13th Key Symposium 2016: Bioelectronic Medicine — Technology Targeting Molecular Mechanisms

13th Key Symposium 2016: Bioelectronic Medicine — Technology Targeting Molecular Mechanisms

Wednesday, September 21, 2016 - Friday, September 23, 2016

The New York Academy of Sciences

Technology is changing the world and bioelectronic medicine is at the forefront of this technological revolution. The pharmaceutical industry's history is based on therapies that target molecular mechanisms, yet these therapies are expensive, difficult to administer, often toxic, and may be accompanied by lethal side effects. Bioelectronic medicine — the convergence of molecular medicine; neuroscience and biology; and electronics and computing to develop cures — may change the future of therapies for a wide variety of diseases. This groundbreaking discipline is aimed at interfacing electronics with nerves to specifically target the biological processes underlying disease. Bioelectronic medicine is now at the epicenter of where healthcare, technology, and science converge. A unique moment exists to characterize the challenges and opportunities facing the future of this scientific domain.

The Key Symposium 2016: Bioelectronic Medicine — Technology Targeting Molecular Mechanisms, will convene thought leaders who have the potential to explore, define, and create this new field. Session topics include: Defining Circuits, Cell Biology and Cancer, Molecular Sensing, Clinical Updates, Brain Interfaces, Processing the Future, and Funding the Field. By harnessing the power of technology spanning disciplines from microfluidics to computer processing to molecular technology, we step closer to the promise of bioelectronic medicine — to naturally reproduce a drug's therapeutic reaction by mobilizing the body's natural reflexes to develop effective, safe and economical alternatives to pills and injectables.

Dinner Boat Cruise

There will be a complimentary dinner boat cruise around New York City for symposium attendees on Thursday, September 22, 2016, departing at 6:00 PM. To attend the dinner boat cruise, this social event option must be selected during the registration process.

The final day to register and select this option is September 6, 2016.

Registration Pricing

Before 08/22/2016After 08/22/2016Onsite
Member$350$400$450
Member (Student / Postdoc / Resident / Fellow)$150$200$250
Nonmember (Academia)$450$500$550
Nonmember (Corporate)$900$1,000$1,100
Nonmember (Non-profit)$450$500$550
Nonmember (Student / Postdoc / Fellow)$200$250$300

Agenda

* Presentation times are subject to change.


Wednesday, September 21, 2016

5:00 PM

Registration and Poster Set-Up

5:30 PM

Welcome Remarks
Ellis Rubinstein, President and CEO of The New York Academy of Sciences
Jan Andersson, MD, PhD, Professor in Infectious Disease at Karolinska Institutet, Director for Research at Stockholm County Council, and Editor of JIM Journal of Internal Medicine
Kevin J. Tracey, MD, The Feinstein Institute for Medical Research

5:45 PM

Networking Reception and Poster Session

8:00 PM

End of Symposium Day 1

Thursday, September 22, 2016

7:45 AM

Registration and Continental Breakfast

8:30 AM

Welcome Remarks
Melanie Brickman Borchard, PhD, MSc, The New York Academy of Sciences
Jan Andersson, MD, PhD, Professor in Infectious Disease at Karolinska Institutet, Director for Research at Stockholm County Council, and Editor of JIM Journal of Internal Medicine
Kevin J. Tracey, MD, The Feinstein Institute for Medical Research

Session I: Defining Circuits

Session Chair: Kevin J. Tracey, MD, The Feinstein Institute for Medical Research

8:45 AM

Mapping Reflexes in Immunity
Kevin J. Tracey, MD, The Feinstein Institute for Medical Research

9:15 AM

Somatosensory Neurons in Bacterial Detection and Host Defense
Isaac Chiu, PhD, Harvard Medical School

9:45 AM

Optical Tools for Analyzing and Repairing Complex Biological Systems
Ed Boyden, PhD, Massachusetts Institute of Technology

10:15 AM

Networking Coffee Break

Session II: Clinical Updates

Session Chair: Paul-Peter Tak, MD, PhD, Academic Medical Centre, University of Amsterdam

10:45 AM

Restoring the Balance of the Autonomic Nervous System in Rheumatoid Arthritis: From Preclinical Models to Patients
Paul-Peter Tak, MD, PhD, Academic Medical Centre, University of Amsterdam

11:15 AM

The Cholinergic Anti-inflammatory Pathway in the Gut: From Bench to Bedside
Guy E. Boeckxstaens, MD, PhD, University Hospital Leuven

11:45 AM

Vagus Nerve Stimulation in Inflammatory Bowel Disease
Bruno Bonaz, MD, PhD, Grenoble Faculty of Medicine and Hospital; Grenoble Institute of Neuroscience

12:15 PM

Networking Lunch

Session III: Brain Interfaces

Session Chair: Chad E. Bouton, Northwell Health, The Feinstein Institute for Medical Research

1:30 PM

Cracking the Neural Code, Treating Paralysis, and the Future of Bioelectronic Medicine
Chad E. Bouton, Northwell Health, The Feinstein Institute for Medical Research

2:00 PM

Sequencing the Connectome
Anthony Zador, MD, PhD, Cold Spring Harbor Laboratory

2:30 PM

Active-Sensing to Remodel Brain-Scale Networks in Health and Disease
Bijan Pesaran, PhD, Center for Neural Sciences, New York University

3:00 PM

Networking Coffee Break

Session IV: Molecular Sensing

Session Chair: Agneta Richter-Dahlfors, PhD, Karolinska Institutet

3:30 PM

Interrogating Neural Function with Optoelectronic and Magnetic Materials
Polina Anikeeva, PhD, Massachusetts Institute of Technology

4:00 PM

Real-time Biosensors for Continuously Measuring Specific Biomolecules In Vivo
H. Tom Soh, PhD, Stanford University

4:30 PM

Organic Bioelectronics in Neuroscience and Infection
Agneta Richter-Dahlfors, PhD, Karolinska Institutet

5:00 PM

Closing Remarks

5:10 PM

End of Symposium Day 2

6:00 PM

Dinner Boat Cruise around New York City
Advance Registration Required

Boarding begins at 5:30 PM, cruise departs at 6:00 PM

Friday, September 23, 2016

8:00 AM

Continental Breakfast

Session V: Cell Biology & Cancer

Session Chair: William Doyle, SB, MBA, Novocure

8:30 AM

Metabolic Adaptation in Cancer Cells
Tak W. Mak, PhD, Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network

9:00 AM

Tumor Treating Fields — A Novel Cancer Therapy Utilizing Alternating Electric Fields
William Doyle, SB, MBA, Novocure

9:30 AM

Remote Control of Neural Activity in an Electromagnetic Field
Jeffrey Friedman, MD, PhD, The Rockefeller University, Howard Hughes Medical Institute

10:00 AM

Networking Coffee Break

Session VI: Processing the Future

Session Chair: Peder S. Olofsson, MD, PhD, Karolinska Institutet

10:30 AM

Organic Bioelectronics and Electronic Plants
Magnus Berggren, MSc, PhD, Linköping University

11:00 AM

Symmetries and Abstraction of Information from Vagal Nerve Recordings
Patrick Lincoln, PhD, SRI International

11:30 AM

Acetylcholine-producing T Cells Regulate Blood Pressure
Peder S. Olofsson, MD, PhD, Karolinska Institutet

12:00 AM

Networking Lunch

Session VII: Funding the Field

Session Chair: Nick Langhals, PhD, National Institute of Neurological Disorders and Stroke, U.S. National Institutes of Health

1:00 PM

National Institute of Neurological Disorders and Stroke and NIH Initiatives for Funding Research in Bioelectronic Medicine
Nick Langhals, PhD, National Institute of Neurological Disorders and Stroke, U.S. National Institutes of Health

1:30 PM

The Neurophysiology and Emerging Technologies of the Defense Advanced Research Projects Agency's ElectRx Program
Doug Weber, PhD, U.S. Defense Advanced Research Projects Agency

2:00 PM

Stimulating Peripheral Activity to Relieve Conditions (SPARC): An NIH Common Fund Program
Gene Civillico, PhD, National Institutes of Health

2:30 PM

Panel Discussion:
What Life Will Be Like When We Can Fully Modulate the Nervous System? The Impact on Disease, Drugs, the Healthcare Industry, Personal Freedom, and Privacy
 
Introduction:
Kevin J. Tracey, MD, The Feinstein Institute for Medical Research
 
Moderator:
Miles O'Brien, Science Correspondent, PBS NewsHour
 
Panelists:
Polina Anikeeva, PhD, Massachusetts Institute of Technology
Chad E. Bouton, Northwell Health, The Feinstein Institute for Medical Research
Peder S. Olofsson, MD, PhD, Karolinska Institutet
Doug Weber, PhD, U.S. Defense Advanced Research Projects Administration

3:15 PM

Closing Remarks

3:30 PM

Symposium Ends

Featuring

Peder S. Olofsson, MD, PhD

Karolinska Institutet

Kevin J. Tracey, MD

The Feinstein Institute for Medical Research
website

Scientific Organizing Committee

Melanie Brickman Borchard, PhD, MSc

The New York Academy of Sciences

Meredith L. Burcyk, MHA

The Feinstein Institute for Medical Research

Peder S. Olofsson, MD, PhD

Karolinska Institutet

Erick T. Tatro, PhD

The New York Academy of Sciences

Kevin J. Tracey, MD

The Feinstein Institute for Medical Research

Speakers

Polina Anikeeva, PhD

Massachusetts Institute of Technology
website

Magnus Berggren, MSc, PhD

Linköping University
website

Guy E. Boeckxstaens, MD, PhD

University Hospital Leuven
website

Bruno Bonaz, MD, PhD

Grenoble Faculty of Medicine and Hospital; Grenoble Institute of Neuroscience

Chad Bouton

The Feinstein Institute for Medical Research
website

Ed Boyden, PhD

Massachusetts Institute of Technology
website

Isaac Chiu, PhD

Harvard Medical School
website

Gene Civillico, PhD

National Institutes of Health

William Doyle, SB, MBA

Novocure
website

Jeffrey Friedman, MD, PhD

The Rockefeller University; Howard Hughes Medical Institute

Nick Langhals, PhD

National Institute of Neurological Disorders and Stroke, U.S. National Institutes of Health
website

Patrick Lincoln, PhD

SRI International

Tak W. Mak

Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network

Miles O'Brien

Science Correspondent, PBS NewsHour
website

Bijan Pesaran, PhD

Center for Neural Science, New York University
website

Agneta Richter-Dahlfors, PhD

Karolinska Institutet
website

H. Tom Soh, PhD

Stanford University
website

Paul-Peter Tak, MD, PhD

Academic Medical Centre, University of Amsterdam

Doug Weber, PhD

U.S. Defense Advanced Research Projects Agency
website

Anthony Zador, MD, PhD

Cold Spring Harbor Laboratory

Abstracts

Mapping Reflexes in Immunity
Kevin J. Tracey, MD, The Feinstein Institute for Medical Research

Neural reflexes establish homeostasis in organ systems. Recent advances in neuroscience and immunology have established the identity of reflex mechanisms that regulate innate and adaptive immunity. The first such mechanism, termed the "inflammatory reflex," maintains immunological homeostasis by regulating cytokine production. Molecular products of infection or injury activate sensory neurons traveling to the brainstem within the vagus nerve. Brain stem nuclei respond to the incoming signals and generate action potentials that travel from the brainstem to the spleen and other organs. These signals regulate T cells in spleen to trigger acetylcholine release, the ligand for α7 nicotinic acetylcholine receptors (α7 nAChR) on immunocompetent cells that inhibits inflammasome activity and cytokine release in macrophages. These and other findings in collagen-induced arthritis, colitis, and other experimental models established that neural mechanisms are fundamental to regulating cytokines. Recent clinical trial results first assessed this mechanism and revealed that it is feasible to target the inflammatory reflex in humans with rheumatoid arthritis and colitis. This molecular mechanism approach to therapeutic devices, termed "bioelectronic medicine," offers patients an alternative to biological agents and drugs.

Somatosensory Neurons in Bacterial Detection and Host Defense
Isaac Chiu, PhD, Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School

The somatosensory nervous system densely innervates peripheral barrier tissues including skin, gut, and respiratory tract. Pain is mediated by a subset of somatosensory neurons termed nociceptors, which are able to respond to harmful / noxious stimuli. Two thousand years ago, Celsus defined pain as a major symptom of inflammation. It is increasingly clear that nociceptor neurons not only produce pain, but also play an active role in modulating the immune responses that accompany pain. Our laboratory is interested in determining the role of nociceptor neurons in infection, inflammation, and host defense. We find that nociceptors are able to directly respond to bacterial pathogens and their molecular mediators to induce ionic influx, generate action potentials, and produce pain-like behavior in mice. In turn, these neurons release neuropeptides, which play a role in modulating cytokine production and immune recruitment. Specific ablation of nociceptors or silencing their activity affects the ability of the host to combat bacterial infections in the skin and respiratory tract. Therefore, the peripheral somatosensory nervous system is integrated into host defense by their ability to detect pathogenic dangers and modulate inflammation.
 
Coauthors: Pankaj Baral, PhD1, Kimbria Mills, BS1, Felipe Ribeiro, MSc1, Yan Zhou, MD1, Clifford J. Woolf2
 
1. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts, United States
2. F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States

Optical Tools for Analyzing and Repairing Complex Biological Systems
Ed Boyden, PhD, Department of Biological Engineering, Department of Brain and Cognitive Sciences, Media Lab and McGovern Institute, Massachusetts Institute of Technology

To enable the understanding and repair of complex biological systems such as the brain, we are creating novel optical tools that enable molecular-resolution maps of large scale systems, as well as technologies for observing and controlling high-speed physiological dynamics in such systems. First, we have developed a method for imaging large 3-D specimens with nanoscale precision, by embedding them in a swellable polymer, homogenizing their mechanical properties, and exposing them to water, which causes them to expand isotropically several fold. This method, which we call expansion microscopy (ExM), enables scalable, inexpensive diffraction-limited microscopes to do large-volume nanoscopy. Second, we have collaboratively developed strategies to image fast physiological processes in 3-D with millisecond precision, and are using them to acquire neural activity maps throughout small organisms. Third, we have collaboratively developed nanotechnological and robotic methods to record high-speed electrical events with single cell resolution in living mammalian brain. Finally, we have developed a set of genetically-encoded reagents, known as optogenetic tools, that when expressed in specific neurons, enable their electrical activities to be precisely driven or silenced in response to millisecond timescale pulses of light. In this way we aim to enable the systematic mapping, dynamical observation, and control of complex biological systems like the brain.

Restoring the Balance of the Autonomic Nervous System in Rheumatoid Arthritis: From Preclinical Models to Patients
Paul-Peter Tak, MD, PhD, Academic Medical Centre, University of Amsterdam

We have found lower parasympathetic activity in established rheumatoid arthritis (RA) patients compared to healthy controls, but also in subjects at risk of developing RA (AR). Resting heart rate (RHR), reflecting the balance between sympathetic and parasympathetic activity, was significantly higher in AR individuals who subsequently developed arthritis. AR subjects with RHR ≥70 bpm demonstrated lower levels of the nicotinic acetylcholine receptor type 7 (α7nAChR) on peripheral monocytes than subjects with RHR <70 bpm. It is tempting to speculate that this might be explained by activity of the sympathetic nervous system or hypothalamic–pituitary–adrenal axis if the two autonomic branches counterbalance each other.
 
By screening an adenoviral short hairpin RNA library, we discovered that knockdown of the α7nAChR in RA fibroblast-like synoviocytes results in an increased production of mediators of inflammation and degradation. The α7nAChR is intimately involved in the cholinergic anti-inflammatory pathway (CAP). We could show that treatment with α7nAChR agonists improved arthritis in animal models of RA. Accordingly, stimulation of the CAP by vagus nerve stimulation improved experimental arthritis. Conversely, we found aggravation of arthritis activity in α7nAChR-knockout mice.
 
These data supported exploration of vagus nerve stimulation in RA patients. We found that an implantable vagus nerve stimulating device inhibited monocyte TNF production in RA. Clinical signs and symptoms were significantly improved, even in patients with therapy-resistant disease. Together, these data support the notion that implanted nerve stimulating devices may become a useful treatment alternative for patients with RA and other immune-mediated inflammatory disorders.

The Cholinergic Anti-inflammatory Pathway in the Gut: From Bench to Bedside
Guy E. Boeckxstaens, MD, PhD, Division of Gastroenterology, Translational Research Center for Gastrointestinal Disorders, KU Leuven, University Hospital Leuven, Leuven, Belgium

The gastrointestinal tract is continuously exposed to vast amounts of foreign antigens, mainly of dietary and bacterial origin. Although the intestinal mucosa creates a tight barrier against intraluminal proteins and bacteria, it remains very vulnerable to pathogens, obviating the need for an efficient defense mechanism. Conversely, innocent microorganisms such as commensal bacteria or food antigens should be recognized as harmless to avoid unnecessary inflammation and collateral tissue damage, a mechanism referred to as oral tolerance. The balance between activation of the immune system versus tolerance therefore should be tightly regulated to maintain immune homeostasis not only to prevent chronic inflammation and tissue damage, but also to prevent lethal infection or uncontrolled growth of tumor cells. We recently showed that the enteric nervous system, to a large extent driven by the vagus nerve, exerts an important immune-modulatory role via interaction with CX3CR1high macrophages. In a murine model of postoperative ileus, vagus nerve stimulation prevented manipulation-induced intestinal inflammation and resulted in faster postoperative recovery. In situ Ca2+ imaging revealed dampening of macrophage activation by nicotine and electrical field stimulation, an effect mediated by α7 nicotinic acetylcholine receptors. This anti-inflammatory effect of vagus nerve stimulation was further shown in models of colitis and food allergy, further showing the therapeutic potential of this pathway. Currently, several clinical studies are evaluating the therapeutic effect of vagus nerve stimulation in inflammatory bowel disease and in patients undergoing surgery. To what extent the bench data are indeed translated to the bedside will hopefully become evident soon.

Vagus Nerve Stimulation in Inflammatory Bowel Disease
Bruno Bonaz, MD, PhD, University Clinic of Hepato-Gastroenterology, Grenoble Faculty of Medicine and Hospital; and University Grenoble Alpes, Grenoble Institute of Neuroscience, Inserm, Grenoble, France

Inflammatory bowel disease [IBD; Crohn's disease (CD) and ulcerative colitis] affect an estimated 1.5 million Americans and 2.2 million people in Europe. The pathophysiology of IBD is multifactorial involving immunologic, genetic, infectious, and environmental factors. Medical treatment does not cure IBD but is only suspensive. Anti-tumor necrosis factor (TNF) therapies are the gold standard in the treatment of IBD but are not devoid of adverse events and 20% to 40% of IBD patients are not compliant with their treatment. Thus, a treatment targeting TNF using an intrinsic anti-TNF pathway, with few side effects, devoid of the problem of compliance, and cheaper than biologicals (i.e., anti-TNF) should be of interest.
 
The vagus nerve (VN) has anti-inflammatory properties through its afferents (hypothalamic–pituitary–adrenal axis) and efferents (cholinergic anti-inflammatory pathway: anti-TNF effect). Thus, VN stimulation (VNS), as a non-drug therapy, could be of interest in IBD. We have reported that vagal tone is blunted in CD patients and is associated with a high plasmatic TNF level. We have shown that VNS improves colitis in rats and we recently reported a six month follow-up pilot study of chronic VNS in seven patients with active CD. VNS was feasible and well-tolerated in all patients. Among the seven patients, two were removed from the study at three months for clinical worsening and five evolved toward clinical, biological, and endoscopic remission with a restored vagal tone. These results provide the first evidence that VNS is feasible and appears as an interesting tool in the treatment of active CD.

Cracking the Neural Code, Treating Paralysis, and the Future of Bioelectronic Medicine
Chad E. Bouton, Northwell Health, The Feinstein Institute for Medical Research, Manhasset, New York

Bioelectronic Medicine is a field where devices are developed to treat a wide variety of conditions, including: paralysis, rheumatoid arthritis, diabetes, and even cancer. In paralysis, a "bioelectronic neural bypass" is being developed to circumvent disconnected pathways to reconnect the brain to the affected muscles. Intracortically-recorded signals can be decoded to produce information related to motion allowing primates and paralyzed humans to control computers and robotic arms through imagined movements. In a first-in-human clinical study, we have shown that intracortically-recorded signals can be linked in real-time to muscle activation to restore movement in a paralyzed human. We applied machine-learning algorithms to decode the neuronal activity and control stimulation of the participant's forearm muscles through a custom-built, high-resolution, neuromuscular electrical stimulation system. The participant achieved isolated finger movements and continuous cortical control of six different wrist and hand motions, and completed functional tasks relevant to daily living. The participant's motor impairment level improved from C5-C6 to a C7-T1 level unilaterally, giving him the abilities to grasp, manipulate, and release objects. This is the first demonstration of successful control of muscle contraction utilizing intracortically-recorded signals in a paralyzed human and has significant implications in advancing bioelectronic technology for people living with paralysis. Future work includes developing improved machine-learning algorithms and high-resolution implantable neural interface technology to support highly dexterous movement in hands and lower extremities. These methods are being adapted to deepen our understanding of neural coding in other parts of the nervous system to develop new ways to treat conditions.
 
Coauthors: Jesper Gantelius, PhD, MD, Jorge Dias, PhD, Lara Lama, MSc, Philippa Reuterswärd, MSc, Lourdes Rivas, PhD, and Gustav Svedberg, MSc, Royal Institute of Technology, Stockholm, Sweden

Sequencing the Connectome
Anthony Zador, MD, PhD, Cold Spring Harbor Laboratory

To study the connectivity of neural circuits at high resolution, we have developed an approach based on DNA sequencing that allows us to determine the connectivity of single neurons. The key idea is to tag each neuron with a random nucleotide sequence (a "barcode"), which can be read out by high-throughput sequencing. By recasting neuroanatomy, which is traditionally viewed as a problem of microscopy, as a problem of sequencing, MAPseq harnesses advances in sequencing to permit high-throughput interrogation of brain circuits.

Active-Sensing to Remodel Brain-Scale Networks in Health and Disease
Bijan Pesaran, PhD, Center for Neural Sciences, New York University

The development of advanced neural technologies to understand the healthy brain and treat brain disorders depends on manipulating neural dynamics across large-scale brain networks. In this talk I will present an active-sensing paradigm to resolve and precisely target networks in the primate brain by combining multisite neural recordings with spatiotemporal multisite patterned stimulation. I will demonstrate how this approach can reveal the functional organization of frontal-parietal, mesolimbic and basal ganglia systems involved in attending, deciding and planning. Active-sensing provides new ways to identify neural signatures for closed-loop stimulation protocols with the goal of remodeling neuronal networks in the healthy and diseased brain.

Interrogating Neural Function with Optoelectronic and Magnetic Materials
Polina Anikeeva, PhD, Department of Materials Science and Engineering, Research Laboratory of Electronics, Massachusetts Institute of Technology

Our ability to understand the signaling complexity of the nervous system is currently limited by the lack of tools capable of multifunctional interfaces with neurons without causing a foreign body response. We have recently applied fiber-based and nanomagnetic approaches to monitoring and modulating neuronal function in the brain, spinal cord, and the periphery. Using fiber-drawing techniques we have produced multifunctional flexible probes for electrophysiological recording, optical stimulation, and delivery of pharmacological compounds and viral vectors into the brain and spinal cord. Furthermore, we have shown that these devices are suitable for guiding the repair of the damaged nerves. In parallel with the fiber-based platforms, we have been pursuing magnetic nanomaterials as transducers of wireless neuromodulation in deep tissue. Specifically, synthetic magnetic nanoparticles have been functionally coupled to heat-sensitive ion channels, allowing for magnetothermal neuromodulation with alternating magnetic fields.

Real-time Biosensors for Continuously Measuring Specific Biomolecules In Vivo
H. Tom Soh, PhD, Department of Electrical Engineering and Department of Radiology, Stanford University, Stanford, California, United States

A biosensor capable of continuously measuring specific molecules in the bloodstream in vivo would give clinicians a valuable window into patients' health and their response to therapeutics. Unfortunately, continuous, real-time measurement is currently only possible for a handful of targets (i.e., glucose and oxygen) and existing platforms for continuous measurement are not generalizable for monitoring other biomolecules. Here, we will present a "universal" real-time biosensor technology capable of continuously tracking a wide range of circulating molecules in living animals. Our real-time biosensors require no exogenous reagents, operates at room temperature, and can be reconfigured to measure different target molecules by exchanging probes in a modular manner. To demonstrate the system’s versatility, we will present real-time measurement of doxorubicin (a chemotherapeutic) and kanamycin (an antibiotic) in live rats with sub-minute temporal resolution. Finally, we will present the first real-time, closed loop feedback control of drug concentration in live animals using the real-time biosensor system and discuss potential applications of our technology.

Organic Bioelectronics in Neuroscience and Infection
Agneta Richter-Dahlfors, PhD, Karolinska Institutet, Stockholm, Sweden

Over the last decade, organic bioelectronics have become more popular and widely used in biological research and medicine. Organic bioelectronic devices are based on conductive polymers — materials that show great flexibility, optical transparency, as well as electrical and ionic conductivity. Further, they can be adapted and functionalized in a wide variety of ways thanks to organic chemistry methods. This combination of structural and functional flexibility makes them especially well-suited to applications in the medical field since it allows precise modeling of various attributes of cells and human tissues. This presentation will highlight a series of organic bioelectronic devices that function based on the principle of iontronics. Further, we will introduce a panel of active surfaces based on organic bioelectronics, which help to mimic dynamic biological environments and allow modulating cell behavior with high degrees of spatiotemporal control. Since self-controlled systems are the ultimate goal in bioelectronic interfaces aiming to alleviate pathological states, sensing applications based on organic bioelectronics are also included. The focus will be placed on specific applications of organic bioelectronics in neuroscience and infection.
 
Coauthor: Susanne Löffler, PhD, Karolinska Institutet, Stockholm, Sweden

Metabolic Adaptation in Cancer Cells
Tak W. Mak, PhD, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network

The regulation of oxidative stress ("fire") is an important factor in both tumor development and responses to anti-cancer therapies. Many metabolic signaling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. For example, isocitrate dehydrogenases 1 and 2 (IDH1/2), carnitine palmitoytransferase 1c (CPT1c), PARK-7, estrogen, UDPase, HMGB1, AhR etc. High ROS levels are generally detrimental to a cell and trigger its death. As a consequence, the redox ("water") status of cancer cells differs from normal cells and cancer cells often exhibit an elevation of ROS. These observations suggest that ROS may constitute a barrier to tumorigenesis. However, ROS can also promote tumor formation by inducing mutations. These contradictory effects have important therapeutic implications for the modulation of ROS as an antitumour strategy. In this presentation, we address the controversial role of ROS in tumor development and in responses to anti-cancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells has a positive therapeutic impact. In this context, we have developed two inhibitors that affect cell cycle and apoptosis. We are targeting two mitotic enzymes PLK4 and TTK involved in centriole duplication and spindle assembly checkpoints, respectively.

Tumor Treating Fields — A Novel Cancer Therapy Utilizing Alternating Electric Fields
William F. Doyle, SB, MBA, Novocure Ltd., New York, New York, United States

Tumor Treating Fields (TTFields) is a novel cancer treatment modality utilizing 100–1000 kHz, electric fields to exert forces on charged intracellular proteins interrupting cell division and causing cancer cell death. Cell death occurs through multiple pathways including apoptosis, chromosome miss-segregation with subsequent reduced clonogenic potential of cellular progeny, and immunogenic cell death. TTFields has been shown to be frequency specific for different cell types, affording it a high therapeutic index. In 2015 the United States Food and Drug Administration approved TTFields for the treatment of newly diagnosed glioblastoma, the most common primary brain cancer, based on the results of a phase 3 clinical trial demonstrating significant improvements in progression-free and overall survival. Promising phase 2 clinical trial results have also been shown in non-small cell lung cancer (NSCLC) and pancreatic cancer. Ongoing clinical trials are being conducted in ovarian cancer, mesothelioma, and brain metastases from NSCLC. TTFields therapy requires tumor exposure to electric fields of 1–3 volts per centimeter for at least 18 hours per day for a period of up to 2 years. Exposure is accomplished with a portable electric field generator and transducer arrays attached to the skin surrounding the tumor region. These arrays are insulated by a high dielectric constant (ε > 5,000), non-porous, Lead Magnesium Niobate – Lead Titanate (PMN-PT) ceramic layer to provide maximum electric field intensity while minimizing tissue damage at the sites of application. Device size and power consumption are minimized by utilizing novel digital signal generating technologies specifically designed to operate within the TTFields frequency and load ranges.

Remote Control of Neural Activity in an Electromagnetic Field
Jeffrey Freidman, MD, PhD, The Rockefeller University, Howard Hughes Medical Institute, New York, New York, United States

Targeted, temporally regulated neural modulation using light or drugs has proven invaluable for determining the physiological roles of specific neural populations or circuits. Recently, we have developed an alternative method enabling non-invasive temporal activation or inhibition of neuronal activity using electromagnetic waves. We have used this method in vivo to control gene expression and to study the central nervous system control of glucose homeostasis and feeding in mice. Neuronal activation using radio waves or magnetic fields is achieved by co-expressing a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP–TRPV1). Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. Acute activation of glucose-sensing neurons in the hypothalamus was found to increase plasma glucose and glucagon, lower insulin levels, and stimulate feeding; while inhibition reduced blood glucose, raised insulin levels, and suppressed feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behavior. The method we developed allows neural regulation on a more rapid time scale than drugs and obviates the need for permanent implants. The transduction mechanism by which the electromagnetic wave gates TRPV1 has not been precisely defined with temperature, motion, and local voltage changes all potentially contributing.
 
Current studies focus on the application of the method to study a variety of biologic process in neurons and other cell types.

Organic Bioelectronics and Electronic Plants
Magnus Berggren, MSc, PhD, Laboratory of Organic Electronics, Linköping University, Linköping, Sweden

Organic electronics is explored as the signalling bridge between biological systems and electronics targeting new opportunities in diagnostics, therapy, and biotechnology. Using the coupled charge accumulation and ion exchange of conjugated polymer–polyelectrolyte systems different sensor and actuator devices have been developed. Included in circuits, these can simultaneously record and regulate physiology and functions at high spatiotemporal resolution. As artificial nervous systems, such circuits have successfully been applied, in vivo, to combat for example, pathological pain and epileptic seizures, in tissue and animal models. Applied to, and manufactured inside, the vascular systems of plants, e.g., Rosa floribunda, analogue and digital organic circuits have successfully been achieved, thus open up for new "green" energy technologies and electronic control over growth and production processes in living plants.
 
Coauthors: E. Gabrielsson1, A. Jonsson1, K. Tybrandt1, D. Simon1, E. Saitanidou1, E. Gomez1, R. Gabrielsson1, Ove Nilsson2, B. Meyersson3, G. Malliaras4, G. Gustafsson5, D. Nilsson5
 
1. Laboratory of Organic Electronics, Linköping University, Linköping, Sweden
2. Umeå Plant Science Center, Umeå, Sweden
3. Karolinska Sjukhuset, Stockholm, Sweden
4. EMSE, Gardanne, France
5. Printed Electronics, Acreo Swedish ICT, Kista, Sweden

Symmetries and Abstraction of Information from Vagal Nerve Recordings
Patrick Lincoln, PhD, SRI International

Dr. Lincoln will discuss novel machine learning, symbolic reasoning, and signal process steps that he and his collaborators at SRI and the Feinstein Institute have performed on neurograms, supporting attempts to create partially or completely synthetic neurograms optimized for specific targeted effects. In the fullness of time, the research aims to provide researchers powertools to analyze natural signals and create synthetic signals with designed effect.

National Institute on Neurological Disorders and Stroke and National Institutes of Health Initiatives for Funding Research in Bioelectronic Medicine
Nick Langhals, PhD, National Institute on Neurological Disorders and Stroke, U.S. National Institutes of Health, Bethesda, Maryland, United States

The National Institutes of Health (NIH), and in particular, the National Institute of Neurological Disorders and Stroke (NINDS), are actively participating in several funding initiatives in the area of bioelectronic medicine and peripheral neuromodulation therapies. Active NIH efforts include "Stimulating Peripheral Activity to Relieve Conditions" (SPARC) as well as the "Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative." NINDS is also participating in several efforts focused around small molecule, biologic, and therapeutic devices. During this talk, I will present an overview of the efforts in this area as well as outline details of current funding opportunities for participating in this area of research.

Acetylcholine-producing T Cells Regulate Blood Pressure
Peder S. Olofsson, MD, PhD, Karolinska Institutet

Modulation of neural reflex activity potentially represents a groundbreaking advance in treatment options for inflammation, but knowledge of the involved components and signals is still incomplete.
 
The current understanding of the efferent arc of the inflammatory reflex is that signals travel in the vagus nerve to the celiac ganglion where the adrenergic splenic nerve arises. Splenic nerve endings are found in proximity of choline acetyltransferase (ChAT) + T cells (CD4 TChAT) in spleen. CD4 TChAT release acetylcholine in response to norepinephrine-exposure, and provide ligands to activate acetylcholine receptors on immune cells in spleen. This cholinergic signal is essential for the integrity of the inflammatory reflex.
 
The discovery that CD4 TChAT relay neural signals affords a mechanism for providing cholinergic signals to tissues devoid of cholinergic innervation. Vascular endothelial cells express cholinergic receptors, but most blood vessels lack cholinergic innervation. Activation of endothelial cholinergic receptors reduces blood pressure by relaxing vascular smooth muscle cells through a nitric oxide-dependent mechanism. ChAT+ lymphocytes increase endothelial cell release of nitric oxide, CD4 TChAT are found in murine blood, and mice deficient in CD4 TChAT show significantly increased blood pressure and signs of increased vascular resistance. The observations indicate that CD4 TChAT regulate blood pressure.
 
This improved understanding of lymphocyte-derived acetylcholine to mediate arterial relaxation suggests that enhancing cellular acetylcholine release in the vasculature can regulate blood pressure. Moreover, CD4 TChAT cells are regulated by neural signals traveling in the vagus and splenic nerves. Studies of these mechanisms may offer another strategy to control the activity of blood pressure-regulating ChAT+ lymphocytes and reduce hypertension.

The Neurophysiology and Emerging Technologies of the Defense Advanced Research Projects Agency's ElectRx Program
Doug Weber, PhD, Defense Advanced Research Projects Agency / Biological Technologies Office, Arlington, Virginia

To advance DARPA's mission to enable breakthrough technologies for National Security, the DARPA ElectRx program is funding efforts to unravel the neurophysiology governing inflammatory disease and post-traumatic stress disorder (PTSD) while simultaneously investing in disruptive neural interface and biosensor technologies. Combined, the DARPA ElectRx portfolio is driving towards an integrated solution for atraumatic, closed-loop neuromodulation to treat disease in humans. In this talk, Dr. Weber, program manager of ElectRx, will discuss the science, technology, and strategy that DARPA is undertaking to realize a vision where bioelectronic medicines are no longer therapies of last resort, but instead are recognized as effective, safe, and minimally invasive enough to use as frontline interventions.

Stimulating Peripheral Activity to Relieve Conditions (SPARC): an NIH Common Fund Program
Gene Civilico, PhD, Office of the Director, United States National Institutes of Health

Therapeutic neuromodulation via peripheral nerve transmission has produced some recent successes, ranging from proof of concept to demonstrated clinical utility, across several model systems and indications. Nevertheless, the relatively poor mechanistic understanding of such interventions remains limiting with regard to their further improvement. More detailed study of nerve and organ anatomy and physiology, as well as in vitro, in vivo, and in silico model systems with greater predictive value in humans, are urgently needed. To address these gaps, the NIH Common Fund has launched Stimulating Peripheral Activity to Relieve Conditions (SPARC), with the goal of advancing the mechanistic understanding of peripheral nerve control of end-organ function. In this presentation I will outline the current architecture of the SPARC program and highlight ongoing opportunities and future goals. I will share highlights from SPARC-funded efforts to the present, including promising animal models and technical approaches. Finally, I will touch on some process innovations that power the SPARC program and provide a view of our data coordination and resource sharing plans.
 
About the NIH Common Fund:
The NIH Common Fund supports short term, exceptionally high impact, trans-NIH programs. These programs represent strategic and nimble approaches to key roadblocks in biomedical research that impede basic scientific discovery and its translation into improved human health. The Common Fund is managed by the Office of Strategic Coordination, part of the Division of Program Coordination, Planning, and Strategic Initiatives in the NIH Office of the Director.

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