Tag Archives: DARPA genetic engineering

How to Prepare for Deadly Flu and Nuclear Fallout

Breakthroughs in the science of programmable gene expression inspired DARPA to establish the PReemptive Expression of Protective Alleles and Response Elements (PREPARE) program with the goal of delivering powerful new defenses against public health and national security threats. DARPA has now selected five teams to develop a range of new medical interventions that temporarily and reversibly modulate the expression of protective genes to guard against acute threats from influenza and ionizing radiation, which could be encountered naturally, occupationally, or through a national security event.

The program builds from the understanding that the human body has innate defenses against many types of health threats, but that the body does not always activate these defenses quickly or robustly enough to block the worst damage. To augment existing physiological responses, PREPARE technologies would provide a programmable capability to up- or down-regulate gene expression on demand, providing timely, scalable defenses that are proportional to anticipated threats. Service members and first responders could administer these interventions prior to threat exposure or therapeutically after exposure to mitigate the risk of harm or death.

Influenza: “Researchers working within the PREPARE program seek to improve rates of survival and recovery in catastrophic scenarios for which reliable and scalable countermeasures don’t currently exist,” said Dr. Renee Wegrzyn, the PREPARE program manager….Three PREPARE teams are pursuing multi-pronged approaches to influenza defense and treatment that use programmable gene modulators to boost the human body’s natural defenses against influenza and also weaken the virus’ ability to cause harm by directly neutralizing the viral genomes. If successful, their approaches would potentially protect against virtually all influenza strains — regardless of whether a virus is newly emergent or has developed drug resistance — and would provide near instantaneous immunity, in contrast to traditional vaccines. Additionally, the teams are designing their countermeasures so that they are simple to deliver — for example, as intranasal sprays — reducing the logistical challenge of protecting large numbers of people.A team led by DNARx LLC, under principal investigator Dr. Robert Debs, aims to develop a new DNA-encoded gene therapy that helps patients fight influenza by boosting the natural immune response and other protective functions of their nasal passages and lungs.

Radiation Hazard Symbol

Ionizing Gamma Radiation: Other PREPARE teams are pursuing treatments to protect the body from the effects of ionizing gamma radiation. In humans, radiation poisoning primarily affects stem cells in the blood and gut, yet existing treatments only help to regenerate blood cells, and only with limited effect. There is no possibility for prophylactic administration of these drugs, and most must be delivered immediately following radiation exposure to provide any benefit. There are no existing medical countermeasures for radiation damage to the gut
A team led by the University of California, San Francisco, under principal investigator Dr. Jonathan Weissman, also aims to develop gene therapies to enhance resilience against ionizing radiation. The team’s approach should result in an intravenous or orally available treatment that activates innate defenses in gut and blood stem cells for a period of several weeks.

A Dose of Inner Strength to Survive and Recover from Potentially Lethal Health Threats
New tools for programmable modulation of gene expression could yield enhanced resilience against influenza and ionizing radiation for service members and first responders, DARPA Press Release, June 27, 2019

Unsafe Genes: DARPA

DARPA created the Safe Genes program to gain a fundamental understanding of how gene editing technologies function; devise means to safely, responsibly, and predictably harness them for beneficial ends; and address potential health and security concerns related to their accidental or intentional misuse. Today, DARPA announced awards to seven teams that will pursue that mission, led by: The Broad Institute of MIT and Harvard; Harvard Medical School; Massachusetts General Hospital; Massachusetts Institute of Technology; North Carolina State University; University of California, Berkeley; and University of California, Riverside. DARPA plans to invest $65 million in Safe Genes over the next four years as these teams work to collect empirical data and develop a suite of versatile tools that can be applied independently or in combination to support bio-innovation and combat bio-threats.

Gene editing technologies …[can] selectively disable cancerous cells in the body, control populations of disease-spreading mosquitos, and defend native flora and fauna against invasive species, among other uses. The potential national security applications and implications of these technologies are equally profound, including protection of troops against infectious disease, mitigation of threats posed by irresponsible or nefarious use of biological technologies, and enhanced development of new resources derived from synthetic biology, such as novel chemicals, materials, and coatings with useful, unique properties.

Achieving such ambitious goals, however, will require more complete knowledge about how gene editors, and derivative technologies including gene drives, function at various physical and temporal scales under different environmental conditions, across multiple generations of an organism. In parallel, demonstrating the ability to precisely control gene edits, turning them on and off under certain conditions or even reversing their effects entirely, will be paramount to translation of these tools to practical applications…

Each of the seven teams will pursue one or more of three technical objectives: develop genetic constructs—biomolecular “instructions”—that provide spatial, temporal, and reversible control of genome editors in living systems; devise new drug-based countermeasures that provide prophylactic and treatment options to limit genome editing in organisms and protect genome integrity in populations of organisms; and create a capability to eliminate unwanted engineered genes from systems and restore them to genetic baseline states. Safe Genes research will not involve any releases of organisms into the environment; however, the research—performed in contained facilities—could inform potential future applications, including safe, predictable, and reversible gene drives….

A Harvard Medical School team led by Dr. George Church seeks to develop systems to safeguard genomes by detecting, preventing, and ultimately reversing mutations that may arise from exposure to radiation. This work will involve creation of novel computational and molecular tools to enable the development of precise editors that can distinguish between highly similar genetic sequences. The team also plans to screen the effectiveness of natural and synthetic drugs to inhibit gene editing activity.

A North Carolina State University (NCSU) team led by Dr. John Godwin aims to develop and test a mammalian gene drive system in rodents. The team’s genetic technique targets population-specific genetic variants found only in particular invasive communities of animals. If successful, the work will expand the tools available to manage invasive species that threaten biodiversity and human food security, and that serve as potential reservoirs of infectious diseases affecting native animal and human populations….

A University of California, Berkeley team led by Dr. Jennifer Doudna will investigate the development of novel, safe gene editing tools for use as antiviral agents in animal models, targeting the Zika and Ebola viruses. The team will also aim to identify anti-CRISPR proteins capable of inhibiting unwanted genome-editing activity, while developing novel strategies for delivery of genome editors and inhibitors….

A University of California, Riverside team led by Dr. Omar Akbari seeks to develop robust and reversible gene drive systems for control of Aedes aegypti mosquito populations.

Excerpts from Building the Safe Genes Toolkit, DARPA Press Release, July 19, 2017

Pandemic Counter-Measures: DARPA

The US military supports US Government responses to public health emergencies such as Ebola, which can cause regional destabilization and spread through global travel. Warfighters must also operate in regions where diseases like chikungunya and dengue are endemic, and even seemingly mild challenges like seasonal influenza affect force readiness. In addition to these naturally occurring threats, terrorists and other potential adversaries have a growing palette of biological tools to engineer new biological threats. Existing capabilities to respond to an outbreak and develop therapeutics often take years or even decades to achieve results. Recent examples of public health emergencies have demonstrated a national and global inability to develop effective preventive or therapeutic solutions in a relevant timescale when an infectious threat emerges. The threat of infectious agents on US and global national security can be mitigated if the DoD has the capability to rapidly deploy and impart near-immediate immunity to military personnel and civilian populations for known and newly emerging pathogens.

The goal of P3 is to achieve an integrated capability that can deliver pandemic prevention countermeasures to patients within 60 days of an outbreak. P3 aims to revolutionize outbreak response by enabling rapid discovery, characterization, production, and testing of efficacious medical countermeasures. P3 will innovate in the following areas: (1) Generation of virus stock (including viral unknowns); (2) Rapid evolution of antibody candidates; and (3) Gene-encoded antibody delivery methods.

Excerpts from  The Biological Technologies Office (BTO) of the Defense Advanced Research Projects Agency (DARPA) Proposers Day March 2, 2017 

The Manipulation of Insects: DARPA

DARPA’s Biological Technologies Office s working on new Insect Allies program. Insect Allies will seek to develop vector[insect]-mediated modification technologies for mature plants to rapidly counter environmental and biological threats to crops. Threats might include pathogens, pests, drought, and salinity, among others. DARPA believes that the high specificity of genetic modification coupled with quick plant gene uptake could allow crops to be protected from threats within a single growing season.The Proposers Day will be held on November 18, 2016

Excerpt from  DARPA Press Release Insect Allies Proposers Day, Nov. 2016

Synthetic Biology and the Military

Twist Bioscience announced that it raised $26 million in a Series B financing to commercialize the company’s semiconductor-based synthetic gene manufacturing process. Nick and Joby Pritzker, through their family’s firm Tao Invest, led the round, with participation from ARCH Venture Partners, Paladin Capital Group, Yuri Milner and additional strategic corporate and venture investors. All existing investors participated in the round.

The company also received a $5.1 million contract from the Defense Advanced Research Projects Agency (DARPA) to fund development of Twist’s technology platform for the large-scale, high-throughput construction of genetic designs. DARPA granted the contract under the Living Foundries: 1000 Molecules Program, which seeks to build a scalable, integrated, rapid design and prototyping infrastructure for the facile engineering of biology…

Said Emily Leproust, Ph.D., chief executive officer of Twist Bioscience. “Today, we have all the necessary components in place to automate and scale our synthetic gene manufacturing process and staff strategically, with the goal of bringing our first products and services to the market in 2015.”

According to to Twist Bioscience “At Twist Bioscience, our expertise is synthetic DNA. We have developed a proprietary semiconductor-based synthetic DNA manufacturing process featuring a 10,000-well silicon platform capable of producing synthetic biology tools, such as oligonucleotides, genes, pathways, chassis and genomes. By synthesizing DNA on silicon instead of on traditional 96-well plastic plates, our platform overcomes the current inefficiencies of synthetic DNA production, and enables cost-effective, rapid, high-quality and high throughput synthetic gene production. The Twist Bioscience platform has the potential to greatly accelerate the development of personalized medicine, sustainable chemical production, improved agriculture production as well as new applications such as in vivo diagnostics, biodetection and data storage. 

Twist Bioscience Secures $31.1 Million,  PRESS RELEASE, May 27, 2014

 

Human – Machine Interfaces

From the DARPA website

The mission of the Biological Technologies Office (BTO) is to foster, demonstrate, and transition breakthrough fundamental research, discoveries, and applications that integrate biology, engineering, and computer science for national security. BTO seeks to establish and invest in new communities of scientific interest at the intersection of traditional and emerging disciplines. Its investment portfolio goes far beyond life sciences applications in medicine to include areas of research such as human-machine interfaces, microbes as production platforms, and deep exploration of the impact of evolving ecologies and environments on U.S. readiness and capabilities. BTO’s programs operate across a wide range of scales, from individual cells to complex biological systems including mammalian and non-mammalian organisms and the macro- and micro-environments in which they operate.

BTO Focus Areas

Restore and Maintain Warfighter Abilities Military readiness depends on the health and wellbeing of military service members. A critical part of BTO’s mission is to cultivate new discoveries that help maintain peak warfighter abilities and restore those abilities as quickly and fully as possible when they are degraded or lost. This focus area is grounded in the development of new techniques and therapeutic strategies for addressing current and emerging threats, but extends beyond medical applications to include exploration of complex biological issues that can impact an individual’s ability to operate and interact in the biological and physical world. The research portfolio includes neuroscience to drive a deeper understanding of the human brain, how it interfaces with the body and the external world, and how it directs and coordinates behavior, including decision-making in demanding environs. BTO will extend work involving human participants and apply insights from physiology, biochemistry, psychology, sociology, and related sciences to such emerging-science domains as bioengineering, bioinformatics, and microbiomics.

Harness Biological Systems The highly evolved functional and synthetic capabilities of biological systems can be harnessed to develop new products and systems in support of national security with advantages over what even the most advanced conventional chemistry and manufacturing technologies can achieve. This space and its opportunities are just becoming tangible due to the rapid, simultaneous development of genome-scale engineering tools, enormous genomic datasets, new analytical capabilities, and the convergence of several engineering and scientific disciplines with biology. BTO seeks to establish a fundamental understanding of natural processes and the underlying design rules that govern the behavior of biological systems, and apply that knowledge to forward-engineer new systems and products with novel functionality. To support this work, BTO develops techniques at the intersection of automation, computer science, and biology to explore biological data at massive scales.

Apply Biological Complexity at Scale Biological systems operate over an enormous range of spatial, physical, and temporal scales. Some organisms thrive as individual cells, while many others, including humans, are colonized by communities of foreign cells that greatly outnumber their own and have potentially significant but still largely mysterious impacts on metabolism, psychological state, performance, and health. Disease vectors migrate around the globe slowly and stealthily at times, and at other times in devastating waves of breathtaking speed—poorly understood dynamics that can threaten national security. And because they are so difficult to parse from larger biological and ecological phenomena, population-level effects of relevance to agriculture and food security remain largely unplumbed. BTO is looking into pursuing new insights derived from biological complexity and living-system dynamics with the goal of developing applications to enhance global-scale stability and human wellbeing.

See DARPA Pushes for Industrial Revolution in Genetic Engineering

Industrial Revolution in Genetic Engineering: Military

From DARPA’s Website: Living Foundries

Current approaches to engineering biology rely on an ad hoc, laborious, trial-and-error process, wherein one successful project often does not translate to enabling subsequent new designs. As a result, the state of the art development cycle for engineering a new biologically manufactured product often takes 7+ years and tens to hundreds of millions of dollars (e.g. microbial production of artemisinic acid for the treatment of malaria and the non-petroleum-based production 1,3-propanediol).

[DARPA Goal]

Transforming biology into an engineering practice would enable on-demand production of new and high-value materials, devices and capabilities for the Department of Defense (DoD) and address complex challenges that today have no or few solutions.

The Living Foundries Program seeks to create the engineering framework for biology, speeding the biological design-build-test cycle and expanding the complexity of systems that can be engineered. The Program aims to develop new tools, technologies and methodologies to decouple biological design from fabrication, yield design rules and tools, and manage biological complexity through abstraction and standardization. These foundational tools would enable the rapid development of previously unattainable technologies and products, leveraging biology to solve challenges associated with production of new materials, novel capabilities, fuel and medicines. For example, one motivating, widespread and currently intractable problem is that of corrosion/materials degradation. The DoD must operate in all environments, including some of the most corrosively aggressive on Earth, and do so with increasingly complex heterogeneous materials systems. This multifaceted and ubiquitous problem costs the DoD approximately $23 Billion per year. The ability to truly program and engineer biology, would enable the capability to design and engineer systems to rapidly and dynamically prevent, seek out, identify and repair corrosion/materials degradation.

Accomplishing this vision requires an approach that is more than multidisciplinary – it requires a new engineering discipline built upon the integration of new ideas, approaches and tools from fields spanning computer science and electrical engineering to chemistry and the biological sciences. The best innovations will introduce new architectures and tools into an open technology platform to rapidly move new designs from conception to execution.  Performers must ensure and demonstrate throughout the program that all methods and demonstrations of capability comply with national guidance for manipulation of genes and organisms and follow all guidance for biological safety and Biosecurity.

A Broad Agency Announcement (BAA) solicitation for phase one, Advanced Tools and Capabilities for Generalizable Platforms (ATCG), closed in November, 2011. The BAA called for the development of the advanced, translatable tools and capabilities that will make up an end-to-end technology platform for rapidly, safely and predictably engineering biological production systems. The goals of these advanced tools and capabilities are to compress the biological design-build-test cycle by at least 10x in both time and cost while increasing the complexity of the systems that can be designed and executed by orders of magnitude. These advancements should enable the ability to rapidly design and build new systems to create novel capabilities and to address complex challenges.