- MemberOctober 11, 2021 at 1:44 am
Excerpts from DARPA
DARPA program aims to develop an implantable neural interface able to provide unprecedented signal resolution and data-transfer bandwidth between the human brain and the digital world. The interface would serve as a translator, converting between the electrochemical language used by neurons in the brain and the ones and zeros that constitute the language of information technology. The goal is to achieve this communications link in a biocompatible device no larger than one cubic centimeter in size, roughly the volume of two nickels stacked back to back.
The program, Neural Engineering System Design (NESD), stands to dramatically enhance research capabilities in neurotechnology and provide a foundation for new therapies.
“Today’s best brain-computer interface systems are like two supercomputers trying to talk to each other using an old 300-baud modem,” said Phillip Alvelda, the NESD program manager. “Imagine what will become possible when we upgrade our tools to really open the channel between the human brain and modern electronics.”
Among the program’s potential applications are devices that could compensate for deficits in sight or hearing by feeding digital auditory or visual information into the brain at a resolution and experiential quality far higher than is possible with current technology.
Neural interfaces currently approved for human use squeeze a tremendous amount of information through just 100 channels, with each channel aggregating signals from tens of thousands of neurons at a time. The result is noisy and imprecise. In contrast, the NESD program aims to develop systems that can communicate clearly and individually with any of up to one million neurons in a given region of the brain.
Achieving the program’s ambitious goals and ensuring that the envisioned devices will have the potential to be practical outside of a research setting will require integrated breakthroughs across numerous disciplines including neuroscience, synthetic biology, low-power electronics, photonics, medical device packaging and manufacturing, systems engineering, and clinical testing. In addition to the program’s hardware challenges, NESD researchers will be required to develop advanced mathematical and neuro-computation techniques to first transcode high-definition sensory information between electronic and cortical neuron representations and then compress and represent those data with minimal loss of fidelity and functionality.
To accelerate that integrative process, the NESD program aims to recruit a diverse roster of leading industry stakeholders willing to offer state-of-the-art prototyping and manufacturing services and intellectual property to NESD researchers on a pre-competitive basis. In later phases of the program, these partners could help transition the resulting technologies into research and commercial application spaces.
Atom-width Graphene Sensors Could Provide Unprecedented Insights into Brain Structure and Function
New technology funded by DARPA’s RE-NET program enables monitoring and stimulation of neurons using optical and electronic methods simultaneously
Conventional metal electrode technologies (top left) are opaque, obstructing views of underlying neural tissue. DARPA’s RE-NET program has developed new graphene sensors that are electrically conductive but only 4 atoms thick—hundreds of times thinner than current contacts (top middle). Their extreme thinness enables nearly all light to pass through across a wide range of wavelengths. Placed on a flexible plastic backing that conforms to the shape of tissue (bottom), the sensors are part of a proof-of-concept tool that demonstrates much smaller, transparent contacts that can measure and stimulate neural tissue using electrical and optical methods at the same time (top right).
Understanding the anatomical structure and function of the brain is a longstanding goal in neuroscience and a top priority of President Obama’s brain initiative. Electrical monitoring and stimulation of neuronal signaling is a mainstay technique for studying brain function, while emerging optical techniques—which use photons instead of electrons—are opening new opportunities for visualizing neural network structure and exploring brain functions. Electrical and optical techniques offer distinct and complementary advantages that, if used together, could offer profound benefits for studying the brain at high resolution. Combining these technologies is challenging, however, because conventional metal electrode technologies are too thick (>500 nm) to be transparent to light, making them incompatible with many optical approaches.
To help overcome these challenges, DARPA has created a proof-of-concept tool that demonstrates much smaller, transparent contacts that can measure and stimulate neural tissue using electrical and optical methods at the same time. Researchers at the University of Wisconsin at Madison developed the new technology with support from DARPA’s Reliable Neural-Interface Technology (RE-NET) program. It is described in detail in a paper in Nature Communications (http://www.nature.com/articles/ncomms6258).
“This technology demonstrates potentially breakthrough capabilities for visualizing and quantifying neural network activity in the brain,” said Doug Weber, DARPA program manager. “The ability to simultaneously measure electrical activity on a large and fast scale with direct visualization and modulation of neuronal network anatomy could provide unprecedented insight into relationships between brain structure and function—and importantly, how these relationships evolve over time or are perturbed by injury or disease.”
The new device uses graphene, a recently discovered form of carbon, on a flexible plastic backing that conforms to the shape of tissue. The graphene sensors are electrically conductive but only 4 atoms thick—less than 1 nanometer and hundreds of times thinner than current contacts. Its extreme thinness enables nearly all light to pass through across a wide range of wavelengths. Moreover, graphene is nontoxic to biological systems, an improvement over previous research into transparent electrical contacts that are much thicker, rigid, difficult to manufacture and reliant on potentially toxic metal alloys.
The technology demonstration draws upon three cutting-edge research fields: graphene, which earned researchers the 2010 Nobel Prize in Physics; super-resolved fluorescent microscopy, which earned researchers the 2014 Nobel Prize in Chemistry; and optogenetics, which involves genetically modifying cells to create specific light-reactive proteins.
RE-NET seeks to develop new tools and technologies to understand and overcome the failure mechanisms of neural interfaces. DARPA is interested in advancing next-generation neurotechnologies for revealing the relationship between neural network structure and function. RE-NET, and subsequent DARPA programs in this field, plan to leverage this new tool by simultaneously measuring the function, physical motion and behavior of neurons in freely moving subjects. This technology provides the capability to modulate neural function, by applying programmed pulses of electricity or light to temporarily activate neurons. Therefore, it could not only provide better observation of native functionality but also, through careful modulation of circuit activity, enable exploration of causal relationships between neural signals and brain function.
The DARPA Panacea program generated and published the first human: SARS-CoV-2 protein interactome map in the journal Nature, which describes how the SARS-CoV-2 proteins interact with human cells. Developed by performers at performers at UCSF’s Quantitative Bioscience Institute (QBI) and the Icahn School of Medicine at Mt. Sinai (ISMMS), this map has been used worldwide in the fight against COVID-19. The drug zotatifin, a protein synthesis inhibitor identified by the Panacea performers with their interactome map, is entering a Phase 1 clinical trial in Q1FY21 with investment support from the Defense Health Agency.
In January 2021, these performers published findings in Science demonstrating that Plitidepsin, a compound originally discovered in Mediterranean sea squirts, currently used as a therapeutic for the treatment of multiple myeloma, is 27.5-fold more potent against SARS-CoV-2 than remdesivir in vitro. Remdesivir received FDA emergency use authorization in 2020 for the treatment of COVID-19.
Researchers at Los Alamos National Laboratory (LANL), supported by DARPA’s INTERCEPT program, are modeling in-person and population-based spread of COVID-19 by combining clinical data and mathematical modeling to provide a quantitative understanding of the SARS-CoV-2 infection process within infected individuals and derive principles for therapeutic treatments for the purpose of limiting spread, reducing disease severity, and minimizing the risk of resistance. In a manuscript published in Clinical Pharmacology & Therapeutics, the researchers review current literature on using within-host models to understand SARS-CoV-2 infection dynamics and their relationship with infectiousness, immune responses, and disease severity. This work provides an up-to-date synthesis of what is known about quantitative SARS-CoV-2 viral dynamics and their implication to both non-pharmaceutical and pharmaceutical interventions, such as therapeutics and vaccines.
Another INTERCEPT performer, Autonomous Therapeutics, Inc (ATI), is developing therapeutics to provide protection against any coronavirus – from novel mutational strains of COVID-19 to the next (unpredictable) threat. Known as Therapeutic Interfering Particles (TIPs), these broad-spectrum antivirals can be developed and stockpiled before the next threat emerges or is even known. TIP development is being supported by the INTERCEPT effort, with additional backing for clinical transition from leading private investors and a partnership with BARDA and Johnson and Johnson known as Blue Knight.
ATI is also developing non-invasive platform technologies to enable the at-home, self-administered distribution of next-generation, gene-encoded antivirals. The technology would surmount a major barrier to the distribution of leading vaccine and monoclonal antibody approaches, which require intramuscular (IM) or intravenous (IV) delivery in centralized clinical settings.
On February 3, 2021 a PREPARE performer team at Georgia Tech and colleagues published a paper in Nature highlighting a new mRNA treatment as a potential therapeutic against both influenza A virus and SARS-COV-2 using Cas13a constructs they developed as part of the program.
The COVID-19 pandemic has highlighted vulnerabilities in the U.S. pharmaceutical supply chain. Work being done under DARPA’s Make-It program furthers the development and commercialization of technology that directly addresses these vulnerabilities to enable an end-to-end, deployable and scalable capability for the production of medicines made from readily available commodity materials that can be sourced within the U.S.
AMD performers are collaborating with the Walter Reed Army Institute of Research (WRAIR) to apply artificial Intelligence (AI) techniques to accelerate the discovery of drugs to combat SARS-CoV-2. Under this program, the NIH National Center for Advancing Translational Sciences (NCATS) and WRAIR provide medicinal chemistry expertise to MIT and SRI, and also conduct in vitro testing of the AI predictions to validate and inform the models.
Researchers at MIT are concentrating efforts on the development of new AI algorithms that specifically address the problem of data scarcity inherent in studying a novel virus, and are looking to apply such techniques to identify synergistic combination therapies in the future. They recently posted blog posts on results from their model trained to predict antiviral activity against COVID-19, and efforts towards the development machine-learning tools to aid in identifying molecules with therapeutic effects against the disease.
AMD performers at SRI International are developing AI tools that incorporate chemists’ expert knowledge, in addition to that learned through data, to discover analogs of existing therapeutics with potency against SARS-CoV-2. They have also recently published data on the use of machine learning models to identify inhibitors of the virus.
Under Make-It, Active Pharmaceutical Ingredient (API) production was further automated and expanded to enable the flexible and scalable manufacture of a broad range of APIs. Current efforts are focused on addressing regulatory approval requirements and expanding the capability to enable production of critical medicines and precursors needed to treat critical care COVID-19 patients.
Make-It performers are building a suite of flexible manufacturing capabilities for scalable, resilient production of important medicines:
On Demand Pharmaceuticals’ (ODP) focus is on the production of fine chemical reagents and active pharmaceutical ingredients (APIs), and their technology is based on small-footprint chemical manufacturing devices that were developed in DARPA’s Battlefield Medicine and Make-It programs. Their effort is jointly funded by DARPA and HHS under the CARES Act, and the company enjoyed a visit from FDA Commissioner, Dr. Stephen Hahn, as well as DARPA’s Deputy Director, Dr. Peter Highnam, on 3 December.
SRI International is developing an approach that enables simple scaling of flow-based pharmaceutical production from bench-top to production scale in a single step.
Virginia Commonwealth University is building tools to analyze and optimize U.S. based chemical manufacturing to enable rapid reallocation of existing on-shore process streams to critical APIs in a time of need.
For more information on the highlighted programs, we invite you to visit the appropriate program page. In addition, please continue to follow this space for timely updates on DARPA’s efforts
- MemberOctober 15, 2021 at 11:40 pm
“graphene is nontoxic to biological systems”? they are full of crap. a blatant lie.
- MemberOctober 19, 2021 at 1:54 pm
Absolutely!! A simple search of graphene “toxicity” on PubMed yields thousands of papers.