The major focus of the Material Measurement Laboratory’s (MML’s) Biomolecular Measurement Division (BMD) is to develop measurement science, standards, and reference data for accurate and reproducible characterization of proteins, nucleic acids, glycans, metabolites, and lipids for use in biotechnology, DNA forensics, biomedical and bioscience research, and health care. The BMD has five groups that interact and cross fertilize their work, although in some instances cross-disciplinary interactions could be enhanced. They are as follows: Biomolecular Structure and Function; Mass Spectrometry Data Center; Applied Genetics; Bioprocess Measurement; and Bioanalytical Science.
The BMD main areas of research are in forensic genetics and illicit drugs, clinical diagnostics using protein and nucleic acid markers, mass spectrometry reference data and library, and advanced biotherapeutics, which include the biomanufacturing and the engineering biology programs. Core competencies are clearly at the cutting edge. Examples include the following: mass spectrometry (MS), liquid chromatography (LC), nuclear magnetic resonance (NMR), X‐ray, neutron, and cryo‐electron microscopy methods for determining biomolecular composition, structure, and amount; MS data analysis and building reference data products for chemical and biochemical identification; biophysical characterization of biologics and biological particle sizing; CE (capillary electrophoresis), digital polymerase chain reaction (dPCR), and NGS (next-generation sequencing) characterization of clinical and forensic genetic markers; development of protein, nucleic acid, and other biological reference methods (RMs); and cell culture/protein expression for R&D and development of RMs. The customers and stakeholders for BMD currently include four major research communities—clinical medicine, biopharmaceutical, forensic, and mass spectrometry. BMD has excellent partners in industry, federal government institutions, and laboratories. These include, but are not limited to, AstraZeneca, Novavax, the Food and Drug Administration (FDA), and NIH.
BMD currently consists of 81 staff members and 27 associates. BMD conducts research in two buildings on the main NIST campus and at the Institute for Biosciences and Biotechnology Research (IBBR) located on the University of Maryland, Shady Grove, campus in nearby Rockville, Maryland. BMD’s operating budget for 2020 was $32 million. IBBR is a joint institute between NIST’s BMD and the University of Maryland Baltimore (UMB) and the University of Maryland, College Park (UMCP). Joint research activities with Maryland at IBBR are supported through a cooperative agreement of $3.14 million from NIST to UMCP. A highlight of this collaboration since 2017 has been the establishment of cryo-EM measurement capabilities, which includes the installation of two new cryo-EMs at IBBR and a new sample preparation laboratory. The costs were shared by NIST, UMB, and UMCP.1
1 Michael Tarlov, NIST, 2020, “Biomolecular Measurement Division Overview: NASEM Panel Meeting,” presentation to the panel, September 9.
ASSESSMENT OF TECHNICAL PROGRAMS
BMD’s scientific and technical portfolio is impressive, cutting across three areas—basic science and technology, stakeholder-driven research, and mission-based products. BMD is producing advanced and needed reference materials and standards that are addressing the current and pre-competitive markets in bioscience by providing high-impact products and processes with respect to reference materials and standard reference data (SRD). A few notable achievements resulting from the basic science and technology are the Next Generation Protein Sequencing (NIST phe/Trp NAAB), the Sub-Zero Chromatography System for HDX-MS, and the Deep Neural Networks to predict gas chromatography retention indexes.
BMD has continued to develop and apply formidable capabilities across a range of measurement science and tools. These include the following:
- NIST Mass Spectrometry Data Center and libraries;
- DNA forensics, which was recently leveraged for advancing and ensuring quality of nucleic acid-based testing for COVID-19;
- Biomolecular reference materials for applications in clinical diagnostics, food safety, and biopharmaceutical development and manufacturing;
- NIST’s biomanufacturing program (as lead), resulting in reference standards for monoclonal antibodies (e.g., NISTmAb RM 8671), accurate measurement of protein aggregates in drug products (RM 8634), and a polymer-based reference material; and
- NISTCHO (CHO cells) as an open innovation platform for fostering fundamental understanding and development of mammalian cell lines employed in the manufacture of protein biotherapeutics.
Analytical, Reference Materials (and Software), Research Capabilities
These analytical capabilities and reference materials have been developed under a well-defined structure led by the chief and deputy chief of the division. Within the division, the Biomolecular Structure and Function Group, located at the IBBR in Rockville, develops advanced biomolecular structure measurements relevant to the biopharmaceutical and biotechnology industries. The Mass Spectrometry Data Center Group “measures, compiles, evaluates and disseminates” standard reference data and analysis software for GC-MS (mass spectrometry) and LC (liquid chromatography)-MS, with current emphasis on proteomics, metabolomics, and forensics. The Applied Genetics Group leads in the development of standards and measurement technology for human identification and biometric law enforcement using genetic information. Bioprocess Measurements addresses measurement needs relevant to biological industrial processes including protein particles and novel sensors for health care. The U.S. requirements for determining composition, structure, quantity, and function of proteins, peptides, and metabolites are in part addressed by BMD’s Bioanalytical Science group. Staffing for these capabilities, based on 108 people (total), includes 69 scientists (ZP), 4 technicians (ZT), 6 support staff (ZS), and 27 associates.
BMD has addressed its stakeholder needs by developing the NIST20 Mass Spectrometry Libraries, the 2D-NMR for HOS of mAb therapeutics, and advancing NGS technology for human
identification. Finally, BMD has developed three outstanding mission-based products: NISTmAb8671 reference material, the RM8634 ethylene tetrafluoroethylene for particle sizing, and the SARS-CoV-2 research-grade test material. The latter product has assisted a number of companies in their development efforts for antibody test kits for COVID-19.
In the budget for BMD, approximately one-third the funding is allocated to the MS Data Center, with the remaining budget being divided among the other four groups and division headquarters. Overall, these groups have shown significant accomplishments with the stated goals and the resources allocated. Accomplishments range from characterization of protein stability, protein structure, and production cell science, all of which are of significant interest to the biopharma industry. Concurrently, other accomplishments include methods for characterizing proteins from high order structure to biophysical characterization. Customer outreach through interlaboratory Measurement Comparisons, CRADAs (cooperative research and development agreements), and biopharmaceutical measurement roundtable are other examples of the effectiveness of BMD’s work.
BMD staff are applauded for their quick pivot to tackle the COVID-19 pandemic. The flexibility and creativity of their high-quality staff enabled a rapid re-orientation to provide COVID-19 RNA standards, form COVID-19 serology partnerships, e.g., with Lab Corp, initiation of COVID-19 spike protein MS library, and development of strategies to assess vaccine manufacturing quality and consistency.
Challenges and Opportunities
BMD provides a range of measurement services of value to industry. This is exemplified by the services provided in forensics, in which the Applied Genetics Group of BMD shows exemplary cooperation, and impact with law enforcement agencies. Cooperation across BMD is encouraged and could be strengthened in some instances. The inherent challenge will be for management to encourage cooperation across various groups while obtaining additional resources when needed to carry out the additional work and for achieving longer-term diversity.
FINDING: There are opportunities for BMD to further serve the industry by continuing to develop its reference materials (structure analysis, standards, reference proteins, and living cells). The challenge will be to stay up to date with the latest industry developments and to amplify cross-disciplinary, cross-division, and interagency cooperation.
The applications of artificial intelligence (AI) and machine learning (ML) have now permeated the science and engineering fields, enabling discoveries and insights not previously possible. Indeed, these methods have now become common and indispensable components of virtually all analytical or measurement methods. The list of BMD applications includes MS spectra/databases, NMR library
contours, retention index analyses, forensics, and others. An AI/ML expert would likely provide novel insights into the embedding of these methods throughout the division as well as playing an educational role.
RECOMMENDATION 8-1: The Biological Measurement Division (BMD) should evaluate its portfolio of expertise of staff with expertise in artificial intelligence and machine learning as applied to the measurement tools specifically in BMD. BMD might want to consider a joint hire with another division to leverage additional expertise and resources, or develop a more centralized collaboration model (i.e., community of practice) to make enhanced use of AI/ML expertise.
Non-Human Application Areas of Measurement Science
The majority of BMD’s application areas are human based, that is forensics, biotherapeutics, Chimeric antigen receptor T cells (CAR T cells), and so forth. Significant opportunities may be present in areas beyond that applied to humans; these include agriculture, veterinary science, biocatalysis, and environmental and marine research areas.
RECOMMENDATION 8-2: The Biological Measurement Division (BMD) should develop a strategy to assess agriculture, veterinary science, biocatalysis, and environmental and marine research areas as possible opportunities for growth and sources of additional collaborations and funding.
PORTFOLIO OF SCIENTIFIC EXPERTISE
The quality of scientific expertise within the BMD represents the best that the MML has to offer. BMD has deep expertise in biomolecular technologies, including mass spectrometry, forensics, biopharmaceuticals, and NMR. Further extending the division’s areas of expertise is the application of these and other methods to the measurement of a multitude of biologically important species: proteins, nucleic acids, sugars, lipids, and metabolites. The division has worked to grow its expertise in protein drug manufacture as well as cell-based drug production strategies via its work on CHO cells and CAR T cells. Additionally, the division possesses abilities that are among the best in the world for standards design, production, and distribution including NIST mAb (monoclonal antibody), NIST CHO (Chinese Hamster Ovary cells), protein aggregate standards and others. As an example, NIST mAb has been purchased and used by nearly all of top 20 global pharmaceutical companies, indicating the trust that the community places on BMD’s scientific expertise.
BMD’s staff are critical to the provision of high-quality reference materials, providing tools across the world that enable quality control, new instrument development, facile benchmarking, and comparison of results across platforms. BMD has also forged a high-value partnership with the University of Maryland through the aforementioned IBBR. This collaboration enables the BMD to access the deep knowledge base at the University of Maryland, adding to the available expertise. The expertise of the division is widely recognized both internally and externally. Internal recognition is evidenced by their many collaborations with other NIST divisions—for example, for AI/ML applications, protein sequencing efforts, and forensic partnerships. External expertise recognition is accorded by their broad collaborations with other governmental groups—for example, the National Institutes of Health, the Food and Drug Administration, Department of Justice, and many others.
ADEQUACY OF FACILITIES, EQUIPMENT, AND HUMAN RESOURCES
The facilities for BMD are excellent and likely help to attract (and retain) the best and brightest scientists. The equipment and instruments are state of the art, and the transition from chemical sciences and standards research approximately 5 to 10 years ago to the new frontiers of bioprocess and biotherapeutic developments has been handled with amazing continuity between existing missions and future opportunities. This is a tribute to the leadership of BMD, but also presents challenges and opportunities, summarized below.
During the review, there were special discussion sessions stratified into early-, mid-, and late-career stage. This offered anecdotal insight into how these staff—including both full-time equivalents and associates—at all three stages were recruited and their talent developed. It appears that the MML attracts the absolute best and brightest postdoctoral employees. The NRC research associates (i.e., postdocs) hired by NIST2 are on the cutting edge of research in their respective fields. The postdoctoral cadre is energetic, bright, and dynamic and a window to the future. The MML could capitalize on this, as well as develop the potential of these early-career people. The postdoctoral employees (i.e., associates and NRC postdocs) are mainly junior career and have noted that they would like better definition of pathways for achieving permanent status, or alternately assistance and mentoring for academic or industry careers outside of NIST, since only a fraction (30 percent) of postdoctoral or temporary employees achieve permanent status.
In discussions, mid-career staff expressed similar sentiments to the early-career researchers in that they sought a clear pathway to future career advancement—whether at NIST, academia, or industry. Bi- or tri-yearly reviews for mid-career staff is a procedure used in many European research institutions and has worked well to enable mid-career employees to move on. A clear goal that the mid-career employees seek is to become a NIST fellow. This was perceived to be out of reach or hard to obtain, absent mentors that would make the case for deserving people or areas and guide activities and priorities to achieve this status.
Challenges and Opportunities
There is an ongoing challenge in finding resources for maintaining existing infrastructure (leaky roofs, HVAC [heating, ventilation and cooling] in need of repair, etc.). Although equipment and staff are appropriately prioritized over buildings, there have been instances where failures of the infrastructure compromised equipment and had impact on mission delivery. The buildings on the main NIST campus may have exceeded their design life and are otherwise in need of repair. Finding resources to address this is difficult but critical to maintaining infrastructure that is consistent with, and will support operations of, exquisitely sensitive instruments and the brand for excellence that is associated with NIST worldwide.
2 “The NIST NRC Postdoctoral Program supports a nationwide competitive postdoctoral program administered in cooperation with the National Academies/National Research Council (NRC).” See NIST, “NIST NRC Postdoctoral Research Associateships Program,” https://www.nist.gov/iaao/academic-affairs-office/nist-nrc-postdoctoral-research-associateships-program, accessed December 19, 2020.
Some locations have space limitations to growth, and yet the workload is increasing. There was not a strong sense of the importance of mentoring, although it was stated that a matched mentoring program was not as fruitful as ad hoc mentoring.
Many nonprofits have succession programs in place, and these have strengthened the overall morale as well as provided the feeling that the research legacies created will continue.
FINDING: An overarching goal on achieving diversity and inclusion for performance-based, qualified individuals continues to be important. There appears to be an underlying sentiment that the diversity and inclusion policy (across disciplines, genders, ethnic groups) needs to be developed, when in fact, it has been developed and acted upon.3
Enhancing Learning Opportunities for Existing Staff
The measurement field is a fast-paced technical area with novel methods and instruments coming online on a yearly if not monthly basis. Thus, it is important that existing staff have structured or NIST-endorsed avenues to grow and expand their knowledge base. Considerations include offering sabbatical-like opportunities at other governmental agencies and universities (locally and globally). “Changes in duty station” that permit staff to pursue rotations through other NIST divisions, within BMD, or at nearby universities would also fulfill this need. Short industry-based learning experiences might further enhance the ability of NIST to understand and serve the needs of industry. Given that BMD is within the fourth largest biopharma zone in the United States, it has a geographical advantage in establishing unique educational experiences on which it might capitalize. The new “virtual” environment provides a basis whereby BMD staff could maintain a significant presence at NIST while on a learning opportunity or rotation.
Enhance Diversity to Enhance Expertise and Problem Solving
There is now ample evidence that diverse teams with varying experience and backgrounds provide better outcomes in problem solving than nondiverse groups.4,5 Additional viewpoints and backgrounds provide the basis for creative solutions to tough problems. To this end, BMD can strive for increased diversity in its workforce. A clear structure with strategies and milestones would be of value. Discussions with young, mid-career, and senior researchers further illuminated how the staffing, retention, and diversity of the NIST’s outstanding research staff needs to be addressed.
DISSEMINATION OF OUTPUTS
The BMD, as noted earlier, has shown excellence at all levels of dissemination—publications, reports, reference materials, and workshops. BMD researchers have published 174 papers since 2017, many in top-tier peer-reviewed journals. In addressing the NIST mission, they have produced 18
3 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.
4 L. Hong and S.E. Page, 2004, “Groups of Diverse Problem Solvers Can Outperform Groups of High-Ability Problem Solvers,” Proceedings of the National Academy of Sciences U.S.A. 101(46): 16385–16389.
5 K.W. Phillips, 2014, “How Diversity Works,” Scientific American 311(4): 42-47.
reference materials and three standard reference data libraries. These reference standards include NISTmAb 8671, RM 8634 for particle sizing, and the SARS-CoV-2 research-grade test material RGTM 10169.
Recent high-impact areas that deserve particular recognition include the licensing of BMD’s protein sequencing technology to QuantumSi. BMD members also continue to be highly productive as evidenced by their large number of publications in high-quality journals—Analytical Chemistry, Journal of Proteome Research, Clinical Chemistry and Laboratory Medicine, and DNA Repair. This includes a recent top 10 downloaded paper in the Journal of Forensic Science which was also a top 5 percent cited paper in Wiley Altimetrics. Other impressive numbers include 100 publications citing NIST mAb with over 200 collaborations and 1,000 units/year sold. Notable evidence of BMD’s high expertise and respect within the broader community include BMD’s MS library citations, which tally over 7,000/year and its electron ionization (EI) library distribution at 6,000/year. BMD’s other numerical attributes are equally impressive, reflecting the expertise of the division’s scientists. The industry views BMD with high esteem. This is apparent from its collaborations and CRADAs spanning pharma and analytical/scientific measurement companies. These companies include some of the largest and most well-respected enterprises, such as AstraZeneca, Amgen, Thermo-Fisher, and Agilent. The ability of BMD to lead successful roundtables, workshops, and conferences clearly demonstrates that the scientific community recognizes the value of BMD. Of note are BMD-led interlaboratory measurement comparisons of the NIST mAb involving over 100 industrial, academic, and regulatory participants from around the world, including HDX-MS, glycosylation analysis, higher-order structure assessment by NMR, and a MultiAttribute Method (MAM) Consortium.
Opportunities and Challenges
Current challenges are how to maintain contact during the current COVID-19 pandemic where contacts must be done virtually, and finding ways to safely carry out in-person training and communications in situations where virtual discussions are insufficient.