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!

Democratization of HPC Part 3: Ninth Graders Tap HPC in the Cloud to Design Flying Boats

October 18, 2018

This is the third in a series of articles demonstrating the growing acceptance of high-performance computing (HPC) in new user communities and application areas. In this article we present UberCloud use case #208 on how Read more…

By Wolfgang Gentzsch and Håkon Bull Hove

Penguin Computing Launches Consultancy for Piecing AI Strategies Together

October 18, 2018

AI stands before the HPC industry as a beacon of great expectations, yet market research repeatedly shows that AI adoption is commonly stuck in the talking phase, on the near side of a difficult chasm to cross. In respon Read more…

By Tiffany Trader

When Water Quality—Not Quantity—Hinders HPC Cooling

October 18, 2018

Attention has been paid to the sheer quantity of water consumed by supercomputers’ cooling towers – and rightly so, as they can require thousands of gallons per minute to cool. But in the background, another factor can emerge, bottlenecking efficiency and raising costs: water quality. Read more…

By Oliver Peckham

HPE Extreme Performance Solutions

One Small Step Toward Mars: One Giant Leap for Supercomputing

Since the days of the Space Race between the U.S. and the former Soviet Union, we have continually sought ways to perform experiments in space. Read more…

IBM Accelerated Insights

Paper Offers ‘Proof’ of Quantum Advantage on Some Problems

October 18, 2018

Is quantum computing worth all the effort being poured into it or should we just wait for classical computing to catch up? An IBM blog today posed those questions and, you won’t be surprised, offers a firm “it’s wo Read more…

By John Russell

Penguin Computing Launches Consultancy for Piecing AI Strategies Together

October 18, 2018

AI stands before the HPC industry as a beacon of great expectations, yet market research repeatedly shows that AI adoption is commonly stuck in the talking phas Read more…

By Tiffany Trader

When Water Quality—Not Quantity—Hinders HPC Cooling

October 18, 2018

Attention has been paid to the sheer quantity of water consumed by supercomputers’ cooling towers – and rightly so, as they can require thousands of gallons per minute to cool. But in the background, another factor can emerge, bottlenecking efficiency and raising costs: water quality. Read more…

By Oliver Peckham

Paper Offers ‘Proof’ of Quantum Advantage on Some Problems

October 18, 2018

Is quantum computing worth all the effort being poured into it or should we just wait for classical computing to catch up? An IBM blog today posed those questio Read more…

By John Russell

Dell EMC to Supply U Michigan’s Great Lakes Cluster

October 16, 2018

The University of Michigan (U-M) today announced Dell EMC is the lead vendor for U-M’s $4.8 million Great Lakes HPC cluster scheduled for deployment in first Read more…

By John Russell

Houston to Field Massive, ‘Geophysically Configured’ Cloud Supercomputer

October 11, 2018

Based on some news stories out today, one might get the impression that the next system to crack number one on the Top500 would be an industrial oil and gas mon Read more…

By Tiffany Trader

Nvidia Platform Pushes GPUs into Machine Learning, High Performance Data Analytics

October 10, 2018

GPU leader Nvidia, generally associated with deep learning, autonomous vehicles and other higher-end enterprise and scientific workloads (and gaming, of course) Read more…

By Doug Black

Federal Investment in Exascale – What It Really Means

October 10, 2018

Earlier this month, the EuroHPC JU (Joint Undertaking) reached critical mass, and it seems all EU and affiliated member states, bar the UK (unsurprisingly), have or will sign on. The EuroHPC JU was born from a recognition that individual EU member states, and the EU as a whole, were significantly underinvesting in HPC compared to the US, China and Japan, who all have their own exascale investment and delivery strategies (NSCI, 13th 5 Year Plan, Post-K, etc). Read more…

By Dairsie Latimer

NERSC-9 Clues Found in NERSC 2017 Annual Report

October 8, 2018

If you’re eager to find out who’ll supply NERSC’s next-gen supercomputer, codenamed NERSC-9, here’s a project update to tide you over until the winning bid and system details are revealed. The upcoming system is referenced several times in the recently published 2017 NERSC annual report. Read more…

By Tiffany Trader

TACC Wins Next NSF-funded Major Supercomputer

July 30, 2018

The Texas Advanced Computing Center (TACC) has won the next NSF-funded big supercomputer beating out rivals including the National Center for Supercomputing Ap Read more…

By John Russell

IBM at Hot Chips: What’s Next for Power

August 23, 2018

With processor, memory and networking technologies all racing to fill in for an ailing Moore’s law, the era of the heterogeneous datacenter is well underway, Read more…

By Tiffany Trader

Requiem for a Phi: Knights Landing Discontinued

July 25, 2018

On Monday, Intel made public its end of life strategy for the Knights Landing "KNL" Phi product set. The announcement makes official what has already been wide Read more…

By Tiffany Trader

CERN Project Sees Orders-of-Magnitude Speedup with AI Approach

August 14, 2018

An award-winning effort at CERN has demonstrated potential to significantly change how the physics based modeling and simulation communities view machine learni Read more…

By Rob Farber

House Passes $1.275B National Quantum Initiative

September 17, 2018

Last Thursday the U.S. House of Representatives passed the National Quantum Initiative Act (NQIA) intended to accelerate quantum computing research and developm 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

New Deep Learning Algorithm Solves Rubik’s Cube

July 25, 2018

Solving (and attempting to solve) Rubik’s Cube has delighted millions of puzzle lovers since 1974 when the cube was invented by Hungarian sculptor and archite Read more…

By John Russell

D-Wave Breaks New Ground in Quantum Simulation

July 16, 2018

Last Friday D-Wave scientists and colleagues published work in Science which they say represents the first fulfillment of Richard Feynman’s 1982 notion that Read more…

By John Russell

Leading Solution Providers

HPC on Wall Street 2018 Booth Video Tours Playlist

Arista

Dell EMC

IBM

Intel

RStor

VMWare

TACC’s ‘Frontera’ Supercomputer Expands Horizon for Extreme-Scale Science

August 29, 2018

The National Science Foundation and the Texas Advanced Computing Center announced today that a new system, called Frontera, will overtake Stampede 2 as the fast Read more…

By Tiffany Trader

HPE No. 1, IBM Surges, in ‘Bucking Bronco’ High Performance Server Market

September 27, 2018

Riding healthy U.S. and global economies, strong demand for AI-capable hardware and other tailwind trends, the high performance computing server market jumped 28 percent in the second quarter 2018 to $3.7 billion, up from $2.9 billion for the same period last year, according to industry analyst firm Hyperion Research. Read more…

By Doug Black

Intel Announces Cooper Lake, Advances AI Strategy

August 9, 2018

Intel's chief datacenter exec Navin Shenoy kicked off the company's Data-Centric Innovation Summit Wednesday, the day-long program devoted to Intel's datacenter Read more…

By Tiffany Trader

GPUs Power Five of World’s Top Seven Supercomputers

June 25, 2018

The top 10 echelon of the newly minted Top500 list boasts three powerful new systems with one common engine: the Nvidia Volta V100 general-purpose graphics proc Read more…

By Tiffany Trader

Germany Celebrates Launch of Two Fastest Supercomputers

September 26, 2018

The new high-performance computer SuperMUC-NG at the Leibniz Supercomputing Center (LRZ) in Garching is the fastest computer in Germany and one of the fastest i Read more…

By Tiffany Trader

MLPerf – Will New Machine Learning Benchmark Help Propel AI Forward?

May 2, 2018

Let the AI benchmarking wars begin. Today, a diverse group from academia and industry – Google, Baidu, Intel, AMD, Harvard, and Stanford among them – releas Read more…

By John Russell

Aerodynamic Simulation Reveals Best Position in a Peloton of Cyclists

July 5, 2018

Eindhoven University of Technology (TU/e) and KU Leuven research group conducts the largest numerical simulation ever done in the sport industry and cycling discipline. The goal was to understand the aerodynamic interactions in the peloton, i.e., the main pack of cyclists in a race. Read more…

Houston to Field Massive, ‘Geophysically Configured’ Cloud Supercomputer

October 11, 2018

Based on some news stories out today, one might get the impression that the next system to crack number one on the Top500 would be an industrial oil and gas mon Read more…

By Tiffany Trader

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