Synthetic biology is the application of science, technology and engineering to facilitate and accelerate the design, manufacture and/or modification of genetic materials in living organisms, as defined by the European Commission. It envisions the redesign of natural biological systems for greater efficiency, as well as create new organisms as well as molecules with desired bio-attributes. Among the potential applications of this new field is the creation of bioengineered microorganisms (and possibly other life forms) that can produce pharmaceuticals, detect toxic chemicals, break down pollutants, repair defective genes, destroy cancer cells, and generate hydrogen for the post petroleum economy.
Synthetic Biology is also predicted to transform Defense and Security. New techniques to edit and modify the genome may allow scientists to harness organisms or biological systems as weapons or to perform engineering tasks typically impractical with conventional methods. DARPA wants to utilize the potential of Synthetic biology, to provide on-demand bio-production of novel drugs, new materials, food, fuels, sensors and coatings whatever suits the military’s needs. Future advances might include the construction of new biological parts and brain-computer interfaces.
While DARPA was providing almost no funding to synthetic biology in 2010, the organization had increased its investment to $100 million per year by 2014. Funding increases were followed by the creation of the DARPA program Living Foundries: Advanced Tools and Capabilities for Generalizable Platforms, which sought to increase the speed and decrease the cost of generating new production strains of organisms. This program started in 2012, and in 2014, Living Foundries transitioned to a new program, Living Foundries: 1000 Molecules, which will invest $110 million through 2019 to enable facilities to generate organisms capable of producing 1,000 molecules of industrial and defense interests. These funds are going to a diverse group of projects. Some are incredibly broad, such as funding provided to MIT’s Broad Institute to advance our ability to assemble large genetic systems. Other projects have a specific, discrete purpose, such as the DARPA–funded biotech startup Ginkgo Bioworks, which is developing probiotics to help prevent common infections for soldiers.
Recognizing the importance of biotechnology, in 2014 the DOD created the Biology Technology Office (BTO), which houses the Living Foundries program as well as numerous others, such as Battlefield Medicine, which is developing platforms for creating medicine on demand in the field, and Safe Genes, a program to create tools for safe genome editing. While the purview of the BTO is greater than synthetic biology alone, further development of synthetic biology tools will result in the application of synthetic biology tools and techniques in greater numbers of projects. Synthetic biology is one of the most important research fields in the present day, and the DARPA approach to synthetic biology research has proven successful so far: the first iteration of Living Foundries succeeded in increasing the speed of creating production strains of new organisms by 7.5-fold, while decreasing the cost 4-fold.
Microbes are found in nearly every realm on earth, ranging from thermal vents to Antarctic ice. The spectrum of sensing and metabolic activities that microbes exhibit to thrive in these environments has long inspired efforts to harness microbial biology for sensing and metabolic engineering applications. Sensing, for example, has been achieved with a wide range of different biological components, including enzymes, antibodies, receptor proteins, and nucleic acids
Natural and synthetic biological systems can already sense a wide variety of phenomena of interest, from specific chemicals to light and ionizing radiation. The DoD is looking to utilize natural biologically occurring sensing for their benefit. For example, certain biological systems can naturally or synthetically detect electromagnetic waves, light and ionizing radiation. These organisms can produce physical or chemical signals, which scientists can harvest to create living sensors and detect changes in an environment.
Because of their small size, high sensitivity, ability for self-replication, multiple stimulus sensing ability and the difficulty of distinguishing synthetic vs. organic organisms in the environment, synthetic organisms can become very accurate and discrete sensors for military applications. Potential applications include: distributed tag, track and trace systems and persistent clandestine sensors.
Researchers with the University of Tennessee Institute of Agriculture will lead a new effort worth up to $7.5 million to use plants to detect environmental threats to deployed troops and help protect civilians living in post-conflict settings. The goal is to innovate a new, revolutionary sensor platform. Awarded by the U.S. Defense Advanced Research Projects Agency, also known as DARPA, under its Advanced Plant Technologies program, the 4-year effort will combine the expertise of plant biologists, biochemists and engineers. Researchers at UT and the Massachusetts Institute of Technology will work to modify potato plants to detect and report potential threats such as nerve agents, radiation and plant pathogens.
US Naval Research Laboratory (Naval Research Laboratory, NRL) has allocated $ 45 million for the implementation of a program to study the prospects for the use of genetic engineering for the navy. Part of the program was the development of genetically modified microorganisms capable of detecting the presence of enemy ships, submarines, underwater drones and divers.
Soldier: Medical and Human Performance Modification
One of the defence applications is maintaining a soldier’s fighting ability at peak levels by creating medical advances like vaccines before an outbreak, healing soldiers who have severely damaged their bodies, and ensuring the mental health of soldiers is sound.
It involves everything from better field cares to improved prosthetics, prophylactic application of bacteria on the skin to prevent infection and to help heal wounds and probiotics that decrease the effects of stress and enhance mental performance. It also involves basic research in molecular genetics and genomics that will enable optimization of soldier cognitive and physical performance.
Defense against Biological and Chemical Warfare
“Synthetic biology may enable potential adversaries to develop chemical and biological threat agents with new characteristics. DoD has a responsibility to stay abreast of this field to enable protection for our military personnel, but because biological and chemical weapons defense is focused on threat mitigation instead of enhancing overall DoD capabilities, it is important to keep its size relative to its importance and not allow this aspect to overshadow the major opportunities provided by the field,” according to DOD report titled Technical Assessment: Synthetic Biology.
The historical DARPA approach to protecting against novel bio-threats is appropriate. By developing the capability to respond to any new pathogen, R&D resources benefit DoD and the nation by improving emerging infectious disease preparedness while also enhancing defenses against novel threats. The DoD (mainly DARPA) and healthcare organizations are creating treatments for potential biological and chemical threats to protect both citizens and warfighters. Synthetic biology can assist to combat biological warfare through protein design processes, and by providing a platform to create new biosensor circuits by connecting diverse sensing parts with information processing modules. BTO’s Rapid Threat Assessment program, aims to develop methods and technologies that can map the complete molecular mechanism of a threat agent within 30 days of its exposure to a human cell.
DARPA THoR – Technologies for Host Resilience
The Defense Advanced Research Projects Agency (DARPA) has launched Host Resilience (THoR) program to catalyze the development of breakthrough interventions that would increase the ability of patients own bodies to tolerate a broad range of pathogens. The rising prevalence of multi-drug-resistant pathogens, as well as emerging biological threats, makes developing new medical countermeasures a national security priority. The THoR program will explore the fundamental biology of host tolerance in animal populations with the goal of expanding treatment options for humans in the future.
DARPA and the Army Research Laboratory (ARL) are supporting the research through a $6.4 million contract to Researchers at Emory University, the University of Georgia, and the Georgia Institute of Technology. The research partnership is part of DARPA’s THoR (Technologies for Host Resilience) program and is termed the HAMMER (Host Acute Models of Malaria to study Experimental Resilience) project.
“Malaria is a potentially lethal disease, but resilience in some people and non-human primates allows them to control the disease and avoid adverse outcomes, so that the infection is not incapacitating,” says Mary R. Galinski, Ph.D., professor of medicine and infectious diseases at Emory University School of Medicine, Emory Vaccine Center and Yerkes National Primate Research Center. “Our goals are to identify host features associated with resilience, thinking beyond the host’s immune response into the realms of physiology, biochemistry and pathogenesis, and develop interventions that could enhance that resilience.”
“Our aim with THoR is to lay the foundation for new treatments that would enable the body to more easily and safely cope with infection,” said Col. Matt Hepburn, DARPA program manager. “Among other potential advantages, these new treatments would prevent the body’s overreaction to infection and buy time for the individual’s natural recovery mechanisms to kick in. We want to help patients ‘weather the storm’ during the critical phases of acute illness.” If THoR is successful, it could provide substantial benefits to warfighter health and military readiness. New treatments would help reduce reliance on antibiotics and complement ongoing efforts both to fight microbes themselves and slow the emergence of antibiotic resistance.
Some biological systems are able to naturally produce materials that are difficult, expensive, or impossible to produce by traditional means. Potential defense applications include: sensor active materials, high strength polymers for armor, stealth materials, corrosion resistant coatings, biological computing; data storage and cryptographic materials. Arti Prabhakar said that she expects synthetic biology to produce materials “better” by borrowing tricks from nature. Spider silk, for example, is stronger than steel, and abalone shells are tougher than glass and more flexible than plastic. More powerful fuels might also come from genetically engineered microbes, she said.
Commodity materials that the DoD can create using synthetic biology include cheaper textiles and fuels. In the commodity sector, the DoD is investing most in the production of fuels in warzones, such as in Afghanistan, where a gallon of fuel can cost as much as $400.
Synthetic biologists get $1.7 million to engineer world’s strongest biomaterial
Synthetic biologists are attempting to manufacture sporopollenin, the extremely durable biopolymer that forms the outer walls of pollen grains. This naturally occurring polymer coats and protects individual grains of plant pollen, and it’s been found in 500 million-year-old sediments. They’ll get there thanks to a $1.7 million grant from the Defense Advanced Research Projects Agency (DARPA), part of the U.S. Department of Defense.
Synthetic biologists at Colorado State University are attempting to manufacture sporopollenin in the lab using plants, and to control its properties using gene parts designed for specific functions, known as genetic circuits. Their goal is to produce coatings that could one day protect ships, bridges and other infrastructure that crack as they age.
Making sporopollenin in quantities large enough to become commercially viable is a challenge no scientist has yet overcome. This polymer is nature’s original tough nut to crack: So resistant is it to degradation, that scientists have trouble taking it apart and identifying how the polymer is formed.
“The biosynthetic pathway of this polymer is very complex,” Antunes said. “In order to replicate it, we will need to precisely coordinate the expression of several genes in plant tissues that do not naturally produce this polymer.” If the scientists are successful, they will produce a tunable, scalable polymer that can be sprayed onto bridges, hulls and ships, making them impervious to rust or decay.
With proven expertise in making genetic circuits and inserting them in plants, the team plans to transform the tissue of Arabidopsis roots and moss, using their specially designed DNA. Then, the plants should express new genes, and produce the polymer. Plants are ideal to use because they already have a basic biosynthetic pathway in place that the scientists can build on. “Life has existed for billions of years,” Medford said. “Plants have come up with a better way to live on our planet, than we have with concrete and metal. If we can engineer living materials, we can come up with sustainable ways to copy what life has already done so well.”
DARPA gives MIT lab $32 million to program living cells
MIT has announced its contract with DARPA under which the lab will receive $32 million for engineering cells to find better treatments for disease, make new biofuels, or create fabrics woven with life. “Living cells are the ultimate engineering substrate. They are the most difficult thing out there to be able to control,” says Christopher Voigt, a professor of biomedical engineering and one of the lab’s co-founders, in a video. “Imagine being able to engineer a living cell that can navigate the human body, identify disease, and correct that disease. That requires that the cell be able to sense where they are in the body, be able to detect it, and deliver a therapeutic. And that’s something that biology, we know it can do. But we don’t know how to harness that as part of a medicine.”
The press release states that the grant will enable the Foundry to “offer critical new products in human health, agriculture, and chemistry, and serve as a mechanism for tackling some of the big problems of the world,” over the coming decades. The lab has already created hundreds of man-made nucleotides, and has even found a less resource-intensive way to make fertilizer.
Creating Synthetic Life
DARPA under their BioDesign program wants to create living organisms, that can be programmed to live indefinitely, that shall be tamper proof through genetic locks, can be traced using DNA manipulation and could be killed as last-resort through genetically coded kill switch. It’s not totally far-fetched. A team at the NYU Langone Medical Center’s Institute for Systems Genetics has announced the creation a fully functional synthetic chromosome from baker’s yeast, Saccharomyces cerevisiae.
Alicia Jackson, the deputy director for DARPA’s biological program, said biology can do things “that no other technology can come close to doing.” “Biology can replicate itself, it can adapt, it can evolve,” she said. “It can scale from one to millions, to billions, effortlessly in a day, and it’s programmable through its genetic code.” Jackson also suggested that genetically engineered microbes might someday transform Mars and other planets into livable habitats.
Gene Manipulation using CRISPR
During the second biennial Department of Defense Lab Day May 18, 2017, One AFRL exhibit, called Military Applications of Gene Editing Technology, highlighted research into how geneticists and medical researchers edit parts of the genome by removing, adding or altering sections of the DNA sequence in order to remove a virus or disease caused by harmful chemical, biological or environmental agents a warfighter may have contact with.
The most dramatic possibility raised by the primate work, of course, would be using CRISPR to change the genetic makeup of human embryos during in vitro fertilization. Pentagon scientists are researching gene manipulation to build the soldiers of tomorrow that will be able to run at Olympic speed, and won’t need food or sleep. It will also be possible to trigger the cells of injured soldiers’ bodies to rebuild lost limbs.
In 2016, a Chinese group has become the first to inject a person with cells that contain genes edited using the revolutionary CRISPR–Cas9 technique. On 28 October, a team led by oncologist Lu You at Sichuan University in Chengdu delivered the modified cells into a patient with aggressive lung cancer as part of a clinical trial at the West China Hospital, also in Chengdu.
Using Crispr to cure disease “is probably ethical,” said Eric Hendrickson, a professor at the University of Minnesota Medical School, whose research uses Crispr techniques for DNA repair. “To use that technology to make your child run faster or jump higher is uniformly frowned upon. The technology to do that, however, will soon be in place.” The DARPA’s Safe Genes program aims to deliver novel biological capabilities to facilitate the safe and expedient pursuit of advanced genome editing applications, while also providing the tools and methodologies to mitigate the risk of unintentional consequences or intentional misuse of these technologies.
Control Systems and Biology
Biological Control program seeks to build the foundations for multiscale control of biological systems. DARPA seeks to develop new capabilities for the control of biological systems across scales—from nanometers to centimeters, seconds to weeks, and biomolecules to populations of organisms—using embedded controllers made of biological parts to program system-level behavior.
This program will apply and advance existing control theory to design and implement generalizable biological control strategies analogous to conventional control engineering, for example, for mechanical and electrical systems. The resulting advances in fundamental understanding and capabilities will create new opportunities for engineering biology.
Biological Robustness in Complex Settings (BRICS) program
To date, the work in synthetic biology has focused primarily on manipulating a micro-organism to make a substance, such as penicillin. However, these organisms tend to be fragile, requiring precise environmental controls to survive, and often lose their engineered advantages during the production process.
DARPA under their Biological Robustness in Complex Settings (BRICS) program seeks to develop the fundamental understanding and component technologies needed to increase the biological robustness and stability of engineered organisms while maintaining or enhancing the safe application of those organisms in complex biological environments. The goal is to create the technical foundation for future engineered biological systems to achieve greater biomedical, industrial and strategic potential.
DARPA’s Living Foundries Program
According to the DARPA website, the goal of the Living Foundries program is “to leverage the unparalleled synthetic and functional capabilities of biology to create a revolutionary, biologically-based manufacturing platform to provide access to new materials, capabilities and manufacturing paradigms for the DoD and the nation.”
Living Foundries seeks to transform biology into an engineering practice by developing the tools, technologies, methodologies, and infrastructure to increase the speed of the biological design-build-test-learn cycle while significantly decreasing the cost and expanding the complexity of systems that can be engineered. The technologies and infrastructure developed as part of this program are expected to enable the rapid and scalable development of transformative products and systems that are currently inaccessible. Examples include novel materials, industrial chemicals, pharmaceuticals, and improved agricultural products.
The Living Foundries program is comprised of two components: 1) Living Foundries: Advanced Tools and Capabilities for Generalizable Platforms (ATCG) and 2) Living Foundries: 1000 Molecules.
The first component, Living Foundries: ATCG, is now complete. It focused on the development of next-generation tools and technologies for engineering biological systems with the goal of compressing the biological design-build-test-learn cycle by at least ten times in both time and cost, while increasing the complexity of systems that are created. Technical areas of interest included design and automation tools, modular genetic parts and devices, standardized test platforms and chassis, tools for rapid physical construction of biological systems, editing and manipulation of genetic designs, and new characterization and debugging tools for synthetic biological networks.
The ongoing Living Foundries: 1000 Molecules component seeks to further refine this initial capability to significantly decrease the cost, improve the scalability, and expand the complexity of engineered systems for biomanufacturing. Aim is to create a scalable, integrated, rapid design and prototyping infrastructure. Efforts are focused on using automation, novel genome editing tools, and machine learning technologies to alleviate the challenges of prototyping.
As a proof of concept, DARPA aims to produce 1,000 molecules and material precursors spanning a wide range of defense-relevant applications including industrial chemicals, pharmaceuticals, coatings, and adhesives that can be customized to continuously evolving DoD needs while ensuring continued leadership of the United States in the rapidly evolving field of synthetic biology.
“Traditionally we use chemistry to make new compounds or new drugs. But recently we’ve realized that microbes like yeast and bacteria can also produce compounds, and we can program them to make those compounds by first understanding the chemical pathways they use. Take yeast. Yeast uses sugar for a variety of pathways to produce alcohols. If you reprogram those pathways, however, you could potentially have yeast build a variety of different compounds that they weren’t initially designed to make and we would still use the same feedstocks—like sugar. Our teams design the genetic codes that would be needed to reprogram the yeast, explains director of its BTO, neuroprosthetic researcher Justin Sanchez. “They are on milligram quantities of these new compounds, but ultimately, throughout the course of the program, they are scaling up to kilograms.”
The program is looking, for example, at developing a type of plastic that won’t melt when heated. This type of material could conceivably replace metal parts in aircraft, making them incredibly lightweight, Jackson says. They are working on creating a new type of conductive wire. “Can you imagine having conductive wires that you could actually stretch and wrap around — so you could truly just roll up your phone or fold it in half?” Jackson says on an interview.
“We’re interested in something called gene-encoded antibodies,” Jackson says on an interview. “Instead of just giving you a protective antibody straight — the protein itself — we want to encode the blueprint for that antibody in DNA or RNA. The magic about DNA or RNA is that all the cells in your body can read it .The blueprint of DNA/RNA is first read from antibody of recovering patient, these RNA/DNA can be chemically synthesized and transferred to patients. The cells in your body can read that code and generate the antibodies itself. We can give you immunity within hours against any infectious disease.”
Evolvable Living Computing — Understanding and Quantifying Synthetic Biological Systems’ Applicability, Performance, and Limits
National Science Foundation (NSF) has awarded a $10 million “Expeditions in Computing” grant to the Living Computing Project, a comprehensive effort to quantify synthetic biology using a computing engineering approach, and to create a toolbox of carefully measured and catalogued biological parts that can be used to engineer organisms with predictable results.
The field of synthetic biology has made great strides and yielded tremendous benefits in recent years. For example, early synthetic biology efforts led to the production of antimalarial drug precursors in quantities not seen in nature. Using biological building blocks to engineer biological systems, however, has been difficult without a clear design methodology and supporting quantitative metrics that researchers can use to make decisions.
This NSF grant will support efforts to create a systematic set of guidelines to carefully measure and catalogue biological parts that can be used to engineer biological systems with predictable results. These guidelines will allow researchers to better understand what computing principles can be applied repeatedly and reliably to synthetic biology. “This puts a stake in the ground to make synthetic biology more rigorous,” said Douglas Densmore, associate professor at Boston University. “We want to build a foundation that’s well understood and that can serve as an open-source starting place for many advanced applications.”
The grant marks the first time researchers will explicitly explore computing principles in multiple living organisms and will openly archive the results. “Computation is important for moving any field forward, and that’s what we’re trying to do with synthetic biology,” Douglas Densmore, a College of Engineering associate professor of electrical and computer engineering says. “We’re trying to build a library based on computing principles for the whole community, an open-source repository of biological pieces that use those principles reliably, repeatedly, and with broad applicability.”
“Programming a flower to change color, a cell to repair damaged tissue, or a mosquito to defeat malaria is likely to require a different computational model than programming an app for your laptop,” says Bhatia. “Discovering this new type of computational thinking in partnership with synthetic biologists is what I am most excited about.”
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