SDSC Supercomputer Modeling Reveals Acrobatics of CRISPR-Cas9 Technology

September 13, 2016

Sept. 13 — A team led by researchers at the University of California San Diego has captured in step-by-step atomic detail the surgical editing of DNA strands by CRISPR-Cas9, the innovative gene-splicing technology that in recent years has transformed the field of genetic engineering.

Simulations performed by the Comet supercomputer at the San Diego Supercomputer Center (SDSC) at UC San Diego describe the “striking plasticity” of CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 and how it identifies, merges, and slices its target DNA strand. What’s more, the findings offer for the first hints at a key role played by the leftover non-target DNA strand, whose part in this biological cast of characters previously was unclear.

The goal of this study — published in the September 8 issue of ACS Central Science, the new flagship journal of the American Chemical Society — is to provide a foundation for the design of other novel, highly accurate genome-splicing technologies that don’t yield the “off-target” DNA breaks currently frustrating the potential of the current CRISPR-Cas9 system, particularly for clinical uses.

“CRISPR-Cas9 is not perfect since it can cause off-target effects or non-selective cleavage of DNA sequences, creating unwanted collateral damage,” said Giulia Palermo, a postdoctoral scholar with the UC San Diego Department of Pharmacology and lead author of the study.

“If we can design a very specific genome editing machinery, we can target the modification of genes controlling several diseases, including rare diseases and brain diseases, that are difficult to cure with available drugs,” added the study’s principal investigator J. Andrew McCammon, the Joseph E. Mayer Chair of Theoretical Chemistry, a Howard Hughes Medical Institute investigator, and Distinguished Professor of Pharmacology, all at UC San Diego.

“The rational design of more specific Cas9s, which are economically and environmentally friendly, and free from ethical issues, is our ultimate goal,” he said.

As its name implies, CRISPR-Cas9 is a dual entity with dual functions. The first consists of a short RNA guide molecule, part of which matches a target DNA sequence; the second is a Cas9 enzyme that recognizes and slices the DNA in a precise spot, whose location or address is post-marked by a nucleotide sequence called a protospacer adjacent motif, or PAM. The result is an RNA-DNA hybrid with a displaced non-target DNA strand.

Dubbed Science magazine’s “breakthrough of the year” in 2015, enthusiastic researchers around the world are just now scratching the surface of CRISPR-Cas9’s potential, with hopes of treating diseases through gene therapy, or driving advances in areas from crop engineering to the production of biofuels. What the technology ideally offers is specificity: the ability to target, edit, and insert new fragments of DNA sequences into the vast genome of the human and other species of animals and plants.

However, this transformative technology – known for the ease with which it can be programmed to cleave specific DNA targets – isn’t without its flaws. Studies have revealed that the RNA guide used to direct the cleaving enzyme to its target can sometimes go astray, landing on other DNA strands with similar but not identical sequences. The result is “off-target” mutations, severely limiting the technology’s vast array of potential applications, particular for human therapy.

Although extensive studies of the CRISPR-Cas9 systems, including X-ray crystallography and cryoelectron microscopy (cryoEM), have revealed detailed views of the system’s structure and biological activity, the dynamics of Cas9 and its step-by-step acrobatics with nucleic acids during its merger and cleavage of DNA have remained fuzzy at best.

To produce a motion picture-like view of this molecular interplay, UC San Diego researchers turned to the Comet supercomputer to perform atomistic molecular dynamics – a method that captures a more complete vision of the myriad shapes and conformations that a target protein molecule may go through – at petascale speeds (one quadrillion arithmetic calculations per second).

“Access to Comet, greatly facilitated by SDSC, was essential to completing this work in a reasonable timeframe,” said McCammon, also an SDSC Fellow and chemistry and biochemistry professor in UC San Diego’s Division of Physical Sciences. “The power of high-performance computing at the petascale-level and atomistic molecular dynamics simulations are needed to obtain key insights and relevant biophysical information that otherwise are inaccessible with currently available experimental techniques.”

The resulting simulations, performed over multi-microsecond timescales, revealed for the first time what the research team called the “remarkable” plasticity of the Cas9 system, and identified key factors underlying the myriad structural changes taking place during the merger and preparation for cleaving of its target DNA strand.

Of particular interest, the researchers were surprised to find that the leftover non-target DNA strand, whose role was generally considered unimportant, is actually a critical player in the system, serving as a type of starter key that triggers the final stage of the process.

“The motion and position of the non-target DNA strand triggers local conformational changes that result in a shift of an active domain site (HNH) of Cas9 towards the cleavage site on the target DNA for catalysis,” said McCammon, recently named the winner of the 2016-17 Joseph O. Hirschfelder Prize in Theoretical Chemistry, awarded by the Theoretical Chemistry Institute at the University of Wisconsin-Madison. “These molecular simulations strongly suggest the presence of non-target DNA as a key factor for the conformational activation of the HNH domain.”

Also participating the study, called “Striking plasticity of CRISPR-Cas9 and key role of non-target DNA, as revealed by molecular simulations”, were: Yinglong Miao, a research specialist with the Howard Hughes Medical Institute at UC San Diego and research scientist with the UC San Diego Department of Pharmacology; Ross C. Walker, associate research professor at SDSC, NVIDA Fellow, and adjunct associate professor in the Department of Chemistry and Biochemistry at UC San Diego; and Martin Jinek, currently an assistant professor at the University of Zurich who first discovered, in Jennifer Doudna’s lab at UC Berkeley, the ability of Cas9 to be programmed with single RNA strands for efficient DNA cleavage.

Funding for the study was provided by the Swiss National Science Foundation, in addition to grants to the McCammon lab from the National Institutes of Health, the National Science Foundation, and Howard Hughes Medical Institute; and research fellowships to Ross Walker from Intel and NVIDIA.

About SDSC

As an Organized Research Unit of UC San Diego, SDSC is considered a leader in data-intensive computing and cyberinfrastructure, providing resources, services, and expertise to the national research community, including industry and academia. Cyberinfrastructure refers to an accessible, integrated network of computer-based resources and expertise, focused on accelerating scientific inquiry and discovery. SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from earth sciences and biology to astrophysics, bioinformatics, and health IT. SDSC’s Comet joins the Center’s data-intensive Gordon cluster, and are both part of the National Science Foundation’s XSEDE (Extreme Science and Engineering Discovery Environment) program.


Source: SDSC

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!

Scalable Informatics Ceases Operations

March 23, 2017

On the same day we reported on the uncertain future for HPC compiler company PathScale, we are sad to learn that another HPC vendor, Scalable Informatics, is closing its doors. Read more…

By Tiffany Trader

‘Strategies in Biomedical Data Science’ Advances IT-Research Synergies

March 23, 2017

“Strategies in Biomedical Data Science: Driving Force for Innovation” by Jay A. Etchings is both an introductory text and a field guide for anyone working with biomedical data. Read more…

By Tiffany Trader

HPC Compiler Company PathScale Seeks Life Raft

March 23, 2017

HPCwire has learned that HPC compiler company PathScale has fallen on difficult times and is asking the community for help or actively seeking a buyer for its assets. Read more…

By Tiffany Trader

Google Launches New Machine Learning Journal

March 22, 2017

On Monday, Google announced plans to launch a new peer review journal and “ecosystem” Read more…

By John Russell

HPE Extreme Performance Solutions

HFT Firms Turn to Co-Location to Gain Competitive Advantage

High-frequency trading (HFT) is a high-speed, high-stakes world where every millisecond matters. Finding ways to execute trades faster than the competition translates directly to greater revenue for firms, brokerages, and exchanges. Read more…

Swiss Researchers Peer Inside Chips with Improved X-Ray Imaging

March 22, 2017

Peering inside semiconductor chips using x-ray imaging isn’t new, but the technique hasn’t been especially good or easy to accomplish. Read more…

By John Russell

LANL Simulation Shows Massive Black Holes Break ‘Speed Limit’

March 21, 2017

A new computer simulation based on codes developed at Los Alamos National Laboratory (LANL) is shedding light on how supermassive black holes could have formed in the early universe contrary to most prior models which impose a limit on how fast these massive ‘objects’ can form. Read more…

Quantum Bits: D-Wave and VW; Google Quantum Lab; IBM Expands Access

March 21, 2017

For a technology that’s usually characterized as far off and in a distant galaxy, quantum computing has been steadily picking up steam. Read more…

By John Russell

Intel Ships Drives Based on 3D XPoint Non-volatile Memory

March 20, 2017

Intel Corp. has begun shipping new storage drives based on its 3D XPoint non-volatile memory technology as it targets data-driven workloads. Intel’s new Optane solid-state drives, designated P4800X, seek to combine the attributes of memory and storage in the same device. Read more…

By George Leopold

HPC Compiler Company PathScale Seeks Life Raft

March 23, 2017

HPCwire has learned that HPC compiler company PathScale has fallen on difficult times and is asking the community for help or actively seeking a buyer for its assets. Read more…

By Tiffany Trader

Quantum Bits: D-Wave and VW; Google Quantum Lab; IBM Expands Access

March 21, 2017

For a technology that’s usually characterized as far off and in a distant galaxy, quantum computing has been steadily picking up steam. Read more…

By John Russell

Trump Budget Targets NIH, DOE, and EPA; No Mention of NSF

March 16, 2017

President Trump’s proposed U.S. fiscal 2018 budget issued today sharply cuts science spending while bolstering military spending as he promised during the campaign. Read more…

By John Russell

CPU-based Visualization Positions for Exascale Supercomputing

March 16, 2017

In this contributed perspective piece, Intel’s Jim Jeffers makes the case that CPU-based visualization is now widely adopted and as such is no longer a contrarian view, but is rather an exascale requirement. Read more…

By Jim Jeffers, Principal Engineer and Engineering Leader, Intel

US Supercomputing Leaders Tackle the China Question

March 15, 2017

Joint DOE-NSA report responds to the increased global pressures impacting the competitiveness of U.S. supercomputing. Read more…

By Tiffany Trader

New Japanese Supercomputing Project Targets Exascale

March 14, 2017

Another Japanese supercomputing project was revealed this week, this one from emerging supercomputer maker, ExaScaler Inc., and Keio University. The partners are working on an original supercomputer design with exascale aspirations. Read more…

By Tiffany Trader

Nvidia Debuts HGX-1 for Cloud; Announces Fujitsu AI Deal

March 9, 2017

On Monday Nvidia announced a major deal with Fujitsu to help build an AI supercomputer for RIKEN using 24 DGX-1 servers. Read more…

By John Russell

HPC4Mfg Advances State-of-the-Art for American Manufacturing

March 9, 2017

Last Friday (March 3, 2017), the High Performance Computing for Manufacturing (HPC4Mfg) program held an industry engagement day workshop in San Diego, bringing together members of the US manufacturing community, national laboratories and universities to discuss the role of high-performance computing as an innovation engine for American manufacturing. Read more…

By Tiffany Trader

For IBM/OpenPOWER: Success in 2017 = (Volume) Sales

January 11, 2017

To a large degree IBM and the OpenPOWER Foundation have done what they said they would – assembling a substantial and growing ecosystem and bringing Power-based products to market, all in about three years. Read more…

By John Russell

TSUBAME3.0 Points to Future HPE Pascal-NVLink-OPA Server

February 17, 2017

Since our initial coverage of the TSUBAME3.0 supercomputer yesterday, more details have come to light on this innovative project. Of particular interest is a new board design for NVLink-equipped Pascal P100 GPUs that will create another entrant to the space currently occupied by Nvidia's DGX-1 system, IBM's "Minsky" platform and the Supermicro SuperServer (1028GQ-TXR). Read more…

By Tiffany Trader

Tokyo Tech’s TSUBAME3.0 Will Be First HPE-SGI Super

February 16, 2017

In a press event Friday afternoon local time in Japan, Tokyo Institute of Technology (Tokyo Tech) announced its plans for the TSUBAME3.0 supercomputer, which will be Japan’s “fastest AI supercomputer,” Read more…

By Tiffany Trader

IBM Wants to be “Red Hat” of Deep Learning

January 26, 2017

IBM today announced the addition of TensorFlow and Chainer deep learning frameworks to its PowerAI suite of deep learning tools, which already includes popular offerings such as Caffe, Theano, and Torch. Read more…

By John Russell

Lighting up Aurora: Behind the Scenes at the Creation of the DOE’s Upcoming 200 Petaflops Supercomputer

December 1, 2016

In April 2015, U.S. Department of Energy Undersecretary Franklin Orr announced that Intel would be the prime contractor for Aurora: Read more…

By Jan Rowell

Is Liquid Cooling Ready to Go Mainstream?

February 13, 2017

Lost in the frenzy of SC16 was a substantial rise in the number of vendors showing server oriented liquid cooling technologies. Three decades ago liquid cooling was pretty much the exclusive realm of the Cray-2 and IBM mainframe class products. That’s changing. We are now seeing an emergence of x86 class server products with exotic plumbing technology ranging from Direct-to-Chip to servers and storage completely immersed in a dielectric fluid. Read more…

By Steve Campbell

Enlisting Deep Learning in the War on Cancer

December 7, 2016

Sometime in Q2 2017 the first ‘results’ of the Joint Design of Advanced Computing Solutions for Cancer (JDACS4C) will become publicly available according to Rick Stevens. He leads one of three JDACS4C pilot projects pressing deep learning (DL) into service in the War on Cancer. Read more…

By John Russell

BioTeam’s Berman Charts 2017 HPC Trends in Life Sciences

January 4, 2017

Twenty years ago high performance computing was nearly absent from life sciences. Today it’s used throughout life sciences and biomedical research. Genomics and the data deluge from modern lab instruments are the main drivers, but so is the longer-term desire to perform predictive simulation in support of Precision Medicine (PM). There’s even a specialized life sciences supercomputer, ‘Anton’ from D.E. Shaw Research, and the Pittsburgh Supercomputing Center is standing up its second Anton 2 and actively soliciting project proposals. There’s a lot going on. Read more…

By John Russell

Leading Solution Providers

HPC Startup Advances Auto-Parallelization’s Promise

January 23, 2017

The shift from single core to multicore hardware has made finding parallelism in codes more important than ever, but that hasn’t made the task of parallel programming any easier. Read more…

By Tiffany Trader

HPC Technique Propels Deep Learning at Scale

February 21, 2017

Researchers from Baidu’s Silicon Valley AI Lab (SVAIL) have adapted a well-known HPC communication technique to boost the speed and scale of their neural network training and now they are sharing their implementation with the larger deep learning community. Read more…

By Tiffany Trader

CPU Benchmarking: Haswell Versus POWER8

June 2, 2015

With OpenPOWER activity ramping up and IBM’s prominent role in the upcoming DOE machines Summit and Sierra, it’s a good time to look at how the IBM POWER CPU stacks up against the x86 Xeon Haswell CPU from Intel. Read more…

By Tiffany Trader

Trump Budget Targets NIH, DOE, and EPA; No Mention of NSF

March 16, 2017

President Trump’s proposed U.S. fiscal 2018 budget issued today sharply cuts science spending while bolstering military spending as he promised during the campaign. Read more…

By John Russell

IDG to Be Bought by Chinese Investors; IDC to Spin Out HPC Group

January 19, 2017

US-based publishing and investment firm International Data Group, Inc. (IDG) will be acquired by a pair of Chinese investors, China Oceanwide Holdings Group Co., Ltd. Read more…

By Tiffany Trader

US Supercomputing Leaders Tackle the China Question

March 15, 2017

Joint DOE-NSA report responds to the increased global pressures impacting the competitiveness of U.S. supercomputing. Read more…

By Tiffany Trader

Quantum Bits: D-Wave and VW; Google Quantum Lab; IBM Expands Access

March 21, 2017

For a technology that’s usually characterized as far off and in a distant galaxy, quantum computing has been steadily picking up steam. Read more…

By John Russell

Intel and Trump Announce $7B for Fab 42 Targeting 7nm

February 8, 2017

In what may be an attempt by President Trump to reset his turbulent relationship with the high tech industry, he and Intel CEO Brian Krzanich today announced plans to invest more than $7 billion to complete Fab 42. Read more…

By John Russell

  • arrow
  • Click Here for More Headlines
  • arrow
Share This