels.

For more information contact Mingyong Han, a researcher with IMRE and NUS, at my-han@imre.a-star.edu.sg

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