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!

A Beginner’s Guide to the ASC19 Finals

April 22, 2019

Three thousand watts. That's how much power the competitors in the 2019 ASC Student Supercomputer Challenge here in Dalian, China, have to work with. Everybody would like more juice to run compute-intensive HPC simulatio Read more…

By Alex Woodie

Is Data Science the Fourth Pillar of the Scientific Method?

April 18, 2019

Nvidia CEO Jensen Huang revived a decade-old debate last month when he said that modern data science (AI plus HPC) has become the fourth pillar of the scientific method. While some disagree with the notion that statistic Read more…

By Alex Woodie

At ASF 2019: The Virtuous Circle of Big Data, AI and HPC

April 18, 2019

We've entered a new phase in IT -- in the world, really -- where the combination of big data, artificial intelligence, and high performance computing is pushing the bounds of what's possible in business and science, in w Read more…

By Alex Woodie with Doug Black and Tiffany Trader

HPE Extreme Performance Solutions

HPE and Intel® Omni-Path Architecture: How to Power a Cloud

Learn how HPE and Intel® Omni-Path Architecture provide critical infrastructure for leading Nordic HPC provider’s HPCFLOW cloud service.

powercloud_blog.jpgFor decades, HPE has been at the forefront of high-performance computing, and we’ve powered some of the fastest and most robust supercomputers in the world. Read more…

IBM Accelerated Insights

Bridging HPC and Cloud Native Development with Kubernetes

The HPC community has historically developed its own specialized software stack including schedulers, filesystems, developer tools, container technologies tuned for performance and large-scale on-premises deployments. Read more…

Google Open Sources TensorFlow Version of MorphNet DL Tool

April 18, 2019

Designing optimum deep neural networks remains a non-trivial exercise. “Given the large search space of possible architectures, designing a network from scratch for your specific application can be prohibitively expens Read more…

By John Russell

A Beginner’s Guide to the ASC19 Finals

April 22, 2019

Three thousand watts. That's how much power the competitors in the 2019 ASC Student Supercomputer Challenge here in Dalian, China, have to work with. Everybody Read more…

By Alex Woodie

At ASF 2019: The Virtuous Circle of Big Data, AI and HPC

April 18, 2019

We've entered a new phase in IT -- in the world, really -- where the combination of big data, artificial intelligence, and high performance computing is pushing Read more…

By Alex Woodie with Doug Black and Tiffany Trader

Interview with 2019 Person to Watch Michela Taufer

April 18, 2019

Today, as part of our ongoing HPCwire People to Watch focus series, we are highlighting our interview with 2019 Person to Watch Michela Taufer. Michela -- the Read more…

By HPCwire Editorial Team

Intel Gold U-Series SKUs Reveal Single Socket Intentions

April 18, 2019

Intel plans to jump into the single socket market with a portion of its just announced Cascade Lake microprocessor line according to one media report. This isn Read more…

By John Russell

BSC Researchers Shrink Floating Point Formats to Accelerate Deep Neural Network Training

April 15, 2019

Sometimes calculating solutions as precisely as a computer can wastes more CPU resources than is necessary. A case in point is with deep learning. In early stag Read more…

By Ken Strandberg

Intel Extends FPGA Ecosystem with 10nm Agilex

April 11, 2019

The insatiable appetite for higher throughput and lower latency – particularly where edge analytics and AI, network functions, or for a range of datacenter ac Read more…

By Doug Black

Nvidia Doubles Down on Medical AI

April 9, 2019

Nvidia is collaborating with medical groups to push GPU-powered AI tools into clinical settings, including radiology and drug discovery. The GPU leader said Monday it will collaborate with the American College of Radiology (ACR) to provide clinicians with its Clara AI tool kit. The partnership would allow radiologists to leverage AI techniques for diagnostic imaging using their own clinical data. Read more…

By George Leopold

Digging into MLPerf Benchmark Suite to Inform AI Infrastructure Decisions

April 9, 2019

With machine learning and deep learning storming into the datacenter, the new challenge is optimizing infrastructure choices to support diverse ML and DL workfl Read more…

By John Russell

The Case Against ‘The Case Against Quantum Computing’

January 9, 2019

It’s not easy to be a physicist. Richard Feynman (basically the Jimi Hendrix of physicists) once said: “The first principle is that you must not fool yourse Read more…

By Ben Criger

Why Nvidia Bought Mellanox: ‘Future Datacenters Will Be…Like High Performance Computers’

March 14, 2019

“Future datacenters of all kinds will be built like high performance computers,” said Nvidia CEO Jensen Huang during a phone briefing on Monday after Nvidia revealed scooping up the high performance networking company Mellanox for $6.9 billion. Read more…

By Tiffany Trader

ClusterVision in Bankruptcy, Fate Uncertain

February 13, 2019

ClusterVision, European HPC specialists that have built and installed over 20 Top500-ranked systems in their nearly 17-year history, appear to be in the midst o Read more…

By Tiffany Trader

Intel Reportedly in $6B Bid for Mellanox

January 30, 2019

The latest rumors and reports around an acquisition of Mellanox focus on Intel, which has reportedly offered a $6 billion bid for the high performance interconn Read more…

By Doug Black

It’s Official: Aurora on Track to Be First US Exascale Computer in 2021

March 18, 2019

The U.S. Department of Energy along with Intel and Cray confirmed today that an Intel/Cray supercomputer, "Aurora," capable of sustained performance of one exaf Read more…

By Tiffany Trader

Looking for Light Reading? NSF-backed ‘Comic Books’ Tackle Quantum Computing

January 28, 2019

Still baffled by quantum computing? How about turning to comic books (graphic novels for the well-read among you) for some clarity and a little humor on QC. The Read more…

By John Russell

IBM Quantum Update: Q System One Launch, New Collaborators, and QC Center Plans

January 10, 2019

IBM made three significant quantum computing announcements at CES this week. One was introduction of IBM Q System One; it’s really the integration of IBM’s Read more…

By John Russell

Deep500: ETH Researchers Introduce New Deep Learning Benchmark for HPC

February 5, 2019

ETH researchers have developed a new deep learning benchmarking environment – Deep500 – they say is “the first distributed and reproducible benchmarking s Read more…

By John Russell

Leading Solution Providers

SC 18 Virtual Booth Video Tour

Advania @ SC18 AMD @ SC18
ASRock Rack @ SC18
DDN Storage @ SC18
HPE @ SC18
IBM @ SC18
Lenovo @ SC18 Mellanox Technologies @ SC18
NVIDIA @ SC18
One Stop Systems @ SC18
Oracle @ SC18 Panasas @ SC18
Supermicro @ SC18 SUSE @ SC18 TYAN @ SC18
Verne Global @ SC18

IBM Bets $2B Seeking 1000X AI Hardware Performance Boost

February 7, 2019

For now, AI systems are mostly machine learning-based and “narrow” – powerful as they are by today's standards, they're limited to performing a few, narro Read more…

By Doug Black

The Deep500 – Researchers Tackle an HPC Benchmark for Deep Learning

January 7, 2019

How do you know if an HPC system, particularly a larger-scale system, is well-suited for deep learning workloads? Today, that’s not an easy question to answer Read more…

By John Russell

Arm Unveils Neoverse N1 Platform with up to 128-Cores

February 20, 2019

Following on its Neoverse roadmap announcement last October, Arm today revealed its next-gen Neoverse microarchitecture with compute and throughput-optimized si Read more…

By Tiffany Trader

Intel Launches Cascade Lake Xeons with Up to 56 Cores

April 2, 2019

At Intel's Data-Centric Innovation Day in San Francisco (April 2), the company unveiled its second-generation Xeon Scalable (Cascade Lake) family and debuted it Read more…

By Tiffany Trader

France to Deploy AI-Focused Supercomputer: Jean Zay

January 22, 2019

HPE announced today that it won the contract to build a supercomputer that will drive France’s AI and HPC efforts. The computer will be part of GENCI, the Fre Read more…

By Tiffany Trader

Oil and Gas Supercloud Clears Out Remaining Knights Landing Inventory: All 38,000 Wafers

March 13, 2019

The McCloud HPC service being built by Australia’s DownUnder GeoSolutions (DUG) outside Houston is set to become the largest oil and gas cloud in the world th Read more…

By Tiffany Trader

Intel Extends FPGA Ecosystem with 10nm Agilex

April 11, 2019

The insatiable appetite for higher throughput and lower latency – particularly where edge analytics and AI, network functions, or for a range of datacenter ac Read more…

By Doug Black

UC Berkeley Paper Heralds Rise of Serverless Computing in the Cloud – Do You Agree?

February 13, 2019

Almost exactly ten years to the day from publishing of their widely-read, seminal paper on cloud computing, UC Berkeley researchers have issued another ambitious examination of cloud computing - Cloud Programming Simplified: A Berkeley View on Serverless Computing. The new work heralds the rise of ‘serverless computing’ as the next dominant phase of cloud computing. 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