David Liu (Casey Atkins Photography courtesy Broad Institute)

In­tel­lia an­nounced a new tool for gene edit­ing. Aca­d­e­mics said they rewrote his­to­ry

Alex­is Ko­mor

David Liu, the Har­vard bio­chemist, was sit­ting in a meet­ing last week when his phone start­ed buzzing re­peat­ed­ly.

Un­be­knownst to him, min­utes pri­or the CRISPR com­pa­ny In­tel­lia had fin­ished un­veil­ing their ap­proach to base edit­ing at a Cold Spring Har­bor Lab con­fer­ence. First pi­o­neered by Liu and his lab in 2016, the method al­lows you to change in­di­vid­ual DNA bases with­out break­ing the dou­ble he­lix, an ad­vance that could prove crit­i­cal for treat­ing a long list of can­cers and ge­net­ic dis­eases.

In­tel­lia, though, didn’t cite or ac­knowl­edge any of Liu’s work, or any of dozens of pa­pers pro­duced by his stu­dents and out­side re­searchers. Im­me­di­ate­ly af­ter the ses­sion closed, for­mer grad­u­ate stu­dents, post­docs and mem­bers of oth­er labs start­ed mes­sag­ing Liu, ask­ing if he had seen the ap­par­ent snub.

Liu re­spond­ed pub­licly on Twit­ter four days lat­er, call­ing out In­tel­lia for fail­ing to ac­knowl­edge the two then-post­docs, Alex­is Ko­mor and Nicole Gaudel­li, who led the base edit­ing stud­ies. He then named 37 oth­er re­searchers he said con­tributed to re­search In­tel­lia “pre­sent­ed as its own.”

In an in­ter­view Tues­day, Liu said he hoped In­tel­lia suc­ceed­ed in bring­ing ther­a­pies for pa­tients. But he ar­gued the com­pa­ny’s de­ci­sion to not cite ear­ly pa­pers could be par­tic­u­lar­ly dam­ag­ing to young sci­en­tists’ ca­reers.

“Whether some­body cites a pa­per I au­thored or not at a con­fer­ence prob­a­bly isn’t go­ing to af­fect my ca­reer,” he said. “But it could re­al­ly im­pact the op­por­tu­ni­ties for a grad­u­ate stu­dent or a post doc, or a re­cent grad­u­ate stu­dent or a post doc whose sci­en­tif­ic ac­com­plish­ments may large­ly [be that] work.”

Sam Stern­berg

In­tel­lia nev­er claimed in the pre­sen­ta­tion, a video of which was ob­tained by End­points News, to have in­vent­ed base edit­ing. But Sam Stern­berg, a gene edit­ing re­searcher at Co­lum­bia Uni­ver­si­ty un­af­fil­i­at­ed with Liu or his com­pa­nies, said In­tel­lia pre­sent­ed their ed­i­tors as new and ex­cit­ing with­out cred­it­ing Liu or ex­plain­ing how the ed­i­tors were dif­fer­ent.

It seemed “there was a cal­cu­lat­ed in­tent to present these as new,” Stern­berg, who at­tend­ed the con­fer­ence, said in an in­ter­view.

In­tel­lia de­clined to make the em­ploy­ees who made the pre­sen­ta­tion avail­able for an in­ter­view. In an emailed state­ment, they ac­knowl­edged “Liu’s pi­o­neer­ing work” but said, “We be­lieve our base edit­ing sys­tem is dif­fer­en­ti­at­ed com­pared to oth­er sys­tems we are aware of, and for this pre­sen­ta­tion we met all re­quire­ments for da­ta dis­clo­sure as in­di­cat­ed by Cold Spring Har­bor Lab­o­ra­to­ry.”

A Cold Spring Har­bor Lab­o­ra­to­ry spokesper­son said they were made aware of the is­sue through so­cial me­dia and are re­view­ing the sit­u­a­tion with the com­mit­tee who or­ga­nized the meet­ing.

A screen­shot of In­tel­lia’s Chris­t­ian Dom­brows­ki walk­ing through their base ed­i­tor

Click on the im­age to see the full-sized ver­sion

The con­tro­ver­sy no­tably comes af­ter near­ly a decade of bit­ter dis­putes over who should re­ceive the cred­it and patents for in­vent­ing the first gen­er­a­tion of CRISPR gene edit­ing.

In 2016, when Broad In­sti­tute chief Er­ic Lan­der wrote a re­view ar­ti­cle on the his­to­ry of CRISPR, he was ac­cused by some of try­ing to rewrite his­to­ry in a way that min­i­mized Jen­nifer Doud­na and Em­manuelle Char­p­en­tier’s role and el­e­vat­ed the role of Broad re­searcher Feng Zhang. When the No­bel com­mit­tee picked Doud­na and Char­p­en­tier but not Zhang for the 2020 chem­istry award, it was read as the com­mit­tee’s ver­dict on who should claim cred­it.

Base edit­ing has large­ly been free of such strife, in part thanks to con­scious ef­forts by its lead­ing fig­ures. And nei­ther Liu nor Ko­mor are con­cerned about run­ning in­to in­tel­lec­tu­al prop­er­ty is­sues with In­tel­lia. In a state­ment, Beam Ther­a­peu­tics, the com­pa­ny Liu found­ed with Zhang and Mass Gen­er­al sci­en­tist Kei­th Joung, said they had “a strong lead­er­ship po­si­tion” in base edit­ing and “an ex­ten­sive patent port­fo­lio.”

The pair feared, how­ev­er, that In­tel­lia was rewrit­ing his­to­ry in a way that could be detri­men­tal to young re­searchers. Ko­mor, who start­ed her own lab at UC-San Diego af­ter leav­ing Har­vard, said the suc­cess of her new re­search group de­pends in part on oth­ers rec­og­niz­ing her grad­u­ate and post­doc work as im­por­tant.

“You have no idea how dif­fi­cult it is,” she said. “Any time I want to pub­lish some­thing, I need to lever­age my pre­vi­ous ac­com­plish­ments to get my foot in with this ed­i­tor, to tell this ed­i­tor, ‘I did this great work be­fore, re­mem­ber? So what I’m do­ing now is re­al­ly great too.'”

Al­ready, she said, she sees peo­ple on Twit­ter who are new to the field or who lack a strong sci­en­tif­ic back­ground talk­ing about a new in­ven­tion from In­tel­lia called a base ed­i­tor. “That’s sad to see,” she said.

In­tel­lia ti­tled the pre­sen­ta­tion, “Spe­cial Edi­tion: Ex­pand­ing In­tel­lia’s Tool­box with Base Edit­ing.” Chris­t­ian Dom­brows­ki, se­nior di­rec­tor of the biotech’s Gene Edit­ing Plat­form group, walked through the com­pa­ny’s CRISPR ef­forts, in­clud­ing for cell ther­a­py, be­fore ex­plain­ing that to “un­lock the full po­ten­tial of the T cells,” they might need new forms of gene edit­ing.

“So this was sort of us look­ing to the fu­ture and say­ing, ‘What is the tool that we are go­ing to need?'” Dom­brows­ki said.

He said they set­tled on a base ed­i­tor for the DNA base cy­to­sine. He walked through the well-es­tab­lished com­po­nents for such an ed­i­tor: a de­ac­ti­vat­ed Cas9 en­zyme that can bind to but not cut the DNA, di­rect­ed to the right lo­ca­tion by an RNA strand; an en­zyme called cy­to­sine deam­i­nase that can change a cy­to­sine base to a dif­fer­ent base; and a small pro­tein that blocks the body from cor­rect­ing that change.

Chris­t­ian Dom­brows­ki

Dom­brows­ki then pre­sent­ed a se­ries of slides show­ing how ef­fec­tive­ly their base ed­i­tor could ma­nip­u­late T cells and the ad­van­tages they of­fer over old­er CRISPR sys­tems. But he didn’t men­tion Liu or his lab’s work, or ex­plain how their ap­proach dif­fered from the ones he, Gaudel­li, Ko­mor or Kobe Uni­ver­si­ty’s Kei­ji Nishi­da laid out in 2016 and 2017 — a fact that didn’t es­cape Gaudel­li, who was tuned in­to the pre­sen­ta­tion.

In a sub­se­quent Q&A pe­ri­od, she asked in a mes­sage box how their ap­proach dif­fered, writ­ing, “I didn’t see any ref­er­ences to all the work that has al­ready been es­tab­lished.” Stern­berg, speak­ing by video, echoed her ques­tion.

In­tel­lia CSO Lau­ra Sepp-Loren­zi­no, who was mod­er­at­ing the ses­sion, read out the ques­tion. Dom­brows­ki de­murred.

“As you can imag­ine, as it stands to­day, we aren’t dis­clos­ing the com­po­si­tion of the base ed­i­tor that we’ve built,” he said. “Stay tuned.”

Nicole Gaudel­li

Stern­berg said in the in­ter­view that he’s got­ten used to com­pa­nies re­fus­ing to dis­close de­tails for con­fi­den­tial­i­ty rea­sons. And even as an aca­d­e­m­ic, he said, he of­ten has to choose what to present and what’s not yet ready to be dis­closed, be­cause CRISPR is such a hot­ly com­pet­i­tive field. But In­tel­lia’s pre­sen­ta­tion was un­usu­al.

“It was a bit sur­pris­ing that there was no at­tri­bu­tion,” he said. “These aca­d­e­m­ic and sci­en­tif­ic con­fer­ences are here to pro­mote sci­en­tif­ic ex­change and trans­par­ent ad­vance­ment of sci­en­tif­ic knowl­edge.”

Most sci­en­tists in the gene edit­ing world know the pa­pers and aca­d­e­mics that es­tab­lished base edit­ing, Stern­berg said. But con­fer­ences are al­so at­tend­ed by non-aca­d­e­mics or peo­ple who are new to the field. They might come away from such a pre­sen­ta­tion think­ing In­tel­lia in­vent­ed a new form of edit­ing, as Ko­mor said she’s al­ready seen.

Liu echoed the con­cern. And he won­dered about how the var­i­ous pub­li­ca­tions and pre­sen­ta­tions would look years lat­er if ear­ly work goes un­no­ticed.

“We don’t want to rewrite his­to­ry,” Ko­mor said.

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