Stopping CRISPRs genomeediting scissors from snipping out of control

first_imgIn an episode of the resurrected X-Files TV show that ran earlier this year, aliens attack Earth with a bioweapon based on CRISPR, the genome-editing tool that vastly simplifies the ability to modify DNA. Agent Dana Scully, one of the show’s main characters, resists the attack because her genome earlier had incorporated some alien DNA that had anti-CRISPR defenses. Now, the art that imitated the science is being followed by the science imitating the art: Researchers have found for the first time anti-CRISPR proteins that shut off the genome editor and shown they can use them to control the cutting of DNA in human cells.In Cell yesterday, molecular biochemist Erik Sontheimer of the University of Massachusetts Medical School in Worcester and colleagues describe three proteins in Neisseria meningitidis that inhibit its version of Cas9, an enzyme that some CRISPR systems employ to cut the DNA. (N. meningitidis is a bacterium that causes a form of meningitidis in humans.) “Any time you have greater control over a useful technology, the utility improves,” says Sontheimer, whose pioneering work (published in Science in 2008) first suggested that CRISPR—an immune system in bacteria and archaea—could be adapted to editing the DNA of other organisms.Many research groups have begun using CRISPR’s Cas9 molecular scissors to create potential therapies for humans, mutate genes in lab animals, or even craft “gene drives” in mosquitoes that render them incapable of transmitting malaria. These interventions hold great promise for humans, but they also present what Sontheimer and his co-authors call “practical difficulties and safety concerns” because there are no “off switches” to prevent Cas9 from making cuts in the wrong places or to stop gene drives using the enzyme from running amok. Sign up for our daily newsletter Get more great content like this delivered right to you! 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Required fields are indicated by an asterisk (*) Emailcenter_img Country * Afghanistan Aland Islands Albania Algeria Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia, Plurinational State of Bonaire, Sint Eustatius and Saba Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory Brunei Darussalam Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Congo, the Democratic Republic of the Cook Islands Costa Rica Cote d’Ivoire Croatia Cuba Curaçao Cyprus Czech Republic Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands (Malvinas) Faroe Islands Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Gambia Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and McDonald Islands Holy See (Vatican City State) Honduras Hungary Iceland India Indonesia Iran, Islamic Republic of Iraq Ireland Isle of Man Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Korea, Democratic People’s Republic of Korea, Republic of Kuwait Kyrgyzstan Lao People’s Democratic Republic Latvia Lebanon Lesotho Liberia Libyan Arab Jamahiriya Liechtenstein Lithuania Luxembourg Macao Macedonia, the former Yugoslav Republic of Madagascar Malawi Malaysia Maldives Mali Malta Martinique Mauritania Mauritius Mayotte Mexico Moldova, Republic of Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island Norway Oman Pakistan Palestine Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Qatar Reunion Romania Russian Federation Rwanda Saint Barthélemy Saint Helena, Ascension and Tristan da Cunha Saint Kitts and Nevis Saint Lucia Saint Martin (French part) Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Sint Maarten (Dutch part) Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Islands South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syrian Arab Republic Taiwan Tajikistan Tanzania, United Republic of Thailand Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu Uganda Ukraine United Arab Emirates United Kingdom United States Uruguay Uzbekistan Vanuatu Venezuela, Bolivarian Republic of Vietnam Virgin Islands, British Wallis and Futuna Western Sahara Yemen Zambia Zimbabwe In 2013, biochemists Karen Maxwell and Alan Davidson at the University of Toronto in Canada, who study the viruses known as phages that infect bacteria and are co-authors on the new study, reported in Nature that they had found anti-CRISPR genes in a bacterial system that uses a different DNA-cutting enzyme than Cas9. Other groups have also shown that various artificial strategies—like small molecules or light—can shut down Cas9. But Rodolphe Barrangou, a functional genomics specialist who in 2007 published a landmark CRISPR paper in Science, notes that the proteins revealed in the new work offer “a nature-driven approach” to controlling Cas9. “This is very powerful,” says Barrangou, who is at North Carolina State University in Raleigh. “It’s awesome.”In addition to offering a handy way to manipulate the CRISPR technology, the anti-Cas9 proteins have “profound” evolutionary implications, the authors of the Cell paper suggest. These proteins likely emerged first in phages as a way for those viruses to counter the Cas9-based immune defense of bacteria. But the essence of the CRISPR defense mechanism is that bacteria incorporate the phage genetic material into their own DNA and use it against the parasite if it reinfects. So N. meningitidis ended up with anti-CRISPR genes in its own genome, which may limit both the bacteria’s ability to stop subsequent invasions from a familiar phage and to build an effective CRISPR defense against novel phages.Sontheimer himself cautions that “there are a lot of things to work out.” The CRISPR system that most research teams now use to modify human cells and those of other complex organisms was adapted from the bacterium Streptococcus pyogenes, not N. meningitidis, and the three newfound proteins can’t shut off its Cas9. But Sontheimer and others predict they will find ones that do. “This paper is a proof of principle,” he says. “There definitely are going to be other Cas9 inhibitors. Now, the search is on.”For more related coverage on CRISPR, visit our topic page.last_img

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