Novel Nucleic Acid Sequencing Technology Development (R43/R44)

This Funding Opportunity Announcement (FOA)  seeks R43/R44 SBIR grant applications from small businesses to develop novel technologies that will enable at least one order of magnitude improvement in DNA sequencing, and practical methods for direct RNA sequencing.  Advances in genomics and more broadly in biomedical research have been greatly facilitated by significant and sustained DNA sequencing throughput increases and cost decreases.  The goal now is to improve the quality and efficiency of DNA sequencing and enable direct RNA sequencing (e.g., longer read lengths, faster turn-around time, greater accuracy, and higher-throughput etc.) at reasonable costs with the anticipation that significant advances in any of these and related areas would make significant contributions to the mission of NHGRI and the field of genomics, including to many of NHGRI’s other technology development goals.

The ability to sequence large and ever growing numbers of complete genomes and transcriptomes coupled with the free dissemination of sequence data have dramatically changed the nature of biological and biomedical research.  DNA and direct RNA sequence in combination with other genomic data have the potential to lead to remarkable improvement in many facets of human life and society, including the understanding, diagnosis, treatment and prevention of disease; advances in agriculture, environmental science and remediation; and our understanding of evolution and ecological systems.

The ability to sequence many genomes and transcriptomes has been made possible by the enormous reduction of the cost of sequencing in the past three decades, from tens of dollars per base in the 1980s to a small fraction of a cent per base today.  Technology advances, and in particular the development of a new generation of sequencing systems, have enabled the launch of many projects that are producing stunning insights into biology and disease.  Nevertheless, the cost to completely sequence very large numbers of entire genomes of individual cells or people remains very high, and we remain far from achieving the low costs and high quality needed to enable the use of comprehensive genomic and transcriptomic sequence information in individual health care.

One of the major contributions by NHGRI has been in the genomic technology domain.  Those efforts have been so transformative that it is hard to remember genomics without, for example, a reference human genome, inexpensive short-read sequencing, efficient bacterial artificial chromosome methods, microarrays, defined common human haplotypes, single molecule sequencing, and many other significant technical advances.  Bright prospects for future success motivate investing in genomic technology development specifically for novel sequencing methodologies.

NHGRI seeks to fund research efforts in novel chemistries, physical approaches and instrumentation for DNA and direct RNA sequencing.  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 DNA or direct RNA sequencing, or both, in a single application.

The FOA deliberately does not specify cost, quality, throughput or read lengths since achievable endpoints are likely to improve over the life of the opportunity, and applicants are encouraged to optimize and balance these key attributes for the technology approach proposed.  It is expected that awardees will develop scientific and practical definitions of optimal cost, quality and read lengths relative to enabling significant genomics opportunities. Priority will be given to applications that propose improvements of at least an order of magnitude (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.

For DNA sequencing, novel methods that generate large numbers of long reads of high quality with a low cost are sought.  New physical or chemical detection methods for sequencing are especially encouraged along with substantive (at least an order of magnitude) improvement to current high-throughput DNA sequencing technologies.  Those methods that yield novel sequence based insights or that solve existing limitations in the field (e.g., de novo assembly of human genomes, base modification determination, complete and quantitative sequencing of all the DNA in a sample, essentially complete genomes of single cells, very small quantities of starting material down to a single cell, very long reads of at least 150Kb, etc.) are of especially high interest.

For RNA sequencing, the need is for quantitative and high-throughput direct sequencing of entire transcripts from the transcriptome.  Awardees are expected to develop novel methods for quantitatively assessing the sequence of full length RNA without a cDNA intermediate.  Enabling new approaches to RNA analysis is a key goal of direct RNA sequencing (e.g., exhaustive sequencing of every RNA molecule in a sample or precise quantification across the entire very high dynamic range of RNA transcripts, determination of base modifications, determining RNA secondary structural elements while sequencing, cost-effective and statistically-robust single cell transcriptomics, etc.).

High-risk and high-reward proposed research may plan to develop complete systems or novel key components for nucleic acid sequencing.  Very novel physical or chemical approaches to sequencing are solicited along with novel enzymatic methodologies.  The technology developed can either develop an entirely new way of sequencing or significantly improve existing sequencing methodology.