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3
Biochemical Science Division
INTRODUCTION
The Biochemical Science Division (BSD) has the charge of biochemically and
biologically based measurement methods, data, reference materials, and predictive models. It
has a diverse staff that includes 56 scientists and 45 guest researchers. The division is
structured as six research groups: Cell Systems Science, Applied Genetics, Macromolecular
Structure and Function, Multiplexed Biomolecular Science, Bioassay Methods, and DNA
Science. There are four cross-boundary teams: Nanotoxicity, Microfluidics, Biosecurity, and
Cellular Biometrology. As described below, the panel reviewed the six research groups and
one of the cross-boundary teams (Nanotoxicity) as an example of how the team concept
functions.
The BSD budget is derived primarily from the scientific and technical research
services (STRS) funding (68 percent). Mission-focused research from other agencies
contributes 22 percent to the budget. The division also generates approximately $0.8 million
annually from measurement services. Sixty-five percent of the budget is invested in
bioscience and health-related activities. The BSD also receives approximately $500,000 per
year to purchase capital equipment.
In addition to the broad assessment criteria described in Chapter 1, the panel
considered the following issues in its assessment of the Biochemical Science Division:
1. What are the unique contributions made by the division that result from its
being at NIST?
2. Does work in the division result in a NIST product?
3. Is the division operating at a state-of-the-art level in each of its component
groups?
4. Is the division greater than the sum of its parts?
TECHNICAL MERIT
Overall, the reorganization of the Biochemical Science Division over the past 2 years
has produced positive outcomes. The division has been restructured into six groups, each
with a group leader. Cohesion within the division has been addressed by establishing
crosscutting technology teams. These teams were not well defined; how they function was
not made clear to the panel. One of these intramural teams, the Nanotoxicity Team, served as
a sample to provide insights into how this concept functions. The Nanotoxicity Team was
very enthusiastic, but the strategy for technical management of the team was not made clear—
for example, how the staff interact through regular meetings, research presentations, and joint
laboratory meetings. Therefore, how these teams add synergistic value to the division was not
made evident.
Comments made to the panel by every group leader and by younger staff and
postdoctoral researchers interviewed suggest that staff perceive the reorganization of the
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division to be a general success. Communication among the division management was
reported to have improved. The groups are smaller than before, with an average staff of 8 to
10 people, allowing group leaders to devote more time to research and mentoring. However,
there was insufficient information to permit assessment of the effectiveness of communication
among the groups.
Research Groups
Cell Systems Science Group
The Cell Systems Science Group has as its vision to assist in the evolution of biology
to a quantitative science and as its goal to model data on complex biosystems. Its focuses
include stem cells, nanoparticles toxicity, imaging signaling pathways, and data and
informatics. To accomplish its goals, the group has three core areas: bioinformatics, cell
quantitation, and predictive models of complex processes. The group, which consists of
biologists, biochemists, and bioengineers, is almost completely funded by STRS. While this
cushions the group from large shifts in funding, it does not encourage the group to seek peer-
reviewed recognition of its work.
The group has developed several innovative technologies that have potential for
making a real difference to cell biology, but it has not yet been able to successfully engage
outside groups such as the ATCC (the Global Bioresource Center) to achieve this goal. There
is need for coordination between the group and the technology licensing office at NIST. A
major challenge is the need for the laboratories to grow, not only within the group but through
partnerships with other laboratories throughout NIST.
While the databases (HIV Structural Database, BIOFUEL Database, Bio Imaging
Database, and Thermodynamics of Enzyme-Catalyzed Reactions) created within the group are
well received, there is a need to move bioinformatics to a more forward position, which will
require additional staff members who understand the domain. The group has done
commendable work with the U.S. Food and Drug Administration (FDA) and ASTM
International in the development of guidance documents for cell imaging. The group’s
biggest challenge is the possibility that funding could erode over time. One way that this
challenge can be addressed is by partnering with other government agencies, including the
FDA and the National Institute of General Medical Sciences.
Applied Genetics Group
The main mission of the Applied Genetics Group is to provide reference material for
human, animal, and plant identification through genetic testing. The group has had a very
successful program in partnership with (and funded by) the National Institute of Justice (NIJ).
This work constitutes approximately 60 percent of the group’s funding and should be stable
for a number of years to come, because the group has met or exceeded the NIJ’s expectations
over the years. This work is widely recognized by the forensics community; the group leader
is frequently invited to present talks and has written the definitive textbook on the topic.
The Applied Genetics Group needs to build on the significant base that it has
established in developing technology and standards for DNA forensics. A number of
opportunities are being pursued, including being part of a proposed national institute of
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forensic science. If such a center is created, NIST has to play a major role; therefore, the
highest level of NIST management should be engaged in pursuing this opportunity.
Developing standards (reference materials and databases) for clinical genetic assays may be
another good opportunity, but there are many challenges that need to be overcome. One of
these is overcoming the technical gap with the state of the art in sequencing technology.
Short tandem repeat (STR) may be state of the art for forensics, but is old technology for the
rest of the genomic field. The sequencing technologies are evolving exponentially, and to
maintain a state-of-the-art program NIST will have to devote significant resources to acquire
staff and equipment. A second challenge is that of overcoming regulatory hurdles. Working
with clinical samples requires a considerable amount of regulatory and legal approvals; at
present, NIST appears to be hesitant about and very slow in granting these. Another
challenge is to address the lack of clinical partnerships. The group identified two examples
(Huntington’s disease and cytomegalovirus) where work has started in these areas, but a
considerably larger effort will be needed to identify the clinical applications for which NIST
can provide unique value. Partnering with clinical researchers will be helpful in identifying
relevant clinical problems. The group should form a strategic partnership with NIH to identify
areas of unmet need and opportunities for future funding.
The Applied Genetics Group has suggested forming a partnership with the ATCC to
help them improve quality control of cell lines; this is an excellent opportunity and would be a
great fit for this group. A successful NIST program in this area would result in saving
significant amounts of money and time for experimenters relying on these cell lines for their
work.
Macromolecular Structure and Function Group
The Macromolecular Structure and Function Group (MSFG) has as its charge to
develop novel measurement methods and models to assess structure and function. The work
in this group has applications in drug discovery, homeland security, protein engineering,
biomanufacturing, and nanotechnology. The group is housed at the Center for Advanced
Research in Biotechnology (CARB) and consists of seven staff scientists and one NRC
Fellow. (CARB is a partnership among the University of Maryland Biotechnology Institute,
NIST, and Montgomery County, Maryland.) The efforts of the group are augmented by one
PhD student and five postdocs in the laboratory at the University of Maryland. While the
MSFG receives impressive core funding from STRS, it also is able to apply for NIH grants
through CARB and thereby to increase its total available dollars for research. The group was
awarded $5 million in stimulus funding through the American Recovery and Reinvestment
Act of 2009 (Public Law 111-5) to purchase an ultrahigh-field 950 MHz NMR system and has
access to standard as well as state-of-the-art protein analytical instrumentation. The
investment made in this quality of equipment will require a dedicated staff person to ensure
that it retains its value. Given the real need in the biological and medical communities for
solid standards for follow-on biological drugs, this is an important investment for NIST.
The MSFG is involved in a variety of research projects, including the processing of
signal proteins and complex assemblies, ribonucleic acid (RNA) binding proteins, biological
membranes and membrane proteins, and glycoproteins and biologics. Group members have
also begun to investigate “green” (environmentally friendly) protocols for processing carbon
nanotubes and are in the process of patenting and licensing the technology. Despite its many
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successes, the group has significant challenges. It must make strategic hires to remain
competitive. More funding is needed to develop the biologics program fully. Because CARB
provides off-site facilities, there needs to be more effort in harmonizing and maximizing the
multi-institutional relationships involved.
Multiplexed Biomolecular Science Group
The vision of the Multiplexed Biomolecular Science Group is to use its expertise in
physical and chemical sciences to enable genome-scale multiplexed measurements of
biological systems. The group proposes to do so by developing infrastructure for standards
and measurement science tools. The major efforts in the group are in the application of
metrology to microarray data analysis and in microfluidics. Emerging programs include next-
generation sequencing, the development of microbiological genomic standards, and metrology
for multiplexed disease signatures.
This group is the most innovative in the division, as evidenced by the large number of
publications, two Innovations in Measurement Science (IMS) projects (the only two in the
division), and most of the patents in the CSTL. The IMS on microarray metrology is ending
this year and was an extremely successful program. It led to the formation of the External
RNA Control Consortium, hosted by NIST and its participants, which includes virtually every
major genetic-analysis instrument and reagent manufacturer, many pharmaceutical and
diagnostic companies, and numerous federal agencies and universities. This effort also
resulted in the inclusion of sequence as a certified property by the International Organization
for Standardization (ISO).
Another major effort of this group is the application of microfluidics technology to
develop novel protein separation and quantification techniques. This team is innovation-
driven and is charting its own course, somewhat independently of the mission of the division.
While there is no doubt about the technical quality of this team’s work, its alignment with the
mission was unclear to the panel. Microfluidics is a strong capability for NIST, and the
management and the researchers should find a better fit with the mission of the division.
While the current work of the Multiplexed Biomolecular Science Group is of very
high quality, its plans for future work were not as concrete and clear. The group intends to
become a major player in next-generation sequencing, metrology for disease signatures, and
single-cell transcriptomics, but no concrete plans were presented to identify the unmet need or
the driving biological or clinical problem, overall goals, and alignment with the NIST
mission. The group does not have the critical mass of expertise in either genome biology or
bioinformatics to match or exceed the state of the art in biomarker discovery, next-generation
sequencing, or single-cell transcriptomics.
Bioassay Methods Group
The Bioassay Methods Group pursues research into new bioassay formats and
materials, promoting standardization and defensible measurement claims through methods
optimization and validation. This group also provides standard reference materials and
reference data to support a broad range of health-, defense-, environmental-, and energy-
research-related customers. This is the largest and most diverse group in the Biochemical
Science Division, and as such it faces strong challenges in terms of the management of
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personnel and resources. The group has strong technical leadership, but the effort lacks a
coherent vision statement.
The Bioassay Methods Group has a good mix of funding from core sources and
external sources. Of all of the groups in the Biochemical Science Division, this one displays
the best balance between the research and the traditional NIST mission of generating standard
reference materials. The current mixture of employees, however, relies too heavily on
contractors. Further, a long-term plan is needed to transfer the expertise and knowledge from
the retired NIST cohort to the rest of the group.
The task of generating reference materials is nicely represented here. In order for the
reference material and database area to flourish, the leadership of NIST must continually
place adequate emphasis on these tasks and incentivize employees, including postdocs, for
supporting this key function.
There are several areas of growth that this productive group could explore in order to
increase its influence. A vision statement should be developed to encompass the major
activities of the Bioassay Methods Group and allow for a continued balance between research
and SRM activities. The criteria to evaluate employee performance may place greater
emphasis on service, patents, publications, fundraising, and, more importantly, generation and
support of SRMs. Alternatives to the Hirsch index (which measures the impact factor of
publication) should be considered. The exact focus for the biofuel activities should be
explored and optimized. Instead of defining standards for biofuels that may not have large
economic impact, the group could partner with the leaders in the field and move its effort
toward generic methods for biofuel standard classification. As another growth area, the
Bioassay Methods Group should place more emphasis on protein measurements. Current
efforts for protein characterization in other NIST divisions focus on structural aspects of
protein characterization. The bioassay elements of protein measurements are not well covered
by other NIST efforts, but they are key to homeland security and to clinical and general
research activities.
DNA Science Group
The DNA Science Group has achieved highly significant results and recognition for its
research in oxidatively induced DNA damage and repair. These research accomplishments
reflect a long-term investment at NIST in a relatively specific area that integrates deep
understanding of mass spectrometry and genetic science. Today, changes in DNA structure
are more important than ever, as researchers can potentially develop new biomarkers,
diagnostics, and therapies employing this understanding, and these advancements should
continue through appropriate external partnerships. Within NIST, there is opportunity to
extend these core competencies in mass spectrometry and DNA biochemistry across other
project areas and applications that could benefit by this expertise. The group’s strong team
and leadership could help enable this broader influence and impact. Retirements have led to
key gaps in other parts of the division, and it is important that NIST leadership ensure that the
group leader’s expertise propagates to his team.
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Crosscutting Research Team
Nanotoxicity
Nanoparticles represent a globally important area in need of improved, more
standardized measurement methodology. Toxicity, the focus identified within the
Biochemical Science Division, is especially relevant as these new components are becoming
increasingly prevalent in advancing materials, electronics, and life science and health care
applications. The emerging crosscutting program in nanotoxicity is encouraging, but current
efforts may not be sufficiently focused or distinct to elevate NIST into a leadership position in
this area. The division should develop a comprehensive view of the needs and efforts
underway in the United States, Europe, and Asia in order to identify the unmet needs that
could best be advanced by the talent and capabilities at NIST. Once that view is attained,
NIST should set clear objectives and leverage across university, government agency (FDA,
EPA), and industrial stakeholders to achieve its goals. Efforts should perhaps include
organizing workshops or consortia for this scientific community.
INFRASTRUCTURE
It is encouraging that stimulus funding is being used to address some large equipment
needs of the division, but this may not be adequate to ensure that the investigators will be
operating at a state-of-the-art level. It is not necessary for NIST to have the best and finest of
each type of instrument, given the quality of expertise nationwide. However, NIST is often
the only group to apply many of these instruments and techniques to the analysis of a given
material or method, so it is essential that the investigators in the Biochemical Science
Division have access to top-level instrumentation. If funding is not available within NIST, it
is critical that the division be willing to strike strategic partnerships with other divisions and,
whenever possible, avoid the duplication of equipment and expertise. The panel believes that
this collaborative spirit would also improve buy-in from other divisions toward the mission of
the BSD, because those divisions would be better informed and would be stakeholders.
As noted above, the Applied Genetics Group must overcome the technical gap with
the state of the art in sequencing technology. The sequencing technologies are evolving
exponentially, and NIST will have to devote significant resources to acquire staff and
equipment to maintain a state-of-the-art program.
The Macromolecular Structure and Function Group has received funding to purchase
an ultrahigh-field 950 MHz NMR system and has access to standard and state-of-the-art
protein analytical instrumentation. The investment made in this high-quality equipment will
require a dedicated staff person to ensure that it retains its value; this is an important
investment for NIST.
OBJECTIVES AND IMPACT
The role of the Biochemical Science Division as the home of biology within NIST
needs to be strengthened. NIST, like many institutions, has embraced the concept that
biology-inspired technologies are important going into the 21st century, but it has not yet
assigned the leadership role to the BSD in this. The BSD has formed strong alliances with
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appropriate standards organizations in the extramural community, including academia (the
Microarray Gene Expression Data Society), industry (ASTM International’s Committee F04
on Medical and Surgical Materials and Devices), data management and database
organizations, and the ISO (nanotoxicity). It is partnering with other institutions such as the
Institute for Systems Biology. The BSD should develop similar strategic relationships NIST-
wide. One possibility would be to provide internal review of all biologically related research
projects being considered by NIST for funding. Another possibility is to establish a seed
grant program in which members of the division partner with scientists in other NIST
laboratories.
Importantly, the division needs to forge a unifying strategic plan and promulgate a
vision that clearly reinforces its importance to biological activities and that elucidates the fact
that the division consists of more than a concatenation of groups doing work in biology. Many
of the BSD’s groups are looking for new opportunities, but the interactions were initiated and
managed at the group-leader level. It is always good to develop bottom-up interactions
whenever possible, as is the case with the partnership with the National Renewable Energy
Laboratory, but without an overall strategy the likelihood of success is reduced. The BSD
chief should work with her group and team leaders to establish a unifying strategic plan that
reflects input at all levels.
CONCLUSIONS
Overall, the depth and breadth of the research program in the Biochemical Science
Division are impressive. The division leadership and staff share a common vision. It is
important now to articulate this vision upward throughout the NIST management group and to
assert the central role of the division in biological standards and technology. This may
require additional strategic hires, particularly biologists and clinicians to complement the
bioengineers and analytical chemists. Partnering is another approach that should be
considered. This can be achieved by developing consortia that include the medical
community and industry. NIST is not structured to deal with human tissues and human
clinical trials. Perhaps the division could best contribute by serving as a calibrator and
developer of standard reference materials and methods.
The Biochemical Science Division should identify what it considers to be success in
the context of NIST. There may be too many small efforts to make a major impact. An
overarching strategy should be articulated and priorities set, based on identifying what kinds
of activities can best be done in the NIST environment. Many of the groups have done this,
but a top-down alignment of research with the division mission is missing. Once this is
achieved, the management team will have less difficulty in sifting through the projects to
determine which are the most important to pursue going forward.
Specific recommendations are as follows:
1. The nanoparticles research should focus on toxicology and should identify the
most important problem for NIST to solve. Technologies for assessing the quality
of nanoparticles are needed. The group should focus on what is happening in the
broader community and should connect with it. This crosscutting team is close to
being a core program within the division. The group needs strong input from
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FDA/Environmental, Health and Safety, as well as input from clinicians and
industry.
2. The Cell Systems Science (CSS) databases are good, but they need strengthening
with respect to bioinformatics. The studies on fluorescence imaging address an
important problem. The staff at that laboratory should be a focus on setting
standards and quantitative methods for doing assays. Similarly, the microfluidics
laboratory should consider the development of protocols and standards. Overall,
the Cell Systems Science Group has strength in the quantitative measurement of
cells, but there is need for more external validation of the group’s work through
extramural funding.
3. The Applied Genetics Group is well aligned with the NIST mission and is a model
for group funding. If the overarching mission of the division includes medicine,
this group should strengthen its applications to the medical community through the
Centers for Disease Control and Prevention and to the ATCC.
4. The DNA Science Group’s work in DNA damage and repair is among the best.
The group should take the opportunity to collaborate with other groups,
particularly with respect to biological mass spectrometry. A leadership transition
plan is needed.
5. The research in the Macromolecular Structure and Function Group is outstanding.
This group is a model of creative partnering, but it is important that the CARB
laboratory fully embrace the NIST mission. NIST should clarify what it wants for
its impressive investment in this laboratory. This group should address the issue
of biosimilars (versions of existing biopharmaceuticals whose patents have
expired).
6. The Bioassay Methods Group is the largest in number of staff, but it relies on
contractors, perhaps too much. This group provides the best balance of science
with measurement standards within the division. It may not be necessary to use
senior scientists’ time for this when technical staff can do the follow-through more
effectively. The leadership should develop a forward-looking vision to unite the
SRM teams with the research teams.
7. The Multiplexed Biomolecular Science Group has diversified funding and has
successfully competed for two IMS grants. This group is making an impact on the
field outside NIST with respect to microarrays. By interacting with other
laboratories in the division, the group should broaden its expertise to include
proteomics.
8. Overall, the microfluidics competence within the Biochemical Science Division is
excellent, but it may not be being used to its greatest advantage. The management
team should consider how to better align this expertise with the NIST mission.
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