NSF-XLabsTopicAnnouncement-XLabsSequencetoFunction.pdf

NSF-Topic4-FY26-Sequence-to-Function

FROM SEQUENCE TO FUNCTION

TOPIC ANNOUNCEMENT FOR THE NSF X-LABS INITIATIVE

1.0 Purpose:

The National Science Foundation (NSF) Directorate for Technology, Innovation and Partnerships (TIP) announces its intent to solicit Written Proposals for NSF X-Labs teams in the technical domain of bioengineering. This NSF X-Labs announcement is issued under the Other Transactions Agreement Solutions Offering (OTASO), NSF-OTASO-FY26-XLabsInitiative.

2.0 The NSF X-Labs Initiative:

NSF X-Labs represent a bold, flexible, and outcomes-driven initiative designed to build and accelerate novel platform technologies capable of unlocking entirely new sectors, including new fields of scientific inquiry. The program will support full-time research and development (R&D) teams focused on use-inspired scientific breakthroughs and foundational platform technologies that traditional university and industry labs cannot easily address. NSF X-Labs teams will benefit from ambitious R&D goals, operational autonomy, milestone-based funding, and the ability to engage across academia, industry, national laboratories, and nonprofit sectors. NSF X-Labs will bet on ambitious, full-time teams working with urgency and purpose, and provide them with the structure, resources, and flexibility necessary to cultivate early-stage platform technologies that will accelerate breakthroughs and unlock entirely new sectors of the economy.

See Section 3 of NSF-OTASO-FY26-XLabsInitiative or the latest amendment issued for information on the NSF X-Labs initiative’s strategic objectives.

2.1 NSF X-Labs Topics and Missions

NSF will release specific Topic areas under the NSF X-Labs initiative via Topic Announcements. Topics will center on fields of research where breakthroughs could create or reshape entire scientific fields and technology sectors where U.S. competitiveness is a priority.

Proposing teams will specify their Mission, defined as the novel platform technology and key use-inspired research solutions that the proposed NSF X-Lab is uniquely suited to tackle.

Missions must align with a current Topic Announcement released by NSF. Proposing teams should have a clear vision of how their Mission will result in an end-state that creates or reshapes an entire field of scientific research or sector of technology, and how their Mission is currently unmet by existing organizational structures and funding mechanisms.

3.0 Topic Description:

It is time for the next leap in the study of biology. By reliably linking protein sequence and structure to biological function, the United States can unlock a new era of biological engineering in which biological components are designed rather than discovered. Platform technologies that enable precise control over protein function will open the door to entirely new products and processes that use engineered biological components and outputs, such as enzymes. These capabilities will reshape the economics of biomanufacturing, chemical engineering, biosensing, and agriculture, among other sectors.

Although recent advances allow us to predict the static structure of proteins, we lack insight into their dynamic behavior. Even in minimal cells, the function of many genes and proteins remains unknown. NSF X-Labs in this space will close that gap by creating platform technologies that enable the intentional design of individual proteins or entire genomes whose function is predictable and/or controllable. Teams will pioneer and integrate advances in protein design/synthesis, genome assembly, synthetic cells, or experimental functional discovery and validation. Additionally, NSF X-Labs might use super intelligence (SI) to dramatically accelerate our ability to engineer the behavior of designed proteins or synthetic cells, including their metabolic requirements, stability, functional outputs, by-products, or system-level interactions.

Examples of relevant Missions include, but are not limited to: the creation of models that enable the prediction of protein–molecule interactions, including novel approaches to the collection or integration of SI training data; the design and application of nanoscale protein-based molecular motors; an enzyme function platform to discover and engineer enzyme pathways that have specific molecular behaviors; and a synthetic cell/genome platform to design and instantiate genomes with predictable and controllable biological function.

An NSF X-Labs Mission in this Topic must be transformative, accelerating breakthroughs in our understanding of the relationship between sequence and function, and catalyzing capabilities to engineer proteins or entire genomes with exceptional new capabilities. Successful teams will develop platform technologies, demonstrate measurable impact on the U.S. biotechnology landscape, and position their technologies for widespread use by overcoming technical barriers that limit implementation and investment. Although NSF X-Labs in this space will have widespread applicability, each team should identify 2-3 high-utility domains and should eventually establish projects in them. Teams proposing to this topic should identify how their approach to biosafety and biosecurity is tailored to their Mission and its pilot application domains including an assessment of dangerous gain-of-function and an accompanying plan to mitigate unintended consequences.

Examples of challenges not considered in scope for this Topic include: development of technologies where the impact is narrow and not widely deployable; fundamental research without potential for application in platform technologies; incremental advancement of the state of the art; standalone predictive models that do not generate or integrate new experimental data;

and advancement of technologies that are already developed or supported by existing R&D investments by the U.S. public or private sectors.

4.0 Other Transaction (OT) Award Details:

In response to this Topic Announcement, NSF anticipates issuing one or more Other Transaction (OT) contracts pursuant to NSF’s statutory authority at 42 U.S.C. § 19116. Refer to NSF- OTASO-FY26-XLabsInitiative or latest amendment issued for more information on period and place of performance, instrument and approach, eligibility, performance objectives for NSF X- Labs teams, programmatic phase structure, milestones and milestone-based payments, Written

Proposal format and instructions, Oral Proposal Packages, NSF selection criteria, and the review and selection process. Proposers are expected to closely review NSF-OTASO-FY26- XLabsInitiative, including its latest amendment, before submitting a Written Proposal in response to this Topic Announcement.

An eligible organization can submit a maximum of two Written Proposals per Topic Announcement for Phase 0 as a lead organization. Senior/Key Personnel may be listed on a maximum of one Written Proposal per Topic Announcement.

5.0 Topic Timeline:

NSF anticipates awarding selected teams a 9-month Phase 0 with a Go/No Go selection period beginning after 7 months. NSF anticipates awarding teams selected for Phase 1 an approximately 24-to-36-month period of performance with the intention of renewing high performing teams for Phase 2 following subsequent Go/No Go selections.

NSF anticipates the following schedule for OT awards made in response to this Topic Announcement:

Written Proposal Submission Deadline February 8, 2027; 5:00 p.m. Eastern Beginning of Phase 0 September 2027 Beginning of Phase 1 Go/No Go Selection April 2028 Beginning of Phase 1 June 2028

6.0 Submission Details:

The NSF X-Labs initiative involves a two-step competitive evaluation, as described in NSF- OTASO-FY26-XLabsInitiative. NSF will accept Written Proposals in response to this Topic Announcement and then invite a smaller number of proposing teams to submit an Oral Proposal Package and deliver an oral presentation. All Written Proposals submitted in response to this notice must comply with the content and format described in Section 10 of NSF-OTASO-FY26- XLabsInitiative or the latest amendment issued.

Questions concerning this Topic Announcement may be submitted to the Government through 5:00 p.m. Eastern on December 14, 2026 to be included in a frequently asked questions (FAQ) document posted to SAM.gov. Questions must be submitted as an email attachment using the provided question submission template (Attachment C) to XLabs@nsf.gov. The subject line of any submitted questions must include the topic title: NSF-Topic4-FY26-Sequence-to-Function.

NSF anticipates that not all submitted questions may receive a direct answer.

Written Proposals will not be accepted after 5:00 p.m. Eastern on February 8, 2027. Proposals must be submitted electronically via the NSF submission website at https://nsfgov.my.site.com/xlabs.

https://nsfgov.my.site.com/techlabs

NSF may share proposal information with other Federal research funding agencies for the purpose of considering potential co-funding. Prior to that occurring, NSF will contact individual vendors for permission to share its proposal information outside of NSF.

7.0 From Sequence to Function NSF X-Labs Webinar:

Join the NSF TIP team for a webinar, including a brief presentation on key materials in the OTASO and Topic Announcement. A Q&A will follow the presentation. Respondents are recommended to review NSF-OTASO-FY26-XLabsInitiative and this Topic Announcement before the webinar to maximize the effectiveness of the Q&A session.

Q&A Webinar for NSF X-Labs – From Sequence to Function November 18, 2026 at 2-3 p.m. Eastern Register here: https://nsf.zoomgov.com/webinar/register/WN_a-Ik_TCBSM- DM7dFPYUEcA#/registration https://nsf.zoomgov.com/webinar/register/WN_a-Ik_TCBSM-DM7dFPYUEcA#/registration https://nsf.zoomgov.com/webinar/register/WN_a-Ik_TCBSM-DM7dFPYUEcA#/registration