IARPA-RFI-24-01_Multiomic Instruments_C.pdf

Request for Information (RFI) on The Future of Multiomic Analytical Instruments for Systems Biology

IARPA-RFI-24-01

IARPA is seeking information on the current state of the art (SOTA) and future direction of analytical instruments capable of detecting, identifying, and characterizing the multitude of biomolecules that constitute or are associated with biological systems and materials. Such molecules include but are not limited to the macromolecules of carbohydrates (saccharides or sugars), nucleic acids (DNA and RNA, canonical and non-canonical), proteins (amino acids, peptides, and fully functional protein or proteins), and lipids (fatty acids) as well as metabolites, other small molecules, and inorganic metals. This RFI is issued for planning purposes only and does not constitute a formal solicitation for proposals or suggest the procurement of any material, data sets, etc.

Background

Biology is an inherently challenging discipline to study due to the variety of molecules, complexity of the molecules and their interactions, and the dynamic environments (temporal, spatial, and interactive) forming the constitutive “biological system”. Study of one or a type of biomolecule(s), even in controlled experiments, may cause changes to the whole system or be inherently limited in the knowledge gained due to linkages to other biological features, making research very challenging.1,2 Current methodologies and instruments predominantly focus on single biomolecule characterization – Polymerase Chain Reaction (PCR) and Next Generation Sequencing (NGS) for nucleotides and often Mass Spectrometry (MS) for peptides, proteins, metabolites, and lipids.3,4 These workhorses of biology have seen drastic improvement in the past decades in throughput, sensitivity, specificity, and cost but the fundamental concepts behind these instruments have not evolved beyond their original constraints, even with noticeable improvements to supporting hardware and software.

In the past decade, there have been attempts to reimagine how biological systems are interrogated working towards a ‘systems biology’ capability. One branch of development has honed in on the pursuit of single cell analysis. In some cases, single cell analysis has been combined with targeted multiomic analysis and/or sample preprocessing to enable spatial resolution.1,5 Alternatively, other entities are pursuing highly multiplex approaches capable of detecting a swath of biomolecules through pore based detection, Raman analysis, or targeted antibody linked pulldowns.6–13 However, these approaches have predominately focused on protein molecule types. A third approach postulates that combining existing analytical tools is the most likely path forward for achieving a molecule extensible analytical instrument.14,15 While attempts have been made to adapt these modalities to interrogate multiple molecule types, none have demonstrated similar capabilities to existing, single target instrumentation.16

While R&D is occurring on multiple fronts, these novel concepts have not achieved the same advancement in capabilities as was seen during the 1990s and early 2000s with DNA sequencing. Furthermore, in cases where success seemed likely, expectations have often fallen short, leading towards valuable advances supporting specific niche use-cases without achieving the breadth of capabilities envisioned by the research and development communities. This RFI seeks to understand the current state of the art and the potential metrics for measuring the development of the analytical instruments for the future capable of interrogating the entirety of a biological system or material, without the limitations of existing platforms or an inherent focus on a single molecule type.

Scope

IARPA recognizes and encourages the investments other entities are pursuing for improving single ‘omic’ or analyte characterization, especially focused on enabling improved single molecule sequencing of distinct analytes. IARPA’s mission is distinct from these entities with the mission to pursue even higher risk, higher impact activities and this RFI reflects IARPA’s interest in understanding what possible future capabilities may be achieved within a challenging concept space.

IARPA seeks to understand potential future concepts and multi-analyte extensible instruments/analytical platforms able to detect, identify, and/or characterize the range of biomolecules and other elements associated with biological systems and materials. IARPA’s interests align with single modality, analyte extensible, platforms or instruments which can conceivably be integrated into a single workflow matching or exceeding current SOTA capabilities. Critically, IARPA seeks to understand what advances can be achieved with (i) incremental improvements to current capabilities and (ii) with investments towards higher-risk, further afield research which have not been proven.

Below are specific questions IARPA seeks improved understanding, answers should be submitted from the perspective of the researcher or end-user, answers to all questions are suggested but not required:

Future Instrument Concepts:

1. What analytical platforms and processes, hardware focused, do you envision revolutionizing the multiomics field(s) in the next twenty years and why?

2. What instruments, with investment and scaling, have the potential to match or exceed current analytical modalities in terms of throughput, run cost, and data output?

3. What approaches can be taken now to future-proof new instruments from a perspective of instrument, data outputs, and data breadth to enable a sustainable and long-lasting role in future biological research?

4. What approaches, outside of controls or standards, can help overcome batch effect variation seen with current analytical approaches?

Multi-analyte detection:

The following questions focus on multi-analyte processing, either using analytical platforms (i.e.

suites of instruments seamlessly integrated) or single instrument with novel extensibility.

Responses to these questions should inherently focus on instruments capable of multianalyte analysis, not on instruments inherently limited to a single analyte even if it could inform towards other analytes in the sample.

1. What analytical platforms or extensible instrument have the possibility to detect, identify, and/or characterize the range of analytes associated with biological systems?

2. What multi-analyte platforms or extensible instrument are dependent upon targeted (known analytes) vs. untargeted (unknown analyte) approaches?

3. What analytical platforms or extensible instrument have the potential to displace existing capabilities for discovery of novel targets?

4. What analytical platforms or extensible instrument may effectively deploy a combination of targeted and untargeted detection modalities?

5. What analytical platforms or extensible instrument provide the greatest dynamic range, enabling capture of the variety of molecules present within organic systems (e.g. the human proteome estimated at >1,000,000 proteoforms in a single cell)?

6. What instruments have the possibility to characterize not just primary structures but also secondary, tertiary, and quaternary interactions (in the case of proteins) or other inter-molecule interactions?

Below is a list of proposed qualitative metrics. Respondents are encouraged to provide corresponding quantitative metrics where possible based upon what they see as viable technologies for the future. Alternatively, they can propose their vision of what future SOTA should hope to achieve to revolutionize the multiomic community (this table is not counted towards the RFI page limit).

a) If a metric, from a responder’s perspective, is missing, responders are welcome to add it to the table.

b) The Current SOTA is from the responder's perspective of commercial instruments available today.

c) The 10-year Stretch Capabilities should reflect values a responder envisions are possibilities in the next 10 years, answers to every row are not proscribed - modify and add as appropriate.

Metric Current SOTA Potential Stretch Capabilities

Breadth of molecule types ((i) multiple pieces of equipment in conjunction (ii) a single multiomics platform) Structural Characterization Capability Dynamic Range Potential (from one biomolecule or target to another, maximum preferred) Biomolecule mass range Instrument detection limit Limit of quantification Run time Potential for multiplex of biomolecule targets or samples in a single run Potential size, weight, and power requirements to run (not inclusive of reagents or consumables)

Preparation Instructions to Respondents:

IARPA requests that respondents submit responses to the above questions for use by the Government in formulating a potential program. IARPA requests that submittals address one or more of the above questions and include a brief technical description of potential approach(es) or concept, outline critical technical issues/obstacles, describe how the approach may address those issues/obstacles and comment on the expected performance and robustness of the proposed approach. If appropriate, respondents may also choose to provide a non-proprietary rough order of magnitude (ROM) estimate regarding what such approaches might require in terms of funding and other resources for one or more years to execute the respondent’s vision for novel multianalyte instrument research and development. This announcement contains all the information required to submit a response. No additional forms, kits, or other materials are needed.

IARPA welcomes responses from all capable and qualified sources including academia, industry, government, national laboratories, and other federally funded research entities from within and outside of the U.S. This includes perspectives and associated capabilities for effectively evaluating potential research approaches.

In response to submissions to this RFI, IARPA may organize an invitation-only workshop for the purpose of reviewing and discussing relevant current and future research. Should a workshop occur, participants may be asked to make formal presentations based on their RFI submissions or associated research. Written submissions and information discussed at a workshop may assist in the formulation of future U.S. Government research.

Reponses must meet the following formatting requirements:

1. A one-page cover sheet that identifies the title, organization(s), respondent's technical and administrative points of contact - including names, addresses, phone and fax numbers, and email addresses of all co-authors, and clearly indicating its association with IARPA-RFI-24- 01;

2. A substantive, focused, one-half page executive summary;

3. A response to one, some, or all the questions posed above with a maximum of three (3) pages, not inclusive of the metric table above;

4. A description (limited to two (2) pages) of the technical challenges associated with the above topic and potential research approaches to address the interests described;

a. A single quad-chart depicting the described approach, key ideas, and potential impact

– may include supportive figures or illustrations. This quad chart can be submitted as a single slide Power Point or single page PDF. This does not count against the 2-page limit.

5. A list of references (any significant claims or reports of success must be accompanied by citations – citations do not count against the page limit); and

6. All documents are limited to 12-point Times New Roman font, appropriate for single-sided, single-spaced 8.5 by 11-inch paper with 1-inch margins.

Submission Instructions to Respondents:

Responses to this RFI are due no later than 5:00 p.m. 12 January 2024, Eastern Time. All submissions must be electronically submitted as a PDF document. Inquiries and submissions to this RFI must be submitted to DNI-IARPA-RFI-24-01@iarpa.gov. Do not send questions with proprietary content. No telephone inquiries will be accepted.

Disclaimers and Important Notes:

This is an RFI issued solely for information and planning purposes and does not constitute a solicitation or authority to enter into negotiations for a contract. Respondents are advised that IARPA is under no obligation to acknowledge receipt of the information or to provide feedback to respondents with respect to any information submitted under this RFI. Responses to this notice are not offers and cannot be accepted by the Government to form a binding contract. Respondents are solely responsible for all expenses associated with responding to this RFI. IARPA will not provide reimbursement for costs incurred in responding to this RFI. It is the respondent's responsibility to ensure that the submitted material has been approved for public release by the information owner.

The Government does not intend to award a contract on the basis of this RFI or to otherwise pay for the information solicited, nor is the Government obligated to issue a solicitation based on responses received. No proprietary and no classified concepts or information shall be included in the submittal. However, should a respondent wish to submit classified concepts or information, prior coordination must be made with the IARPA Program Security Officer (PSO). Email the Primary Point of Contact with a request for coordination with the IARPA PSO using the RFI email address. Input on technical aspects of the responses may be solicited by IARPA from non- Government consultants/experts who are bound by appropriate non-disclosure requirements.

Contracting Office Address:

Office of the Director of National Intelligence, Intelligence Advanced Research Projects Activity Washington, District of Columbia 20511 United States

Primary Point of Contact:

Dr. Michael Patterson Program Manager, Office of Analysis Intelligence Advanced Research Projects Activity

References

1. Alexandrov, T., Saez-Rodriguez, J. & Saka, S. K. Enablers and challenges of spatial omics, a melting pot of technologies. Mol. Syst. Biol. 19, e10571 (2023).

2. Čuklina, J. et al. Diagnostics and correction of batch effects in large-scale proteomic studies:

a tutorial. Mol. Syst. Biol. 17, e10240 (2021).

3. Satam, H. et al. Next-Generation Sequencing Technology: Current Trends and

Advancements. Biology 12, 997 (2023).

4. Collins, S. L., Koo, I., Peters, J. M., Smith, P. B. & Patterson, A. D. Current Challenges and

Recent Developments in Mass Spectrometry–Based Metabolomics. Annu. Rev. Anal. Chem.

14, 467–487 (2021).

5. Heumos, L. et al. Best practices for single-cell analysis across modalities. Nat. Rev. Genet.

24, 550–572 (2023).

6. Martin-Baniandres, P. et al. Enzyme-less nanopore detection of post-translational modifications within long polypeptides.

http://biorxiv.org/lookup/doi/10.1101/2023.02.09.527483 (2023) doi:10.1101/2023.02.09.527483.

7. Restrepo-Per, L. & Joo, C. Label-Free Detection of Post-translational Modifications with a

Nanopore. Nano Lett 8 (2019).

8. Zhao, Y., Iarossi, M., De Fazio, A. F., Huang, J.-A. & De Angelis, F. Label-Free Optical

Analysis of Biomolecules in Solid-State Nanopores: Toward Single-Molecule Protein

Sequencing. ACS Photonics 9, 730–742 (2022).

9. Altangerel, N. et al. Label-free drug interaction screening via Raman microscopy. Proc.

Natl. Acad. Sci. 120, e2218826120 (2023).

10. Huang, J.-A. et al. SERS discrimination of single DNA bases in single oligonucleotides by electro-plasmonic trapping. Nat. Commun. 10, 5321 (2019).

11. Proteomics at Scale: Current Approaches and Emerging Technologies.

https://www.nautilus.bio/wp-content/uploads/2023/04/Proteomics-at-Scale-Current-

Approaches-and-Emerging-Technologies-Re-fit-03-23.pdf?hsCtaTracking=87d7812f-643c-

4640-8a5f-4706c2e79181%7C395d352b-1ea9-4e28-a2ee-ee2806256f71.

12. Reed, B. D. et al. Real-time dynamic single-molecule protein sequencing on an integrated semiconductor device.

13. MacCoss, M. J. et al. Sampling the proteome by emerging single-molecule and mass spectrometry methods. Nat. Methods 20, 339–346 (2023).

14. Jaber, M. et al. Comparative parallel multi-omics analysis during the induction of pluripotent and trophectoderm states. Nat. Commun. 13, 3475 (2022).

15. Zielinski, J. M., Luke, J. J., Guglietta, S. & Krieg, C. High Throughput Multi-Omics

Approaches for Clinical Trial Evaluation and Drug Discovery. Front. Immunol. 12, (2021).

16. Misra, B. B., Langefeld, C., Olivier, M. & Cox, L. A. Integrated omics: tools, advances and future approaches. J. Mol. Endocrinol. 62, R21–R45 (2019).