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2. Photolithographic fabrication of high-density DNA microarrays - GeneChip® arrays
In the late 1980s, combinatorial chemistry was developed to perform fast and effective drug discovery research using the parallel synthesis of compounds and high-throughput screening systems. Some of the early features of combinatorial chemistry include building up versatile combinatorial compound libraries using solid-phase synthesis of linear compounds such as peptides, and high-throughput random screening for bioactive compounds using highly sensitive biological systems such as antigen-antibody reactions. In 1988, Fodor joined Affymax, an early combinatorial chemistry venture, and started working to fabricate high-density arrays of biomolecules. His background in biochemistry and biophysics, and his experience in combinatorial chemistry led Fodor to combine the technologies of different fields, such as electronics, biology, and combinatorial chemistry, to produce high-density oligonucleotide arrays. The technologies included the photolithographic fabrication method used in semi-conductor fabrication, the parallel synthesis strategy and solid-phase synthesis of nucleic acids from combinatorial chemistry11-13). Although there were some technical issues to be resolved, the photolithographic fabrication of high-density oligonucleotide arrays became more and more promising and the potential commercial possibilities became more and more clear. Bearing these in his mind, in 1993 Fodor co-founded Affymetrix, a spin-off of Affymax, to develop the technology for high-density oligonucleotide arrays14). In 1994, Affymetrix commenced manufacturing and selling the first DNA microarray, GeneChip® arrays, which were loaded with hundreds of thousands oligonucleotides on the supports. Their technology is one of the rare cases of happy marriage between technologies used in the information and electronic fields, and those in the life science field15).
Figure 1 shows the process for the photolithographic fabrication of high-density oligonucleotide arrays. In this process, bases attached to the surface are protected by photo-labile protecting groups. Before initiating the coupling reaction, the protecting groups can be photo-chemically eliminated by light in a predefined region, and the coupling reaction commences when bases are added. By continuing this process, hundreds of thousands of different oligonucleotides can be synthesized on a very small area of glass support16). Since the yield of coupling reaction on the support is less 100%, the length of oligonucleotide is limited.
The GeneChip® array was the first commercial DNA microarray, and swiftly spread into laboratories because of its ready availability as off-the-shelf products, notwithstanding the inflexibility of custom production.
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