DARPA’s role and investments in defense-related research and development (R&D), including biological defense, has potential significance for the science and technology available to address the Coronavirus Disease 2019 (COVID-19) pandemic and any future biological threats. In 2018, the Biological Technologies Office (BTO) of the Defense Advanced Research Projects Agency (DARPA) launched an ambitious new program to counter-proliferation of weapons of mass destruction. DARPA was interested in diminishing the threat posed by state or non-state actor use of weapons of mass destruction (WMD) and improving diagnostics for troops who may have been exposed to threat agents.
“Current forensic and diagnostic screening technologies can only detect the immediate presence of many materials and require sensitive instruments,” Stuart Sealfon, director of the Center for Translational Systems Biology at the Icahn School of Medicine and the DARPA contract’s principal investigator, said in a statement. DARPA launched the Epigenetic CHaracterization and Observation (ECHO) program in Feb 2018, with the aim to develop a portable device that could identify–within 30 minutes—which pathogen you have been exposed to and when? It could be caused by a virus, bacteria, or in the most extreme catastrophe, a biological agent from a weapon of mass destruction. It would be pretty remarkable for soldiers in the field, but also for civilians seeking medical treatment.
Its success depends on a biological phenomenon known as the epigenome. The epigenome is biology’s recordkeeper. Though DNA does not change over a single lifetime, a person’s environment may leave marks on the DNA that modify how that individual’s genes are expressed. This is one way that people can adapt and survive in changing conditions, and the epigenome is the combination of all of these modifications. Though modifications can register within seconds to minutes, they imprint the epigenome for decades, leaving a time-stamped biography of an individual’s exposures that is difficult to deliberately alter. It’s thanks to the epigenome that identical twins – who share identical DNA – can differ in health, temperament, and appearance. DARPA’s ECHO seeks to develop technologies that enable the use of an individual’s epigenome to reveal their history of exposure to WMD and WMD precursors
DARPA’s new Epigenetic CHaracterization and Observation (ECHO) program aims to build a field-deployable platform technology that quickly reads someone’s epigenome and identifies signatures that indicate whether that person has ever been exposed to materials that could be associated with weapons of mass destruction. Whereas current forensic and diagnostic screening technologies only detect the immediate presence of contaminants, the envisioned ECHO technology would read someone’s epigenome from a biological sample, such as a finger prick or nasal swab, to reveal possible exposure to WMD or WMD precursors, even when other physical evidence has been erased.
The new technology exploits our own internal “flight data recorder,” known as the epigenome, explained Eric Van Gieson, the ECHO program manager. The epigenome is a collection of chemical and structural modifications that happen to the DNA in every cell of your body after you’ve been exposed to something. It could be anything—an infection, alcohol consumption, psychological trauma, literally anything that happens to you can leave a mark on your epigenome for decades. (Think of how a tree ring inside a tree can leave a timestamp of an environmental event that occurred in the tree’s past.) Each of these marks is unique to a given type of experience, and we have billions of potential marks to be left in patterns that are unique to a very specific life experience or exposure (i.e. infection). What is especially interesting and unique about the platform is that it can uncover evidence of exposure events immediately after they happen (within hours) and also long after other physical evidence is gone. Detection is not dependent upon the infectious disease or other contaminant being present.
It turns out our bodies are better sensors than anything we can build synthetically to date. For example, we’ve realized that our body’s reaction to an infection happens two or three days before one can even detect the pathogen, so why not use our own body for early detection? The technology that we are developing in DARPA’s ECHO program allows us to decode those marks to diagnose disease, and also predict the potential upcoming outcomes from that disease. This prediction or “prognosis” could provide us with a new tool to figure out how to treat someone more effectively for diseases such as COVID or even cancer. If this truly pans out, we will now have the ability to guide therapy, triage patients, and plan response resources for infectious disease patients (including COVID-19) more efficiently than we ever have before. Essentially, we will get ahead of the disease to maximize survival.
This technology is being built on a diagnostic platform that will be roughly the size of a shoebox and capable of running up to 192 samples in the field in about 1-2 hours. So, the inspiration of the ECHO Program has been to avoid disastrous consequences by building a better early warning system that is also more accurate and believable. It saves long-term costs and consequences downstream, and it fills the gaps that we have right now for an effective early warning system for different types of diseases and exposures (both known and unknown).
We hope that with the capabilities developed within ECHO, someone in the field will immediately know if a suspected adversary has handled or been exposed to threat agents. The same technology could also serve as a diagnostic tool for our own troops, to diagnose an infectious disease or reveal exposure to threat agents, so that medical countermeasures can be applied in time to make a difference.” “Additionally, by making it possible to deploy an analytical capability to vastly more locations, we would enhance our ability to conduct global, near-real-time surveillance of emerging threats.” “In an outbreak,” says Dr. Thomou, “it will help everyone on the ground immediately to have a rapidly deployable machine that will give you very quick answers to issues that could have far-reaching ramifications for public health safety.”
The ability to partially reconstruct an individual’s history through analysis of the epigenome, however, could have application well beyond national security and thus raise privacy concerns. Accordingly, DARPA intends to proactively engage with several independent ethical and legal experts to help inform the Agency’s research plans, think through potential issues, and foster broader dialogue in the scientific community on social implications.
By measuring the body’s response to an invading infection, the technologies developed within the ECHO program can potentially diagnose infection 2-3 days before conventional tests that are used today for diagnosing COVID and other infectious diseases. An awardee from DARPA’s Epigenetic Characterization and Observation (ECHO) program, Fluidigm, in collaboration with a consortium of medical schools, is developing an early detection test for SARS-CoV-2, the novel virus that causes COVID-19.
We started applying it [these tools] to COVID in March 2020, as we got our first samples from the folks in Japan from the Diamond Princess cruise ship in February. Even before people were really taking this seriously from a public health response perspective, DARPA was already developing either therapies, like antibody therapies under my colleague Dr. Amy Jenkins’ Pandemic Prevention Platform (P3), or diagnostics under the ECHO program along with other responses. We were working feverishly to try to put together some sort of response.
Researchers in the ECHO program plan to create a database of signatures for exposure events, so that their envisioned device will be able to quickly scan someone’s epigenome and refer to the database to sort out a diagnosis. The same technology could also serve as a tool for U.S. troops to diagnose infectious disease or reveal exposure to threat agents so that medical countermeasures can be applied in time to make a difference.
The program will last four years and be divided into two missions. Researchers on the ECHO program will solve two primary challenges: to identify and discriminate epigenetic signatures created by exposure to threat agents; and to create technology that performs highly specific forensic and diagnostic analyses to reveal the exact type and time of exposure. To develop this capability, researchers will have to assemble a foundational training dataset of pre-and post-exposure epigenetic readouts in biological samples.
“One difficult part is to put a time stamp on this result, in addition to the sign of which exposure it was — to tell us when this exposure happened,” says Thomas Thomou, a contract scientist who is providing technical assistance to the ECHO program manager. Other questions remain up in the air for now: Do all humans have the same epigenetic response to the same exposure events? Is it possible to distinguish viral from bacterial exposures? Does dose and duration of exposure affect the signature of epigenome modification?
They will also have to create a device capable of performing multiple molecular analyses and onboard bioinformatics in 30 minutes or less, compared to an average of two days using current lab-centered processes. By the end of the effort, DARPA’s goal is to deliver ECHO capability in a man-portable device that can be used by an operator with minimal training.
Mount Sinai Gets $27.8M DARPA Grant for Epigenetic Tech to Measure WMD Exposure
The Icahn School of Medicine at Mount Sinai announced that it has been awarded a $27.8 million contract from the Defense Advanced Research Projects Agency (DARPA) to find epigenetic markers in blood that identify previous exposures and time of exposure to materials that could be associated with weapons of mass destruction.
The four-year contract also includes the development of a field-deployable instrument that can perform highly specific forensic and diagnostic analyses to reveal the type and time of exposure, Mt. Sinai said, and covers markers for infectious agents, chemicals, and radiation.
The agreement is part of DARPA’s new Epigenetic Characterization and Observation (ECHO) program, which will develop new approaches to analyze epigenetic markers and new instrumentation that can be used in the field by operators with minimal training. Mount Sinai noted that its researchers will lead a consortium that includes six other academic partners and two industry collaborators.
“The human body logs exposures in a rich biographical record that we carry around with us in our epigenomes. The ECHO technology we and our partners are developing through the DARPA program will enable us to quickly read someone’s epigenome from a small amount of blood to reveal possible exposure to infectious agents, chemicals, or radiation, even when other physical evidence has been erased.”
The researchers are also hoping that the technology they develop through the ECHO program could also be used to diagnose infectious disease. DARPA said it intends to proactively engage with several independent ethical and legal experts to help inform its research plans.
Duke awarded $6.2 million
In a project dubbed MEMENTO—Mapping Epigenetic Memory of Exposure to Observe—Duke has been awarded $6.2 million over the next four years to help make this idea a reality.
Led by co-principal investigators Xiling Shen, the Hawkins Family Associate Professor of Biomedical Engineering at Duke, and Christopher Woods, professor of medicine and global health at Duke and chief of the infectious diseases section at the Durham VA Medical Center, the project draws on a treasure trove of rare biological samples to help researchers across the ECHO program discover specific epigenetic signatures associated with various exposures.
Duke Global Health Institute researchers will also collect a number of new sample cohorts for use in the DARPA projects to study how epigenetic markers persist over time. Gayani Tillekeratne, assistant professor of medicine and global health, will collect samples from subjects with confirmed dengue virus infection in southern Sri Lanka, where Dharshan de Silva, director and senior scientist at Genetech Research Institute, will pursue a similar cohort of subjects with Burkholderia pseudomallei, the cause of melioidosis. Woods will work with colleagues from Tulane in Sierra Leone to gather specimens from survivors of the Ebola-like hemorrhagic disease Lassa fever and with UCLA investigators in the Democratic Republic of Congo to gather samples from survivors of Ebola outbreaks, including from the very first in 1976.
The resources also include a 20-year historical library of Methicillin-resistant Staphylococcus aureus (MRSA) samples collected by Duke School of Medicine professor Vance Fowler. Lisa Satterwhite, assistant research professor of civil and environmental engineering at Duke, will provide samples from an ongoing program studying the effects of farmworkers’ exposures to organophosphates, which are used in insecticides and are precursors to nerve agents used in chemical warfare.
“Our clinical team has an overarching responsibility to design studies and provide samples to both DARPA projects,” said Woods. “It’s a novel, exciting program that is looking at epigenetic signatures in both real-time exposures as well as their evolution over time. And while there’s a clear defense angle to the work, there’s also a practical clinical understanding that will be beneficial as well.”
On the engineering side, Duke researchers will use their expertise in three challenging RNA and epigenetic analysis techniques and machine learning to identify regions of DNA called enhancers activated by exposure to these diseases.
While only about one percent of the human genome encodes directions for the making of proteins, buried within the remaining “dark genome” are regions called enhancers that can turn on the protein-makers on. “Enhancers are these control knobs that remotely dial up or down the activity genes,” said Shen. “Our hypothesis is that these enhancers are most likely where the epigenetic memories of exposures to harmful agents are kept.”
To get a full picture of DNA activity, Duke researchers are combining three separate techniques. In Shen’s laboratory, research assistant professor Shengli Ding and PhD student Nick Giroux will perform total RNA sequencing to discover which segments of the dark genome are active and microRNA sequencing to reveal molecules released to stop other RNA from delivering their instructions. Purushothama Rao Tata, assistant professor of cell biology, and Yoshihiko Kobayashi, postdoctoral associate of cell biology, will perform a cutting-edge technique named Mint-ChIP to identify sections of DNA packed away by proteins called histones, allowing researchers to isolate them and remove the proteins to discover which segments of DNA they were activating or silencing.
“We have to use all three of these profiling techniques to infer their activity,” said Shen. “By pursuing a multi-omics approach that compiles a wide variety of profiling techniques, we can develop a comprehensive signature that tells us if a person has had a harmful exposure and to what specific agent.”
Other partners in the collaboration will also be analyzing these rare exposure samples, but through different methods focused on other alterations to the epigenome and the DNA itself. They will also work with exposures to different types of WMDs, such as radiation, chemical weapons and explosives.Once signatures are discovered, partner institutions will begin developing a compact, lightweight device capable of scanning biological fluids to detect them.
“The human body registers exposures and logs them in the epigenome,” explained Eric Van Gieson, the ECHO program manager, in a release announcing the program. “We are just beginning to understand this rich biographical record that we carry around with us. We hope that with the capabilities developed within ECHO, someone in the field will immediately know if a suspected adversary has handled or been exposed to threat agents. The same technology could also serve as a diagnostic tool for our own troops, to diagnose infectious disease or reveal exposure to threat agents, so that medical countermeasures can be applied in time to make a difference.”
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