I Gene EditingGene ArtistAn in BIOLOGY &MEDICINE_PersonalPortrait Max Planck Institute for Infection Biology Planck Institute forInfection Max have in changed French woman’s the life. at Berlin-based aDirector the She became CRISPR-Cas RNA and as trio and molecules known moment. The comprisedtwo ofoneenzyme such a was deciphering functioning the previously only toexperts known ofan enzyme Sometimes asingle change can discovery life. awhole For mer. Sheseems a littlestressedfromall temperatures thatmadeita hotsum- tists ofourtime. and oneofthemostimportant scien- propriate locationforamicrobiologist –anap- the endof19thcentury against thetuberculosis bacteriumat Infectious Diseases,beganhisbattle ert Koch,atthePrussianInstitutefor teaching hospital.ThisiswhereRob- grounds ofCharité,Berlin’s renowned ground inthemiddleofcity:on Planck InstituteforInfectionBiology. will beappointedDirectorattheMax ing totheGermancapital.InBerlin,she for InfectionResearch, sheisnowmov- twoyearsattheHelmholtzCentre after French womanisonthemoveagain: 48 TEXT MaxPlanckResearch 1 MaxPlanckResearch For Charpentier, itwasn’t justthe Her newinstitutestandsonhistoric She tapsherfoot.Thedainty schweig, deepinconcentration. tier sitsinherofficeBraun- mer 2015.EmmanuelleCharpen- t‘s oneofthelasthotdayssum- UTA DEFFKE 9 made headlines ofscience. world far the beyond Since then, alot ofthings | 16 at a very specific locationinthebacte- at avery piece oftheviralDNAandintegrate it abacterium,enzymescutout attack name ofCRISPR-Cas9.When viruses rial genome:theCRISPRsequence. The ria part oftheimmunesystembacte- is The mainprotagonistinthestory ence’s mostremarkablesuccessstories. Charpentier’s isoneofsci- discovery As themanyawardsandprizesshow, A SCALPELFORRESEARCHERS Leibniz Prize. Prize inLifeSciencesandthe2016 for Medicine,the2015Breakthrough Prize forMedicine,theErnstJung Technical Research, theLouisJeantet cess ofAsturiasAward forScientificand science awards,amongthemthePrin- 2015 aloneincludesseveralprestigious The listofprizesshewasawardedin overthelasttwoyears. her discovery the fussthathassurroundedherand and goesbytheunpronounceable in early October in October early Emmanuelle Charpentier Emmanuelle 2015 . den workedwithJennifer Doudna’s human geneticdisorders. specifically targetinggenesand treating could openupnewwaysof discovery pentier hadalreadyforeseen thather the CRISPR-RNA.EmmanuelleChar- viral DNAatthelocationdefinedby ed bythetwoRNAmoleculestocut the DNAcleavageprocess.Cas9isguid- thattracrRNAisalsoinvolvedin covery paper inS pentier andhercolleaguespublisheda and nowknownasCas9.In2012,Char- and anenzymeinitiallynamedCsn1 known asCRISPR-RNAandtracrRNA– in theprocess:twoRNAmolecules– that threecomponentsareinvolved new mechanisminN the pathogens. of invadingviruses,thusincapacitating The proteinCas9thencutsthegenome an RNAmolecule,theCRISPR-RNA. cell thentranscribesthissequenceinto Charpentier’s groupinUmeå,Swe- In 2011,Charpentierdescribedthe CIENCE outliningtheirdis- , ATURE , showing

Photo: Hallbauer and Fioretti xxxxxxxx as possible after the move. the after possible as soon as research her on working begin to was inOctober Biology Infection for Institute Planck Max Berlin-based the to moved Charpentier Emmanuelle here: Finally plication oftheCRISPR-Cas9tool,since molecule. Thisstepsimplifiedtheap- bine thetwoRNAmoleculesintoone group inBerkeley, Californiatocom- in HIVandmalariaresearch. netic diseases.Itisalreadybeing used use ittocorrectmutationsand curege- multitude ofdiseases.Doctors could micetotreatmentsfora ic laboratory breeding andtheof transgen- verse rangeofapplications:fromplant has thepotentialforanextremelydi- been successful.CRISPR-Cas9therefore plant, animalandhumancellshave addition tomanylabs. previous methods,itisalreadyavital precise, efficientandcosteffectivethan a tooltostudygenes.Asitismuchmore further. Buttheyareusingitmainlyas CRISPR-Cas9 andwanttodevelopit world arenowtakingacloserlookat this year. Scientistsfromalloverthe could risetomorethan1,100studies number skyrocketedtoalmost500,and figure hadrisento277.In2015,the subject ofCRISPR-Cas9;by2013the in 2012,127publicationscoveredthe sors havetakenlaboratoriesbystorm: Cas9 mechanism,themolecularscis- on oroff. snippet atthecutandthusswitchgenes Researchers cantheninsert anewDNA matching RNAmoleculemanufactured. sequence needstobeknownanda desired location,onlytherelevantgene gene sequencethatCas9wastocleave. to programoneRNAmoleculeinthe it meantthatresearchers onlyneeded To date,allexperimentsinvolving oftheCRISPR- Since thediscovery In orderfortheDNAtobecutata 1 | MaxPlanckResearch 16MaxPlanckResearch 2015 . Her objective objective . Her 49 >

An immune mechanism in bacteria, than school, university seemed to her But she didn’t want to make a career until recently known only to hard- to be the place of learning and intel- out of this talent: not only because it is core microbiologists, could soon be- lectual debate. difficult to make a living from it, but, come a medical treatment for millions for dancers in particular, their active of patients. CRISPR-Cas9 is therefore a FROM MUSIC TO BIOLOGY years are soon over. Scientists, on the prime example of one of Charpentier’s other hand, can always keep making core beliefs: “Basic research is essen- That she would one day be a biologist, progress, even as they get older. tial for progress,” she stresses at every however, wasn’t determined until later. Biology, with its complexity and di- opportunity – a view that resonates “According to my mother, when I was rect relationship with people, was the perfectly with the Max Planck Society, 11 or 12 years old, I told her that I area that fascinated her most. Biochem- of course. would work at the Pasteur Institute – istry was the area she initially focused The driving force behind Charpen- and that is where I actually did my doc- on, but bacteria soon took over the tier’s research is, above all, an un- torate,” she recalls with a smile. “But I main role in her life as a researcher. In quenchable curiosity about the world actually enjoyed all my subjects at her doctoral thesis, she examined and its complex relationships, a char- school. So I could have also followed a mechanisms that lead bacteria to devel- acteristic that she displayed even as a very different path.” op resistance to antibiotics. It was al- child. Charpentier grew up south of In her spare time, Charpentier en- ready apparent back then that the Paris, where she was exposed to a mul- joys art, music and dance. She played number of multi-resistant pathogens tifaceted range of interests. Her moth- the piano and practiced ballet and would rapidly increase. er worked in psychiatry; her father modern dance for several years – a At the same time, there was a was responsible for planning green good exercise, not least for discipline growing awareness that we could also spaces in the city. One of her sisters and creative power. As she herself learn a lot from them. Thus, the re- began her studies at university just as says: “Art has had a significant influ- search that was conducted on bacte- Emmanuelle started school, and from ence on my scientific career: you need ria in the 1970s resulted in important then on, one thing was clear to her: to be rigorous, but you also need to be new laboratory techniques, such as

she wanted that, too. Even more so able to let yourself go.” the gene cloning. Photo: Hallbauer and Fioretti

50 MaxPlanckResearch 1 | 16 Graphic: Massih Media for the Max Planck Society the mousegenomeinsucha wayasto learned howarduousitwas tomodify trigger skininfections.Indoing so,she velopment andhowmicroorganisms research onmice,focusingskinde- instead totheirhosts,andcarried out leaving herbacteria.Charpentierturned tant tofindone’s niche. all, inthescientificworld,it’s impor- critically byscientificcolleagues.After ter, evenif that wassometimesviewed restrict herselfintermsofsubjectmat- students. Similarly, shedidn’t wantto she says,alsorecommendingittoher ably exactlywhatIneedformywork,” tweaking herownwork.“Thisisprob- ing hercomfortzone,scrutinizingand ent placesalsomeansconstantlyleav- for Charpentier. Afterall,leavingdiffer- on themove.” York, Ihave actuallybeenconstantly to me.ButsincemyarrivalinNew Up tothen,itdidn’t much mean very adventurous lifewithconstantchange. as ayoungchild:thatIwouldhavean a missionary, hadoncepredictedforme I rememberedsomethingthatmyaunt, Memphis, Tennessee. “Atthatmoment, working groupwouldbemovingto day shearrived,foundoutthather doctoral positioninNewYork. Onthe her scientificpilgrimagewithapost- in termsofsubjectmatter. Shebegan adventures –bothgeographicallyand work, tocontinuouslyembarkonnew following herstudiesanddoctoral what motivatedheratanearlystage, so excitinginherdiscipline.Thisisalso It issurpriseslikethesethatshefinds Leaving homeinitiallyalsomeant This isalsoasource of inspiration Right Left identifying the interface for Cas for interface the identifying sequence, DNA asuitable to itself attaches sequence, recognition its with together CRISPR-RNA, The Bottom: CRISPR-Cas use to iteasier makes –this merged be can molecules RNA two The Center: tracrRNA. and (red), sequence DNA acertain for sequence Cas Top: The infections. against themselves protect and infections cause microbes the how understand to wants She attention. full Charpentier’s have Bacteria study: her of object the and researcher The enzyme needs two RNA molecules to find its target: the so-called CRISPR-RNA, with a recognition arecognition with CRISPR-RNA, so-called the target: its find to molecules RNA two needs 9 enzyme 9 . This is how genes can be cut out or new ones inserted. ones new or out cut be can genes ishow . This right decision.”Notleastbecauseshe mits. “Butultimatelyitwasexactlythe to Umeåwascertainlyrisky,” shead- was abitcrazyatthetime.“Themove More thanafewpeoplethoughtshe Vienna toUmeåUniversityinSweden. manage withscantresources.” ply forresearch funding, aswellto learned tothinkonalargerscale,ap- and workcompletelyindependently. I and Icouldchoosemyownsubjects research andoutstanding colleagues, to Europe.“Vienna offeredstrongbasic enna. Thiswasarealincentivetoreturn in theBiocenteratUniversityofVi- nity toestablishherownresearch group in theUS,shewasofferedopportu- tion tools. starting pointfornewgenemanipula- to bacteria,astheywerefrequentlya ultimately broughttheresearcher back systems fordiseases.Thisexperience make theanimalssuitableasmodel ond World War, she herselflearned life. Herparentsexperienced theSec- hasalways beenapresenceinher try ing inGermanysince2013. Thecoun- terest inCRISPR-Cas9. colleagues inthegrouptotakeanin- important roleinencouragingother ter’s studentElitzaDeltchevaplayedan plement herideainthelab.Hermas- find astudentwhoalsowantedtoim- between thetwolocations. the planeduringherinitialcommutes ing togetherCRISPRandRNAwhileon came upwiththeradicalideaofbring- In 2009,Charpentiermovedfrom Charpentier hasnowbeenresearch- It thentookheralmostayearto After sixyearsofpostdoctoralwork BIOLOGY &MEDICINE_PersonalPortrait schweig andtheHannover Medical professorship. The connection with the professorship. Theconnection withthe things, anAlexandervon Humboldt School enticedherwith,among other Sweden werealsofromGermany. and colleaguesintheUS,Austria gion fortwoweeks.Manyofherfriends family inasmalltowntheRhinere- bylivingwithaGerman the country dent exchange,shegotatasteoflifein German atschool,andaspartofastu- 9 for research purposes. The HelmholtzCentrein Braun- 1 | MaxPlanckResearch 16MaxPlanckResearch 51 BIOLOGY & MEDICINE_Personal Portrait

Hannover Medical School gave Char- timately, it is the responsibility of pol- tacts with colleagues from the neigh- pentier access to clinical practice – a icy makers to ensure that the enor- boring institutes of the two universities connection that she would now like to mous potential of the DNA scissors in Berlin and Charité. build on in a similar way at Charité. But isn’t abused to create designer babies. In terms of subject matter, under- she still stays in touch with her col- Charpentier is looking forward to standing regulation mechanisms in leagues in Hanover. the new challenge at the Max Planck pathogens will continue to be the focus Institute in Berlin. The location offers of her attention. First and foremost, she LEGAL FRAMEWORK ABSENT the ideal conditions for her research: “I wants to finish what she started with IN MANY COUNTRIES have always looked for a place where I CRISPR-Cas9. Her main objective is to can freely develop my ideas and prac- gain an even better understanding of In addition, two of the companies that tice science under excellent conditions. the biochemistry, specificity and effi- she co-founded are driving the devel- And I have always dreamed of working ciency of the system: “We can see that opment of CRISPR-Cas9: CRISPR Ther- in a major city like Paris, London or it works and we understand the funda- apeutics was set up to make the tech- Berlin.” In particular, the unconven- mentals, but we’re still studying the de- nology commercially viable as a meth- tional spirit of the city on the Spree Riv- tails of how the DNA sequences are od of treatment for genetic diseases. er resembles her own, and could inspire identified and how the cutting works.” The company wants to remove cells her research. She also wants to investigate other from patients, treat them with CRISPR- For the time being, however, the CRISPR-Cas systems, as there may be Cas9, and then return them to the daily commute to the institute may other cutting tools in the realm of bac- body. Alternatively, CRISPR-Cas9 could well have to suffice, as she will have teria that are even more suitable for also be inserted into the body via spe- very little time to enjoy the cultural life studying genes. cific transport containers, such as fat of Berlin in the coming months. After On top of all that, Charpentier wants bubbles or nanoparticles. Charpentier all, it’s full steam ahead for the estab- to strengthen the field of microbiology also helped co-found ERS Genomics, lishment of her new “Regulation in In- at the institute and attract excellent ju- and has transferred the licenses for use fection Biology” department, and it’s nior scientists to this biological disci- on other organisms to the company. something that will require a huge pline. This is also a matter of urgency, However, it will still be a few years amount of energy: labs will be modi- as many microbiologists will be retiring before humans can be treated with fied, and some of her colleagues who in the coming years. Compounding CRISPR-Cas9. Before that, more clari- are coming with her from the Helm- this is the fact that microbiology isn’t ty about potential risks is needed. Al- holtz Centre will be busy setting up the exactly seen as a discipline with a great though CRISPR-Cas9 is considerably labs so that the research can continue future. Charpentier is convinced this more precise than other techniques, it as seamlessly as possible. At the same is an error of judgment – one that she still makes mistakes and occasionally time, she also wants to cultivate con- hopes to correct. cuts the genome at the wrong place.

Added to this are ethical issues that the use of CRISPR-Cas9 could raise. Chinese researchers recently modified GLOSSARY the genes in human embryonic stem CRISPR-Cas9: CRISPR stands for “Clustered Regularly Interspaced Short Palindromic cells. While the embryos weren’t viable, Repeats” and describes a genome sequence in bacteria. Cas9 is an endonuclease – an the experiments nevertheless show that enzyme that cuts DNA. In viral infections, the bacteria cut sequences out of the viral society and policy makers urgently genome and insert them into the CRISPR sequence. The bacteria can use the resulting need to dictate what is and isn’t al- transcribed CRISPR-RNA and an additional RNA molecule to identify the viral genome if it attacks again. They can cut through it, incapacitating the pathogens. In this way, lowed. “CRISPR-Cas9 can deliver huge the CRISPR-Cas9 system provides the bacterial immune system with a kind of memory. benefits to humanity, but of course we RNA: The DNA molecule contains the assembly instructions for all proteins in an need to handle it responsibly. Inter- organism. These instructions aren’t translated directly into proteins, but rather are first ventions into the human germline, for transcribed into individual, much shorter RNA molecules. The chemical structure of instance, which would influence the RNA, which is a single-stranded nucleic acid, is somewhat different from that of DNA. genome of future generations, is some- There are various types of RNA molecules: some serve as a template for the production of proteins, while others control gene activity. thing that I and most of my colleagues refuse to do,” clarifies Charpentier. Ul-

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