The goal of this project is to develop a DNA synthesizer capable of synthesizing synthetic DNA, called oligonucleotides, a dramatically lower cost than competing technologies. Specifically, we will synthesize oligos in a sample plate that can hold up to 1,536 unique oligonucleotides instead of the industry standard 96 oligonucleotides. By miniaturizing the well geometry, we will be able to synthesize oligonucleotides at a cost that scales linearly with the reduced volume of each well. In this case, the well geometry is a 16-fold reduction compared to current technologies, and thus a 16-fold reduction in cost is anticipated. The instrument will achieve these goals by implementing ultra high speed motion control, and reagent delivery valves that allow very rapid dispense of chemicals to the reaction sites. In addition to reducing the required reagent quantities by miniaturizing the well size, innovations in the solid support used in the process will allow furthe cost reductions by a factor of about 50x. This will dramatically reduce the cost of consumables and will thus have a major impact on overall cost. The design also includes monitoring system(s) that will allow a user, even from a remote location, to visualize the progress of the instrument and detect errors in the reagent dispense steps that are critical to the successful production of high quality oligonucletides. The monitoring system is based on the use of retroreflective laser sensors that can detect if any reagent dispense step is missed or if the volume is not accurate, which should eliminate the need for many costly, downstream tests for quality control. While the project is focused on the development of the synthesizer, the impact of the project on the fields of Biology and Medicine is extraordinary: Because oligonucleotides are used extensively in nearly every phase of research, diagnostic, and human therapy, the impact that the synthesizer will have is dramatic. It is likely that access to this technology will preciptate an expansion of research as many technologies that are limited by the cost of oligonucleotides will now be possible. Regarding cancer research, the use of synthetic RNA and DNA oligonculeotides in siRNA, gene therapy, construction of synthetic cancer genes, or engineering microorganisms to attack cancer cells are just a few areas where this technology would have a large impact on research scope and cost. In addition, technologies that are useful in cancer research yet are by no means limited to cancer research, but utilize large numbers of synthetic oligonucleotides include Next-Gen gene sequencing, the Polymerase Chain Reaction (PCR) and real time PCR, the use of Molecular Inversion Probes (MIPs), DNA microarrays, and hybridization-based sample enrichment, to name just a few. Synthomics, Inc. is a startup company whose goal is to provide synthetic RNA, DNA, and synthetic genes to the research community. The synthesizer technology described herein will be the basis for producing the synthetic DNA, RNA, and genes.

Public Health Relevance

The proposed research is expected to have an enormous impact on biological research, medical research, diagnostics, and therapeutics. Because synthetic RNA and DNA are used extensively in each of these areas, a cost decrease of at least one order of magnitude is expected to have a two-pronged effect. First, the reduction in cost will make the research less expensive and thus treatment may ultimately cost less. Second, the reduction in cost should enable more study to take place than was possible before, so every dollar of investment into research should produce more relevant data. This also extends to research areas that are now not possible because oligonucleotide cost is a bottleneck, making new areas of research possible for the first time.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1-IMST-S (12))
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Smith, Michael
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Synthomics, Inc.
Moss Beach
United States
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