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JSTO in the news
DTRA.MIL
JSTO in the newsLead DoD science and technology to anticipate, defend, and safeguard against chemical and biological threats for the Warfighter and the Nation.
October 2015 Vol. 5 No. 10
Approved for public release, distribution is unlimited
From Supercomputers to Artificial DNA: New Genetic Advances Aim to Protect WarfightersDeoxyribonucleic acid, more commonly known as DNA, is our body’s biological computer, and it stores information and carries genetic instructions vital to our everyday functions. DNA does this so well, in fact, that scientists are exploring new ways to leverage its capabilities in a way to protect the warfighter.
One exciting new technology on the horizon is to create a DNA-based computer. With more than 10 trillion DNA molecules able to fit into one cubic centimeter, a DNA computer smaller than a gumball could hold 10 terabytes of data and perform more than 10 trillion simultaneous calculations; much more powerful than today’s typical computing process. This technology could
DTRA Leads U.S. Government Transition of TaCBRD Response, Resiliency Training to PolandWith the goal of improving a government’s response to a large-scale biological incident, the Transatlantic Collaborative Biological Resiliency Demonstration, otherwise known as TaCBRD, officially transitioned to Polish partners in late September.
The program began in 2012 as a joint effort between the U.S. Department of Defense, spearheaded by the Defense Threat Reduction Agency’s Chemical and Biological Technologies
Department, the U.S. Department of State, the U.S. Department of Homeland Security and the government of Poland.
Led by program manager Mr. Ryan Madden, TaCBRD trains partner nations – such as Poland – how to respond to a large scale biological attack. TaCBRD includes both response and resiliency training. Resiliency focuses on how to rehabilitate an area after the chemical or biological (continued on Page 2)
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Crystal structures of a functional RNA molecule with a single Z:P pair in the stem (blue) bound to a regulatory ligand (red). The green strand represents RNA with an organic basis, whereas the purple strand introduces an artificial basis.
Showing the structures of the extra Z:P pair in addition to the structures of the natural C:G and U:A pairs. Courtesy of Dr. Steven Benner, Foundation for Applied Molecular Evolution.
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JSTO IN THE NEWS2
TaCBRD Response ... (continued from Page 1)
Fantastic Journey: Transporting Life Saving Drugs by MicromotorsRed blood cell membrane coated artificial nanomotor sponges capable of moving in body fluids will provide rapid, accelerated neutralization of membrane-damaging toxins, protecting warfighters, and others who are exposed to a threat.
The work is a collaborative effort managed by Dr. Brian Pate from the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department and conducted by Dr. Liangfang Zhang and Dr. Joseph Wang from the University of California, San Diego.
Natural red blood cell-based micromotors, made by fusing or encapsulating small red blood cell membrane derived vesicles onto gold nanowire surfaces, can simultaneously carry multiple types of cargo, including quantum dots, anti-cancer drugs and magnetic nanoparticles.
Quantum dots and anti-cancer drugs fluoresce at two different wavelengths inside the red blood cell motors. This allows for direct monitoring of the nanomotors while delivering the drug to the desired target. Magnetic nanoparticles enable the nanomotors to be guided to a specific target and also enable the micromotors to be used for magnetic resonance imaging, allowing for more accurate diagnostics.
The ability of these red blood cell micromotors to transport imaging and therapeutic agents at high speed and spatial precision through a complex microchannel network bridges the longstanding gap between synthetic motors and biological systems. It represents a new generation of medical micromotor based point-of-care theranostic (diagnostic and therapeutic) capabilities for treating a variety of injuries and diseases including treating warfighters exposed to deadly chemical or biological agents.
The article may be found in the Advanced Functional Materials article “Cell-Membrane-Coated Synthetic Nanomotors for Effective Biodetoxification.”
Cell-based micromotor, fabricated by loading magnetic nanoparticles into natural RBCs. The RBC motor is powered by ultrasound and guided magnetically. Images courtesy of Dr. Liangfang Zhang, UCSD.
POC: Brian Pate, [email protected]
incident is identified including treating those exposed to the agent, disposal of the biological waste, resource allocation and how to reestablish the infrastructure.
The program hit another milestone when Polish Armed Forces and governmental crisis managers collaborated with U.S. TaCBRD personnel at the Polish Epidemiological Response Centre for the TaCBRD tool transition, training and operation demonstration.
The series of training provided to Polish participants was on selected capabilities of the TaCBRD toolset and combined an operational demonstration type event with practical field training (sampling and analysis) through the use of the toolset.
The latest exercise also served as formal culmination of the official TaCBRD cooperation between Poland and U.S. and included the TaCBRD software and tablet (called TaCBoaRD) transition signing ceremony to signify completion of the project.
The event took place simultaneously in two locations in Poland; in Warsaw at the National Defence Academy – Chemical, Biological, Radiological and Nuclear Training Centre and at the Epidemiological Response Centre in Ryn.
The three-year project demonstrates our nation’s commitment to protecting warfighters, both within the U.S. and abroad, through extended training and increased capability toolsets.
POC: Ryan Madden, [email protected]
Polish exercise commander Maj Łukasz Krzowski briefs DTRA’s Ryan Madden on response efforts during the TaCBRD exercise.
Lead DoD science and technology to anticipate, defend, and safeguard against chemical and biological threats for the Warfighter and the Nation. JSTO IN THE NEWS 3
POC: Dr. Ilya Elashvili, [email protected]
also have tremendous benefits towards our national security such as allowing for greater logistical efficiencies and more rapid DNA code cracking.
Scientists funded by the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department are continuing to expand the functionality of DNA by combining organic nucleic acids, the building blocks of DNA, RNA, mRNA and tRNA, with synthetically engineered ones.
Managed by DTRA’s Dr. Ilya Elashvili and led by Dr. Steven Benner from the Foundation for Applied Molecular Evolution and Firebird Biomolecular Sciences, and Dr. Joseph Piccirilli from the University of Chicago, scientists are exploring how to build a fully artificial molecular biology system by expanding our knowledge of nucleic acids.
Following a “synthetic biology” paradigm, the project aimed to enlarge the building block makeup of DNA and RNA by introducing synthetic nucleotides to expand their genetic information packing capacity and functionality. As such, the research has made large discoveries in support of new strategies for threat protection.
One discovery highlights the first crystal structures of DNA and RNA built from synthetic nucleotides. The synthetic nucleotides, named P and Z, fit seamlessly into the organic DNA’s structure. Building on the first breakthrough, another discovery demonstrates that this artificial genetic system could evolve to give new functional molecules. Both achievements were reported in the Journal of the American Chemical Society articles “Structural Basis for a Six Nucleotide Genetic Alphabet” and “Evolution of Functional Six-Nucleotide DNA.”
Although building synthetic nucleic acids is advanced for DNA, the research is still emerging for RNA. The team recently reported the first crystal structure of a functional RNA molecule that contained artificial nucleotides in the Angewandte Chemie article “A Crystal Structure of a Functional RNA Molecule Containing an Artificial Nucleobase Pair.” Researchers stressed that the molecule retained its riboswitch functionality and maintained ligand specificity with high sensitivity.
The researcher team then applied these new capabilities to detect viruses in environmental samples, including West Nile virus in mosquitoes and the virus that causes Middle East Respiratory Syndrome, which is currently active in
South Korea. These latter findings are published in a recent Analytical Biochemistry article titled “Detecting respiratory viral RNA using expanded genetic alphabets and self-avoiding DNA.”
The scientists engineered six different nucleotide building blocks, two more than seen in natural DNA, which
expanded the nucleotide’s information packing capacity and functionality. If the understanding
of natural DNA is correct, the team should be able to construct artificial chemical
systems that replicate, evolve and adapt.
The structural biology and biophysics reported by the team demonstrates that the artificial DNA displays all of the conformational dynamics that natural DNA needs to do its job. These include
an ability to change shape, respond to different functional environments, and
adapt to meet different functional challenges.
The team also showed that their artificial DNA evolved in response to selective pressures, creating
molecules that bind selectively to cancer cells, distinguish cancer cells from normal cells, and bind to antigens from Bacillus anthracis, the bacterium that causes anthrax. The team is now using laboratory in vitro evolution (live) to create catalysts, as well as receptors and ligands.
This project is in a basic research program; however, the heightened understanding of DNA and RNA gives scientists increased command over their behavior. From this control comes an extraordinary manifold of new technological capabilities for both the warfighter and general population.
Recently, a single assay detected 22 viruses that were carried in a single mosquito carcass. These viruses include West Nile, dengue, and yellow fever, but also the less well-known chickungunya, Murray Valley fever, and encephalitis viruses, all of which could be engineered as biological weapons.
The research was published in the Journal of Virological Methods article “High-throughput multiplexed xMAP Luminex array panel for detection of twenty two medically important mosquito-borne arboviruses based on innovations in synthetic biology.”
By combining the functional diversity of proteins with the replicability of DNA, this artificial molecular system is now yielding receptors, ligands, and catalysts “on demand.” These will appear in devices used throughout homeland defense, giving our nation an agile platform to manage threats, both natural and man-made.
From Supercomputers to Artificial DNA ...(continued from Page 1)
JSTO IN THE NEWS4
The Defense Threat Reduction Agency’s (DTRA)
Research and Development Directorate (J9),
Chemical and Biological (CB) Technologies
Department, serves as the Joint Science and
Technology Office for Chemical and Biological
Defense. This publication highlights the
organization’s accomplishments to protect
warfighters and citizens through the innovative
application of science and technology research.
POC: Dr. Brian Pate, [email protected]
DTRA CB, UCSD Working to Find “On-Off” Switch For Detection and Point-of-Care CountermeasuresCollaborative efforts between the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department and the University of California, San Diego, focusing on novel sensing and toxicant penetration and scavenging, are accelerating the development of real-time, single-cell, sensing medical countermeasures.
This innovative research will provide warfighters in the field with a single-step point of care diagnostic tool to identify MicroRNAs (miRNAs) which may be used as disease biomarkers, a tool that may also be utilized by the general population.
MicroRNAs are small, single-stranded non-protein coding ribonucleic acids found in the genomes of plants, animals and some viruses. The miRNAs are important for regulating biological processes and as indicators for diagnosing diseases such as Ebola, cancer and diabetes. They are also instrumental in developing new medical countermeasures for the warfighter.
Current methods for detecting miRNAs include northern blotting, real time quantitative polymerase chain reactions and both electrochemical and fluorescent sensors. But only a few of these methods have been able to function as sensors in human serum or in cells and all are time consuming and require a large quantity of cells to function. Single-cell analysis, if available, would avoid the loss of data that results when thousands of cells are profiled for detection and is therefore of great clinical significance.
The new approach, managed by Dr. Brian Pate of DTRA CB and conducted by Dr. Liangfang Zhang and Dr. Joe Wang from the University of California, San Diego, highlights a nanomotor-based strategy that uses rapid single-step intracellular biosensing of a target miRNA to screen cancer cells based on the endogenous cell content.
This progressive approach utilizes ultrasound propelled fluorescent dye-tagged single-stranded DNA graphene-oxide coated gold nanowires that are capable of penetrating intact cancer cells. Once the nanomotor is inside the cell, the “off” or quenched fluorescence signal is recovered, or turned “on” when the dye probe from the motor binds with the target of interest.
The faster internalization process of the ultrasound powered nanomotors
and their rapid movement into the cells increase the likelihood of probe–target contacts, leading to a highly efficient and rapid hybridization. This attractive intracellular “Off-On” fluorescence switching sensing approach may enable rapid “on the move” specific detection of target cells and allow for precise and real-time monitoring of intracellular expression.
The main clinical advantage of this new nanomotor fluorescent sensing technology is the ability to perform in situ single-step target miRNA analysis within a single intact cell within a short time; therefore, enabling novel rapidly fieldable point-of-care diagnostics for the warfighter.
The full articles is in the ACS Nano article, “Single Cell Real-Time miRNAs Sensing Based on Nanomotors.”
Schematic illustration of the intracellular detection of miRNAs by ultrasound propelled fluorescent dye-tagged single-stranded DNA graphene-oxide coated gold nanowires for detection in intact cancer cells. Image courtesy of Dr. Liangfang Zhang, University of California, San Diego.
