Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Speeding up Gene Discovery

Published: Friday, December 13, 2013
Last Updated: Friday, December 13, 2013
Bookmark and Share
New gene-editing system enables large-scale studies of gene function.

Since the completion of the Human Genome Project, which identified nearly 20,000 protein-coding genes, scientists have been trying to decipher the roles of those genes. A new approach developed at MIT, the Broad Institute, and the Whitehead Institute should speed up the process by allowing researchers to study the entire genome at once.

The new system, known as CRISPR, allows researchers to permanently and selectively delete genes from a cell’s DNA. In two new papers, the researchers showed that they could study all the genes in the genome by deleting a different gene in each of a huge population of cells, then observing which cells proliferated under different conditions.

“With this work, it is now possible to conduct systematic genetic screens in mammalian cells. This will greatly aid efforts to understand the function of both protein-coding genes as well as noncoding genetic elements,” says David Sabatini, a member of the Whitehead Institute, MIT professor of biology, and a senior author of one of the papers, both of which appear in this week’s online edition of Science.

Using this approach, the researchers were able to identify genes that allow melanoma cells to proliferate, as well as genes that confer resistance to certain chemotherapy drugs. Such studies could help scientists develop targeted cancer treatments by revealing the genes that cancer cells depend on to survive.

Feng Zhang, the W.M. Keck Assistant Professor in Biomedical Engineering and senior author of the other Science paper, developed the CRISPR system by exploiting a naturally occurring bacterial protein that recognizes and snips viral DNA. This protein, known as Cas9, is recruited by short RNA molecules called guides, which bind to the DNA to be cut. This DNA-editing complex offers very precise control over which genes are disrupted, by simply changing the sequence of the RNA guide.

“One of the things we’ve realized is that you can easily reprogram these enzymes with a short nucleic-acid chain. This paper takes advantage of that and shows that you can scale that to large numbers and really sample across the whole genome,” says Zhang, who is also a member of MIT’s McGovern Institute for Brain Research and the Broad Institute.

Genome-wide screens

For their new paper, Zhang and colleagues created a library of about 65,000 guide RNA strands that target nearly every known gene. They delivered genes for these guides, along with genes for the CRISPR machinery, to human cells. Each cell took up one of the guides, and the gene targeted by that guide was deleted. If the gene lost was necessary for survival, the cell died.

“This is the first work that really introduces so many mutations in a controlled fashion, which really opens a lot of possibilities in functional genomics,” says Ophir Shalem, a Broad Institute postdoc and one of the lead authors of the Zhang paper, along with Broad Institute postdoc Neville Sanjana.

This approach enabled the researchers to identify genes essential to the survival of two populations of cells: cancer cells and pluripotent stem cells. The researchers also identified genes necessary for melanoma cells to survive treatment with the chemotherapy drug vemurafenib.

In the other paper, led by Sabatini and Eric Lander, the director of the Broad Institute and an MIT professor of biology, the research team targeted a smaller set of about 7,000 genes, but they designed more RNA guide sequences for each gene. The researchers expected that each sequence would block its target gene equally well, but they found that cells with different guides for the same gene had varying survival rates.

“That suggested that there were intrinsic differences between guide RNA sequences that led to differences in their efficiency at cleaving the genomic DNA,” says Tim Wang, an MIT graduate student in biology and lead author of the paper.

From that data, the researchers deduced some rules that appear to govern the efficiency of the CRISPR-Cas9 system. They then used those rules to create an algorithm that can predict the most successful sequences to target a given gene.

“These papers together demonstrate the extraordinary power and versatility of the CRISPR-Cas9 system as a tool for genomewide discovery of the mechanisms underlying mammalian biology,” Lander says. “And we are just at the beginning: We’re still uncovering the capabilities of this system and its many applications.”

Efficient alternative

The researchers say that the CRISPR approach could offer a more efficient and reliable alternative to RNA interference (RNAi), which is currently the most widely used method for studying gene functions. RNAi works by delivering short RNA strands known as shRNA that destroy messenger RNA (mRNA), which carries DNA’s instructions to the rest of the cell.

The drawback to RNAi is that it targets mRNA and not DNA, so it is impossible to get 100 percent elimination of the gene. “CRISPR can completely deplete a given protein in a cell, whereas shRNA will reduce the levels but it will never reach complete depletion,” Zhang says.

Michael Elowitz, a professor of biology, bioengineering, and applied physics at the California Institute of Technology, says the demonstration of the new technique is “an astonishing achievement.”

“Being able to do things on this enormous scale, at high accuracy, is going to revolutionize biology, because for the first time we can start to contemplate the kinds of comprehensive and complex genetic manipulations of cells that are necessary to really understand how complex genetic circuits work,” says Elowitz, who was not involved in the research.

In future studies, the researchers plan to conduct genomewide screens of cells that have become cancerous through the loss of tumor suppressor genes such as BRCA1. If scientists can discover which genes are necessary for those cells to thrive, they may be able to develop drugs that are highly cancer-specific, Wang says.

This strategy could also be used to help find drugs that counterattack tumor cells that have developed resistance to existing chemotherapy drugs, by identifying genes that those cells rely on for survival.

The researchers also hope to use the CRISPR system to study the function of the vast majority of the genome that does not code for proteins. “Only 2 percent of the genome is coding. That’s what these two studies have focused on, that 2 percent, but really there’s that other 98 percent which for a long time has been like dark matter,” Sanjana says.

The research from the Lander/Sabatini group was funded by the National Institutes of Health; the National Human Genome Research Institute; the Broad Institute, and the National Science Foundation. The research from the Zhang group was supported by the NIH Director’s Pioneer Award; the NIH; the Keck, McKnight, Merkin, Vallee, Damon Runyon, Searle Scholars, Klingenstein, and Simon Foundations; Bob Metcalfe; the Klarman Family Foundation; the Simons Center for the Social Brain at MIT; and Jane Pauley.

Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,500+ scientific posters on ePosters
  • More Than 5,100+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Achieving “Green” Desalination
Workshop explores ways to reduce or eliminate the carbon footprint of seawater desalination plants.
Thursday, October 20, 2016
Optical Fibers for Implanting in the Body
Biocompatible fibers could use light to stimulate cells or sense signs of disease.
Tuesday, October 18, 2016
New Strategy for Choosing Cancer Drugs
Device can predict tumor responses by measuring cell growth after drug exposure.
Monday, October 10, 2016
Nanosensors Could Determine Tumours’ Ability to Remodel Tissue
Researchers design nanosensors that can profile tumours, focusing on protease levels.
Thursday, September 29, 2016
High-Capacity Nanoparticles
New type of nanoparticle can now have three or more drugs packaged within it, allowing for customised cancer therapy.
Thursday, September 15, 2016
Delivering Beneficial Bacteria
Method that transports microbes through the stomach to the intestine may benefit human health.
Thursday, September 15, 2016
Linking RNA Structure and Function
Biologists have deciphered a lncRNA structure and used the information to investigate its cellular protein interactions.
Friday, September 09, 2016
Hacking Microbes
Startup’s engineered yeast helps clients produce fragrances and flavors more efficiently.
Thursday, September 08, 2016
Guided Needles Hit the Mark
New sensor could help anesthesiologists place needles for epidurals and other medical procedures.
Thursday, September 08, 2016
Changing Ocean Chemistry Due To Human Activity
More anthropogenic carbon in the northeast Pacific means weaker shells for many marine species.
Wednesday, September 07, 2016
Targeting Neglected Diseases
New enzyme-mapping advancement could help drug development for combating diseases in the developing world.
Wednesday, August 17, 2016
Protecting Privacy in Genomic Databases
System helps ensure databases used in medical research will not leak patients’ personal information.
Wednesday, August 10, 2016
Biopharmaceuticals on Demand
Portable production system would use microbes for manufacturing small amounts of vaccines and therapeutics.
Monday, August 01, 2016
Triple-Action Therapy Patch Shows Promise
Patch that delivers drug, gene, and light-based therapy to tumor sites shows promising results in mice.
Wednesday, July 27, 2016
New Device can Study Electric Field Cancer Therapy
Microfluidic device allows study of electric field cancer therapy through low-intensity fields, preventing malignant cells spreading.
Friday, July 08, 2016
Scientific News
Integrated Omics Analysis
Studying multi-omics promises to give a more holistic picture of the organism and its place in its ecosystem, however despite the complexities involved those within the field are optimistic.
Unravelling the Role of Key Genes and DNA Methylation in Blood Cell Malignancies
Researchers from the University of Nebraska Medical Center have demonstrated the role of Dnmt3a in safeguarding normal haematopoiesis.
Salford Lung Study - The First Real World Clinical Trial
In this podcast, we learn about the Salford Lung Study and its potential to revolutionize the way we assess new drugs and treatments around the world.
Point of Care Diagnostics - A Cautious Revolution
Advances in molecular biology, coupled with the miniaturization and improved sensitivity of assays and devices in general, have enabled a new wave of point-of-care (POC) or “bedside” diagnostics.
Mass Spec Technology Drives Innovation Across the Biopharma Workflow
With greater resolving power, analytical speed, and accuracy, new mass spectrometry technology and techniques are infiltrating the biopharmaceuticals workflow.
Structure of Primary Cannabinoid Receptor is Revealed
The findings provide key insights into how natural and synthetic cannabinoids including tetrahydrocannabinol —a primary chemical in marijuana—bind at the CB1 receptor to produce their effects.
Illumina Contributes to ClinVar Database
The contribution includes variants of all classifications, from pathogenic to benign, identified during interpretation of whole genome sequences generated in the CLIA-certified, CAP-accredited Illumina Clinical Services Laboratory.
Overlooked Molecules Could Revolutionise our Understanding of the Immune System
Researchers have discovered that around one third of all the epitopes displayed for scanning by the immune system are a type known as ‘spliced’ epitopes.
Study Finds Key Regulator in Pulmonary Fibrosis
Researchers identify an enzyme that could open the way to therpies for chronic fatal lung disease.
Signaling Pathway Could Be Key to Improved Osteoporosis Treatment
Inhibition of SIK2 enzyme both stimulates bone formation and reduces bone breakdown in animal model.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,100+ scientific videos