Title of proposed idea: Disruptive Proteomics Technologies: Comprehensive Protein Identification in Clinical Samples
Nominator: NIH Institutes/Centers
Major obstacle/challenge to overcome: Our ability to detect and quantify proteins in complex (e.g., clinical) samples is progressing steadily, but it is increasingly clear that order-of-magnitude improvements in the associated technologies would enable very significant advances over a range of biomedical research areas. In other word, the current state-of-the-art is good, but limiting. A few of the specific limits are:
- Expensive technology/instrumentation
- Because of the above, labs have limited access, but demand is high
- Current technology is not capable of proteome-wide measurements
Although NIH does fund some technology development in this area, there are not programs specifically aimed at development of so-called “disruptive” technologies, i.e., those that could afford very rapid, very significant gains, similar to those that occurred in DNA sequencing technology.
Emerging scientific opportunity ripe for Common Fund investment: The history of technology development for genome sequencing teaches that successfully fostering very significant technological advances in basic methods and instrumentation requires a sustained effort, significant funds, encouragement of diverse approaches, a tolerance for taking risks (moderated by ongoing evaluation across the portfolio) and very focused, precisely articulated, assessable program goals.
We propose an analogous technology development effort that aims to produce order-of-magnitude improvements in the detection, identification, and quantification of proteins in complex samples. Moreover, the effort would explicitly emphasize an end-point relevant to clinical applications.
Several NIH institutes do fund technology development in this area. However, the program proposed here is justified as a Common Fund effort both because its benefits will cut across NIH (see below) and because it requires concerted management of all the grants under one program towards
precise program goals (see below) to maximize the chances for success. Similarly, it is important that this proposed program not be combined with other technology development efforts.
Common Fund investment that could accelerate scientific progress in this field: In a long-term technology development effort such as the one proposed here, it is difficult to anticipate what basic methodology holds the best potential for very significant improvement. The current dominant methodology for high-throughput detection and quantification of proteins is mass spectrometry (MS); it holds good potential for further incremental improvement, and it is possible that order-of-magnitude improvements could be stimulated by a well-targeted program. In addition, there are other technologies that hold promise for significant improvements, though they are currently less developed than MS, and not well-supported. We therefore propose projects covering both MS and non-MS approaches.
Specific funding components proposed:
FOA 1: Technology Development: MS-based protein ID and quantitation . (Years 1-5)
i. 10-fold decrease in instrumentation cost (e.g., a $50,000 mass spectrometer)
ii. 100-fold or 1000-fold increase in dynamic range
iii. 10-fold increase in throughput
FOA 2: Technology Development: Non-MS-based protein ID and quantitation. )
i. Develop protein ID/quant technologies that approach/exceed MS-based methods with respect to: accuracy, dynamic range, throughput, cost, and ability to analyze PTMs.
ii. Demonstrate orders-of-magnitude improvements with respect to dynamic range, throughput, cost.
FOAs 1 and 2 would need to justify their approaches relative to eventual advantages for translational or clinical use, for example:
- Improved discovery and/or assessment of biomarkers
- Rapid sample turn-around time
- Small input volume (1 mL of blood, etc.)
- Stored or banked samples, resilience to sample handling variability
- Analysis of clinically relevant sample sizes (100s to 1000’s), with no loss of specificity
For FOA’s 1 and 2 it is likely that a phased approach with milestones will be advantageous for incenting rapid development and managing risks. For example these FOA’s might encourage many applications and a high level of risk/reward with an initial three-year period, followed by an option to renew for a larger amount of funds contingent on reaching milestones.
One issue not explicitly considered above is the development of computational tools for data analysis and integration for large protein datasets. There are advantages in asking that this be integrated into the development of the technologies, and also the alternate approach of writing a separate FOA. Staff will need to research this issue.
If FOA’s 1 and 2 are successful, a follow-on FOA focusing on specific clinical applications would be considered.
Potential impact of Common Fund investment: Orders-of-magnitude improvements in this area would enable very significant advances across the NIH portfolio. In basic research, it would enable the assessment of all proteins in a mixture; which in turn would enable, for example, more comprehensive assessment of gene expression, now largely inferred indirectly from RNA expression. In discovery research, it would enable a more comprehensive assessment of the molecular consequences of variation (eg, an addition to GWAS, GTEx, large cohort studies); for translational research it is likely to afford many advantages for disease biomarker discovery and assessment. Finally, if all the goals are realized, there are clear ramifications for the clinic (patient sample testing, drug response/disease progression, etc.).