News from January 2020
Researchers build a particle accelerator that fits on a chip
- January 2, 2020
- Stanford University
- For the first time, scientists have created a silicon chip that can accelerate electrons -- albeit at a fraction of the velocity of the most massive accelerators -- using an infrared laser to deliver, in less than a hair's width, the sort of energy boost that takes microwaves many feet.
On a hillside above Stanford University, the SLAC National Accelerator Laboratory operates a scientific instrument nearly 2 miles long. In this giant accelerator, a stream of electrons flows through a vacuum pipe, as bursts of microwave radiation nudge the particles ever-faster forward until their velocity approaches the speed of light, creating a powerful beam that scientists from around the world use to probe the atomic and molecular structures of inorganic and biological materials.
Now, for the first time, scientists at Stanford and SLAC have created a silicon chip that can accelerate electrons -- albeit at a fraction of the velocity of that massive instrument -- using an infrared laser to deliver, in less than a hair's width, the sort of energy boost that takes microwaves many feet.
Writing in the Jan. 3 issue of Science, a team led by electrical engineer Jelena Vuckovic explained how they carved a nanoscale channel out of silicon, sealed it in a vacuum and sent electrons through this cavity while pulses of infrared light -- to which silicon is as transparent as glass is to visible light -- were transmitted by the channel walls to speed the electrons along.
The accelerator-on-a-chip demonstrated in Science is just a prototype, but Vuckovic said its design and fabrication techniques can be scaled up to deliver particle beams accelerated enough to perform cutting-edge experiments in chemistry, materials science and biological discovery that don't require the power of a massive accelerator.
"The largest accelerators are like powerful telescopes. There are only a few in the world and scientists must come to places like SLAC to use them," Vuckovic said. "We want to miniaturize accelerator technology in a way that makes it a more accessible research tool."
Team members liken their approach to the way that computing evolved from the mainframe to the smaller but still useful PC. Accelerator-on-a-chip technology could also lead to new cancer radiation therapies, said physicist Robert Byer, a co-author of the Science paper. Again, it's a matter of size. Today, medical X-ray machines fill a room and deliver a beam of radiation that's tough to focus on tumors, requiring patients to wear lead shields to minimize collateral damage.
"In this paper we begin to show how it might be possible to deliver electron beam radiation directly to a tumor, leaving healthy tissue unaffected," said Byer, who leads the Accelerator on a Chip International Program, or ACHIP, a broader effort of which this current research is a part.
In their paper, Vuckovic and graduate student Neil Sapra, the first author, explain how the team built a chip that fires pulses of infrared light through silicon to hit electrons at just the right moment, and just the right angle, to move them forward just a bit faster than before.
To accomplish this, they turned the design process upside down. In a traditional accelerator, like the one at SLAC, engineers generally draft a basic design, then run simulations to physically arrange the microwave bursts to deliver the greatest possible acceleration. But microwaves measure 4 inches from peak to trough, while infrared light has a wavelength one-tenth the width of a human hair. That difference explains why infrared light can accelerate electrons in such short distances compared to microwaves. But this also means that the chip's physical features must be 100,000 times smaller than the copper structures in a traditional accelerator. This demands a new approach to engineering based on silicon integrated photonics and lithography.
Vuckovic's team solved the problem using inverse design algorithms that her lab has developed. These algorithms allowed the researchers to work backward, by specifying how much light energy they wanted the chip to deliver, and tasking the software with suggesting how to build the right nanoscale structures required to bring the photons into proper contact with the flow of electrons.
"Sometimes, inverse designs can produce solutions that a human engineer might not have thought of," said R. Joel England, a SLAC staff scientist and co-author on the Science paper.
The design algorithm came up with a chip layout that seems almost otherworldly. Imagine nanoscale mesas, separated by a channel, etched out of silicon. Electrons flowing through the channel run a gantlet of silicon wires, poking through the canyon wall at strategic locations. Each time the laser pulses -- which it does 100,000 times a second -- a burst of photons hits a bunch of electrons, accelerating them forward. All of this occurs in less than a hair's width, on the surface of a vacuum-sealed silicon chip, made by team members at Stanford.
The researchers want to accelerate electrons to 94 percent of the speed of light, or 1 million electron volts (1MeV), to create a particle flow powerful enough for research or medical purposes. This prototype chip provides only a single stage of acceleration, and the electron flow would have to pass through around 1,000 of these stages to achieve 1MeV. But that's not as daunting at it may seem, said Vuckovic, because this prototype accelerator-on-a-chip is a fully integrated circuit. That means all of the critical functions needed to create acceleration are built right into the chip, and increasing its capabilities should be reasonably straightforward.
The researchers plan to pack a thousand stages of acceleration into roughly an inch of chip space by the end of 2020 to reach their 1MeV target. Although that would be an important milestone, such a device would still pale in power alongside the capabilities of the SLAC research accelerator, which can generate energy levels 30,000 times greater than 1MeV. But Byer believes that, just as transistors eventually replaced vacuum tubes in electronics, light-based devices will one day challenge the capabilities of microwave-driven accelerators.
Meanwhile, in anticipation of developing a 1MeV accelerator on a chip, electrical engineer Olav Solgaard, a co-author on the paper, has already begun work on a possible cancer-fighting application. Today, highly energized electrons aren't used for radiation therapy because they would burn the skin. Solgaard is working on a way to channel high-energy electrons from a chip-sized accelerator through a catheter-like vacuum tube that could be inserted below the skin, right alongside a tumor, using the particle beam to administer radiation therapy surgically.
"We can derive medical benefits from the miniaturization of accelerator technology in addition to the research applications," Solgaard said.
- Neil V. Sapra, Ki Youl Yang, Dries Vercruysse, Kenneth J. Leedle, Dylan S. Black, R. Joel England, Logan Su, Rahul Trivedi, Yu Miao, Olav Solgaard, Robert L. Byer, Jelena Vučkovicć. On-chip integrated laser-driven particle accelerator. Science, 2020; 367 (6473): 79 DOI: 10.1126/science.aay5734
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Pathways that extend lifespan by 500 percent identified
Discovery of cellular mechanisms could open door to more effective anti-aging therapies
- January 8, 2020
- Mount Desert Island Biological Laboratory
- Scientists have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research. The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists.
Scientists at the MDI Biological Laboratory, in collaboration with scientists from the Buck Institute for Research on Aging in Novato, Calif., and Nanjing University in China, have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research.
The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists.
The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.
Because these pathways are "conserved," meaning that they have been passed down to humans through evolution, they have been the subject of intensive research. A number of drugs that extend healthy lifespan by altering these pathways are now under development. The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.
The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.
"Despite the discovery in C. elegans of cellular pathways that govern aging, it hasn't been clear how these pathways interact," said Hermann Haller, M.D., president of the MDI Biological Laboratory. "By helping to characterize these interactions, our scientists are paving the way for much-needed therapies to increase healthy lifespan for a rapidly aging population."
The elucidation of the cellular mechanisms controlling the synergistic response is the subject of a recent paper in the online journal Cell Reports entitled "Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity." The authors include Jarod A. Rollins, Ph.D., and Aric N. Rogers, Ph.D., of the MDI Biological Laboratory.
"The synergistic extension is really wild," said Rollins, who is the lead author with Jianfeng Lan, Ph.D., of Nanjing University. "The effect isn't one plus one equals two, it's one plus one equals five. Our findings demonstrate that nothing in nature exists in a vacuum; in order to develop the most effective anti-aging treatments we have to look at longevity networks rather than individual pathways."
The discovery of the synergistic interaction could lead to the use of combination therapies, each affecting a different pathway, to extend healthy human lifespan in the same way that combination therapies are used to treat cancer and HIV, Pankaj Kapahi, Ph.D., of the Buck Institute, has said. Kapahi is a corresponding author of the paper with Rogers and Di Chen, Ph.D., of Nanjing University.
The synergistic interaction may also may explain why scientists have been unable to identify a single gene responsible for the ability of some people to live to extraordinary old ages free of major age-related diseases until shortly before their deaths.
The paper focuses on how longevity is regulated in the mitochondria, which are the organelles in the cell responsible for energy homeostasis. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysregulation and aging. Rollins' future research will focus on the further elucidation of the role of mitochondria in aging, he said.
The research was conducted at the MDI Biological Laboratory and Nanjing University using information from double mutants developed by Kapahi. Rollins' and Rogers' work was supported by the National Institutes of Health (AG056743), the Morris Scientific Discovery Fund and the National Institute of General Medical Sciences (P20GM103423 and P20GM104318).
- Jianfeng Lan, Jarod A. Rollins, Xiao Zang, Di Wu, Lina Zou, Zi Wang, Chang Ye, Zixing Wu, Pankaj Kapahi, Aric N. Rogers, Di Chen. Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity. Cell Reports, 2019; 28 (4): 1050 DOI: 10.1016/j.celrep.2019.06.078
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Mount Desert Island Biological Laboratory. "Pathways that extend lifespan by 500 percent identified: Discovery of cellular mechanisms could open door to more effective anti-aging therapies." ScienceDaily. ScienceDaily, 8 January 2020. <www.sciencedaily.com/releases/2020/01/200108160338.htm>
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Specific neurons that map memories now identified in the human brain
November 12, 2019
Columbia University School of Engineering and Applied Science
Neuroengineers have found the first evidence that individual neurons in the human brain target specific memories during recall. They studied recordings in neurosurgical patients who had electrodes implanted in their brains and examined how the patients' brain signals corresponded to their behavior while performing a virtual-reality object-location memory task. The researchers identified 'memory-trace cells' whose activity was spatially tuned to the location where subjects remembered encountering specific objects.
An important aspect of human memory is our ability to conjure specific moments from the vast array of experiences that have occurred in any given setting. For example, if asked to recommend a tourist itinerary for a city you have visited many times, your brain somehow enables you to selectively recall and distinguish specific memories from your different trips to provide an answer.
Studies have shown that declarative memory -- the kind of memory you can consciously recall like your home address or your mother's name -- relies on healthy medial temporal lobe structures in the brain, including the hippocampus and entorhinal cortex (EC). These regions are also important for spatial cognition, demonstrated? by the Nobel-Prize-winning discovery of "place cells" and "grid cells" in these regions -- neurons that activate to represent specific locations in the environment during navigation (akin to a GPS). However, it has not been clear if or how this "spatial map" in the brain relates to a person's memory of events at those locations, and how neuronal activity in these regions enables us to target a particular memory for retrieval among related experiences.
A team led by neuroengineers at Columbia Engineering has found the first evidence that individual neurons in the human brain target specific memories during recall. They studied recordings in neurosurgical patients who had electrodes implanted in their brains and examined how the patients' brain signals corresponded to their behavior while performing a virtual-reality (VR) object-location memory task. The researchers identified "memory-trace cells" whose activity was spatially tuned to the location where subjects remembered encountering specific objects. The study is published today in Nature Neuroscience.
"We found these memory-trace neurons primarily in the entorhinal cortex (EC), which is one of the first regions of the brain affected by the onset of Alzheimer 's disease," says Joshua Jacobs, associate professor of biomedical engineering, who directed the study. "Because the activity of these neurons is closely related to what a person is trying to remember, it is possible that their activity is disrupted by diseases like Alzheimer's, leading to memory deficits. Our findings should open up new lines of investigation into how neural activity in the entorhinal cortex and medial temporal lobe helps us target past events for recall, and more generally how space and memory overlap in the brain."
The team was able to measure the activity of single neurons by taking advantage of a rare opportunity: invasively recording from the brains of 19 neurosurgical patients at several hospitals, including the Columbia University Irving Medical Center. The patients had drug-resistant epilepsy and so had already had recording electrodes implanted in their brains for their clinical treatment. The researchers designed experiments as engaging and immersive VR computer games and the bedridden patients used laptops and handheld controllers to move through virtual environments. In performing the task, subjects first navigated through the environment to learn the locations of four unique objects. Then the researchers removed the objects and asked patients to move through the environment and mark the location of one specific object on each trial.
The team measured the activity of neurons as the patients moved through the environment and marked their memory targets. Initially, they identified purely spatially tuned neurons similar to "place cells" that always activated when patients moved through specific locations, regardless of the subjects' memory target. "These neurons seemed only to care about the person's spatial location, like a pure GPS," says Salman E. Qasim, Jacobs' PhD student and lead author of the study.
But the researchers also noticed that other neurons only activated in locations relevant to the memory the patient was recalling on that trial -- whenever patients were instructed to target a different memory for recall, these neurons changed their activity to match the new target's remembered location. What especially excited Jacobs and Qasim is that they could actually decode the specific memory a patient was targeting based on the activity of these neurons.
"Our study demonstrates that neurons in the human brain track the experiences we are willfully recalling, and can change their activity patterns to differentiate between memories. They're just like the pins on your Google map that mark the locations you remember for important events," Qasim says. "This discovery might provide a potential mechanism for our ability to selectively call upon different experiences from the past and highlights how these memories may influence our brain's spatial map."
Jacobs and Qasim plan next to look for evidence that these neurons represent memories in non-spatial contexts to better characterize their role in memory function. "We know now that neurons care about where our memories occur and now we want to see if these neurons care about other features of those memories, like when they occurred, what occurred, and so on," Qasim notes.
Materials provided by Columbia University School of Engineering and Applied Science. Original written by Holly Evarts. Note: Content may be edited for style and length.
- Salman E. Qasim, Jonathan Miller, Cory S. Inman, Robert E. Gross, Jon T. Willie, Bradley Lega, Jui-Jui Lin, Ashwini Sharan, Chengyuan Wu, Michael R. Sperling, Sameer A. Sheth, Guy M. McKhann, Elliot H. Smith, Catherine Schevon, Joel M. Stein, Joshua Jacobs. Memory retrieval modulates spatial tuning of single neurons in the human entorhinal cortex. Nature Neuroscience, 2019; DOI: 10.1038/s41593-019-0523-z
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