The mission of the Material Measurement Laboratory’s (MML’s) Biosystems and Biomaterials Division (BBD) is “to promote U.S. biosciences and biotechnology innovation and industrial competitiveness by advancing measurement science, standards, and technology in ways that enhance economic security and improve our quality of life.”1 BBD is currently focused on four primary areas—engineering biology, advanced therapies, precision medicine, and microbiome—with a drive to “foster innovation and build confidence in quantitative biology and biomaterial measurements across government and industry in support of the bio-economy.”2 Importantly, in response to the COVID-19 pandemic, BBD implemented targeted initiatives by redirecting resources in manpower, collaborations, and equipment.
BBD has five groups—Complex Microbial Systems, Biomarker and Genomic Sciences, Biomaterials, Cell Systems Science, and Cellular Engineering—that are led by group leaders; scientists and an office manager report to each group leader. These cross-functional groups of scientists with expertise in materials, molecular biology, engineering, chemistry, microbiology, statistics, and data management are working well together. The BBD team is one of the world’s best technical teams, if not the best, in the development of advanced standards and innovative measurement technology to address the quantitative metrology needs of biological materials and processes.
In July 2020, BBD had 61 staff members and 24 associates, which represents 10 percent of the MML. The current staff number is an increase from 51 staff members and a decrease from 49 associates in 2017, the latter due to transfer of the collaboration with the American Dental Association Foundation to MSED. One member of BBD’s team has been named a NIST fellow, which is a very high honor and recognition of scientific excellence.
The 2020 budget is approximately $21 million of which approximately $18 million is from the Scientific and Technical Research Services (STRS) funds (an appropriation account), $2.2 million is Other Agency (OA) Agreements, and $0.7 million is Measurement Services. The budget has increased since 2017 ($15 million) with the predominant increase derived from STRS targeted to engineering biology and regenerative medicine measurement standards.
BBD’s primary products are measurement science and protocols, which are disseminated in publications, reference materials, and reference data. Products include, for example, Genome in a Bottle3 (GIAB) DNA, Cancer Biomarker EGFR (Epidermal Growth Factor Receptor) and MET, mixed pathogen DNA, Lentiviral vector, reference materials for flow cytometry and imaging measurement, advanced
1 Sheng Lin-Gibson, National Institute of Standards and Technology (NIST), 2020, “BBD Overview 2020 NASEM,” presentation to the panel, September 9.
3 “The Genome in a Bottle Consortium is a public-private-academic consortium hosted by NIST to develop the technical infrastructure (reference standards, reference methods, and reference data) to enable translation of whole human genome sequencing to clinical practice and innovations in technologies.” For further information, see NIST, “Genome in a Bottle,” https://www.nist.gov/programs-projects/genome-bottle, accessed April 26, 2021.
living reference materials (e.g., cancer and normal cells, Jurkat cells, genetically tagged yeast, microbial whole cell, human gut microbiome materials), validation of methodology, and international biological lexicon standardization.
ASSESSMENT OF TECHNICAL PROGRAMS
BBD is currently divided into five groups, although the fluidity and rapid pace in what are termed focus areas often blurs the lines between groups. The stated focus areas are engineering biology, advanced therapies, precision medicine, and microbiome. Accomplishments were many and overall clear even if, in some cases, assignment to a particular group was not. Accomplishments across the division’s groups include hosting of four consortia, organization of several dozen workshops, and leading or participating in nearly two dozen global standards development organizations. Consortia are flagship efforts involving companies, among many other stakeholders, and require investments of the division. Consortia have been organized in a topic once a critical mass of roughly five expert personnel in the division is achieved and when there is a perceived long-term and sustainable need for standards, especially for industry. NIST’s Genome in a Bottle Consortium seems to be more than several years old and is maintained as an important accomplishment. The other three consortia were more recently created—in genome editing, quantitative flow cytometry, and rapid testing for microbial contaminants. Additional accomplishments beyond consortia over the past few years also include in excess of 130 journal publications, more than 10 ISO (International Organization for Standards) standards published, and multiple awarded patents. It is also an important accomplishment for BBD to have close coordination with the Food and Drug Administration (FDA), which is responsible for key approvals across focus areas of the division such as advanced therapies. One provided example is that NIST chairs ISO’s Biotechnology Analytical Methods working group.
The Complex Microbial Systems Group advances measurements and standards for the exploitation of microbes. The group employs genomic, metagenomics, biochemical, and biophysical approaches to improve measurements on microbiomes, and it is also developing reference methods (RMs)—with attention to stability—on the sensitivity and specificity of pathogen-detection devices. Accomplishments include human gut microbiome (fecal) analysis standards to be used in a large multisite international network, a microbial measurements standards workshop, microbe strain detection and identification within complex populations, and microfluidic development. Bacteria and yeast are the focus.
COVID-19, also caused by a microbe, shut down onsite work at NIST for months in 2020. Accomplishments by many across the division and NIST nonetheless began with remote work, including COVID-19 discovery-oriented analyses of protease function by meta-analyses and molecular simulations.4 Upon restricted re-opening of laboratories, some groups are in the midst of contributing to useful standards, including for virus detection, which is finding application to sewage or wastewater. Expertise in flow-cytometry RM is being applied to antibody tests as a member of the National Cancer Institute’s COVID serology network.
The Biomarker and Genomic Sciences Group develops measurement methods, standards, technology, and data for biomarker genomic sciences, including phenotype, and cell lines, including authentication, in order to support diagnostics and advanced therapeutics for cancer and other diseases. Flow cytometry calibration standards is one accomplishment that addresses multiple needs across a very large and growing community in academia and industry. Additional accomplishments include RM from
the Cancer Biomarkers Program computational resources for detection of different types of mutations or genomic variants as published in multiple papers in field-leading journal Nature Biotechnology.
The Biomaterials Group develops measurement capabilities and standards strategies to quantify biomaterials, biological systems (mammalian and microbial), and their interactions. Efforts extend to imaging and spectral methods and are important to biomanufacturing and translation of cell therapy and regenerative medicine products. Accomplishments include publication of a new theoretical basis for understanding population distributions and their fluctuations,5 with a focus on iPS cells that many in academia and industry employ or plan to translate. The iPS work is done in close consultation with the Allen Institute of Cell Biology, which has parallel goals of quantitative cell biology and illustrates just one of the many strengths of the overall strategy.
The Cell Systems Science Group develops new measurements and models to elucidate complex biological phenomena at the cellular and subcellular levels. It establishes measurement capabilities, including bioimaging and other cytometry techniques, that examine attributes of cells, and develops measurement assurance strategies, including RMs. Accomplishments relevant to advanced therapy include development of an ISO cell counting standard and an ISO cell viability standard, which are generally relevant to dosage effects. In genome editing, which has expanded greatly in academia and industry with new methods over the past few years, the group has so far contributed to ISO lexicon, formed a large genome editing consortium with dozens of stakeholders, and leveraged NIST’s GIAB RM for standards. Accomplishments in tissue engineering and in cell engineering, such as with Chimeric antigen receptor T cells (CAR T cells), include exploiting NIST’s computational strength for artificial intelligence (AI) applications to pattern recognition. This led directly, for example, to a paper in the field-defining Journal of Clinical Investigation.
The Cellular Engineering Group is the newest of the five groups and combines state-of-the-art synthetic biology, automation of bench processes, and machine learning to generate living measurement systems, such as cells, that are engineered and standardized. Collaborators include the world-leading J. Craig Venter Institute as well as academic laboratories. Accomplishments include ISO standards in the area of genome synthesis and patents in the microfluidics realm relevant to synthetic cells.
Challenges and Opportunities
COVID-19 testing and diagnostics are in urgent need of expertise that a well-networked and well-regarded BBD can in principle provide. The need and the efforts exemplify—as a key opportunity—the broader importance of quantitative life sciences research to the nation and to the world.
A challenge is the lack of dedicated resources for COVID-19 efforts. However, with suitable groups and expertise already in place, including recently developed efforts in lentivirus for cell therapy, BBD is pivoting resources to respond quickly to the pressing worldwide challenge. Serology testing is of great relevance to antibody responses and success in vaccine development, and BBD’s expertise in standards-based quantitative flow cytometry assays is now the basis for active collaborations with the FDA, the National Cancer Institute of the National Institutes of Health, the World Health Organization, and various companies. This takes the form of services for standard control samples and also materials to validate tests. Diagnosis of virus in complex materials beyond nasal swabs include fecal material and wastewater as a rapidly emerging opportunity that can exploit BBD expertise in standardized and well-established GIAB material coupled to developing standardization of stable fecal material in earlier development. Although applied to COVID-19, applications are envisioned for other microbes that might range from annual influenza to bacterial contaminations and bio-threats.
Advanced therapy opportunities are emerging from many directions, including regenerative medicine, which is highly complex. BBD is well-poised to impact standards as well as discovery. Two of
5 J.B. Hubbard, M. Halter, S. Sarkar, and A.L. Plant, 2020, “The Role of Fluctuations in Determining Cellular Network Thermodynamics,” PLoS ONE 15(3): e0230076.
the four consortia illustrate the outside interest and the investment in flow cytometry and in rapid microbial testing methods. In the latter, there is a challenge to address the diversity of states of microbes, such as in biofilms that are certainly problematic in biomedical devices. Challenges in resources are incessant across the highly competitive realm of therapies. However, therapy-developing companies, such as AstraZeneca, are collaborating with BBD in standards-related research and innovative quality control measurements using the CRADA (cooperative research and development agreement) mechanism. Challenging overall with living systems and derived standards is the mutation rate in the DNA and other sources of variation, which require extra care about stability of averages and variances; but BBD is not only aware but also exploiting the opportunities provided by NIST’s computational resources, such as in AI, to address some of the issues.
Biotechnology and engineering biology are perhaps less complex and more reductionist than above, providing clear opportunities for standards approaches. BBD is coordinating with other agencies, especially FDA. Laboratory automation combined with machine learning (ML) again exploits unique opportunities provided by NIST, including its resources in hardware and computation. Challenges are perhaps modest but real in integrating non-bio expertise such as automation engineers, chemists, and fluidics experts. Crossing boundaries in bio-discovery is nonetheless a credible opportunity for a multidisciplinary campus such as NIST, even though resource constraints are rightly viewed as a challenge.
Four consortia are flagship efforts with long-lasting opportunities involving NIST, companies, and many other stakeholders. As such, the ongoing challenge is to identify and matriculate into consortia those key efforts that can take off from multi-partner collaborations or networks.
PORTFOLIO OF SCIENTIFIC EXPERTISE
BBD is a recognized leader in biometrology within the United States and internationally as demonstrated by BBD’s standards development (measurement science and technology development) leadership in the BBD-led consortia—Genome in a Bottle Consortium, Mouse Cell-Line Authentication Consortium, Flow Cytometry Quantification Consortium, Genome Editing Consortium, and the newly established Rapid Microbial Testing Methods Consortium. Outcome products from these consortia are reference standards, innovative, reliable reference methods, benchmark sets, data, publications, NCBI (National Center for Biotechnology Information) database inputs, harmonized lexicon, and a repository of relevant microorganisms.
The scientific and technological expertise of BBD is excellent as evidenced by the numerous high-quality peer-reviewed publications (>130) in leading journals such as Nature Biotechnology and Nature Methods. Further, its scientific and technological leadership role in foundational measurement science and technology for complex biological systems is well supported by the fact that many of these publications are the products of collaborative studies with its consortia (66 in total) members.
Since the 2017 review,6 groups in BBD have grown significantly in mammalian and microbial biologics scientific expertise and the groups have also increased in number by one, due to additional support for the Engineering and Biology and Regenerative Medicine initiatives. However, in spite of this scientific project expansion, the total budget of the division has not changed significantly due to (1) decreases in agency funds and (2) also decreases in the number of staff. The success of BBD in enhanced group activities appears to stem from efficient integration of staff among the groups and the use of modular and flexible capabilities. A good example of their efficient way of responding to challenges is the COVID-19 testing and diagnostics.
6 NIST Material Measurement Laboratory (MML), 2020, “National Academies of Sciences, Engineering, and Medicine: 2020 Assessment Read-Ahead Materials for September 9-11, 2020,” Gaithersburg, MD.
BBD’s work has been recognized by numerous awards to its staff externally, by the Department of Commerce (DOC) and NIST. Some noteworthy external award examples are the following: (1) C. William Hall Award by the Society of Biomaterials (2020), (2) Gears of Government Award by the U.S. government (2020), (3) two Presidential Early Career Awards for Scientists and Engineers (2017 and 2019), and (4) both an Outstanding Young Scientist and an Outstanding Young Engineer Award from the Maryland Academy of Sciences (2018 and 2019).
In some of the consortia, BBD’s work is highly futuristic, as in the case of the human gut genome project. Uniquely, the human gut microbiome project has a very strong international presence.
Challenges and Opportunities
Recognizing that complex biological systems are governed by the principles of thermodynamics, fluid mechanics, and colloidal science, BBD has some strength in these fields. Additionally, expanded expertise in virology, immunology, microbiology, and bioinformatics would benefit the BBD’s mission. It is critical that this expertise be maintained and indeed strengthened further through new hires by BBD management and by interactions with other NIST divisions.
Since the 2017 review,7 BBD has lost approximately 20 percent of its laboratory space. It has transitioned to an industry-like collaborative model where laboratories are designed by function, and space is designed to promote cross-team interaction. BBD has embarked on a multiyear laboratory and office space modernization plan.
BBD is responding to the ongoing pandemic and emerging biothreats by contributing to leading-edge measurements and standards. It lacks dedicated resources to sustain these efforts. To address the acute problems with COVID 19, BBD reassigned personnel from other necessary, but more long-term, projects. If standards work is to continue with corona viruses or other infectious disease vectors, this would be better handled with a dedicated set of scientists. However, the research and development (R&D) programs that BBD had developed prior to COVID-19 are vital to U.S. biologics manufacturing and research efforts. This implies that additional staff may be needed to continue both the existing programs and the recent work on coronavirus measurements and standards.
ADEQUACY OF FACILITIES, EQUIPMENT AND HUMAN RESOURCES
BBD designed and built an adaptive, automated, AI-enabled modular unit, the Living Measurements Systems Foundry, which is providing quantitative measurement of complex living systems and processes as a key component of BBD’s design-build-test-learn cycle to predictively engineer biological systems with the intent to accelerate R&D innovation and advance biomanufacturing. Notably, BBD has designed and installed a second modular unit, the Prototype Cell Assay Measurement Platform (P-CAMP), which is also adaptive, automated, and AI-enabled.
BBD has implemented state-of-the-art data sciences for data collection and analysis for imaging, cellular engineering predictive functional metrics, and quantitative assays to characterize CAR-T functionality/lentiviral infectivity. Additional research areas are in the queue for big data retention and analysis. New equipment for automated LN2 biologics storage, BioStore III, is in place. Referring to the 2017 review8 recommendations, BBD’s older chemical laboratories have been renovated to modern biological laboratories.
BBD does not have a gender equality problem as its staff gender ratio (58 percent males, 42 percent females) is similar to that found in the field of biological sciences, which draws the interest of both females and males. The division chief is female as are two of the five group leaders. Of note, there is a broad age range within the scientific staff, which also allows diversity of thought and knowledge.
Challenges and Opportunities
BBD has lost approximately 20 percent of its laboratory space, which negatively impacts program growth. Such growth could be accommodated by space in one of the new laboratory buildings envisaged in the NIST master plan for Gaithersburg,9 while ensuring continued scientific interactions by addition of inside walkways that connect to existing NIST buildings.
Knowledge of complex biological systems is continually evolving with developing manufacturing methods and commercial biological materials. Interwoven knowledge in biology, chemistry, physics, math, and data and informatics is required. For BBD, this translates into a need for additional emphasis on colloidal science and thermodynamics, biofilm biochemists, and fluid mechanics.
It is unknown if underserved minority representation within BBD is reasonable or could be improved and is in need of assessment and elaboration of what steps, if any, need to be taken. At the corporate level, NIST has a working group to consider equity disparity that can further illuminate this issue.10
Postdoctoral fellows seem to be working at BBD for many years instead of moving forward with their careers (and out of postdoctoral positions). Setting term limits for postdoctoral fellows would be one way that BBD management could address this, along with promulgating a progressive plan for postdoctoral fellow placement in synergistic positions in industry, academia, or government.
DISSEMINATION OF OUTPUTS
BBD has strong participation in national and international consortia, national and international working groups, and has a recognized international presence. BBD has published more than 130 peer reviewed articles in high-impact journals, been granted 3 U.S. patents, presented more than 280 invited talks and webinars, participated in numerous National Academies panels, provided standards expertise to State Department and regulatory agencies at international forums (Organisation for Economic Cooperation and Development, Asia-Pacific Economic Cooperation, and the International Organization for Standardization), and promoted commerce and trade by participation in global comparison studies.
BBD maintains more than 110 formal agreements—a very impressive number, organized 34 workshops, and led or participated in more than 20 global standards development organizations. Five NIST consortia—Genome in a Bottle, genome editing, quantitative flow cytometry, mouse cell-line authentication, and rapid microbial testing methods—have been hosted by BBD. BBD received the NIST Technology Maturation Acceleration Program Award in 2020 ($250,000)—a key indicator. BBD is a member of and/or a leader of several working groups/policy forums such as the following: National Science and Technology Council’s (NSTC’s)11 Biosciences Subcommittee and its Synthetic Biology Interagency Working Group and the Multi-agency Tissue Engineering Science Subcommittee (e.g.,
9 For further information, see NIST, 2018, “Gaithersburg Campus Master Plan,” May, https://www.nist.gov/system/files/documents/2018/06/15/nist_gaithersburg_master_plan_may_7_2018.pdf.
10 NIST, 2019, “Inclusivity at NIST: Recent actions supporting equity in career advancement at NIST,” presentation to the Visiting Committee on Advanced Technology, October 24, Gaithersburg, MD.
11 NSTC is an interagency strata of committees created by Executive Order. The Office of Science and Technology Policy is the secretariat.
FDA). BBD is also a member of NSTC’s Committee on Homeland and National Security/Health Security Threat Subcommittee; chair of the ISO TC/276 Biotechnology Analytical Methods International Working Group and U.S. Mirror Technical Committee; a member of ASTM F04 Medical and Surgical Materials and Devices; and a member of American National Standards Institute.
BBD staff serve as the standards expert member in two manufacturing institutes—the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), which is DOC-funded to accelerate sustainable biopharmaceutical manufacturing innovation, and Biofabusa, which is Department of Defense-funded to make practical large-scale manufacturing of engineered tissues and tissue-related technologies. BBD helped to initiate and participates in the International Metagenomics and Microbiome Standards Alliance (IMMSA) whose function is to identify and disseminate microbiome measurements. BBD or its staff are members of the professional societies ISCT (International Society for Cell & Gene Therapy) and ISSCR (International Society for Stem Cell Research) as well as the accreditation bodies AABB and FACT (Foundation for the Accreditation of Cellular Therapy). Of note, the BBD director received the Gear of Government Award, and five other division members received prestigious awards.
Challenges and Opportunities
Despite the plethora of outreach as demonstrated in the paragraph above, BBD has the opportunity to spread the word on its products and capabilities in industries, such as agriculture, that are not its traditional stakeholders or within small and medium enterprises. Additionally, while a challenge, resource uncertainty and erosion can lead to increased innovative opportunities with diversified resource pools.
FINDING: BBD has built an exceptionally strong network of collaborators and stakeholders comprised of government entities, academic institutions, and industry, which has allowed for strong technical programs and scientific capability. The challenge will be to continue to build these assets sustainably and further to enable agility as U.S. economic factors shift.
RECOMMENDATION 7-1: The Biosystems and Biomaterials Division (BBD) should (1) with creativity, develop a business strategy that focuses on BBD’s unique products that may include licensing and further consortia for use of BBD products, services, and expertise; (2) strategically place BBD postdoctoral fellows into industry, academia, and other government positions to improve connectivity with outside current and future collaborators and stakeholders; (3) hire or contract with a communications person with YouTube and other media expertise to reach individuals who are searching for BBD-type expertise, products, and research services; and (4) determine how to connect with quality and manufacturing personnel at small and medium-sized companies in targeted industries. Emphasizing NIST BBD leadership, with thoughtfulness and quantification, in BBD program areas should be addressed by BBD leadership and staff to further enhance leadership with collaborators and stakeholders.
RECOMMENDATION 7-2: The Biosystems and Biomaterials Division should improve awareness of its products and capabilities, especially within small to medium-size enterprises and companies that are not currently stakeholders because they are in different industries (e.g., agriculture).
OVERALL CONCLUSIONS AND RECOMMENDATIONS
A 20 percent reduction of BBD laboratory space has occurred, which impedes further growth of BBD project areas. The new laboratory buildings envisaged in the NIST master plan for Gaithersburg12 would be beneficial and could be improved with the addition of physical connection (sky walks, for instance) to old NIST building(s) so that the benefits of interactions with other divisions are not lost.
Recognizing that complex biological systems are governed by the principles of thermodynamics, fluid mechanics, and colloidal science, BBD has maintained strength in these fields. However, it is critical that this expertise be maintained. Additional expertise in virology, immunology, microbiology, and bioinformatics would benefit the BBD mission. These scientific areas of expertise will need to be strengthened by BBD management further through new hires and by interactions with other divisions.
Continuity of staffing is a problem suffered by all entities, including BBD. BBD leadership might implement cross-training of staff with intent during each year to mitigate the effects of loss of key staff through retirement, illness, or job transition as well as strengthening scientific creativity by increasing each individual’s knowledge.
There is a need to consider the career trajectory of postdoctoral fellows strategically. A logical strategy consistent with the MML mission would be to place postdoctoral fellows within current and potential stakeholders in order to enhance collaborations and cross fertilization of knowledge.
BBD is responding to the ongoing pandemic and emerging biothreats by contributing to leading edge measurements and standards. However, they lack dedicated resources to sustain these efforts.
RECOMMENDATION 7-3: The Material Measurement Laboratory should evaluate whether the square footage assigned the Biosystems and Biomaterials Division is commensurate with the division’s current size and mission.
RECOMMENDATION 7-4: The Biosystems and Biomaterials Division should provide additional resources in thermodynamics, fluid mechanics, colloidal science, virology, immunology, microbiology, and bioinformatics in a manner commensurate with the increasing importance of these specialties.
RECOMMENDATION 7-5: The Biosystems and Biomaterials Division should analyze underserved minority representation among its staff and develop an action plan to address findings both from such study and from NIST’s equity disparity studies.
RECOMMENDATION 7-6: The Biosystems and Biomaterials Division should develop a plan for outplacing long-tenured postdoctoral fellows into synergistic positions in industry, academia, or government. This plan should include an assessment of what shortfall, if any, this might create in its staffing plans.
RECOMMENDATION 7-7: The Biosystems and Biomaterials Division leadership should implement cross-training of staff with intent during each year to mitigate the effects of loss of key staff and ensure continuity.
12 For further information, see NIST, 2018, “Gaithersburg Campus Master Plan,” May, https://www.nist.gov/system/files/documents/2018/06/15/nist_gaithersburg_master_plan_may_7_2018.pdf.