extremely rigorous and forward-thinking. The technical program organization and the cross-cutting nature of the groups, and the high quality of the research products are well aligned to support the division in reaching its overall goals in the quickly changing field of biometrology.

The Regenerative Medicine and Advanced Therapies Program is integral to developing standards for the growing bioeconomy. They have developed numerous standards published by the International Organization for Standardization (ISO), including the development of a common biotechnology genome editing vocabulary to improve communication between stakeholders. They oversee the Genome Editing, Flow Cytometry Standards, and Rapid Microbial Testing Methods consortia. They have developed methods to evaluate the quality of gene delivery systems, infectious virus titer measurements, and are working on extracellular vesicle characterization and reference materials. The standards developed for gene delivery systems are integral to increasing confidence in the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) era of genetic modifications for use in clinical and experimental research.

The Flow Cytometry Standards consortium is a particularly successful public-private partnership to increase the confidence and comparability in flow cytometry data to support the bioeconomy. This consortium has developed calibration standards, standard operating procedures to ensure comparability between different cytometer platforms and is developing a global filename convention for data dissemination. The Rapid Microbial Testing Methods consortium has enabled new characterization of existing materials, including flow-based methods to quantify genomes and feasibility studies of E. coli reference materials. They have also worked to develop and encourage the adoption of reference standards across more than nine parameters of cell function. The Regenerative Medicine and Advanced Therapies Group has also created an open access tool (the Counting Method Evaluation Tool, known widely as COMET¹) to analyze the performance of cell counting methods based on an ISO standard. The group also significantly contributed to the development of this ISO standard. This research team has also developed new microscopy and spectroscopy techniques to improve stem cell throughput and capabilities through liquid media.

The Precision Medicine Program is tasked with identifying and developing the infrastructure to ensure that measurement methods and materials give reproducible results for personalized healthcare. In the period covered by this assessment report, this research area has published 10 papers to develop benchmarks and best practices and collaborated to evaluate and improve methods with 14 papers. They have developed intensity scales for microscopy and a strong evaluation tool of flow cytometers for industrial and academic use. This group also runs the Genome In A Bottle consortium, which has characterized variants in 7 human genomes, developed open consent cell lines to meet clinical needs, and is developing an artificial intelligence model to improve confidence. This consortium improves confidence in genome sequencing and variant calling. More than 50 commercial products are available based on Genome In A Bottle Personal Genome Project cell lines. Precision Medicine researchers also support the Pangenome Reference consortium to further understand the normal and abnormal diversity of the human genome. They are collaborating to develop somatic variant reference samples in order to support the validation of next-generation sequencing of cancer biomarkers for diagnostics. Cancer biomarker reference materials are being developed to improve clinical measurements through interlaboratory studies. The liquid biopsy cancer biomarker project operates under an interagency agreement with the National Institutes of Health (specifically the National Cancer Institute) to improve standards of extracellular vesicle measurements, circulating tumor DNA measurements, and DNA methylation measurements.

The Engineering Biology Program is focused on developing measurement tools and standards to support the control and design of biological functions. This includes living measurement systems, which are focused on growth, manipulation, sample preparation, and measurement of engineered microbes, and systems designed to improve the consistency of biological research and development. They are currently

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¹ For more information, see Standards Coordinating Body, “NIST Develops Cell Counting Method Evaluation Tool (COMET),” https://www.standardscoordinatingbody.org/release-comet.

focused on three main goals: biological sensors, biological computation, and development of a chassis. The chassis refers to a cell-free biological system to use as a testbed of protein synthesis. They have developed a living measurement systems foundry to increase the consistency and throughput of biological systems development. This is designed to be an automated system to improve throughput and consistency.

The Microbial Metrology Program is focused on the human microbiome as a target for diagnostics and therapeutics. Biosurveillance has particular importance in the post-COVID era. This group has hosted workshops on standards for microbiome research and biosurveillance. The biosurveillance group within the microbial metrology research area has partnered with the Defense Advanced Research Projects Agency to develop pathogen detection within samples containing large numbers of microbes. Wastewater surveillance allows diagnostics throughout larger regions of communities. They developed an Mpox² virus assay and positive controls. Considering that the first and second Food and Drug Administration–approved microbiome therapeutics have been approved within the past 2 years, the need for standards has increased. This group has created the human fecal reference material to develop diagnostic standards.

Challenges and Opportunities

Building on the current success of all research areas within the division, but especially the engineering biology and microbiome areas, there is an opportunity to further develop standards and reference materials in the area of biotechnology for agricultural use (clean energy and food sustainability). This would further the division’s broad goals to support the growing bioeconomy and promote customer outreach to an even broader set of academic and industry stakeholders (see the section “Effectiveness of Dissemination Efforts” below).

ASSESSMENT OF SCIENTIFIC EXPERTISE

Accomplishments

The Biosystems and Biomaterials Division is a recognized leader in biometrology within the United States and internationally. This is demonstrated by the division’s leadership in standards development, particularly in the area of advanced therapeutics which has led to more than 40 ISO standards; leading in a number of NIST consortia (Genome In A Bottle, Flow Cytometry Standards, Genome Editing, and Rapid Microbial Testing Methods); and publications in high-quality journals.

The four programmatic research areas have continued from the past review period: engineering biology, regenerative medicine and advanced therapies, precision medicine, and microbial metrology. Expertise in each of these areas is deep, and well aligned to promote the division’s objectives. In engineering biology, expertise has centered around supporting the transition of engineering biological systems from a costly, laborious, trial-and-error approach to a routine, automated, design-build-test-learn workflow. Expertise in the Regenerative Medicine and Advanced Therapies Group allows the researchers to provide measurement infrastructure and platform technologies, as well as standards to promote manufacturing innovation, improve supply chain resilience, and support characterization and testing to facilitate regulatory approval of advanced therapeutics. In precision medicine, expertise has focused on supporting the identification, validation, and accurate measurement of biomarkers, especially for cancer diagnosis and treatment. Expertise in the Microbial Metrology Group allows the researchers to provide complex reference materials and measurement capabilities to support a wide range of industrial activities, including microbial therapeutics to treat disease, soil probiotics that enable more robust agricultural processes, novel approaches to biofuel production, and bioremediation and carbon capture for the

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² Mpox is the new name for monkeypox.

environment and climate. Moreover, the focus of the researchers in each area on a subset of use cases or “test-beds” (e.g., Chinese Hamster Ovaries cells and specific viral vectors for genetic modification) helps to unify the division’s research teams and encourage knowledge sharing among research teams.

Through these consortia, the division team has developed reference standards, innovative and reliable reference methods, benchmark sets, data, publications, and harmonized lexicons. The division’s work has been recognized by numerous awards by the Department of Commerce and NIST awards, including 4 Department of Commerce Gold Medals. In addition, the division’s impact has been recognized by several external awards, including the Outstanding Young Scientist Award from Maryland Science Center, and the Dirks Prize in Molecular Programming from Caltech.

Since 2020, the groups in Biosystems and Biomaterials Division continue to grow in national prominence in the areas of both mammalian and microbial biologics. During this review period, the division’s programs have supported the development of the Executive Order on Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy (Executive Order 14081), the National Biodefense Strategy, and associated research and development strategy documents. The division has built cutting-edge expertise in robotic platforms for bioassays and biomanufacturing to accelerate productivity. The division’s success in enhanced group activities stems from efficient integration of staff among the groups and the use of modular and flexible capabilities (such as a new modular laboratory currently used for cell expansion). This integrated structure allows the division to remain flexible to meet unexpected demands on their expertise, such as the COVID-19 pandemic, where they helped produce a SARS-CoV-2 polymerase chain reaction reference-grade testing material (led by the Biomolecular Measurement Division) and ISO standards on SARS-CoV-2 testing. Another laudable example is that the division’s staff was able to use their collective expertise and creative redeployment of resources to produce a Mpox DNA standard within 30 days in response to this emerging health threat.

Opportunities

Notably, during this review period, the Biosystems and Biomaterials Division has paired extensively with the National Aeronautics and Space Administration’s Jet Propulsion Laboratory (JPL) to build on JPL’s capabilities to provide a well-architected data management environment (LabCAS/LIMS) to support the capture, curation, management, distribution, and analysis of data science activities within the division. This work is currently using the JPL cyberinfrastructure for several test cases within the Biosystems and Biomaterials Division. Data curation and analysis is of utmost importance for further analysis of results from biosystems, biomanufacturing, and bioassays to direct the future of these fields over the next 5–10 years. Given the importance of this capacity across the division, there is an opportunity to further build (1) expertise in the division and (2) data management capacity within the division by both continuing existing programs such as the JPL partnership, as well as continue to partner with data scientists at NIST and externally to develop a cohesive data management plan for all data gathered within the division.

BUDGET, FACILITIES, EQUIPMENT, AND HUMAN RESOURCES

Accomplishments

The division’s leadership works with the six group leaders who oversee the five groups of the division (Complex Microbial Systems, Biomarkers and Genomics Sciences, Biomaterials, Cell Systems Science, and Cellular Engineering). Personnel in these five subgroups in turn are deployed as needed within the division’s four programmatic research areas (or research groups) listed in previous sections. Although most groups have a single leader, the Biomarkers and Genomics Sciences Subgroup is co-led by a team of two leaders. The division leader has been very strategic in deployment of resources to have

maximal impact. The chief and deputy chief have fostered a climate of open discussion necessary for the highest level of work and cultivated a very enthusiastic staff. A pathway to promotion from lab technician to team leader and flexible work options within the division has enabled the retention of talent.

The Biosystems and Biomaterials Division has been very proactive in the incorporation of automated liquid handling and other robotics platforms into work routines. The division has an AI-enabled Living Measurements Systems Foundry and Prototype Cell Assay Measurement Platform. These automated systems aid in reproducible, higher throughput quantitative sample preparation and measurements of complex living systems and processes.

Challenges and Opportunities

The division is supported by a $24.6 million budget. This support comes from appropriations ($20.9 million), funds from interagency agreements ($3.4 million), and additional funds for service work ($306,000). The division also receives episodic and time-limited funding for specific programs such as those related to the COVID-19 pandemic. During this review period, the Biosystems and Biomaterials Division’s programs have supported the development of standards related to COVID-19 and Mpox outbreaks, the development of the Executive Order on Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy (Executive Order 14081), the National Biodefense Strategy, and associated research and development strategy documents. However, despite this growing demand for the division’s expertise, the overall budget has decreased in inflation-adjusted support since the past review in 2020.

Recommendation 4-1: Owing to increasing demands on the unit resulting from new bioeconomy initiatives, the Material Measurement Laboratory should prioritize allocations to the Biosystems and Biomaterials Division within budgetary constraints to ensure adequate support and the Biosystems and Biomaterials Division should continue to prioritize its efforts mindful of its limited budget.

The division works in laboratories spread across two buildings on the NIST campus in Gaithersburg, Maryland. The groups work closely together yet are physically located in separate locations. This separation slows down the work physically (requiring moving of samples a 15-minute or more walk each way), as well as slowing idea transfer. Moreover, the state of these buildings has been well described in the 2023 report Technical Assessment of the Capital Facility Needs of the National Institute of Standards and Technology (NASEM 2023). Room temperatures vary from too hot to too cold such that the reliability of modern scientific equipment and measurements is imperiled. Humidity and power control are also too variable for consistent operation of sensitive equipment, such as lasers.

Recommendation 4-2: The Material Measurement Laboratory leadership should evaluate space allocations to co-locate the Biosystems and Biomaterials Division in a single building with adequate temperature, humidity, and power control for continuous instrument function.

The pandemic restrictions did limit onboarding processes and other processes that contribute to a cohesive work culture. The division’s leadership team is actively working to rebuild these processes, although this work is especially challenging given the spread of people across buildings and the lack of shared public spaces like the cafeteria. Career mentoring and professional development for the population of postdoctoral fellows and other term-limited scientific appointees is uneven. The path to employment within NIST or within its corporate and academic partners or elsewhere is not clear to many of these appointees. Increased mentor training within this population (for horizontal mentorship) and within the division overall (for vertical mentorship and sponsorship) would increase the impact of this population

both within NIST and later in industry, academia, or government positions. A larger strategy consistent with the mission of NIST would be to partially fund NIST postdoctoral fellows in laboratories of stakeholders such as industry, academic, and agency partners in areas of needed expertise development for the division, with the expectation that they would spend time within both NIST laboratories and the partner institution. This practice would enhance collaborations, the cross-fertilization of knowledge, and broader awareness of the work of the Biosystems and Biomaterials Division.

Recommendation 4-3: The Biosystems and Biomaterials Division leadership should require mentorship training for all laboratory employees and increase the number of employees who have formal leadership training to standardize mentoring and onboarding of new personnel and to make career development opportunities more uniform.

EFFECTIVENESS OF DISSEMINATION EFFORTS

Accomplishments

The Biosystems and Biomaterials Division has been very active in disseminating its protocols, materials, and expertise. It has maintained robust participation in national and international consortia and national and international working groups through the pandemic years. It is clearly recognized around the world. Since the past review in 2020, the division has published almost 100 peer-reviewed articles in high-impact journals, published 5 books or book chapters, given 118 invited presentations at conferences, and contributed to a dozen workshop reports. The division has actively engaged the industrial community and others through 22 workshops, 91 cooperative research and development agreements, and almost 60 material and data transfer agreements. They also participate actively in four consortia, including the Flow Cytometry Standards Consortium and the NIST Rapid Microbial Testing Methods Consortium that was launched in June 2020. Four patents have been issued (two in 2020 and two in 2022) and 3 patent applications were filed in 2022.

The division is proactive in maintaining an international presence through participation on 22 standards committees (including 8 leadership positions) and the development of 1 standard reference data product, 1 research grade test material, and 22 standard reference materials. This work is critical for the development and the success of the biotechnology industry. The U.S. Technical Advisory Group to the ISO Technical Committee 276 (which works on Biotechnology), along with the NIST-administered U.S. Mirror Committee, has published more than 50 documentary standards to support biomanufacturing and biotechnology. A living reference material for certain yeast cells was developed to support the Department of Homeland Security’s efforts to benchmark the detection and quantification of microbes. The Biosystems and Biomaterials Division was also instrumental in developing a SRM (standard reference material) (SRM 2917) in collaboration with the Environmental Protection Agency to estimate total fecal pollution and the sources of this type of pollution in water. The Mpox outbreak led to the production of a positive control material (RGTM 10223) to assess Mpox diagnostic kits. This division is very responsive to the development of standards and protocols needed to drive assay development within government and for-profit organizations.

Challenges and Opportunities

The Biosystems and Biomaterials Division maintains exceptionally strong networks of stakeholders and collaborators including other NIST units, other government entities, industry, and academic institutions. These networks contribute to the very strong technical programs and scientific capabilities of the division. The challenge will be to continue to expand these assets sustainably to contribute to the bioeconomy across industries from health to energy, and from chemicals to agriculture. The division has the opportunity to actively reach out to an even broader set of academic institutions

across broader geographic areas of the United States to further promote the dissemination of the division’s products and capabilities. Such broader geographic outreach is particularly important to reach more stakeholders involved in the growing number of bioeconomy initiatives. In addition, NIST also offers very good incentives for the filing of patents, but many staff are not aware of them. There is therefore an opportunity to increase awareness for all staff, including new arrivals, about the process and outcomes of filing patents through NIST.