The Life Sciences Division supports research efforts to advance the Army and nation’s knowledge and understanding of the fundamental properties, principles, and processes governing deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, organelles, prokaryotes, and eukaryotes, as well as multispecies communities, biofilms, individual humans, and groups of humans. The interests of the Life Sciences Division are primarily in the following areas: biochemistry, neuroscience, microbiology, molecular biology, genetics, genomics, proteomics, epigenetics, systems biology, bioinformatics, and social science. The results of fundamental research supported by this division are expected to enable the creation of new technologies for optimizing warfighters’ physical and cognitive performance capabilities, for protecting warfighters, and for creating new Army capabilities in the areas of biomaterials, energy, logistics, and intelligence.1 The division’s core budget of $9.2 million was leveraged against a $67.9 million investment by the Defense Advanced Research Projects Agency (DARPA) and other Department of Defense (DoD) programs and agencies in the life sciences domain. During fiscal year (FY) 2018, a total of 81 single investigator (SI) awards were funded along with nine Short-Term Innovative Research (STIR) awards focused on jump-starting high-risk projects. Five programs were reviewed: Biochemistry, Genetics, Microbiology, Neurophysiology and Cognition, and Social and Behavioral Sciences. The Army Research Office (ARO) Biomathematics and Biotronics programs are not part of the Physical Sciences Directorate (PSD) and were not reviewed.
In general, the division’s metrics are strong, with 624 peer-reviewed publications in the FY 2016 to 2018 period, and funding for 401 graduate students and 227 postdoctoral researchers during the FY 2017 to 2018 period. There were 30 transitions reported for the 3-year period from FY 2016 to 2018, including the development of commercial products. The transition of fundamental life science research funded by ARO to applications developed in the Army Research Laboratory (ARL) intramural laboratories is another good indicator of the success of this program. However, the most impressive achievement was the 2018 Nobel Prize in Chemistry awarded to Dr. Frances H. Arnold of the California Institute of Technology for the directed evolution of enzymes. The ARO Microbiology Program funded the work that led to the 2018 Nobel Prize in Chemistry for Dr. Arnold and has contributed to highly significant scientific advances.
Overall Scientific Quality and Degree of Innovation
Moving biology outside the cellular environment is a promising direction for high-impact discoveries in biochemistry and biomaterials. Determining the structure and function of macromolecules so that we can modify them in useful ways will require an increased understanding of biological pathways,
molecular function, self-assembly, and biomimetic materials. This research area has long been recognized as a potentially useful area to explore for new discoveries. However, the field is still emerging, with much left to discover as new information and technologies become available. The program manager (PM) is focusing on interesting problems and to work with outstanding investigators. The portfolio of the Biochemistry Program encompasses a diverse and healthy range of early career and established investigators.
Use of advanced characterization methods such as cryo-electron microscopy enables the determination of structure at near-atomic resolution and provides new opportunities for rational design of materials and functional assembly of macromolecules. These methods have not been extensively explored thus far in synthetic biomaterials and will be an important method to achieve future growth.
The risk/reward level varies among the research presented. No Short-Term Innovative Research (STIR; proof-of-principle) projects are funded by this program. Such initiatives could help encourage investigation of riskier ideas at an early stage. While some excellent investigators are involved, the information presented is focused on basic research, and the degree to which the successful approaches could be transitioned into impactful devices could be more clearly delineated by the program manager. The Multidisciplinary University Research Initiatives (MURIs) in the Biochemistry Program address current high-visibility topics, but the intended value of these specific projects to the Army is not apparent. That said, none of the projects seem to duplicate of other projects funded by the Department of Defense (DoD) and all include potentially valuable research initiatives.
The Biochemistry Program has three areas of focus and significant findings have been obtained in all three. Of the examples highlighted by the PMs, the integration of biomolecules and plastics into a high-strength composite is particularly innovative, with potential to lead to new high-strength, lightweight materials. The protein assembly project is elegant with a definitive proof-of-principle, but the small lumen size of the protein assemblies is a critical hurdle that will need to be addressed if this project is to result in the development of useful new materials. The program manager is thinking in this direction—research on functional bacterial nano- and micro-compartments is included among the proposals in the research portfolio. The project on structural analysis of multiprotein assemblies is impressive as well, especially if the proposed follow-up studies on computational design are accomplished. For each research thrust, a short description of what else is going on in that research space would have helped to assess the level of innovation of the projects being considered.
In terms of scientific accomplishments, all of the projects described have been successful. The most impressive results came from small complementary teams of two investigators, in which the individual areas of each are very effectively leveraged to yield the most innovative data. This was especially true of the Ellington/Glotzer and Ellis/Lee collaborations, which have already yielded impressive results. Ellington/Glotzer are applying understanding of shape, packing, and assembly of patchy nanoparticles to develop generalizable design principles for protein assembly via charge complementarity. Ellis/Lee are investigating interface synthetic biology and materials science to manipulate the microstructure of bacterial cellulose for reinforcement of lightweight transparent polymeric armor materials. In general, all of the projects presented are productive and demonstrate tangible results suitable for publication.
In order to document the assumption of appropriate risk, it would have been useful to know if there were some failures. Computational modeling relating function and structure is mentioned in several proposals, but it is not clear whether this is an emphasis of the program. Stronger interactions between groups doing biological research and those doing computation and modeling need to be encouraged.
Relevance and Transitions
Some of the results are very interesting from a basic science point of view. It would have been useful to have received further clarifications about the degree to which the work is unique in its field, and its potential for leading to new opportunities for the Army. The following important questions were not answered: Is the program manager thinking about how resultant materials or technologies perform under operational conditions? What are target metrics that are relevant to the program manager? What metrics for the system being studied are actually being measured now? If not already doing so, the program manager could help investigators think in terms of goals that will create new materials or biologically derived functions that will ultimately have high impact.
The program manager is transitioning the projects to the next phase in research and development (R&D) through collaborative research with the Army Research Laboratory (ARL) and through the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs.
The planned expansion of initiatives in hybrid materials could be very rewarding. With regard to force-activated biochemical mechanisms, a stated goal is the translation of solution-based to non-solution-based materials, but none of the projects described seem to exhibit this focus. The implementation of the stated goal of transition to noncellular systems is also not exemplified in the data presented; all of the investigations focused on biological systems. The decision to decrease funding for mechanisms of biomolecular specificity is appropriate, because this area is funded by many other agencies in a wide variety of embodiments. The area that could use more emphasis is integration of the current programs with computational design methods and data science approaches.
Productivity of individual programs nearing completion could be measured in terms of patent applications and publications, but these data were not provided on a project-by-project basis. A list of possible next steps would be helpful to assess the potential impact of projects that PMs view as producing exciting results.
Overall Scientific Quality and Degree of Innovation
The projects presented appeared to be relevant to the Army, despite their very basic and highly diverse nature. Indeed, the projects were so diverse that it is questionable as to whether it is appropriate to consider some of the projects “genetics.” All of the projects presented were marked by their highly innovative nature, including a visionary (but ultimately unsuccessful) project that failed to reach its original objective but may yet produce new avenues to protect warfighter health in the field through simple dietary manipulation. Four projects were presented in detail. The research teams represented a good mix of seasoned star researchers and new investigators.
One project is focused on developing robust DNA barcoding capabilities to identify pollen in mixed samples in order to identify the origin of items of interest including, for example, surface residues on improvised explosive devices. Plant species grow in different niches and bloom at different times, surface samples typically contain pollen from multiple species, and species identification can reveal where the item came from, sometime narrowing the source down to tens of square miles but at other times pointing to a single building. Current state of the art is microscopic analysis, done by an expert forensic palynologist, which requires 2 weeks (and expert forensic palynologists are in short supply). DNA barcoding would enable real-time analysis and eliminate the need for the expert forensic palynologist. A new MURI will continue the development of robust DNA barcoding and will develop models to
incorporate the effects of humans on plant distribution, in order to create a robust framework for interpreting pollen identification results. A potential missed opportunity here is to develop an alternative approach that would take advantage of automated imaging, machine learning, and image recognition algorithms to identify pollen grain types and numbers. This parallel approach could be encouraged through an SBIR or single investigator (SI) grant mechanism to supplement the MURI.
A second innovative project described a program to develop a high-throughput system in S. cerevisiae to screen human polymorphisms in genes that encode enzymes whose activity is affected by the availability of vitamin or mineral cofactors. Polymorphisms in the 600 vitamin- or cofactor-dependent genes are widespread enough that a warfighter has an average of two functional polymorphisms in these 600 genes. Identifying the effects of these polymorphisms and the extent to which these defects in enzymatic activity can be ameliorated with supplementation of specific vitamins or minerals has the potential to significantly improve warfighter health and performance at an extremely low cost.
There is a substantial program of projects on mitochondrial genomic integrity and regulation with the eventual goal of extending warfighters’ health, performance, and longevity in active service. The mitochondrial health project presented is a high-risk/high-payoff project that grew out of an initial observation that zebra fish and rodents can be put into a state of suspended animation, with no heartbeat or brain activity, by exposure to hydrogen sulfide, and that these organisms can be brought back to life after several hours of exposure and suffer no detectable adverse effects. The effect on animals that have been injured resembles that which can be brought about by cooling the body—namely, a marked extension of the time window available for treating wounds. Research was done subsequently to explore the possibility of using hydrogen sulfide to induce suspended animation in warfighters who are critically wounded and expected to die before they can be transported to medical care; however, human trials indicated that the therapeutic index is too narrow for safe use, and this Defense Advanced Research Projects Agency (DARPA)- and ARO-funded initiative was abandoned. There are now indications that iodide ion can reduce the impact of traumatic injuries including stroke, heart attack, and hemorrhagic shock. This particular project is novel, but a priori there is no obvious reason to think that iodide will turn out to be useful in this context. The most compelling evidence that it might be resulted from studies of the dependence of the sizes of infarcts caused by ischemia on iodide levels. While something good may come of the current version of this initiative, it is still early.
The giant African pouched rats (“pouchies”), which are actually giant hamsters, have been used to detect buried land mines in Africa. The objective of this ARO-funded research is to establish a colony in the United States, to investigate reproduction and learning, and to determine whether pouchie psychology can be exploited to automate training. These animals are now established at Cornell University and breeding, and results to date have demonstrated that their reproduction is regulated at the colony level, unlike almost all other mammals. There is good reason to think that the pouchies may prove to be at least as good as dogs for this purpose, with additional benefits coming from their smaller size and from the likelihood of reduced emotional repercussions for their handlers when they are killed, compared to dogs. The level of innovation is high, and the program is unique. How well these animals perform, how to breed them, and ways of training them that are fast and cheap are being addressed. Prior African experience indicates that automation will be feasible.
The Genetics Division is large and has a broad portfolio within the Life Sciences Directorate. The scientific objectives were clearly articulated and mapped onto the research portfolio in a clear-cut manner.
The “pouchie” project was seen as particularly significant for the Army. It was also noteworthy for its potential to win over civilian populations affected by land mines in their homeland. ARO has a substantial portfolio of publications and trainees supported, as well as PI awards and honors in this program.
Relevance and Transitions
Successful transitions of multiple diverse projects to DARPA, the State Department, the Army Medical Command, the Army Soldier Center, Defence Science and Technology Laboratory (U.K.), the Defense Forensic Science Center, intramural research at the Army Research Laboratory, and other agencies have been accomplished. Some examples of these include ARO-funded research leading to characterization of metabolic mechanisms and new therapeutics to potentially extend the time for treatment after severe blood loss and other trauma. With external funding, the safety of this therapeutic has now been established in human clinical trials, and human clinical trials to validate the efficacy are under way. Also, ARO-funded research led to the first successful breeding pairs of pouchies in captivity at Cornell University.
Overall Scientific Quality and Degree of Innovation
The goal of the Microbiology Program is to identify and understand the fundamental principles governing microbial communities and their eukaryotic interactions, with the eventual goal of exploiting microbiome capabilities for biomanufacturing and for enhanced warfighter performance and protection. The program focuses on three general topics—two associated with analysis and understanding of bacterial communities and one focused on metabolic programming under environmental stress. Not discussed in the presentation but highlighted in the ARO in Review 2018 report2 are studies on the human microbiome and its effects on health and cognition, as part of the Tri-Service Microbiome consortium—this focus is clearly relevant to warfighter health and performance. ARO’s complementary initiatives that develop insights into how the microbiome can enhance warfighter performance is well justified. Understanding and dissecting bacterial communities is directly relevant to the microbiome effort, and the approach to accomplishing this is still a challenge. A subset of the currently supported projects was discussed in substantial detail.
Four projects were presented in some depth: two SI projects to study the role of phenazines in pseudomonas biofilms and to study RNAs within B. subtilis spores; one STIR project to investigate how two different Clostridia share metabolic capabilities; and one Young Investigator Program (YIP) project to develop the use of microfluidics to look at interactions within complex communities. The scientific quality of all of these projects was high. Innovation was particularly high for the STIR project, following up on a provocative set of initial observations with supportive experiments. This project has the potential to result in the discovery of unexpected new biology that has significant implications for understanding how bacteria function within complex communities, and how microbes may deliver useful products. In addition, this work on anaerobes emphasized the continuing need for appropriate reporters for anaerobic cell biology. The microfluidics project to develop and study bacterial communities using state-of-the-art approaches may yield significant results in the future, but it is currently focused developing a new type of platform for which funding is very hard to find from other sources. Progress thus far is promising, and the
2 Army Research Laboratory, Army Research Office, https://www.arl.army.mil/www/pages/172/docs/AROinReview2018-online.pdf, accessed October 3, 2019.
opportunity to support a very promising early-career investigator is particularly attractive. The project to study RNAs within B. subtilis spores has resulted in the discovery of a subset of mRNAs within spores that may not be serving as messages, but instead as a source of nucleotides for supporting the metabolic activity of the spores when they germinate. However, this remains to be proven, and it was not made clear how this finding underpins the proposed development of spores as environmental sensors. Similarly, while the observation that phenazines appear to stimulate cell death in a subset of pseudomonas cells when energy is limiting is of interest, the implications, other than that biofilm dynamics are complicated, were less clear.
The current set of projects seem likely to provide some new insight to the objectives, but given the breadth of lifestyles of different microorganisms, the range of relevant environments, and the general nature of the stated objectives, it is unlikely that these objectives will be fully achieved in the near future. The projects focused on development of robust means of biomanufacturing are primarily among the SBIR and STTR projects, and the level of innovation is not clear. Nonetheless, some projects are addressing basic needs for analyzing complex communities.
The more mature of the projects presented have led to advances that are generally significant. The work that has been supported has been productive and reflects ingenuity and development of useful new approaches in some cases. The project to investigate how two different Clostridia share metabolic capabilities and the microfluidics project were at an earlier stage, and at this point, its accomplishments are provocative and promising. It is diffcult to evaluate the overall quality of the entire set of projects being supported because all projects were not presented to the panel. Suffice it to say that this program funded the work that led to the 2018 Nobel Prize in Chemistry for Dr. Frances Arnold and has contributed to highly significant scientific advances.
Relevance and Transitions
Reasonable and useful transitions have occurred for a significant number of projects, including projects on microbiome characterization or manipulation and rapid detection of microbial pathogens, especially in water supplies.
The study of bacterial communities is an important but challenging general aim—with one approach requiring ways to remove specific members of a community to understand their role. Bacteriophages and clustered regularly interspaced short palindromic repeats (CRISPR) might be tools to consider in this context, and in any case, in the long run, phages are undoubtedly important components of natural communities and therefore could eventually be included in thinking about how these communities operate and respond to changing conditions.
Overall Scientific Quality and Degree of Innovation
This program aims to measure and model the neurophysiological underpinnings of perception, sensorimotor integration, and behavior in order to support the development of interfaces that promote cognitive control and rapid decision making. The scientific objectives are (1) to measure and model the structural and functional neural underpinnings of multisensory synthesis and information processing; (2) to determine how brains structure, process, and refine biological neural networks to generate effcient decisions and behaviors; and (3) to determine the neurobiological mechanisms mediating vulnerability of the brain to injury. Pursuit of these goals could result in findings of high significance. Human-machine teaming, augmenting human sensory and cognitive processes, optimizing learning, and adaptive decoding of sensor information were each identified as endpoints—each with unique questions to be answered. The program has been quite successful in coordinating funding through collaborative mechanisms and has focused funding so as to avoid redundancy with other agencies and programs, including intramural programs in the ARL. The program has also been active in coordinating with overseas research endeavors.
The Neurophysiology and Cognition Program has funded innovative approaches, including important collaborative multidisciplinary MURI grants. The specific MURI projects highlighted were (1) developing closed-loop adaptive algorithms and models of multisensory neural activity to maximize brain-computer interface information transfer rate and enhance decision accuracy; and (2) imaging all the synapses of a cortical interneuron. Two other projects highlighted were (1) developing and validating a method to accurately predict transcranial stimulation-induced current flow in the brain and measure interactions with neural activity and plasticity; and (2) elucidating neural mechanisms that underlie camouflage-breaking. Featured research projects included work using multimodal sensing data (spikes, implanted electrical measurements, heart rate, skin conductance, or possibly functional magnetic resonance imaging [fMRI]) to model the mental state of the animal or human to develop systems that predict, and possibly control or modify, behavior. The current portfolio collects data from animals and humans, with the former seeming to be a point of particular emphasis. Animal studies indeed provide a key scientific opportunity for informing the development of human models. That said, to adaptively integrate human function in the context of more complex multiscale modeled systems suggests the importance of incorporating more research focused on human neurocognitive systems in the portfolio.
The scientific quality both in larger scale MURI projects and in single investigator projects presented is very strong. The quality of the scientists who are being funded, and of the science being produced are both excellent. Several projects are usefully integrating neurophysiological research with mathematical or machine learning techniques to generate cutting-edge approaches to fundamental problems. The productivity of the grant portfolio was strong and of high quality.
Relevance and Transitions
The relevance of the work for the Army was clear with respect to the development of novel methods to support optimized performance in human-machine teams and to understand integrated brain-body
dynamics that drive neural processes for performance enhancement and resilience—for example, sleep deprivation, resilience to post-traumatic stress, and the promotion of superior learning rates. The connections between several featured projects focused on cellular or subcellular data and their potential applications were somewhat less clear. However, they may reflect high-risk, longer term investments. There have been a significant number of transitions of research products or successor projects to ARL and other defense agencies or programs, including a transition of brain-computer interface algorithms, development environments, and neural network models. Co-publications or collaborations with ARL scientists and spin-offs of technology to several companies have also occurred. Several previously supported projects had received substantial funding from the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative of the National Institutes of Health (NIH), DARPA, and other large funding sources.
Several important lines of research involving human-agent teams, human-systems integration issues, human-based sensor interpretation, and other research related to the overarching goals of the program seem to be located elsewhere within the ARL structure, as described briefly in the broader documentation. The connections between these programs could be made more apparent. These areas collectively are relevant, and potentially may have a large payoff. The extent to which these other elements incorporate aspects of human-systems integration was not addressed, but symbiotic relationships between the cognitive neuroscience program and more targeted programs might yield benefits.
Overall Scientific Quality and Degree of Innovation
The vision of the Social and Behavioral Sciences Program is to identify and characterize micro-to-macro links tying human characteristics to population dynamics embedded within natural and physical systems to improve detection of emerging social dynamics and security risks in multidomain operations. The program has three strategic objectives: (1) to identify measurement methods that will detect shifts in collective human behavior; (2) to generate predictive models of population behavior; and (3) to model interactions among social, natural, and physical systems with the goal of identifying the complex interdependencies that causally underlie sociopolitical risks. These goals blend well, enabling the program to identify, explain, and predict important sociological, political, and economic outcomes in global contexts. In a relatively short period of time, the program manager has assembled an impressive array of projects that appear to lie on the cutting edge of social science. Examples of these projects highlighted included (1) developing objective measures of individual propensities for aggression and establishing pathways from individual to collective violence; (2) determining the relationships between vocal accommodation in the nonverbal band (below 300 Hz) and influencing dynamics through shifts in the nonverbal band; (3) predicting relationships among group structure, risk, and payoffs in non-kin groups; and (4) investigating interdependencies among environment, infrastructure, and conflict.
The potential for current projects to succeed is very high. If the projects presented are representative of the full portfolio, there is scope to increase the program’s reach into more risky projects. At present, the focus seems to be on methodological development using existing data sets. There is certainly much to learn here, but there is also room to engage with less certain projects (e.g., projects that rely on the
compilation of new data sets or that foster access with new or understudied populations) without exposure to unacceptable levels of risk. Therefore, the program manager’s plans to increase funding for projects that seek to acquire new data regarding the factors affecting the dissemination of knowledge and to decrease funding for projects related to data archives are appropriate.
Relative to peer programs in the division, the program manager seems to rely more heavily on single investigator grants. The relationship between this program and the Minerva Research Initiative is likely very important, although the degree to which these mechanisms of funding are symbiotic is unclear. The Minerva Research Initiative is a DoD social science grant program that funds unclassified basic research relevant to national security. Opportunities for a MURI could be a point of focus; this is an underutilized source of funding within the program, particularly given its rather distinct goals when compared to the other four programs in the division.
Within the review period FY 2016-FY 2018, the program has generated a respectable number of peer-reviewed publications (59) and supported a commendable number of graduate students (115 per year) and postdoctoral researchers (11 per year). The reviewed projects mesh well with the program’s stated goals and display a high degree of scientific rigor.
Relevance and Transitions
The potential long-term applications of the Social and Behavioral Sciences Program’s projects are readily apparent, with the ability to predict social unrest and to understand influence networks being particularly important. Current transitions consists of briefings of results and predictive models of human errors, human behavior, and sociopolitical dynamics delivered to and used by the U.S. Navy Third Fleet Command, the National Security Administration, the 98th Civil Affairs Battalion, NASA, U.S. Army Special Operations Command, U.S. Joint Staff/J9, Headquarters of the Department of the Army/Institute for Business and Defense, U.S. Central Command, and intramural ARL scientists as well as several workshops and seminars within the DoD and other government agencies. It is encouraging to see that data archiving and the reporting of conclusions to Army commands are occurring.
The results of fundamental research supported by this division are expected to enable the creation of new technologies for optimizing warfighters’ physical and cognitive performance capabilities, for protecting warfighters, and for creating new Army capabilities in the areas of biomaterials, energy, logistics, and intelligence.3 Five programs were reviewed: Biochemistry, Genetics, Microbiology, Neurophysiology and Cognition, and Social and Behavioral Sciences.
It is somewhat surprising that the Life Sciences Division is a component of the physical sciences focus area of the ARO. It has an extraordinarily broad range of subjects, which in academia would be housed in quite separate departments. The cross talk that occurs between the disparate projects supported by this division is proving to be extremely useful. However, because the number of people in the division is small, and the amount of money they command is miniscule compared to that available to agencies like NIH, the programs it supports cannot encompass by any means the full range of subjects that might be
relevant to the Army, and it needs to take advantage of all the leverage it can from other DoD agencies, in particular DARPA, to get the projects done that it has elected to support.
The overall quality of the five programs was judged to be very high, with strong and innovative projects in all of the programs. The emphasis is on basic research, although there was an impressive record of transitions of successful projects to customers. Many, but by no means all, projects were deemed to be high risk and high reward and would probably be too risky for funding from more conventional federal agencies. The panel could usually see a clear connection to future Army needs in the projects chosen.
The Life Sciences Division has a well-balanced portfolio that includes support of new investigators, who may be at particularly creative and innovative stages of their careers, as well as new directions for established investigators, through single investigator (SI), Short-Term Innovative Research (STIR), and Young Investigator Program (YIP) funding. The emphasis is thus on important ideas that do not have enough data to support proposals to conventional funding organizations. Here, the division could have a very positive impact on innovation, and this emphasis, which is already evident, needs to be encouraged. In several cases, the PMs funded pairs of principal investigators (not necessarily at the same institution) to work together on a single SI grant. This mechanism for crossing disciplinary boundaries to accomplish innovative studies has produced outstanding results. The division needs to continue to facilitate partnerships between pairs of investigators with orthogonal expertise through appropriate grant mechanisms.