Titan, former world’s fastest supercomputer (credit: Oak Ridge National Laboratory)
President Obama has signed an executive order authorizing the National Strategic Computing Initiative (NSCI), with the goal of creating the world’s fastest supercomputers. The NSCI is charged with building the world’s first-ever exascale* (1,000-petaflops) computer — 30 times faster than today’s fastest supercomputer.
The order mandates:
Accelerating delivery of a capable exascale computing system that integrates hardware and software capability to deliver approximately 100 times the performance of current 10 petaflop systems across a range of applications representing government needs.
Increasing coherence between the technology base used for modeling and simulation and that used for data analytic computing.
Establishing, over the next 15 years, a viable path forward for future HPC systems even after the limits of current semiconductor technology are reached (the “post-Moore’s Law era”).
Increasing the capacity and capability of an enduring national HPC ecosystem by employing a holistic approach that addresses relevant factors such as networking technology, workflow, downward scaling, foundational algorithms and software, accessibility, and workforce development.
Developing an enduring public-private collaboration to ensure that the benefits of the research and development advances are, to the greatest extent, shared between the United States Government and industrial and academic sectors.
Regaining number 1
In 2013, the U.S lost its position as having the world’s fastest supercomputer — Titan, with 17.59 petaflop/s (quadrillions of calculations per second) Rmax on the Linpack benchmark — to China with its Tianhe-2, a supercomputer with 33.86 petaflop/s, developed by China’s National University of Defense Technology, according to the TOP500 lists of the world’s most powerful supercomputers.
There are three lead agencies for the NSCI: the Department of Energy (DOE), the Department of Defense (DOD), and the National Science Foundation (NSF). There are also two foundational research and development agencies for the NSCI: the Intelligence Advanced Research Projects Activity (IARPA) and the National Institute of Standards and Technology (NIST).
Researchers from Berkeley Lab and Columbia University have created the world’s highest-performance single-molecule diode, using a combination of gold electrodes (yellow) and a “TDO” molecule (purple, with molecular structure on the left) in propylene carbonate, an ionic solution (light blue). The circuit symbols on the right represent a battery and an ammeter (A) to measure current flow. (credit: Brian Capozzi et al./Nature Nanotechnology)
A team of researchers from Berkeley Lab and Columbia University has created “the world’s highest-performance single-molecule diode,” using a combination of gold electrodes and an ionic solution.
The diode’s rectification ratio (ratio of forward to reverse current at fixed voltage) is in excess of 200, “a record for single-molecule devices,” says Jeff Neaton, Director of the Molecular Foundry, a senior faculty scientist with Berkeley Lab’s Materials Sciences Division and the Department of Physics at the University of California Berkeley and a member of the Kavli Energy Nanoscience Institute at Berkeley (Kavli ENSI).
Ultimate electronic miniaturization
Single-molecule devices represent the ultimate limit in electronic miniaturization, the researchers say. In 1974, molecular electronics pioneers Mark Ratner and Arieh Aviram theorized that an asymmetric molecule could act as a diode, or rectifier (a one-way conductor of electric current). Diodes have a number of uses in electronic devices.
Since then, development of functional single-molecule electronic devices has been a major pursuit, with diodes — one of the most widely used electronic components — at the top of the list.
A p–n junction (credit: Wikimedia Commons)
A typical current diode consists of a silicon p-n junction between a pair of electrodes (anode and cathode) that serves as the “valve” of an electrical circuit, directing the flow of current by allowing it to pass through in only one “forward” direction. The asymmetry of a p-n junction presents the electrons with an “on/off” transport environment (p–n junctions are elementary “building blocks” of most semiconductor electronic devices such as transistors, solar cells, LEDs, and integrated circuits).
Scientists have previously fashioned single-molecule diodes either through chemical synthesis of special asymmetric molecules (analogous to a p-n junction) or using symmetric molecules with different metals as the two electrodes. However, the resulting asymmetric junctions yielded low rectification ratios and low forward current. Neaton and his colleagues at Columbia University have now discovered a way to address both deficiencies.*
The Berkeley Lab-Columbia University team believes their new approach to a single-molecule diode provides a general route for tuning nonlinear nanoscale-device phenomena that could be applied to systems beyond single-molecule junctions and two-terminal devices, such as ionic liquid gating and two-dimensional materials.
The research is described in Nature Nanotechnology.
* “Electron flow at molecular length-scales is dominated by quantum tunneling,” Neaton explains. “The efficiency of the tunneling process depends intimately on the degree of alignment of the molecule’s discrete energy levels with the electrode’s continuous spectrum. In a molecular rectifier, this alignment is enhanced for positive voltage, leading to an increase in tunneling, and is reduced for negative voltage. At the Molecular Foundry we developed an approach to accurately compute energy-level alignment and tunneling probability in single-molecule junctions. This method allowed myself and Zhenfei Liu to understand the diode behavior quantitatively.”
In collaboration with Columbia University’s Latha Venkataraman and Luis Campos and their respective research groups, Neaton and Liu fabricated a high-performing rectifier from junctions made of symmetric molecules with molecular resonance in nearly perfect alignment with the Fermi electron energy levels of the gold electrodes. Symmetry was broken by a substantial difference in the size of the area on each gold electrode that was exposed to the ionic solution. Owing to the asymmetric electrode area, the ionic solution, and the junction energy level alignment, a positive voltage increases current substantially; a negative voltage suppresses it equally significantly.
“The ionic solution, combined with the asymmetry in electrode areas, allows us to control the junction’s electrostatic environment simply by changing the bias polarity,” Neaton says. “In addition to breaking symmetry, double layers formed by ionic solution also generate dipole differences at the two electrodes, which is the underlying reason behind the asymmetric shift of molecular resonance. The Columbia group’s experiments showed that with the same molecule and electrode setup, a non-ionic solution yields no rectification at all.”
Abstract of Single-molecule diodes with high rectification ratios through environmental control
Molecular electronics aims to miniaturize electronic devices by using subnanometre-scale active components. A single-molecule diode, a circuit element that directs current flow, was first proposed more than 40 years ago and consisted of an asymmetric molecule comprising a donor–bridge–acceptor architecture to mimic a semiconductor p–n junction. Several single-molecule diodes have since been realized in junctions featuring asymmetric molecular backbones, molecule–electrode linkers or electrode materials. Despite these advances, molecular diodes have had limited potential for applications due to their low conductance, low rectification ratios, extreme sensitivity to the junction structure and high operating voltages. Here, we demonstrate a powerful approach to induce current rectification in symmetric single-molecule junctions using two electrodes of the same metal, but breaking symmetry by exposing considerably different electrode areas to an ionic solution. This allows us to control the junction’s electrostatic environment in an asymmetric fashion by simply changing the bias polarity. With this method, we reliably and reproducibly achieve rectification ratios in excess of 200 at voltages as low as 370 mV using a symmetric oligomer of thiophene-1,1-dioxide. By taking advantage of the changes in the junction environment induced by the presence of an ionic solution, this method provides a general route for tuning nonlinear nanoscale device phenomena, which could potentially be applied in systems beyond single-molecule junctions.
The Millennium Project released today its annual “2015-16 State of the Future” report, listing global trends on 28 indicators of progress and regress, new insights into 15 Global Challenges, and impacts of artificial intelligence, synthetic biology, nanotechnology and other advanced technologies on employment over the next 35 years.
“Another 2.3 billion people are expected to be added to the planet in just 35 years,” the report notes. “By
2050, new systems for food, water, energy, education, health, economics, and global governance will be needed to prevent massive and complex human and environmental disasters.”
This “World Report Card” may have “more data, information, intelligence, and wisdom about the future of the world than has ever been assembled in one report,” says Jerome Glenn, CEO of The Millennium Project and lead author of the report.
The 300-page report distills research from UN organizations, national governments, think tanks, and thought leaders around the world, with more than 50 charts and graphs. A free 14-page executive summary is available in English and five other languages.
The key findings include:
The concept of work will change over the next generation or two, but global thought leaders are divided about the best policies to make a smooth transition.
By 2050, new systems for food, water, energy, education, health, economics, and global governance will be needed to prevent massive, complex human and environmental disasters.
Environmental security should be the focus of joint goals to build strategic trust between the U.S. and China.
General human welfare has improved, but at the expense of the environment and with worsening intrastate violence, terrorism, corruption, organized crime, and economic inequality.
The Millennium Project is a global participatory think tank connecting 56 Nodes around the world that identify important long-range challenges and strategies and initiate and conduct foresight studies, workshops, symposiums, and advanced training. Its mission is to improve thinking about the future and make it available through a variety of media for feedback to accumulate wisdom about the future for better decisions today.
In addition to the annual “State of the Future” reports, the Millennium Project produces thew “Futures Research Methodology” series, the Global Futures Intelligence System (GFIS), and special studies. More than 4,500 futurists, scholars, business planners, and policy makers who work for international organizations, governments, corporations, NGOs, and universities have participated in The Millennium Project’s research since its inception in 1992.
Samples of the new hybrid sol-gel material are shown placed on a clear plastic substrate for testing (credit: John Toon, Georgia Tech)
Using a hybrid silica sol-gel material and self-assembled monolayers of a common fatty acid, Georgia Tech researchers have developed a new supercapacitor material that provides electrical-energy storage capacity rivaling some batteries.
Capacitors can provide large amounts of current quickly (high power density), unlike batteries. So if this material can be scaled up from laboratory samples, devices made from it could surpass traditional electrolytic (high-capacity) capacitors for applications in areas where quick-discharge is needed, such as electromagnetic propulsion, electric vehicles, and defibrillators. The new material also has high energy density (ability, like batteries, to store a lot of power).
Schematic representation of new thin-film capacitor using bilayer dielectric formed by self-assembled monolayer (SAM) and sol-gel and electrode layers formed by the gray discs (representing aluminum electrodes) and ITO (indium tin oxide) (not to scale). (credit: Yunsang Kim et al./ Advanced Energy Materials)
The new bilayer dielectric material is composed of a nanoscale self-assembled monolayer (SAM) (insulating) material formed between a sol-gel film and the aluminized mylar film electrodes. The bilayer structure blocks the injection of electrons into the sol-gel material, providing low leakage current, high breakdown strength, and high energy extraction efficiency.
The researchers showed that the capacitor could be rolled and re-rolled several times while maintaining high energy density, demonstrating its flexibility.
The research, supported by the Office of Naval Research and the Air Force Office of Scientific Research, was reported July 14 in the journal Advanced Energy Materials.
Better energy density than thin-film lithium ion batteries
In their structures, the researchers demonstrated maximum extractable energy densities up to 40 joules per cubic centimeter, an energy extraction efficiency of 72 percent at a field strength of 830 volts per micron, and a power density of 520 watts per cubic centimeter.
The performance exceeds that of conventional electrolytic capacitors and thin-film lithium ion batteries, although it doesn’t match the lithium ion battery formats commonly used in electronic devices and vehicles.
The next step will be to scale up the materials to see if the attractive properties transfer to larger devices. If that is successful, the researchers expect to commercialize the material through a startup company or SBIR project.
The U.S. Naval Research Laboratory was also involved in the project.
Abstract of Bilayer Structure with Ultrahigh Energy/Power Density Using Hybrid Sol–Gel Dielectric and Charge-Blocking Monolayer
A hybrid sol–gel dielectric bilayer structure yields a maximum energy density of 40 J cm−3 with high extraction efficiency. The silica sol–gel dielectric is coated by an alkylphosphonic acid monolayer, as a charge-blocking layer. The dense monolayer suppresses charge injection and electrical conduction, leading to high energy extraction efficiency, which exhibits nearly linear dielectric behavior suitable for high energy density applications.
Multiple synapses of the same axon innervate multiple spines of the same postsynaptic cell. An extreme example in which one axon (blue) innervates five dendritic spines (orange, labeled 1–5) of a basal dendrite (green) is shown. Arrows point to other varicosities (swellings) of this axon that are innervating dendritic spines of other neurons. Scale bar, 2 mm. (credit: Narayanan Kasthuri et al./Cell)
Using an electron microscope, researchers have peered down inside the brain of an adult mouse at a scale previously unachievable, generating dramatic color images at 3-nm-pixel resolution. The research was published Thursday July 30 in an open-access paper in the journal Cell.
Focusing on a small area of the mouse brain that receives sensory information from mouse whiskers, the researchers built a system that automatically slices a subject brain into thousands of thin 29-nm coronal brain slices (each section 1 square millimeter) and sticks them to a conveyer belt. After staining the slices to differentiate different tissues, an automated electron microscope took pictures of each slice. A computer then assigned different colors to individual structures and combined the images to produce a 3-D map.
The scientists used a program called VAST, developed by co-author Daniel Berger of Harvard and MIT, to label and piece apart each individual “object” (e.g., neuron, glial cell, blood vessel cell, etc.) using different colors, as well as smaller structures such as dendrites and mitochondria. They also created an annotated inventory of 1700 synapses.
Synapses in contact with a dendrite (the large red object). The white dots are synaptic vesicles inside axons. (credit: N. Kasthuri et al./Cell)
“The complexity of the brain is much more than what we had ever imagined,” says study first author Narayanan “Bobby” Kasthuri, of the Boston University School of Medicine. “We had this clean idea of how there’s a really nice order to how neurons connect with each other, but if you actually look at the material it’s not like that. The connections are so messy that it’s hard to imagine a plan to it, but we checked and there’s clearly a pattern that cannot be explained by randomness.
“If we could make a map of a brain with schizophrenia and compare it to one without schizophrenia, we can look for inappropriate connections that may contribute to the disorder,” he said.
The cost and data storage demands for this type of research are still high, but the researchers expect expenses to drop over time (as has been the case with genome sequencing).
To allow for further inquiries and analyses in the high-resolution volume (80,000 cubic meters), scientists provide access to all of the image data via the Open Connectome Project, along with custom analytic software. They are also partnering with Argonne National Laboratory with the hopes of creating a national brain laboratory that neuroscientists around the world can access within the next few years.
Hauser Studio, Harvard University | Connections in a Cube/ Cell, July 30, 2015 (Vol. 162, Issue 3)
Abstract of Saturated Reconstruction of a Volume of Neocortex
We describe automated technologies to probe the structure of neural tissue at nanometer resolution and use them to generate a saturated reconstruction of a sub-volume of mouse neocortex in which all cellular objects (axons, dendrites, and glia) and many sub-cellular components (synapses, synaptic vesicles, spines, spine apparati, postsynaptic densities, and mitochondria) are rendered and itemized in a database. We explore these data to study physical properties of brain tissue. For example, by tracing the trajectories of all excitatory axons and noting their juxtapositions, both synaptic and non-synaptic, with every dendritic spine we refute the idea that physical proximity is sufficient to predict synaptic connectivity (the so-called Peters’ rule). This online minable database provides general access to the intrinsic complexity of the neocortex and enables further data-driven inquiries.
The Ebola vaccine being prepared for injection (credit: WHO/S. Hawkey)
An Ebola vaccine known as VSV-EBOV, provided by Merck, Sharp & Dohme, has shown 100% efficacy in individuals, according to results from an interim analysis published (open access) today (July 31) in the British journal The Lancet.
“This is an extremely promising development,” said Margaret Chan, M.D., Director-General of the World Health Organization. “The credit goes to the Guinean Government, the people living in the communities and our partners in this project. An effective vaccine will be another very important tool for both current and future Ebola outbreaks.”
An independent body of international experts — the Data and Safety Monitoring Board — conducted the review.
Based on the results, the Guinean national regulatory authority and ethics review committee have approved continuation of the trial to acquire conclusive evidence for the vaccine’s capacity to protect populations through what is called “herd immunity.”
“The ‘ring’ vaccination method adopted for the vaccine trial is based on the smallpox eradication strategy,” said John-Arne Røttingen, Director of the Division of Infectious Disease Control at the Norwegian Institute of Public Health and Chair of the Study Steering Group.
“The premise is that by vaccinating all people who have come into contact with an infected person you create a protective ‘ring’ and stop the virus from spreading further. This strategy has helped us to follow the dispersed epidemic in Guinea, and will provide a way to continue this as a public health intervention in trial mode.”
“This record-breaking work marks a turning point in the history of health R&D,” said Assistant Director-General Marie-Paule Kieny, who leads the Ebola Research and Development effort at WHO. “We now know that the urgency of saving lives can accelerate R&D. We will harness this positive experience to develop a global R&D preparedness framework so that if another major disease outbreak ever happens again, for any disease, the world can act quickly and efficiently to develop and use medical tools and prevent a large-scale tragedy.”
VSV-EBOV was developed by the Public Health Agency of Canada.
Exfoliation setup. Inset: graphite electrode during exfoliation (credit: Mario Hofmann/Nanotechnology)
Taiwanese researchers reported today (July 30) in the journal Nanotechnology that they have developed a simple electrochemical approach that allows for defects to intentionally be created in graphene, altering its electrical and mechanical properties and making the material more useful for electronic devices and drug delivery, for example.
Current graphene synthesis techniques, such as chemical vapor deposition and reduction of graphene oxide, can only produce graphene with a narrow range of characteristics, limiting the usefulness of produced graphene, the researchers say.
The researchers used a technique called electrochemical synthesis to exfoliate, or peel off graphite flakes into graphene layers. By varying the pulsed voltage, they could change the resulting graphene’s thickness, flake area, and number of defects, altering the properties of graphene.
They also found they need to use a solvent for intercalation (adding a fluid or material between layers) as the necessary first step.
To monitor the evolution of the graphene in the solvent they found that simply tracking the solution’s transparency with an LED and photodiode could give them quantitative information on the efficiency and onset of exfoliation.
They next plan to study the effects of adjusting the pulse durations throughout the exfoliation process to improve the amount of exfoliated graphene and to introduce more complex pulse shapes to selectively produce certain types of graphene defects.
Abstract of Controlling the properties of graphene produced by electrochemical exfoliation
The synthesis of graphene with controllable electronic and mechanical characteristics is of significant importance for its application in various fields ranging from drug delivery to energy storage. Electrochemical exfoliation of graphite has yielded graphene with widely varying behavior and could be a suitable approach. Currently, however the limited understanding of the exfoliation process obstructs targeted modification of graphene properties. We here investigate the process of electrochemical exfoliation and the impact of its parameters on the produced graphene. Using in situ optical and electrical measurements we determine that solvent intercalation is the required first step and the degree of intercalation controls the thickness of the exfoliated graphene. Electrochemical decomposition of water into gas bubbles causes the expansion of graphite and controls the functionalization and lateral size of the exfoliated graphene. Both process steps proceed at different time scales and can be individually addressed through application of pulsed voltages. The potential of the presented approach was demonstrated by improving the performance of graphene-based transparent conductors by 30 times.
Climbing a tree or balancing on a beam can dramatically improve cognitive skills, according to a study recently conducted by researchers in the Department of Psychology at the University of North Florida.
The study is the first to show that proprioceptively dynamic activities like climbing a tree, done over a short period of time, have dramatic working memory benefits.
Working memory (the ability to process and recall information), is linked to performance in a wide variety of contexts from grades to sports. Proprioception (awareness of body positioning and orientation) is also associated with working memory.
The results of this research, led by Ross Alloway, a research associate, and Tracy Alloway, an associate professor, recently published in Perceptual and Motor Skills, suggest that working-memory improvements can be made in just a couple of hours with these physical exercises.
The aim of this study was to see if proprioceptive activities completed over a short period of time can enhance working memory performance, and whether an acute and highly intensive period of exercise would yield working memory gains.
The UNF researchers recruited adults ages 18 to 59 and tested their working memory. Next, they undertook proprioceptively dynamic activities, designed by the company Movnat, which required proprioception and at least one other element, such as locomotion or route planning.
Working memory capacity increase of 50 percent; better than yoga
In the study, such activities included climbing trees, walking and crawling on a beam approximately 3 inches wide, moving while paying attention to posture, running barefoot, navigating over, under and around obstacles, as well as lifting and carrying awkwardly weighted objects. After two hours, participants were tested again, and researchers found that their working memory capacity had increased by 50 percent, a dramatic improvement.
The researchers also tested two control groups. The first was a college class learning new information in a lecture setting to see if learning new information improved working memory. The second was a yoga class to see if static proprioceptive activities were cognitively beneficial. However, neither control group experienced working memory benefits.
Proprioceptively dynamic training may place a greater demand on working memory than either control condition because as environment and terrain changes, the individual recruits working memory to update information to adapt appropriately. Though the yoga control group engaged in proprioceptive activities that required awareness of body position, it was relatively static as they performed the yoga postures in a small space, which didn’t allow for locomotion or navigation.
“This research suggests that by doing activities that make us think, we can exercise our brains as well as our bodies,” said Alloway. “This research has wide-ranging implications for everyone from kids to adults. By taking a break to do activities that are unpredictable and require us to consciously adapt our movements, we can boost our working memory to perform better in the classroom and the boardroom.”
Abstract of The working memory benefits of proprioceptively demanding training: A pilot study
The aim of this study was to investigate the effect of proprioception on working memory. It was also of interest whether an acute and highly intensive period of exercise would yield working memory gains. The training group completed a series of proprioceptively demanding exercises. There were also control classroom and yoga groups. Working memory was measured using a backward digit recall test. The data indicated that active, healthy adults who undertook acute, proprioceptively demanding training improved working memory scores compared to the classroom and yoga groups. One possible reason that the training yielded significant working memory gains could be that the training was proprioceptively dynamic, requiring proprioception and at least one other factor—such as locomotion or navigation—at the same time, which may have contributed to the improvements in working memory performance.
Range of voluntary movement prior to receiving stimulation compared to movement after receiving stimulation, physical conditioning, and the drug buspirone. The subject’s legs are supported so that they can move without resistance from gravity. The electrodes on the legs are used for recording muscle activity. (credit: Edgerton Lab/UCLA)
In a study conducted at UCLA, five men who had been completely paralyzed were able to move their legs in a rhythmic motion thanks to a new, noninvasive neuromodulation and pharmacological procedure that stimulates the spinal cord.
The researchers believe this to be the first time voluntary leg movements have ever been relearned in completely paralyzed patients without surgery. The results are reported in an open-access paper in the Journal of Neurotrauma.
“These findings tell us we have to look at spinal cord injury in a new way,” said V. Reggie Edgerton, senior author of the research and a UCLA distinguished professor of integrative biology and physiology, neurobiology and neurosurgery.
Edgerton said although it likely will be years before the new approaches are widely available, he now believes that it is possible to significantly improve quality of life for patients with severe spinal cord injuries, and to help them recover multiple body functions.
Earlier this year, a the researchers demonstrated that they could induce involuntary stepping movements in healthy, uninjured people using noninvasive stimulation. The finding led Edgerton to believe the same approach could be effective for people with complete paralysis.
Reawakening neural connections with electrical charges and a drug
In the new research, five men were given one 45-minute training session per week for 18 weeks. For four weeks, the men were also given twice daily doses of buspirone, a drug often used to treat anxiety disorders, as part of the treatment.
Researchers placed electrodes at strategic points on the skin, at the lower back and near the tailbone and then administered a unique pattern of noninvasive, painless transcutaneous (through the skin) electrical currents*. The electrical charges caused no discomfort to the patients, who were lying down.
“The fact that they regained voluntary control so quickly must mean that they had neural connections that were dormant, which we reawakened,” said Edgerton, who for nearly 40 years has conducted research on how the neural networks in the spinal cord regain control of standing, stepping and voluntary control of movements after paralysis. “It was remarkable.”
* The researchers used monopolar rectangular pulsed stimuli (30 Hz at T11 and 5 Hz at Co1 with 1 ms duration for each pulse) filled with a carrier frequency of 10 kHz and at an intensity ranging from 80 to 180 mA .
Edgerton Lab/UCLA | Non-invasive Neuromodulation to regain voluntary movements after paralysis
Edgerton said most experts, including himself, had assumed that people who were completely paralyzed would no longer have had neural connections across the area of the spinal cord injury.
The researchers do not know yet whether patients who are completely paralyzed can be trained to fully bear their weight and walk. But he and colleagues have now published data on nine people who have regained voluntary control of their legs —four with epidural implants and five in the latest study.
“Many people thought just a few years ago we might be able to achieve these results in perhaps one out of 100 subjects, but now we have nine of nine,” Edgerton said. “I think it’s a big deal, and when the subjects see their legs moving for the first time after paralysis, they say it’s a big deal.”
The men in the newest study ranged in age from 19 to 56; their injuries were suffered during athletic activities or, in one case, in an auto accident. All have been completely paralyzed for at least two years. Their identities are not being released.
The research was funded by the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering (grants U01EB15521 and R01EB007615), the Christopher and Dana Reeve Foundation, the Walkabout Foundation and the Russian Scientific Fund.
“These encouraging results provide continued evidence that spinal cord injury may no longer mean a life-long sentence of paralysis and support the need for more research,” said Dr. Roderic Pettigrew, director of the National Institute of Biomedical Imaging and Bioengineering. “The potential to offer a life-changing therapy to patients without requiring surgery would be a major advance; it could greatly expand the number of individuals who might benefit from spinal stimulation. It’s a wonderful example of the power that comes from combining advances in basic biological research with technological innovation.”
Edgerton estimates that cost to patients of the new approach could be one-tenth the cost of treatment using the surgical epidural stimulator (which is also still experimental) — and, because no surgery is required, it would likely be more easily available to more patients.
The study’s co-authors were Gerasimenko, who conceived the new approach and is director of the laboratory of movement physiology at Russia’s Pavlov Institute and a researcher in the UCLA department of integrative biology and physiology, as well as Daniel Lu, associate professor of neurosurgery, researchers Morteza Modaber, Roland Roy and Dimitry Sayenko, research technician Sharon Zdunowski, research scientist Parag Gad, laboratory coordinator Erika Morikawa and research assistant Piia Haakana, all of UCLA; and Adam Ferguson, assistant professor of neurological surgery at UC San Francisco.
Edgerton and his research team also plan to study people who have severe, but not complete, paralysis. “They’re likely to improve even more,” he said.
The scientists can only work with a small number of patients, due to limited resources, but Edgerton is optimistic that the research can benefit many others. Almost 6 million Americans live with paralysis, including nearly 1.3 million with spinal cord injuries.
“A person can have hope, based on these results,” Edgerton said. “In my opinion, they should have hope.”
Abstract of Noninvasive Reactivation of Motor Descending Control after Paralysis
The present prognosis for the recovery of voluntary control of movement in patients diagnosed as motor complete is generally poor. Herein we introduce a novel and noninvasive stimulation strategy of painless transcutaneous electrical enabling motor control and a pharmacological enabling motor control strategy to neuromodulate the physiological state of the spinal cord. This neuromodulation enabled the spinal locomotor networks of individuals with motor complete paralysis for 2-6 years (AIS B) to be reengaged and trained. We showed that locomotor-like stepping could be induced without voluntary effort within a single test session using electrical stimulation and training. We also observed significant facilitation of voluntary influence on the stepping movements in the presence of stimulation over a four-week period in each subject. Using these strategies we transformed brain-spinal neuronal networks from a dormant to a functional state sufficiently to enable recovery of voluntary movement in 5/5 subjects. Pharmacological intervention combined with stimulation and training resulted in further improvement in voluntary motor control of stepping-like movements in all subjects. We also observed on-command selective activation of the gastrocnemius and soleus muscles when attempting to plantarflex. At the end of 18 weeks of weekly interventions the mean changes in the amplitude of voluntarily controlled movement without stimulation was as high as occurred when combined with electrical stimulation. Additionally, spinally evoked motor potentials were readily modulated in the presence of voluntary effort, providing electrophysiological evidence of the re-establishment of functional connectivity among neural networks between the brain and the spinal cord.
Efficient editing (cutting out) of CXCR4, a protein receptor that HIV can use to infect T cells (credit: Kathrin Schumann et al./PNAS)
In a project led by investigators at UC San Francisco , scientists have devised a new strategy to precisely modify human immune-system T cells, using the popular genome-editing system known as CRISPR/Cas9. T cells play important roles in a wide range of diseases, from diabetes to AIDS to cancer, so this achievement provides a path toward CRISPR/Cas9-based therapies for many serious health problems, the scientists say. It also provides a versatile new tool for research on T cell function.
Specifically, the researchers disabled a protein on the T-cell surface called CXCR4, which can be exploited by HIV when the virus infects T cells and causes AIDS. The group also successfully shut down PD-1. Scientists have shown that using drugs to block PD-1 coaxes T cells to attack tumors.
The CRISPR/Cas9 system makes it possible to easily and inexpensively edit genetic information in virtually any organism. T cells, which circulate in the blood, are an obvious candidate for medical applications of the technology, as these cells are at the center of many disease processes, and could be easily gathered from patients, edited with CRISPR/Cas9, then returned to the body to exert therapeutic effects.
A CRISPR/Cas9 breakthrough
Cas9, an enzyme in the CRISPR system that makes cuts in DNA and allows new genetic sequences to be inserted, is generally introduced into cells by using viruses or circular bits of DNA called plasmids. Then, in a separate step, a genetic construct known as single-guide RNA, which steers Cas9 to the specific spots in DNA where cuts are desired, is also placed into the cells.
Until recently, however, editing human T cells with CRISPR/Cas9 has been inefficient, with only a relatively small percentage of cells being successfully modified. And while scientists have had some success in switching off genes by inserting or deleting random sequences, they have not yet been able to use CRISPR/Cas9 to paste in (or “knock in”) specific new sequences to correct mutations in T cells.
Now, as reported in an open-access paper online in Proceedings of the National Academy of Sciences on July 27, 2015, the team has cracked these problems by streamlining the delivery of Cas9 and single-guide RNA to cells.
In lab dishes, the group assembled Cas9 ribonucleoproteins (RNPs), which combine the Cas9 protein with single-guide RNA. They then used a method known as electroporation, in which electrical field essentially punches tiny holes in membranes to make them more permeable so that these RNPs can we quickly delivered to the interior of the cells.
With these innovations, the researchers successfully edited CXCR4 and PD-1, even knocking in new sequences to replace specific genetic “letters” in these proteins. The group was then able to sort the cells, using markers expressed on the cell surface, to help pull out successfully edited cells for research, and eventually for therapeutic use.
The new work was done under the auspices of the Innovative Genomics Initiative (IGI), a joint UC Berkeley-UCSF program co-directed by Berkeley’s Jennifer Doudna, PhD, who is world-renowned for her pioneering research on CRISPR/Cas9, and Jonathan Weissman, PhD, professor of cellular and molecular pharmacology at UCSF and a Howard Hughes Medical Institute (HHMI) investigator.
Doudna, professor of chemistry and of cell and molecular biology at Berkeley, an HHMI investigator and co-corresponding author of the new paper, said that the research is a significant step forward in bringing the power of CRISPR/Cas9 editing to human biology and medicine.”
‘Designer babies’ concern
Recent reports of CRISPR/Cas9 editing of human embryos for possible heritable germline modification have stirred up an ethical controversy. But with this new protocol, T cells are created anew in each individual, so modifications would not be passed on to future generations, explained Alexander Marson, PhD, a UCSF Sandler Fellow and an affiliate member of the IGI, and senior and co-corresponding author of the new study.
“There’s actually well-trodden ground putting modified T cells into patients. There are companies out there already doing it and figuring out the safety profile, so there’s increasing clinical infrastructure that we could potentially piggyback on as we work out more details of genome editing,” Marson said. “I think CRISPR-edited T cells will eventually go into patients, and it would be wrong not to think about the steps we need to take to get there safely and effectively.”
He hopes that Cas9-based therapies for T cell-related disorders, which include autoimmune diseases as well as immunodeficiencies such as “bubble boy disease,” will enter the clinic in the future.
The research was supported by a gift from Jake Aronov, and by the UCSF Sandler Fellows Program, the National Institutes of Health, the National MS Society, and the Howard Hughes Medical Institute.
Abstract of Generation of knock-in primary human T cells using Cas9 ribonucleoproteins
T-cell genome engineering holds great promise for cell-based therapies for cancer, HIV, primary immune deficiencies, and autoimmune diseases, but genetic manipulation of human T cells has been challenging. Improved tools are needed to efficiently “knock out” genes and “knock in” targeted genome modifications to modulate T-cell function and correct disease-associated mutations. CRISPR/Cas9 technology is facilitating genome engineering in many cell types, but in human T cells its efficiency has been limited and it has not yet proven useful for targeted nucleotide replacements. Here we report efficient genome engineering in human CD4+ T cells using Cas9:single-guide RNA ribonucleoproteins (Cas9 RNPs). Cas9 RNPs allowed ablation of CXCR4, a coreceptor for HIV entry. Cas9 RNP electroporation caused up to ∼40% of cells to lose high-level cell-surface expression of CXCR4, and edited cells could be enriched by sorting based on low CXCR4 expression. Importantly, Cas9 RNPs paired with homology-directed repair template oligonucleotides generated a high frequency of targeted genome modifications in primary T cells. Targeted nucleotide replacement was achieved in CXCR4 and PD-1 (PDCD1), a regulator of T-cell exhaustion that is a validated target for tumor immunotherapy. Deep sequencing of a target site confirmed that Cas9 RNPs generated knock-in genome modifications with up to ∼20% efficiency, which accounted for up to approximately one-third of total editing events. These results establish Cas9 RNP technology for diverse experimental and therapeutic genome engineering applications in primary human T cells.
