Purpose This Funding Opportunity Announcement (FOA) solicits R43/R44 grant applications to develop novel technologies that will enable no less than one order of magnitude improvement in commercial synthetic nucleic acid synthesis and constructs. Advances in genomics and more broadly in biomedical research have been greatly facilitated by significant and sustained synthetic nucleic acid increased throughput and capabilities combined with significant cost decreases. The goal now is to improve the quality and efficiency of commercial nucleic acid synthesis and synthetic constructs (e.g., longer oligonucleotides and constructs, faster turn-around times, greater accuracy, additional and less expensive modified nucleotides, multiplexing, higher-throughput, etc.) at lower costs per base with the anticipation that significant advances in any of these and related areas would make substantial contributions to the mission of NHGRI and the field of genomics, including NHGRI’s other technology development goals. Background The abilities to rapidly commercially synthesize large numbers of individual and multiplexed oligonucleotides, and generate synthetic nucleic acid constructs have dramatically changed the nature of biological and biomedical research. Improvements in these spheres will continue to impact varied areas of genomics and biomedicine (e.g., synthetic genomics, saturation mutagenesis, and functional screens). Enabling significant advances with new nucleic acid synthesis and synthetic construct capabilities has the potential to lead to remarkable improvements in understanding, diagnosis, treatment and prevention of disease; advances in agriculture, environmental science and remediation; and our understanding of evolution and ecological systems. Current abilities to work with a variety of synthetic nucleic acids as oligonucleotides and synthetic constructs has been made possible by the enormous reduction of the cost of oligonucleotide synthesis along with vastly improved techniques for construct assembly in the past three decades. Costs have decreased from dollars in the 1990s to slivers of a cent per base today at scale. Synthetic nucleic acids (DNA, RNA and others that use a nucleic acid backbone) are in high demand and enable many current, emerging and future venues of discovery. However, the cost to completely synthesize DNA on the scale of an entire human genome was recently estimated as $1.5M, and high throughput capabilities, methods and knowledge for chromosome assembly on that scale are not available today. We remain far from achieving the low costs, high quality and scale needed to fully enable transformative research in genomics, biotechnology and clinical utilization. Objectives NHGRI seeks to fund commercial research efforts in novel enzymatic, biological, chemical, and physical approaches along with instrumentation for synthetic nucleic acids. New methodologies, and substantial advances beyond existing approaches are sought that would, if successful, significantly propel forward the field of genomics. Applicants may propose work on oligonucleotide synthesis, construct synthesis, or both, in a single application. The new technology proposed can innovate substantially novel approaches or instead significantly, no less than tenfold, improve existing methodologies for nucleic acid synthesis or synthetic construction. Applications failing to address or proposing less than a ten-fold improvement will be considered non-responsive to the FOA. The FOA deliberately does not specify goals for cost, quality, throughput or nucleic acid lengths since achievable endpoints are likely to improve over the life of the opportunity, and applicants are encouraged to optimize and balance these and other relevant key attributes for the technology approach proposed. It is expected that applicants will develop scientific and practical definitions of optimal cost, quality and lengths relative to enabling significant genomics opportunities. Applicants are expected to propose innovations or improvements of no less than an order of magnitude (at the minimum), based on state of the art at the time the application is submitted. Such improvements may be achieved by focusing on one critical factor, or a combination of important ones to develop complete systems or novel key components for nucleic acid synthesis or constructs. Applications proposing novel methodologies or that solve existing limitations in the field are of especially high interest (e.g., length, accuracy, multiplexing, and natural or useful modifications, etc.). Novel methods that generate at scale large numbers of high-quality DNA or RNA oligonucleotides in pools or individually at low cost are sought. Applicants are also expected to work with a coordinating center NHGRI is seeking to establish to accelerate technology development and progress in the field of genomics (RFA-HG-20-019). Grantees efforts will include actively and fully participating in a yearly meeting; as well as collaborating to synthesize findings and disseminate advances; developing and promoting standards for genomic technologies; facilitating technology transfer to research and clinical utilization, as appropriate; and working with the coordinating center as needed to assist in achieving the goals of this FOA. See Section VIII. Other Information for award authorities and regulations.