Scientists at the Department of Energy’s Lawrence Berkeley National Laboratory ÜBerkeley Lab) are launching three research projects as part of Doe’s Biopreparedness Research Virtual Environment (BRaVE) initiative, which supports national biopreparedness and response capabilities that can be advanced with Doe’s distinctive capabilities.
The Berkeley Lab projects, which are among 10 BRaVE projects announced by Doe Sept. 7, leverage bioimaging expertise to develop better therapies and vaccines for viruses, develop a high-throughput platform to rapidly design countermeasures to drug-resistant pathogens, and enhance a generalized tool for epidemiology and ensure that it will be flexible enough to rapidly incorporate new diseases.
BRaVE builds on the success of Doe’s National Virtual Biotechnology Laboratory (NVBL) that contributed to the fight against COVID-19. During the pandemic, Doe research helped to understand the spread of the virus, delivered manufacturing solutions to stem the shortages of supplies, developed new virus testing protocols, and identified potential candidates for antiviral drugs. Doe also opened its user facilities for research on the virus’ structure and data from these facilities supported the development of all three FDA-approved vaccines, as well as antiviral drugs and antibodies. Berkeley Lab has conducted a wide range of as part of this effort.
Berkeley Lab’s new BRaVE projects include:
A Plug and Play Approach for Emerging Threats: Taskforce 5
During the pandemic, a team of structural biologists at Doe’s synchrotron user facility, the Advanced Light Source (ALS), was asked to support "Task 5" of NVBL, which was developing antibody-based diagnostics. Most of the country’s research labs had shut down due to the pandemic, and the high-throughput automated pipelines at user facilities that typically serve them were sitting idle. This freed up incredible capacity that could be directed at a single biological problem of global significance. The Task 5 team used ALS infrastructure not only for characterizing diagnostics but also to identify therapeutic targets and optimize vaccines.
"During the pandemic, we were responding to a problem. There was so much more we could have done had we been prepared. Our new project, Taskforce 5, takes what we learned from that experience and shifts the focus to biopreparedness," said group lead Greg Hura of Berkeley Lab’s Biosciences Area. Taskforce 5 will continue to advance capabilities at the ALS and two other Doe Office of Science user facilities to develop and test three plug-and-play integrated Doe bioimaging data pipelines for rapid invention of therapeutic, diagnostic, and vaccine countermeasures against emerging biothreats.
The team’s strategy is to improve and combine the strengths in structural biology with multiple biophysical techniques and novel computational infrastructure to rapidly elucidate protein structure-function, identify small molecule leads for therapeutics, identify antibodies that maximize diagnostic signal, and rapidly optimize formulations for use in vaccines. The researchers will train and optimize these biopreparedness pipelines using six model viruses, while allowing the pipelines to enhance the synergistic capabilities of their bioimaging approaches and automate data integration and analysis.
"Our goal is to prepare unique-to-Doe resources in structural biology and computation so that they optimally contribute to the next biothreat response in coordination with other government agencies, academia, and industry," said Hura, a beamline scientist at the ALS’ SIBYLS beamline. The pipelines that Taskforce 5 will form seek to greatly reduce the time it takes to generate therapeutic leads, diagnostics, and vaccine formulations so that identified biothreats are stopped before they become pandemics.
Taskforce 5 will receive $4M/year for three years. Partner institutions include Argonne and Oak Ridge national laboratories; MD Anderson Cancer Center; the University of Arkansas; Auburn University; and the University of Nevada, Reno.
A High-Throughput Platform to Combat Emerging Drug-Resistant Pathogens
A different threat to national health is the rise of antimicrobial-resistant (AMR) infections, which will require novel antibiotics. Bacteriophages (phages) - viruses that target bacteria - offer a powerful alternative approach to combat AMR bacterial infections. While there have been recent advances in using phages to treat recalcitrant AMR infections, the field lacks broad-scale mechanistic understanding of phage-host interactions in clinically and agriculturally relevant bacteria.
Enter the Phage Foundry, which would serve as an open and integrative platform available to researchers, clinicians, and industries in a fair and equitable manner. It would also help to power the bio-based economy by developing other phage-based biotechnologies, including diagnostics and vaccination strategies to treat emerging viral threats in the future.
Under the leadership of Vivek Mutalik , a staff scientist in the Biosciences Area, the Phage Foundry brings together multi-disciplinary and multi-institutional expertise to develop a foundational platform that integrates many aspects of phage research. The researchers will combine in-depth multi-scale characterization of phage-host molecular interactions with high-throughput isolation, phage-host coevolution, machine learning, and engineering design principles to enable rapid development of targeted phage-based therapeutics against AMR pathogens.
"To be prepared for any natural or human-made infectious disease outbreaks, we urgently need to invest in foundational knowledge necessary to develop alternative therapies that can be scaled rapidly as new infections emerge," said Mutalik, who has expertise in screening for antibiotic proteins made by phages and systematic characterization of phage-host interactions. "The ability to rationally design therapeutic phage formulations to overcome AMR pathogens quickly and with seamless adaptability to new pathogens can revolutionize our approach to combat rising instances of AMR," Mutalik added.
The Phage Foundry will receive $3.6M/year for three years. Collaborating institutions are the University of California, Berkeley; the University of Chicago; San Francisco State University; and Sandia National Laboratories.
Epidemiological Modeling in the Exascale Era
Epidemiological models are indispensable tools for predicting, understanding, and mitigating the impact of infectious diseases. In the early days of the COVID-19 pandemic, Berkeley Lab researchers led a multi-institutional effort to develop an agent-based model that could effectively harness the power of cutting-edge exascale supercomputers to speed predictions of disease spread for the Centers for Disease Control and Prevention and other public health agencies.
Now, the Berkeley Lab-led EMERGE (ExaEpi for Elucidating Multiscale Ecosystem Complexities for Robust, Generalized Epidemiology) team will build on their successes and expand the capabilities of ExaEpi, an exascale-ready epidemiological agent-based model to target six diseases: COVID-19, influenza, cholera, Zika, Nipah virus, and Burkholderia pseudomallei. Ultimately, the goal is to make ExaEpi a generalized tool for epidemiology and ensure that it will be flexible enough to rapidly incorporate new diseases, including those that impact plants and other animals.
"To enhance the calibration, workflow, and optimal decision-making of ExaEpi, we must capture a wide enough range of disease types. With these additional contagions, we will have targeted airborne, waterborne, and vector-borne diseases, bacterial and viral diseases, and diseases that are seasonal or sensitive to local climate," said Peter Nugent , a senior scientist in Berkeley Lab’s Applied Mathematics and Computational Research (AMCR) division and principal investigator of EMERGE.
EMERGE will receive $4M/year for three years. The EMERGE collaboration includes researchers from five other national laboratories - Argonne, Brookhaven, Livermore, Los Alamos, and Sandia - as well as from Boston University and Morgan State University.
Helping to Advance Bioenergy Research
In addition, Yasuo Yoshikuni of the Joint Genome Institute will contribute to a Brookhaven National Laboratory-led project entitled "Unlocking the Molecular Basis of Plant-Pathogen Interactions to Create Resilient Bioenergy Crops.”