Fire in the Brain

By Nicole Hemsoth

January 13, 2006

Each time Sergei Rachmaninoff sat down to perform his virtuosic Piano Concerto No. 3, he played more than 28,000 notes in about 30 minutes, his fingers, a blur of muscular energy, striking the keys with the precise force – at the precise instant – the maestro intended. With only faint electrochemical signals running through nerves of greatly varied length, how is it possible for the brain to initiate and control such rapid-fire movement, dozens of muscles simultaneously, with exquisite sensitivity and split-second timing?

Over the past century, scientists have taken many steps toward understanding the biology underlying such feats. The synapse – where nerve cells meet or connect to a muscle fiber – amplifies the tiny voltage generated in the brain into forces large enough to pound out a thunderous finale. Still, these intricately coordinated mind-body processes hold many mysteries.

PSC senior scientist Joel Stiles and his collaborators solved a few recently by using a supercomputing system to recreate the business end of a synapse. Their tools included MCell, powerful software – co-authored by Stiles and Thomas Bartol of the Salk Institute – for simulating the microphysiology of interacting cells, coupled with DReAMM visualization software developed in Stiles' lab at PSC. The computational work relied heavily on Jonas, PSC's 128-processor shared-memory HP system dedicated to biomedical research. Stiles and colleagues modeled two kinds of synapses in unprecedented detail, and their findings, published recently in Science and other journals, overturn some longstanding assumptions about neural communication, offer insight into a family of crippling diseases, and demonstrate the power of computation allied with experimental measurement.

A Barrage of Neurotransmitters

The secret to coordination, says Stiles, is predictability. As a child grows, the motor cortex in the brain develops increasingly sophisticated programs of voluntary muscle control. These programs must anticipate delays that occur as a command impulse travels to the spinal cord, out a peripheral nerve, and across the nanometers-wide synaptic cleft that separates a neuron from the muscle fiber it innervates.

Decades ago, biologists measured the signal delays introduced by nerve-muscle synapses, and found that the lag time is amazingly consistent, varying less than 30 millionths of a second from one synaptic firing to another. How does the body manage this feat of consistency?

Over the years, molecular biologists have filled-in much of the story. On its way from brain to limb, an impulse shoots down the nerve cell to its terminus and arrives in the form of a rapid change in sodium ion concentration. That creates a voltage. The voltage triggers thousands of sphincter-like proteins embedded in the cell wall of the neuron; these protein channels open, and some allow calcium ions to flow into the cell. As the calcium ions enter, they diffuse throughout the interior of the neuron, bumping into tiny spherical containers – called vesicles – arranged in neat rows close to the interior wall.

Loaded with the neurotransmitter acetylcholine, the vesicles are like a battery of fireworks poised to launch a neurotransmitter barrage into the synaptic cleft – where this amplified signal will in turn energize the adjacent muscle fiber. In the last step, what biologists call a “fusion event,” the calcium ions trigger some of the vesicles to fuse with the cell membrane and open outward, allowing their payload to escape.

The details of this critical last step, however, have so far stumped neuroscientists. “We still don't know how calcium binds to receptor areas on the vesicles to lead to this fusion event,” says Stiles. “Nor do we know how many protein channels need to open to admit the calcium, or how far the calcium can diffuse to find the vesicles and cause them to fuse. Does a calcium channel have to open right next to a vesicle, or can the ions come in through a variety of different gates and collectively trigger a variety of vesicles?”

A New Picture of Fusion

To help answer these questions, Stiles teamed up with PSC researcher John M. Pattillo (now at Macon State College) and neurobiologist Stephen D. Meriney of the University of Pittsburgh. With support from the National Institutes of Health, the group was able to take a hybrid approach that combined classic empirical observation with a sophisticated Monte Carlo supercomputer simulation.

Stiles and Pattillo used computer-aided design tools to create a three-dimensional model of an entire “active zone,” the region inside the neuron where dense arrays of vesicles dock and fuse. Then, using MCell they created a simulation that tracks each calcium channel, the calcium binding sites on vesicles, and thousands of diffusing calcium ions inside the micron-wide active zone for several milliseconds of the firing cycle.

In the laboratory, Meriney probed living nerve and muscle cells to record how calcium concentration spikes and then falls following an electrical impulse. “These and other experimental results constrain many of the variables,” explains Stiles, “leaving us with only a few free parameters to play with in the simulations.” Running the simulations over and over, Stiles and Pattillo looked for combinations that would reproduce the recorded behaviors of real synapses: for example, the short and consistent delay between the stimulating impulse and neurotransmitter release.

Long used in high-energy physics, astronomy and other areas of science, such a hybrid approach to modeling, notes Stiles, has been less used in biology. “In part, this is because biology is so complicated and difficult to measure on these scales, and in part because the computational cost is so high. We are only now getting to the point where we have the supercomputer power and the insight into biomolecular dynamics to do computational biology this way.”

To thoroughly explore the plausible range of permutations, Stiles and Pattillo had to run roughly 500,000 simulations. Each run generated thousands of output files, so the group devised a compression scheme, analogous to the MPEG encoding used for DVD movies, that allowed them to efficiently store the results and mine them for insights.

After more than a year of patient work, the data mining struck gold – in a surprising place. Neuroscientists had for years guessed that each synaptic vesicle sports four binding sites for calcium ions, and that fusion occurs only when ions dock at all four. This was one of the first models Stiles and Pattillo tried. “The results made it immediately obvious,” recalls Stiles, “that this wasn't right.” The virtual neuron almost never released transmitter, and no amount of tweaking other variables could produce realistic behavior. “We scratched our head and said, 'OK, let's push up the number of binding sites on each vesicle and see what happens.'”

After testing many different combinations, the group finally discovered one that neatly reproduces the experimental data. In this model, each vesicle is dotted with 25 to 40 binding sites, and fusion occurs when calcium ions fill six to eight of those sites. “The latest data coming in from biochemists now suggest that there are good reasons to expect this is true,” says Stiles. “So that is quite gratifying.”

The achievement builds on another project to which Stiles also contributed, in collaboration with Terrence J. Sejnowski, Thomas M. Bartol and others at the Salk Institute and the University of California, San Diego. That effort similarly constructed a 3-D model of a synapse, in this case one that connects two neurons. Using a model derived from microscope cross-sections of actual synapses, the simulations overturned the conventional view that vesicles release neurotransmitters only within the active zone. Fusion events, they concluded, must be occurring in other regions of the synapse as well.

Such detailed insights into the structure of synapses are especially relevant for a class of diseases, called myasthenias, that arise when synapses are malformed or attacked by the immune system, leading to weakness, motor dysfunction, even paralysis. Because there's a need, and because MCell has proven abilities, prospects are promising for this way of understanding cell-to-cell interactions. With a soon-to-be-released new version of MCell and DReAMM, even more precise answers will be possible. “In the new version, molecules are able to react chemically with each other,” says Stiles, “as they diffuse through space. So much more general phenomena now become potential subjects for MCell simulations.”

For more information, visit http://www.psc.edu/science/2005/stiles

Subscribe to HPCwire's Weekly Update!

Be the most informed person in the room! Stay ahead of the tech trends with industy updates delivered to you every week!

Supercomputer Research Reveals Star Cluster Born Outside Our Galaxy

July 11, 2020

The Milky Way is our galactic home, containing our solar system and continuing into a giant band of densely packed stars that stretches across clear night skies around the world – but, it turns out, not all of those st Read more…

By Oliver Peckham

Max Planck Society Begins Installation of Liquid-Cooled Supercomputer from Lenovo

July 9, 2020

Lenovo announced today that it is supplying a new high performance computer to the Max Planck Society, one of Germany's premier research organizations. Comprised of Intel Xeon processors and Nvidia A100 GPUs, and featuri Read more…

By Tiffany Trader

Xilinx Announces First Adaptive Computing Challenge

July 9, 2020

A new contest is challenging the computing world. Xilinx has announced the first Xilinx Adaptive Computing Challenge, a competition that will task developers and startups with finding creative workload acceleration solutions. Xilinx is running the Adaptive Computing Challenge in partnership with Hackster.io, a developing community... Read more…

By Staff report

Reviving Moore’s Law? LBNL Researchers See Promise in Heterostructure Oxides

July 9, 2020

The reality of Moore’s law’s decline is no longer doubted for good empirical reasons. That said, never say never. Recent work by Lawrence Berkeley National Laboratory researchers suggests heterostructure oxides may b Read more…

By John Russell

President’s Council Targets AI, Quantum, STEM; Recommends Spending Growth

July 9, 2020

Last week the President Council of Advisors on Science and Technology (PCAST) met (webinar) to review policy recommendations around three sub-committee reports: 1) Industries of the Future (IotF), chaired be Dario Gil (d Read more…

By John Russell

AWS Solution Channel

Best Practices for Running Computational Fluid Dynamics (CFD) Workloads on AWS

The scalable nature and variable demand of CFD workloads makes them well-suited for a cloud computing environment. Many of the AWS instance types, such as the compute family instance types, are designed to include support for this type of workload.  Read more…

Intel® HPC + AI Pavilion

Supercomputing the Pandemic: Scientific Community Tackles COVID-19 from Multiple Perspectives

Since their inception, supercomputers have taken on the biggest, most complex, and most data-intensive computing challenges—from confirming Einstein’s theories about gravitational waves to predicting the impacts of climate change. Read more…

Penguin Computing Brings Cascade Lake-AP to OCP Form Factor

July 7, 2020

Penguin Computing, a subsidiary of SMART Global Holdings, Inc., announced yesterday (July 6) a new Tundra server, Tundra AP, that is the first to implement the Intel Xeon Scalable 9200 series processors (codenamed Cascad Read more…

By Tiffany Trader

Max Planck Society Begins Installation of Liquid-Cooled Supercomputer from Lenovo

July 9, 2020

Lenovo announced today that it is supplying a new high performance computer to the Max Planck Society, one of Germany's premier research organizations. Comprise Read more…

By Tiffany Trader

President’s Council Targets AI, Quantum, STEM; Recommends Spending Growth

July 9, 2020

Last week the President Council of Advisors on Science and Technology (PCAST) met (webinar) to review policy recommendations around three sub-committee reports: Read more…

By John Russell

Google Cloud Debuts 16-GPU Ampere A100 Instances

July 7, 2020

On the heels of the Nvidia’s Ampere A100 GPU launch in May, Google Cloud is announcing alpha availability of the A100 “Accelerator Optimized” VM A2 instance family on Google Compute Engine. The instances are powered by the HGX A100 16-GPU platform, which combines two HGX A100 8-GPU baseboards using... Read more…

By Tiffany Trader

Q&A: HLRS’s Bastian Koller Tackles HPC and Industry in Germany and Europe

July 6, 2020

In this exclusive interview for HPCwire – sadly not face to face – Steve Conway, senior advisor for Hyperion Research, talks with Dr.-Ing Bastian Koller about the state of HPC and its collaboration with Industry in Europe. Koller is a familiar figure in HPC. He is the managing director at High Performance Computing Center Stuttgart (HLRS) and also serves... Read more…

By Steve Conway, Hyperion

OpenPOWER Reboot – New Director, New Silicon Partners, Leveraging Linux Foundation Connections

July 2, 2020

Earlier this week the OpenPOWER Foundation announced the contribution of IBM’s A21 Power processor core design to the open source community. Roughly this time Read more…

By John Russell

Hyperion Forecast – Headwinds in 2020 Won’t Stifle Cloud HPC Adoption or Arm’s Rise

June 30, 2020

The semiannual taking of HPC’s pulse by Hyperion Research – late fall at SC and early summer at ISC – is a much-watched indicator of things come. This yea Read more…

By John Russell

Racism and HPC: a Special Podcast

June 29, 2020

Promoting greater diversity in HPC is a much-discussed goal and ostensibly a long-sought goal in HPC. Yet it seems clear HPC is far from achieving this goal. Re Read more…

Top500 Trends: Movement on Top, but Record Low Turnover

June 25, 2020

The 55th installment of the Top500 list saw strong activity in the leadership segment with four new systems in the top ten and a crowning achievement from the f Read more…

By Tiffany Trader

Supercomputer Modeling Tests How COVID-19 Spreads in Grocery Stores

April 8, 2020

In the COVID-19 era, many people are treating simple activities like getting gas or groceries with caution as they try to heed social distancing mandates and protect their own health. Still, significant uncertainty surrounds the relative risk of different activities, and conflicting information is prevalent. A team of Finnish researchers set out to address some of these uncertainties by... Read more…

By Oliver Peckham

[email protected] Turns Its Massive Crowdsourced Computer Network Against COVID-19

March 16, 2020

For gamers, fighting against a global crisis is usually pure fantasy – but now, it’s looking more like a reality. As supercomputers around the world spin up Read more…

By Oliver Peckham

[email protected] Rallies a Legion of Computers Against the Coronavirus

March 24, 2020

Last week, we highlighted [email protected], a massive, crowdsourced computer network that has turned its resources against the coronavirus pandemic sweeping the globe – but [email protected] isn’t the only game in town. The internet is buzzing with crowdsourced computing... Read more…

By Oliver Peckham

Supercomputer Simulations Reveal the Fate of the Neanderthals

May 25, 2020

For hundreds of thousands of years, neanderthals roamed the planet, eventually (almost 50,000 years ago) giving way to homo sapiens, which quickly became the do Read more…

By Oliver Peckham

DoE Expands on Role of COVID-19 Supercomputing Consortium

March 25, 2020

After announcing the launch of the COVID-19 High Performance Computing Consortium on Sunday, the Department of Energy yesterday provided more details on its sco Read more…

By John Russell

Honeywell’s Big Bet on Trapped Ion Quantum Computing

April 7, 2020

Honeywell doesn’t spring to mind when thinking of quantum computing pioneers, but a decade ago the high-tech conglomerate better known for its control systems waded deliberately into the then calmer quantum computing (QC) waters. Fast forward to March when Honeywell announced plans to introduce an ion trap-based quantum computer whose ‘performance’ would... Read more…

By John Russell

Neocortex Will Be First-of-Its-Kind 800,000-Core AI Supercomputer

June 9, 2020

Pittsburgh Supercomputing Center (PSC - a joint research organization of Carnegie Mellon University and the University of Pittsburgh) has won a $5 million award Read more…

By Tiffany Trader

Global Supercomputing Is Mobilizing Against COVID-19

March 12, 2020

Tech has been taking some heavy losses from the coronavirus pandemic. Global supply chains have been disrupted, virtually every major tech conference taking place over the next few months has been canceled... Read more…

By Oliver Peckham

Leading Solution Providers

Contributors

Nvidia’s Ampere A100 GPU: Up to 2.5X the HPC, 20X the AI

May 14, 2020

Nvidia's first Ampere-based graphics card, the A100 GPU, packs a whopping 54 billion transistors on 826mm2 of silicon, making it the world's largest seven-nanom Read more…

By Tiffany Trader

10nm, 7nm, 5nm…. Should the Chip Nanometer Metric Be Replaced?

June 1, 2020

The biggest cool factor in server chips is the nanometer. AMD beating Intel to a CPU built on a 7nm process node* – with 5nm and 3nm on the way – has been i Read more…

By Doug Black

‘Billion Molecules Against COVID-19’ Challenge to Launch with Massive Supercomputing Support

April 22, 2020

Around the world, supercomputing centers have spun up and opened their doors for COVID-19 research in what may be the most unified supercomputing effort in hist Read more…

By Oliver Peckham

Australian Researchers Break All-Time Internet Speed Record

May 26, 2020

If you’ve been stuck at home for the last few months, you’ve probably become more attuned to the quality (or lack thereof) of your internet connection. Even Read more…

By Oliver Peckham

15 Slides on Programming Aurora and Exascale Systems

May 7, 2020

Sometime in 2021, Aurora, the first planned U.S. exascale system, is scheduled to be fired up at Argonne National Laboratory. Cray (now HPE) and Intel are the k Read more…

By John Russell

Summit Supercomputer is Already Making its Mark on Science

September 20, 2018

Summit, now the fastest supercomputer in the world, is quickly making its mark in science – five of the six finalists just announced for the prestigious 2018 Read more…

By John Russell

TACC Supercomputers Run Simulations Illuminating COVID-19, DNA Replication

March 19, 2020

As supercomputers around the world spin up to combat the coronavirus, the Texas Advanced Computing Center (TACC) is announcing results that may help to illumina Read more…

By Staff report

$100B Plan Submitted for Massive Remake and Expansion of NSF

May 27, 2020

Legislation to reshape, expand - and rename - the National Science Foundation has been submitted in both the U.S. House and Senate. The proposal, which seems to Read more…

By John Russell

  • arrow
  • Click Here for More Headlines
  • arrow
Do NOT follow this link or you will be banned from the site!
Share This