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Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
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4

Biosystems and Biomaterials

INTRODUCTION

The overarching goal of the Biosystems and Biomaterials Division (BBD)1 is to develop and disseminate standards and measurement technology to support quantitative biological and biomaterial measurements. The BBD consists of four technical groups: the Microbial Metrology Group, the Bioassay Methods Group, the Biomaterials Group, and the Cell Systems Science Group. Additionally, the Joint Initiative for Metrology in Biology (JIMB) program, in partnership with Stanford University, reports directly to the MML.

The BBD leverages cross-functional teams of material scientists, molecular biologists, engineers, chemists, physicists, statisticians, and data scientists who are some of the world’s best technical experts. These experts carry out fundamental research in biological measurement science and the development of reference methods, advanced analytical instruments, reference data, and methods. The BBD has 101 staff members—90 percent are scientists and associates, and the remainder are technicians and support staff.

The activities of the BBD are focused on existing and anticipated applications of biological and biochemical science in products and processes that influence manufacturing, natural resources, and health care. The BBD approach is to develop technical excellence in core measurements that serve a number of applications, including regenerative medicine and advanced therapies, cancer diagnostics, the engineering of biological systems, nanoparticle safety, dental and oral health, and microbial identification and quantification. To achieve its mission, the BBD employs technical expertise in genomics measurement assurance; the quantitative measurements of cells; the development and deployment of imaging and spectroscopy technologies, including broadband coherent anti-Stokes Raman scattering (BCARS) microscopy and live-cell imaging; and in the development of biomaterials—particularly for dental applications.

ASSESSMENT OF TECHNICAL PROGRAMS

Accomplishments

The Microbial Metrology Group develops advanced measurements and standards for the exploitation of microbes to promote human health, precision medicine, advanced manufacturing, and other industrial applications. The group uses genomic and metagenomic approaches to improve measurements on

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1 Some of the background information within this chapter was derived from the document NIST, “Made to Measure—Building the Foundation for Tomorrow’s Innovation in the Niological, Chemical, and Materials Sciences,” pp. 94-111. 2017.

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

microbiomes, and is also developing RMs for assessing the sensitivity and specificity of pathogen detection devices.2 Additionally, the group utilizes advanced methods, including microfluidics, predictive modeling of engineered microbes, bioinformatics, and state-of-the-art imaging, which are being applied to critical areas, such as combating antibiotic resistance, food safety, clinical diagnostics, and engineering biology.3

The Microbial Metrology Group’s accomplishments include microbial community measurements, pathogen detection and identification, biothreat detection, and microfluidic development.

The Bioassay Methods Group develops standards and methods for improving confidence in fundamental measurements in biology through new and improved techniques, methodologies, and standards based on optical and genomic methods. The group is focused on improving the quantitative measurements of the biological markers of gene expression in eukaryotic cells and biological fluids. It is providing tools that can be used for bioanalytical measurements pertinent to instrument calibration and analytical validation.4 It is also working with stakeholders in the research and clinical analysis communities to determine their needs and opportunities, so that they can determine where to strategically focus their efforts. It has identified existing and future standards needs, ranging from device calibration and instrument performance to the development of biological RMs and procedures.

The group has active projects in the development of genomic standards to support: cancer diagnostics and therapeutics, RMs for quantitative flow cytometry, development of genomic markers for cell line authentication, and measurements for assessing the results of genome editing.5 Their accomplishments include the production of standard reference material (SRM) 2373, a human epidermal growth factor receptor 2 (HER2) genomic DNA standard for gene copy number produced from five breast cancer cell lines. This SRM is discussed in greater detail below.

An ongoing project of the group is the analytical validation and quantitation of circulating tumor DNA (ctDNA) through liquid biopsy. This project is being developed in partnership with SeraCare, an industry partner, and in collaboration with Early Detection Research Network (EDRN)-funded laboratories.

Projects in the planning phase include expanding a suite of RMs to include epigenetic markers, as well as liquid biopsy measurements of gene copy numbers, translocations, and other biomarkers. Other biomarker projects include quantitative flow cytometry assays for chronic lymphocytic leukemia (CLL) and myeloma markers for residual disease during therapy. Another project is to develop SRMs for cell-free DNA noninvasive prenatal screening.

The Biomaterials Group develops advanced measurement capabilities and measurement assurance strategies for characterizing biomaterials, biological systems, and their interactions. The Biomaterials Group aims to provide quantitative measurements and the prediction of chemical, physical, structural, and mechanical properties on multiple length and time scales. One major focus is the development of nonlinear optical spectroscopy and imaging methods for extracting statistically significant information from biological and material systems.6

The Biomaterials Group has also developed and delivered a yeast surrogate biothreat test material, which is engineered yeast material containing a target DNA sequence as a surrogate for pathogenic agents that enables safe on-site training for first responders to increase confidence in biothreat detection. It has been used in field deployment exercises in conjunction with the Department of Homeland Security (DHS) and the Army. The group is also addressing antibiotic resistance—a global health crisis—by developing

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2 NIST, Microbial Metrology Group, https://www.nist.gov/mml/bbd/microbial-metrology, accessed September 25, 2017.

3 Ibid.

4 NIST, Bioassay Methods Group, https://www.nist.gov/mml/bbd/bioassay-methods, accessed September 25, 2017.

5 Ibid.

6 NIST, Biomaterials Group, https://www.nist.gov/mml/bbd/biomaterials, accessed September 25, 2017.

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

microfluidic microenvironment devices that establish antibiotic concentration gradients to challenge bacteria and measure the evolutionary process.

Additionally, the Biomaterials Group develops measurement assurance strategies to obtain high-confidence results when measuring cells (mammalian and bacterial), materials, and their interactions. Collectively, these efforts are expected to facilitate the development and translation of new diagnostics and advanced therapeutics (protein- and cell-based), enable better biothreat detection, and improve the performance of biomaterials.7

Recent developments within the Biomaterials Group include the rapid broadband coherent anti-Stokes Raman scattering (BCARS) microscopy of cells, tissues, and materials; novel spectroscopy for probing higher order molecular structures and orientation; and new methods for probing fast molecular dynamics. The projects integrate experimental and computational approaches to understand multiple material properties during polymerization in order to enable better materials design through chemical and processing controls. Additionally, the methods used by the Biomaterials Group have been applied to the quantitative imaging of stem cell populations and chemical imaging of cells and tissues with Raman spectroscopy—offering an innovative proteomics resource.

The Cell Systems Science Group contributes to the new postgenomic era with research in measurements and models that support the understanding of complex biological phenomena at the cellular and subcellular levels. The group focuses on the cell as a system and on tools that can make measurements and characterize the system’s properties.8 This is achieved through bioimaging and other cytometry techniques, measurements that assess protein and gene function within living cells, experimental design, and bioinformatics.

The group is focusing on measurements for assessing the process of creation, maintenance, and differentiation of pluripotent stem cells, in addition to cell lines and engineered cells, to better understand cellular dynamics. They are also emphasizing new measurement tool developments and protocols that ensure reliability and comparability of cell assay and imaging-based measurements, as well as appropriate data analysis and data handling pipelines. These efforts assist basic biomedical research, biomanufacturing of regenerative medicine products, nonanimal toxicology testing, drug development and testing, precision medicine, and other applications that depend on understanding and predicting complex cellular activities.9 Recent projects include detecting and measuring single-molecule RNA-fluorescence in situ hybridization (RNA-FISH) in bacteria, new approaches for cell counting and RMs, and new methods for flow cytometry.

The JIMB is a joint venture between NIST and Stanford University in Palo Alto, California. The JIMB was conceived to connect NIST science, technology, and metrology to the creative power of Stanford University’s research, faculty groups, and medical school—embedded in the innovation hub of Silicon Valley. The JIMB is powered by the partnership of NIST with Stanford and Bay area commerce in bioscience and biomedical instrumentation. The JIMB’s current focus is on reading and writing DNA, a conscious nod to its Silicon Valley home and its legacy. JIMB arrives at Stanford at a time when Silicon Valley is poised for growth in biology.

The JIMB’s accomplishments include the development of methods and tools for genomics and bioinformatics analyses and continuous collaboration with many stakeholders, such as public-private-academic consortia. The JIMB hosts three consortia: the External RNA Controls Consortium (ERCC); the Genome in a Bottle Consortium (GIAB), and the Synthetic Biology Standards Consortium (SBSC). In total, there are more than 150 different partners in these consortia with varying degrees of engagement, working together to develop standards for RNA measurement, for genomic DNA measurement, and for various elements in the emerging synthetic biology community.

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7 Ibid.

8 NIST, Cell Systems Science Group, https://www.nist.gov/material-measurement-laboratorybiosystems-and-biomaterials-division/cell-systems-science-group, accessed September 25, 2017.

9 Ibid.

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

ERCC measurement science products include the NIST SRM 2374 DNA Sequence Library for External RNA Controls, and the turn-key analysis software, erccdashboard, which evaluates the technical performance of any gene expression experiment. The ERCC is creating new standards and measurement science to support new and emerging quantitative evaluation of transcriptome measurements, ERCC 2.0.

In May 2015 NIST released an RM of a pilot GIAB sample, which has been widely used for technology development, optimization, and demonstration, as well as by clinical and research laboratories to assess performance. Specifically, this project produced the genome in a bottle RMs and includes RM 8398 (a European ancestry genome), which was released in the spring of 2015; three new human genome RMs; and one microbial genome RM, which was released in the fall of 2016. These RMs are supporting the precision medicine initiative.

The JIMB has held several public workshops highlighting the need to understand the quality of results from next-generation sequencing (NGS). At the September 2016 workshop, NIST announced the release of four additional extensively characterized human genomes as NIST RMs, and these cell lines are already included in several commercial products to meet additional reference sample needs.

The JIMB has refined the SBSC strategy to focus on developing standards products that would improve the accuracy and efficiency of transactions in the synthetic biology workflow. Example transactions include nucleic acid sequence information standards to support the accurate use of nucleic acid materials, or technical standards to support the accurate transfer of an organism from a research and development (R&D) bench to an industrial-scale fermenter.

The BBD’s regenerative medicine-related activities include cell counting, live cell imaging, flow cytometry, genome editing, tissue engineering (TE), standards leadership, and customer outreach. Cell counting and viability are key measurements that are critical for decision making—from R&D to manufacturing—but are known to have large measurement variabilities. The BBD recently developed an approach for evaluating the quality of cell counting measurements through experimental design and statistical analysis. The NIST approach represents a paradigm shift from traditional approaches that rely largely on highly specific RMs. In addition, the experimental design and statistical method is agnostic of the cell type and counting method, making it broadly applicable to many counting applications. A user interface is under development to allow broader adoption of this method as an international standard and a research tool.

Live-cell imaging tools allow the BBD to monitor spatial information and population heterogeneity on large numbers of individual cells. High-quality data obtained using benchmark materials may be used to develop predictive models based on stochastic fluctuations and may also provide reference data. Such data may have the potential to be used to validate putative molecular markers for pluripotency and differentiation, and for evaluating markers of product potency. The BBD is also developing advanced measurement capabilities, including quantitative label-free imaging, such as BCARS imaging, for characterizing cell state and cell-biomaterial interactions.

Flow cytometry, while widely used in characterization of cell populations, is notoriously variable from instrument to instrument and location to location. The BBD works with stakeholders to make flow cytometry a quantitative tool that can provide comparable data across laboratories by developing benchmarking materials and protocols—including fluorescence standards for calibrating beads and lyophilized cell RMs.

Genome editing products and processes need reliable methods to ensure sound results of the editing and to add confidence to the safety of the operation, and the likely effectiveness. The BBD is working with stakeholders, including through NIST-organized workshops, to identify precompetitive technology, measurement, and standardization needs and solutions. The current program focuses on evaluating assays and informatics tools and on the development of RMs. It is also in the process of establishing a NIST-led consortium to develop measurement solutions and standards to advance this technology space—specifically, quantitative flow cytometry.

Current efforts of the BBD also include the development, quantification, and modeling of polymeric and inorganic TE scaffolds, as well as quantifying cell-materials interaction. Through the study of many cell types for regenerative purposes, it has developed various methods to produce TE constructs,

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

including electrospinning.

Standards are critically needed to assist in the development and regulation of advanced therapies. The BBD is working to develop documentary standards with key stakeholder input from the American Society for Testing Materials International (ASTMi) and the International Organization for Standardization (ISO). The BBD also coordinates broader industry discussion through administering and chairing the U.S. Mirror Committee to ISO/TC276: Biotechnology, and they also serve as convener of the Working Group on Analytical Methods within ISO/TC276.

The BBD also has collaborations with industry (Lonza, Pluristem, Nexcelom, etc.), federal agencies (the National Institutes of Health [NIH] and the Food and Drug Administration [FDA]), and international metrology institutes (in the United Kingdom, Japan, etc.) on precompetitive measurements. Additionally, they have joint research projects with the FDA to address cell measurement challenges and flow cytometry.

The BBD’s capabilities in metagenomics include microbial community measurements utilizing metagenomics approaches in the microbial community (microbiomes and biofilms). The BBD is also developing prototype RMs, reference data, and reference protocols to identify, understand, and eliminate measurement bias. Additionally, it is developing pathogen detection and identification utilizing metagenomic techniques, which are emerging as superior methods, as they alleviate the need for targeted approaches that are subject to bias in their design. In collaboration with the FDA Center for Devices, the BBD is also developing a mixed pathogen DNA RM that can be utilized to assess the analytical sensitivity and specificity of NGS-based pathogen detection devices in the clinical setting. Metagenomic methods for pathogen detection are also being adopted in the biomanufacturing industry, where determining the presence of a bioburden (microbial or viral contamination) is necessary for current Good Manufacturing Practices (cGMP) biomanufacturing. RMs for biothreat detection are also being developed under an interagency agreement with the DHS. As mentioned, a yeast-based material tagged with a specific genomic sequence served as a surrogate agent in a field test, and continues to be studied for further qualification.

Custom-engineered microfluidic microenvironment devices that can establish chemical (antibiotic) concentration gradients are being used to challenge bacteria and measure the evolutionary process. The emergence and spread of antibiotic resistance is a global health crisis, and the BBD is developing novel measurement tools that will allow it to measure and better understand the process by which bacteria evolve resistance to existing and novel antibiotics. These new measurements can ultimately provide a new metric, known as the resistance potential, that describes the probability that a strain of bacteria can evolve resistance to an antibiotic. Ultimately, this new resistance potential metric can be used to develop novel antibiotics that are more resistant to resistance. Further, these new measurements could be used by health care providers to make better informed clinical decisions.

In reference to the BBD’s customer outreach, the International Metagenomics and Microbiome Standards Alliance (IMMSA) is a nonhierarchical association of microbiome-focused researchers from industry, academia, and government that is hosted by NIST. The IMMSA brings together a broad and diverse community of stakeholders who all have a vested interest in improving confidence in microbiome measurements. IMMSA was formed for the mutual benefit of the entire microbiome and metagenomics community and focuses specifically on coordinating crosscutting efforts that address microbiome and metagenomic measurement challenges. IMMSA members are representative experts for all major microbiological ecosystems (e.g., human, animal, built, and environment). These experts are from various scientific disciplines, including, but not limited to: microbiology, ‘omics, epidemiology, bioinformatics, and statistics.10

In terms of the BBD’s achievements and impact on the scientific community, the BBD was represented on the Fast-Track Action Committee on Mapping the Microbiome, which was organized and

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10 NIST, Biosystems and Biomaterials Division, “IMMSA Mission Statement,” updated January 5, 2017, https://www.nist.gov/mml/bbd/immsa-mission-statement.

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

hosted by the White House’s Office of Science and Technology Policy (OSTP). This committee published a report that was an assessment of microbiome research in the United States and identified gaps or needs for translating basic research to commercial applications for health care and agriculture. This committee found, nearly unanimously, that there is a need for standards and RMs to increase interlaboratory comparability and confidence in microbiome measurements.

The BBD develops RMs for cancer biomarkers that improve measurements in basic and clinical research. The RMs are developed in consultation with cancer experts from industrial, academic, and government laboratories. As mentioned, the BBD developed a NIST SRM for the HER2, gene, which is frequently amplified in breast cancer. The standard consists of purified genomic DNA from five breast cancer cell lines with different amounts of HER2 gene amplification. This RM is available from NIST as SRM 2373.11

The BBD is also currently preparing an RM for measuring the receptor tyrosine kinase for protooncogene MET and epidermal growth factor receptor (EGFR) genes. This new standard, when completed, will be available as RM 8366. The standard consists of purified genomic DNA from six different cancer cell lines. The program will enable new diagnostics and therapeutics for cancer to be made by developing robust and reliable tools for measurement assurance, which includes RMs, protocols, and analysis pipelines.

The BBD supports the National Cancer Institute’s (NCI’s) EDRN as a Biomarker Reference Laboratory by efficiently validating the measurement of specific cancer biomarkers as identified by the EDRN discovery laboratories. It also identifies critical areas where improvements in the measurement infrastructure will significantly impact the quality of the biomarker measurements. An interlaboratory testing program using candidate RMs for ctDNA is in progress to improve the accuracy and reliability of the measurements of new biomarkers for early cancer detection.

The BBD has a long-standing relationship with the NIH/NCI/EDRN, where NIST acts in a network of Biomarker Reference Laboratories. The BBD works with this network of partners by piloting interlaboratory studies in microRNA (miRNA) measurements and measurements of genomic mutations (including in ctDNA), and in evaluating a mitochondrial deletion biomarker of prostate cancer.

The BBD collaboration with SeraCare Life Sciences to advance the development of ctDNA diagnostic assay RMs is ongoing. Under the agreement, NIST will manage an interlaboratory testing program of the EDRN cancer biomarker discovery using RMs developed by SeraCare. NIST is also working with the Foundation for the NIH to plan a much larger testing program of clinical laboratories and commercial testing laboratories using RMs developed by multiple suppliers. The testing program will begin with analytical validation of the methods used in the clinical and commercial laboratories and will be extended to include clinical validation of cancer biomarkers used to determine treatment.

An informal collaboration is ongoing with the Molecular Characterization Laboratory (MCL) at the Frederick National Laboratory for Cancer Research. The MCL is one of four laboratories that does the measurements for the precision medicine NCI, Molecular Analysis for Therapy Choice (NCI-MATCH) clinical trial. The BBD is collaborating in the application of NIST cancer biomarker standards and in developing new standards based on cancer diagnostic and therapeutic needs in order to improve the accuracy and reliability of their measurements. As mentioned, they are also in the process of developing the NIST RM 8366, and have three publications in peer-reviewed journals.

An interlaboratory assessment of ctDNA samples in the EDRN discovery laboratories is also in progress. The initial study includes five leading academic cancer research centers. The BBD will coordinate the samples, data, analysis, and publication of data. More assessments are planned and will include additional materials and laboratories.

The BBD also serves as a reference laboratory for the National Institutes of Health (NIH) project on the development of RMs for validation of clinical measurements of ctDNA in cancer patients. This

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11 NIST, Cell Systems Science Group, https://www.nist.gov/material-measurement-laboratorybiosystems-and-biomaterials-division/cell-systems-science-group, accessed September 25, 2017.

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

project has been approved, and is now in the proposal development and funding stage. Working group members include stakeholders in pharmaceutical companies, the FDA, the College of American Pathologists, the American Society of Clinical Oncology, the NCI, the NIH, the Association for Molecular Pathology, and NIST.

As part of the BBD’s engineering and synthetic biology-related activities, the BBD is also working to develop standardized measurement assays and reporting characteristics for genetic circuit elements. It is also working to establish reference strains and materials to support predictive design—by ensuring comparability of data between different research laboratories and by enabling absolute quantitation of engineered biological functions. The measurement methods that the BBD is developing include flow cytometry, single-molecule RNA-FISH (a single-molecule counting approach that has enabled the BBD to demonstrate measurements of the number of mRNA molecules in each bacterial cell12), as well as other quantitative microcopy approaches.

The BBD research has led to more quantitative measurements for the performance of engineered microbial organisms. This will ultimately lead to improved predictability and reduced trial-and-error in the engineering of biology. It has also developed measurements to characterize the growth and phenotype of genomically minimized bacterial strains during the genome minimization process. Additionally, it is developing predictive capability with genome scale modeling to address questions regarding the sensitivity of promoter activity to the biological response of cells to changes in the environment. It is also supporting Defense Advanced Research Projects Agency (DARPA) in high risk program development through a staff detail.

Opportunities and Challenges

With the awarding of the Manufacturing USA Institutes, NIIMBL, and the Advanced Tissue Biofabrication Manufacturing Innovation Institute (ATB-MII), and the passage of the 21st Century Cures Act, the active role that the BBD division has been playing in supporting regenerative medicine products is poised to ramp up even more. Stakeholder interest in NIST’s contributions to regenerative medicine products has been increasing rapidly over the past few years, but these new activities specifically tag the BBD with additional responsibilities. BBD leadership is needed in laboratory activities that advance measurement science in this field, in educating and coaching practitioners on how to apply measurement assurance principles and materials in their facilities, and in working with them on the development of standards. BBD stakeholders include academic research laboratories, cell manufacturers, biotechnology and pharmaceutical companies, instrument and equipment manufacturers, the FDA, and other federal agency partners. The BBD is working with these communities in several diverse, but related, activities, including cell characterization assays, flow cytometry, microbiome, and genomic editing evaluation.

Since increased federal funding is not predicted, the BBD is looking toward forming collaborations and consortia with instrument manufacturers (such as the producers of cell counting instruments and flow cytometers); developers of ancillary materials and therapies (including establishing a consortium with many of the companies developing or using genome editing technologies); the FDA (by collaborating with them to address their responsibilities dictated by the 21st Century Cures Act and in standards development); and research laboratories—particularly in the CAR-T cell therapy area. Consortia and collaborations will hopefully provide resources and enhance impact. Additional federal funding would increase the efficiency with which the BBD can provide these services.

The NIST Strategic and Emerging Research Initiatives (SERI) program provided two-year funding that helped to initiate a technically advanced and scientifically sophisticated program on engineering biology. That funding has allowed several successes to be achieved. Significant laboratory and modeling

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12 A.K. Neilsen, B.S. Der, J. Shin, P. Vaidyanathan, V. Paralanov, E.A. Strychalski, D. Ross, D. Densmore, and C.A. Voight, Genetic circuit design automation, Science 352(6281):aac7341, 2016.

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

collaborations with the J. Craig Venter Institute, Massachusetts Institute of Technology (MIT), and the University of Maryland (UMD) were established. Two significant co-authored publications have appeared in Science.13 A robust internal program of advanced measurements and theory for engineering biology has been initiated. This program, while currently focused on the analysis and modeling of bacterial systems, has wider implications that include mammalian systems. And so it has potential to greatly impact synthetic biology and regenerative medicine.

The MML is working with the Physical Measurement Laboratory (PML) to identify pan-NIST interests and develop cross-divisional programs in biological-related measurement science. Two areas of synergy include expertise in imaging and interest in precision medicine. The MML has significant work in imaging at the cellular and subcellular scale, and PML has advanced expertise in medical-scale imaging—including phantom development for MRI and other clinical modalities. To help establish collaborative projects that could be built on a request for additional budget authority, NIST’s MML, PML, the Information Technology Laboratory (ITL), and the Center for Nanoscale Science and Technology (CNST) units are holding a workshop to bring NIST scientists together to discuss ongoing and future work in imaging technologies. Bringing the various laboratories within NIST together (there are already significant interactions between MML and ITL in imaging) will expose those technical opportunities that NIST is uniquely positioned to tackle. This effort is in anticipation of a future NIST initiative in precision medicine.

A major challenge is to bridge the intellectual and lexicon gaps between biological needs and physical science capabilities. Although imaging has been identified as an important crosscutting area for the PML and MML laboratories, it will be critical to identify what other crosscutting areas may exist between the laboratories. Having staff members serve as liaisons between the laboratories has been useful for identifying potential in-house collaborations. More postdoctoral support may be required to focus on the powerful measurement science that could emerge from these two laboratories. It is critical for the BBD to productively engage other laboratories at NIST in biorelated activities for two reasons: (1) to take advantage of advanced technological capabilities at NIST in order to address unmet measurement needs in biology, and (2) to increase the appreciation and understanding of the role that NIST needs to play in supporting measurements of biological systems.

Additionally, given the observed high-content and high-throughput biodata (in matter genomics, next generation sequencing, and synthetic biology) that is being generated and accumulated by the BBD, the division needs to expand its working relationships with other NIST divisions that focus on informatics, specifically within the ODI.

A combination of a hiring freeze and anticipated severe reduction in funding will have substantial impact on NIST’s ability to serve stakeholders, carry out its mission, and retain an engaged workforce that can carry out state-of-the-art technical research in measurement science. Since the budget scenario for FY 2018 and on is still largely theoretical, it is difficult to project what responses need to be prepared for. At the moment, the BBD is reviewing programs to identify the highest priorities in a climate where priorities may be changing. Every research area for which the BBD is developing standards, measurement science, and validation of methodology is of great value to the biological and life science arenas.

The ability to identify and retain excellent scientists who can be engaged in interdisciplinary research, including engineers, statisticians, physicists, chemists, and biologists, will be critical to navigate this rapidly advancing field, leverage NIST-wide expertise, and manage resource challenges.

Initiatives that support biological measurement science are not the most widely supported at NIST. Biological measurement science has the potential to be highly impactful in the coming decades, but translation from basic research to application requires strong biological measurement science and reliability.

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13 These two publications were: Hutchison, C. A. et al. “Design and synthesis of a minimal bacterial genome” Science 351, (2016) and Nielsen, A. A. K. et al. “Genetic circuit design automation” Science 352, 53-+, (2016).

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

The microbiome field, as tested by NGS technologies, is challenging given the multitude of testing and informatics analyses pipelines, and such challenges present an opportunity for the Microbial Metrology Group to improve cohesiveness and develop standards. The Microbial Metrology Group and the Biomaterials Group have developed advanced measurements and standards for human pathogen detection and have been valuable partners for the FDA and the DHS by providing NIST mixed microbial DNA RMs and S. cerevisiae NE095 in lieu of biothreat agents. Recent advancements in microbial research supports the idea that the human microbiome plays a major role in human health and disease and represents an understudied diagnostic and therapeutic target. The group is well positioned to provide standards materials and methods to promote human microbial detection as diagnostic and therapeutic biomarkers.

The JIMB, partnered with Stanford University, has many opportunities for collaboration with small and large biotechnology companies in the San Francisco Bay Area, which are diverse and numerous. This group can serve as a conduit for many NIST laboratories that are considering locating staff in the Bay Area to leverage the fast-paced technology development there. The opportunity to hire postdoctoral researchers from Stanford and other eminent research universities to work for NIST, without their having to relocate to the East Coast, provides an advantage with respect to bringing in new talent from the West Coast. This advantage, however, comes with the higher cost of living in the Bay Area.

The BBD noted that there is an urgent need for standard materials for testing and/or calibrating deep-sequencing equipment, procedures, and analyses. In collaboration with their stakeholders (federal agencies or industrial partners), the BBD needs to expedite the development of RMs pertinent to NGS-based biomarkers for precision medicine. Such RMs could be used in diagnostic, prognostic, and predictive markers for therapy. These RMs could also be utilized to assess the metrological and analytical sensitivity and specificity for disease detection and classification (e.g., circulating tumor DNA reference materials).

PORTFOLIO OF SCIENTIFIC EXPERTISE

Accomplishments

Based on the recent developments by the BBD technical groups, as outlined in the previous sections, the BBD evinces scientific expertise on par with that of leading researchers in the areas being researched and developed. The BBD appears to have deep technical expertise in the measurement of biological systems and is developing the same capacity for bioengineering. The caliber of the science being performed at the BBD is excellent. The staff members are very motivated, highly trained in their respective fields, and enjoy working at NIST. The groups are working well together, and morale appears to be high. They choose programs and projects in a strategic manner by integrating strong stakeholder input and aligning outside capabilities to their internal strengths. A good example is the JIMB collaborative program at Stanford University on advances in biological and medical measurement.

The group leaders appear to communicate and work well together. They are respected and admired by the scientists and technicians at the BBD. Their knowledge of what is going on in many fields and their network of scientists outside of NIST is impressive. They know that they have to attend external meetings, deliver presentations, and publish as well as patent their findings. There is a can-do atmosphere, especially on the innovation and entrepreneurial bench-to-bank side of the equation, to meet societal needs.

The Microbial Metrology Group is highly visible and represents NIST on the Fast Track Action Committee on Mapping the Microbiome that was organized and hosted by the White House’s OSTP. The group has the expertise and connections to fulfill the unmet need for standards and RMs to increase interlaboratory comparability and confidence in microbiome measurements.

The Bioassay Methods Group is highly trained and motivated to bring quality assurance and quality control standards and methods for both qualifying and quantifying biological activity, wellness, and

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

disease. This group has impressive researchers who are doing cutting-edge research. They effectively collaborate within and outside of the group to leverage needed talent.

The Biomaterials Group is focusing on areas that are cutting-edge in bioimaging and biotechnology. The group possesses a highly qualified staff and a strong external network of collaborators at federal agencies and in industry and academia. The group is poised to develop, and potentially commercialize, rapid BCARS microscopy of cells, tissues, and materials.

The Cell Systems Science Group has a focus on the cell as a system and tools in medical research, and is at the center of many of the major research programs being undertaken by NIST, NIH, and pharmaceutical and biotechnology companies. The group has extensive expertise in developing measurement tools and protocols to ensure the reliability and comparability of cellular and imaging assays.

Some noteworthy examples of Department of Commerce (DOC) and NIST-named awards won by the BBD staff include the 2015 Bronze Medal for establishing reliability in flow cytometry measurements to improve clinical disease diagnosis, cell therapy manufacturing, and biomedical research, and the 2014 Bronze Medal for the development of a “clinically relevant measurement and standardization program for the critical evaluation of photo-polymerized dental restoratives.”14 One external award won by the BBD was the 2016 Judson C. French Award for the development of the first ever cancer gene copy number diagnostic SRM, NIST SRM 2373. Additionally, one of the JIMB bioengineers was recognized in January 2017 with a Presidential Early Career Award for Scientists and Engineers (PECASE).

Opportunities and Challenges

The JIMB establishes a footprint of NIST on the West Coast and will attract new talent to work on genomic metrology, which is in great need of RMs, measurement science, and validation. The highly creative and trained NIST group at Stanford continues to try to include the NIST staff at the Gaithersburg campus in many platforms and in developing and expanding their capabilities.

Key technical expertise in specialized instrumentation has been lost and not replaced. There needs to be concerted effort to maintain continuity in the staffing of critical positions within the BBD.

ADEQUACY OF FACILITIES, EQUIPMENT, AND HUMAN RESOURCES

Accomplishments

The BBD laboratories that were visited during the review are well-stocked with the latest and best equipment for doing research in biotechnology. In addition, the scientists are very good at tweaking the instruments to do more, and at integrating systems and creating new instruments. Biotechnology is a rapidly evolving technology, and the BBD has been trying to anticipate emerging measurement needs, in addition to hiring and training experts to provide results that have an impact in biotechnology standards and measurements. The division has overall done an excellent job of acquiring the best tools in their respective space to advance the understanding of complex biological systems on many fronts and at many levels.

The facilities visited were designed for maximum output and were very well kept with respect to clean laboratory benches, well-stocked supplies, and a good flow of laboratory capabilities. The equipment of the BBD is state-of-the-art. However, some laboratory infrastructure is not adequate for

___________________

14 NIST, “National Institute of Standards and Technology Presents 2014 Awards to Outstanding Employees,” updated August 15, 2016, https://www.nist.gov/news-events/news/2014/12/national-institute-standards-and-technology-presents-2014-awards.

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

conducting particular experiments, such as a cell culture up to Biosafety Level 2 (BSL-2) standards. This is owed, in part, to aging building infrastructure and excess storage in laboratory space.

Additionally, equipment purchases are difficult, in part due to an institutional overhead for equipment of 50 percent. This equipment tax significantly reduces the amount of equipment that the BBD can purchase. Given that the tools in the biotechnology space are continually being redesigned for more quantitative analysis in order to remain competitive, purchasing new equipment or retrofitting existing equipment will be high on the BBD investigators’ list. Partnering with instrumentation companies is something that the BBD already does extremely well. It is important that it continue to seek companies that have developed the next generation of biotechnology tools for alpha and beta testing and obtain the instruments at a reduced cost.

With respect to human resources, the BBD is a highly productive division. It is effective and efficient regarding output, especially considering it has such a lean staff. The BBD manages to achieve its stated objectives with its small staff, diverse thrust focus areas, four major programs, and its role in the JIMB. The ratio of Ph.D.’s to technicians is high, and in some applications more technicians could be employed to carry out some of the required maintenance of reference standards. The BBD management needs to consider adding more staff to the four divisions if it is going to continue to lead. It also needs to consider forming strategic partnerships for measurement standards, RMs, and validation within the many and varied areas of biotechnology.

Opportunity and Challenges

Working mainly in the biotechnology arena, the BBD has both challenges and opportunities. This unique group of scientists (whose expertise includes biology, chemistry, mathematics, computation, engineering, and physics) is addressing the complex biological sciences that are continually in flux and driven both by policy and regulatory issues that seem to change frequently.

Recognizing that there is a need for better measurements and standards for data sharing, reproducibility, scale-up, and commercialization, the BBD is working on the right things at the right time. For example, it is working in metagenomic microbial measurements, genomics standards, cell manufacturing and therapies, synthetic biology, and predictive biology. However, given the broad space of biological systems, a critical mass of staff and resources may hinder the pace of development that some of these areas demand. Additionally, with respect to human resources, there appear to be some delays in the replacing of critical staffing positions.

DISSEMINATION OF OUTPUTS

Accomplishments

The BBD has hosted a series of NIST-led workshops aimed at engaging with key stakeholders to identify pressing measurement challenges in the regenerative medicine and advanced therapies sectors. These workshops were the Strategies to Achieve Measurement Assurance for Cell Therapies Products Workshop (May 2015); CAR-T Biomanufacturing Symposium (February 2016); Genome Editing Standards Workshop (May 2016); and the NIST-FDA Cell Counting Workshop (April 2017).

The Standards for Microbiome Measurements Workshop was jointly hosted by NIST, the NIH National Institute of Allergy and Infectious Diseases (NIAID), and the Human Microbiome Project (HMP) in August 2016. The Microbial Metrology Group played a leading role in the workshop, which assembled microbiome researchers from federal agencies, academia, and industry in a precompetitive space to prioritize needs and form an action plan to move microbiome standards development forward. The workshop began as an effort to gather input on defining RMs, reference data, and RMs for human microbiome community measurements. While the scope of the workshop was applicable for anyone

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

involved in microbiome-based R&D, there was an emphasis placed on DNA-based measurements of the human microbiome as it pertains to the development of new clinical diagnostics, microbiome therapeutics, epidemiological investigations, and the associated regulatory challenges.

NIST also hosted a series of three workshops—the NIST-FDA Standards for Pathogen Detection Workshop—over the last 3 years, which were also organized by the Microbial Metrology Group. These workshops have focused on standards for pathogen detection and identification and on the use of NGS technologies for clinical diagnostics and biothreat detection. The consensus outcome from the NIST-FDA workshop on microbial NGS-based standards for pathogen detection was for NIST and the FDA to jointly develop a mixed pathogen RM and associated data that will allow the community to assess the performance of their microbial detection systems and enable regulators to vet the performance claims made by the laboratories and companies creating and using these systems. NIST will be hosting its fourth workshop in this series in the summer of 2017, and that workshop will focus on the clinical diagnostics for infectious disease and biothreat detection communities.

As previously mentioned, the JIMB has also held several public workshops that have highlighted the need to understand the quality of results from next-generation sequencing (NGS).

The division has been very productive, with over 140 publications that include top scientific journals such as Science and Nature. These high-impact publications reflect a substantial contribution of BBD scientists in consortia and collaborative groups. Standards activities count the release of 16 SRMs/RMs, 8 SRDs, participation in 44 standards committees, 6 awarded patents (and 11 patents pending), and a number of leadership positions.

The BBD’s engineering and synthetic biology-related activities have produced 148 archival journals, 23 conference proceedings, 23 NIST reports, 13 books, and 7 book chapters. Some noteworthy examples include the following:

  • Hutchison, C.A., Chuang, R., Noskov, V.N., Assad-Garcia, N., Deerinck, T.J., Ellisman, M.H., Gill, J.et al. 2016. Design and synthesis of a minimal bacterial genome. Science, Volume 351, Issue 6280, aad625, DOI: 10.1126/science.aad6253. This paper reports a systematic process of genome minimization, so that a bacterium is engineered to have only 473 genes—the smallest genome of any freely living organism. This organism is an important milestone in biotechnology and evolutionary biology, because it provides a simplified platform to add genes back into the genome one by one to study their effects.
  • Nielsen, A.A.K., Bryan S. Der, B.S., Shin, J., Vaidyanathan, P., Paralanov, V., Strychalski, E.A., Ross, D. et al. 2016. Genetic circuit design automation. Science, Volume 352, Issue 6281, aac7341, DOI: 10.1126/science.aac7341. This paper describes a programming language, called Cello, for cellular logic to compile high-level functional specifications into DNA sequences that can be inserted into bacterial cells, giving them new sensing and response capabilities.
  • Camp C.H., Lee Y.J., Heddleston J.M., Hartshorn C.M., Hight Walker A.R, Rich J.N., Lathia J.D., Cicerone M.T. et al. 2014. High-speed coherent Raman fingerprint imaging of biological tissues. Nature Photonics 8:627-634, DOI: 10.1038/nphoton.2014.145. This paper describes the development of a new BCARS microscopy platform that acquires spectra with unprecedented speed, detection limit, and spectral breadth.
  • Elliott J.T., Rösslein M., Song N.W., Toman B., Kinsner-Ovaskainen A., Maniratanachote R., Salit M.L. et al. 2016. Toward achieving harmonization in a nano-cytotoxicity assay measurement through an interlaboratory comparison study. ALTEX, 34(2):201-218. doi: 10.14573/altex.1605021 This manuscript illustrates the application of advanced measurement science tools such as in-process controls and interlaboratory comparisons to a conventional MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) cell viability assay protocol.
  • Stulberg, E., Fravel, D., Proctor, L.M., Murray, D.M., LoTempio, J., Chrisey, L., Garland, J., et al. 2016. An assessment of U.S. microbiome research. Nature Microbiology. Article number:
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
  1. 15015, doi:10.1038/nmicrobiol.2015.15 This paper summarizes the assessment of the status of U.S. microbiome research by a team of govermental scientists from fourteen governmental organizations. This study has implications for the funding of future microbiome research, in both the United States and internationally.

The BBD has also disseminated key position papers on measurement assurance strategies, including perspective papers in Cell Therapy and Stem Cells Translational Medicine on quality attributes for cell therapy products and on improving measurement assurance.

Outside of workshops, some of the BBD’s impact includes delivering measurement solutions to Lonza, a leading cell contract manufacturing organization, to enable comparison cell enumeration by automated and manual methods. The BBD’s customer outreach includes collaboration with Chris Voigt’s laboratory at MIT to develop measurements and reference objects for synthetic biology. As mentioned, they also have collaborations with the J. Craig Venter Institute and MIT to characterize the phenotype of genomically minimized cell strains and to inform the potential for the minimal cell to serve as a tool for fundamental research and biomanufacturing.

The BBD has also elevated NIST’s profile through the its regenerative medicine-related activities, specifically through the administration of the U.S. Technical Advisory Group (U.S. TAG) for ISO/TC276: Biotechnology, as well as through their leadership in ASTM FO4 on Tissue Engineered Medical Products. The U.S. TAG to ISO/TC276 Biotechnology group is a way for NIST to coordinate national and international standards activities for existing and emerging biotechnology sectors. The primary goal of this technical advisory group is to enhance the global competitiveness of U.S. business and quality of life by promoting and facilitating voluntary consensus standards and ensuring their integrity in biotechnologies. It has developed innovative approaches for evaluating the quality of cell counting measurements through experimental design and statistical analysis. These methods have been implemented by industrial and academic clinical centers to improve the confidence of their critical cell counting measurements and are the basis for an international standard under development in ISO TC 276.

As part of its regenerative medicine-related activities, the BBD has also presented webinars and high-profile lectures to key industry and regulatory stakeholders. It has also established a Memorandum of Understanding (MOU) with the Standards Coordinating Body (SCB) for gene, cell, and regenerative medicine and cell-based drug discovery in order to coordinate standards development for regenerative medicine and advanced therapies.

The BBD’s engineering and synthetic biology-related activities include strong customer engagement. In partnership with the American Type Culture Collection (ATCC) and other consortium members, the BBD is working to design tools, establish data sets, and further develop and standardize NIST’s patented authentication method through the use of NIST-identified short tandem repeat (STR) markers for mouse cell lines. The goal is to develop a commercially available assay kit based on the STR markers and the method for mouse cell line authentication.

NIST is also collaborating with manufacturers of microparticles to develop RMs. These include reference fluorophore solutions and biological RMs. They also include reference data and RMs for assigning an equivalent number of reference fluorophores (ERF) values, and assessing the associated uncertainties and utilities.

The BBD also established interagency agreements between NIST and other federal agency partners: NCI/EDRN; DHS; DARPA; NIH/National Institute of Dental and Craniofacial Research (NIDCR); and the FDA. A Memorandum of Understanding (MOU) was established between NIST and the SCB for gene, cell, and regenerative medicine and cell-based drug discovery to help coordinate standards development for regenerative medicine and advanced therapies.

NCI’s clinical trials reference laboratories have used NIST SRM 2373 to improve the confidence of the human epidermal growth factor receptor 2 (HER2) Gene Copy Number. This SRM has enabled test manufacturers and pharmaceutical companies to produce the secondary RMs required to ensure accurate and reliable clinical measurements of HER2.

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×

The National Renewable Energy Laboratory (NREL) is also using NIST-developed technologies for the measurement of metabolites in processes that employ engineered organisms to convert corn stover to useful chemical products. The BBD is working with the NREL to facilitate this transfer of capabilities.

Another BBD dissemination activity has been through the NIST SRI Program Standard Reference Instrument (SRI) Tensometer, which is a cantilever beam-based tensometer to measure the polymerization stress, polymerization exotherm via temperature monitoring, degree of conversion, and kinetics. This instrument has been made available to industry and university researchers through the NIST SRI program. In addition, NIST has conducted measurements for recent NIDCR U01 grantees to ensure comparability of results. This method is also under consideration as an international standard or technical specification through ISO/TC106 Dentistry.

Some noteworthy examples of BBD’s 17 patents and patents pending include the following:

  • J. Almeida and K. Cole. 2016. U.S. Patent No. 9,556,482: Mouse Cell Line Authentication. An authentication method using NIST-identified noncoding STR markers.
  • M. Halter Peterson and A. Plant. 2015. U.S. Patent No. 20150168300 A1: Article and Process for Modifying Light. This invention enables high spatial resolution surface plasmon resonance imaging (SPRI) through a microscope objective, where no commercialized product yet exists. SPRI allows for the measurement of intrinsic physical properties of materials (refractive index, mass, thickness) at a surface interface in a real-time, label-free format.
  • J. Elliott and A. Christopher. 2016. Non-Provisional U.S. Patent Application: Process for Making an Asymmetric Fluorophore. This invention relates to a process for synthesizing a small molecule asymmetric boron-containing fluorophore. The asymmetric fluorophore was designed to aid in cellular membrane permeability while retaining aqueous solubility. The fluorophore can be conjugated to proteins within live cells or fixed cells and provides whole-cell staining of such cells.

The BBD also maintains leadership of and contributions to roadmaps, planning groups, and policy forums including the National Academies of Sciences, Engineering, and Medicine’s Regenerative Medicine Forum and the National Cell Manufacturing Consortium (NCMC). They also interface with the NIIMBL, which is funded by the DOC and the Department of Defense (DOD) Advanced Tissue Biofabrication Manufacturing Innovation Institute-awarded Advanced Regenerative Manufacturing Institute (ARMI).

Their leadership positions in relevant societies and organizations include the Society for Biomaterials, Tissue Engineering and Regenerative Medicine International Society-Americas (TERMIS-AM), ASTM, and ISOs. They also contribute to interagency activities through the Multi-Agency Tissue Engineering Science (MATES) Working Group with the NIH, FDA, DOD, NSF, and the White House OSTP. They will be assuming the chair of this working group in spring 2017.

The BBD also helped to nucleate and participate in IMMSA, which was founded to identify and disseminate developments related to improving microbiome measurements. The Microbial Metrology Group participated in this alliance.

Opportunities and Challenges

One concern is that the BBD has a relatively limited reach in its communication with a broad customer base and with its stakeholders. While the BBD has developed websites (its current website reflects a significant improvement from its previous one), held workshops, and creates and contributes to consortia, stakeholder outreach currently remains limited, and the BBD needs to pursue and explore mechanisms for reaching its stakeholders.

Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 26
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 27
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 28
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 29
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 30
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 31
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 32
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 33
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 34
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 35
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 36
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 37
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 38
Suggested Citation:"4 Biosystems and Biomaterials." National Academies of Sciences, Engineering, and Medicine. 2017. An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017. Washington, DC: The National Academies Press. doi: 10.17226/24975.
×
Page 39
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An Assessment of the National Institute of Standards and Technology Material Measurement Laboratory: Fiscal Year 2017 assesses the scientific and technical work performed by the National Institute of Standards (NIST). This publication reviews technical reports and technical program descriptions prepared by NIST staff summarizes the findings of the authoring panel.

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