Al­ter­ation of hu­man em­bryos marks a first

Sci­en­tists re­move a malev­o­lent mu­ta­tion from DNA through a gene-edit­ing process.

Los Angeles Times - - FRONT PAGE - By Melissa Healy

Us­ing a pow­er­ful ge­need­it­ing tech­nique, sci­en­tists have rid hu­man em­bryos of a mu­ta­tion re­spon­si­ble for an in­her­ited form of heart dis­ease that’s of­ten deadly to healthy young ath­letes and adults in their prime.

The ex­per­i­ment marks the first time that sci­en­tists have al­tered the hu­man genome to erase a dis­ease­caus­ing mu­ta­tion not only from the DNA of the pri­mary sub­ject but from the genes of his or her prog­eny as well.

The con­tro­ver­sial pro­ce­dure, known as “germ-line edit­ing,” was con­ducted at Ore­gon Health and Sci­ence Univer­sity in Port­land us­ing hu­man em­bryos ex­pressly cre­ated for the pur­pose. It was re­ported Wed­nes­day in the jour­nal Na­ture.

Sci­en­tists’ ul­ti­mate goal is to fix gene mu­ta­tions that lead to de­bil­i­tat­ing or fa­tal dis­eases, and to pre­vent the prop­a­ga­tion of those mu­ta­tions to fu­ture gen­er­a­tions.

Study leader Shoukhrat Mi­tal­ipov, a bi­ol­o­gist at OHSU, said the new find­ings might cor­rect ge­netic vari­ants that can cause breast and ovar­ian cancer, cys­tic fi­bro­sis and mus­cu­lar dys­tro­phy in those who in­herit

them. But oth­ers fret that the tech­nique may be used for less noble pur­poses, such as cre­at­ing de­signer ba­bies with de­sired traits like green eyes, an ath­letic build or an ap­ti­tude for math­e­mat­ics.

In the United States, the Food and Drug Ad­min­is­tra­tion cur­rently for­bids any use of germ-line edit­ing out­side of a re­search set­ting.

But re­cent his­tory has shown that peo­ple who want ac­cess to such tech­niques “can find peo­ple will­ing to per­form them in venues where they’re able to do so,” said Jef­frey Kahn, who di­rects Johns Hopkins Univer­sity’s Ber­man In­sti­tute of Bioethics.

“It will hap­pen whether we dis­cuss it or not, and we need to talk about th­ese things be­fore they hap­pen,” Kahn said. “That’s now.”

The new re­search comes less than six months af­ter the Na­tional Acad­e­mies of Sci­ence, En­gi­neer­ing and Medicine rec­om­mended that sci­en­tists limit their tri­als of hu­man germ-line edit­ing to dis­eases that could not be treated with “rea­son­able al­ter­na­tives” — at least for the time be­ing.

In a bid to make the ex­per­i­ment rel­e­vant to the re­al­life prob­lems faced by par­ents who carry dis­ease­caus­ing mu­ta­tions, the re­searchers fo­cused on a gene vari­ant that causes in­her­ited hy­per­trophic car­diomy­opa­thy.

In this con­di­tion, a par­ent who car­ries one nor­mal and one mu­tated copy of the MYBPC3 gene has a 50-50 chance of pass­ing the faulty copy on to his or her off­spring. If the child in­her­its the mu­ta­tion, his or her heart mus­cle is likely to grow pre­ma­turely weak and stiff, caus­ing heart fail­ure and of­ten early death.

In dis­eases in which one par­ent car­ries a gene like this, a cou­ple will of­ten seek the as­sis­tance of fer­til­ity doc­tors to min­i­mize the risk of pass­ing the mu­ta­tion on to a child. A woman’s eggs and man’s sperm meet in a lab us­ing in vitro fer­til­iza­tion. Then spe­cial­ists in­spect the re­sult­ing em­bryos, cull the ones that have in­her­ited an unwanted mu­ta­tion, and trans­fer un­af­fected em­bryos into a woman’s uterus to be car­ried to term.

In the new re­search, re­searchers set out to test whether germ-line gene edit­ing could make the process of choos­ing healthy em­bryos more ef­fec­tive and ef­fi­cient by cre­at­ing more of them. It could. The tar­geted cor­rec­tion of a dis­ease-caus­ing gene car­ried by a sin­gle par­ent “can po­ten­tially res­cue a sub­stan­tial por­tion of mu­tant hu­man em­bryos, thus in­creas­ing the num­ber of em­bryos avail­able for trans­fer,” the study au­thors re­ported.

The fix was made pos­si­ble by a sys­tem known as CRISPR-Cas9, which has been sweep­ing through bi­ol­ogy labs be­cause it greatly sim­pli­fies the gene-edit­ing process. It uses a small piece of RNA and an en­zyme to snip out unwanted DNA and, if de­sired, re­place it with some­thing bet­ter.

If the process is found to be safe for use in fer­til­ity clin­ics, it “could po­ten­tially de­crease the num­ber of cy­cles needed for peo­ple try­ing to have chil­dren free of ge­netic dis­ease,” said Dr. Paula Amato, a coau­thor and pro­fes­sor of ob­stet­rics and gy­ne­col­ogy at Ore­gon Health and Sci­ence Univer­sity.

The team en­coun­tered sev­eral sci­en­tific sur­prises along the way. Long-feared ef­fects of germ-line edit­ing, in­clud­ing col­lat­eral dam­age to “off-tar­get” ge­netic se­quences, scarcely ma­te­ri­al­ized. And “mo­saicism,” a phe­nom­e­non in which edited DNA ap­pears in some but not all cells, was found to be min­i­mal.

Mi­tal­ipov called th­ese “ex­cit­ing and sur­pris­ing mo­ments.” But he cau­tioned that “there is room to im­prove” the tech­niques for pro­duc­ing mu­ta­tion-free em­bryos. Clin­i­cal tri­als would have to wait un­til the DNA edit­ing showed a nearper­fect level of ef­fi­ciency and ac­cu­racy, he said, and could be lim­ited by state and fed­eral reg­u­la­tions.

“There is still a long road ahead,” said Mi­tal­ipov, who heads the Cen­ter for Em­bry­onic Cell and Gene Ther­apy at OHSU.

Bi­ol­o­gists, fer­til­ity doc­tors and ethi­cists have long an­tic­i­pated that sci­en­tists would one day ma­nip­u­late the DNA of hu­man em­bryos. Now that the mile­stone has been reached, it drew a mix of praise and con­cern from ex­perts in ge­netic medicine.

Dr. Richard O. Hynes, who co-chaired the Na­tional Acad­e­mies’ re­port is­sued in Fe­bru­ary, called the new study “very good sci­ence” that ad­vances the un­der­stand­ing of ge­netic re­pair on many fronts. Hynes, who was not in­volved with the re­search ef­fort, said he was “pleas­antly sur­prised” by the Ore­gon-based team’s “clever mod­i­fi­ca­tions” and their out­comes.

“It’s likely to be­come fea­si­ble, tech­ni­cally — not to­mor­row, not next year, but in some fore­see­able time. Less than a decade, I’d say,” said Hynes, a bi­ol­o­gist and cancer re­searcher at MIT and the Howard Hughes Med­i­cal In­sti­tute.

UC Berke­ley molec­u­lar and cell bi­ol­o­gist Jen­nifer Doudna, one of pi­o­neers of the CRISPR-Cas9 ge­need­it­ing sys­tem, said the new re­search high­lights a prospec­tive use of gene edit­ing for one in­her­ited dis­ease and of­fers some in­sights into the process. But she ques­tioned how broadly the ex­per­i­ment’s re­sults would ap­ply to other in­her­ited dis­eases.

Doudna also said she does not be­lieve us­ing germline edit­ing to im­prove ef­fi­ciency at fer­til­ity clin­ics meets the cri­te­ria laid out by the Na­tional Acad­e­mies of Sci­ences, which urged that the tech­nol­ogy be ex­plored only in cases in which it’s es­sen­tially a last re­sort. “Al­ready, 50% of em­bryos would be nor­mal,” she said. “Why not just im­plant those?”

Doudna said she feared that the new find­ings “will en­cour­age peo­ple to pro­ceed down this road” be­fore the sci­en­tific and eth­i­cal im­pli­ca­tions of germ-line edit­ing have been fully con­sid­ered.

“A large group of ex­perts con­cluded that clin­i­cal use should not pro­ceed un­til and un­less there’s broad so­ci­etal con­sen­sus, and that just hasn’t hap­pened,” she said. “This study un­der­scores the ur­gency of hav­ing those de­bates. Be­cause it’s com­ing.”

The study au­thors — a multi­na­tional team of ge­neti­cists, car­di­ol­o­gists, fer­til­ity ex­perts and em­bry­ol­o­gists from OHSU, the Salk In­sti­tute in La Jolla, and labs in South Korea and China — tested a num­ber of in­no­va­tions in an ef­fort to im­prove the safety, ef­fi­ciency and fi­delity of gene edit­ing. And most yielded promis­ing re­sults.

Af­ter re­triev­ing eggs from 12 healthy fe­male vol­un­teers, the re­searchers si­mul­ta­ne­ously per­formed two steps that had never been com­bined in a lab: fer­til­iz­ing the eggs with sperm and in­tro­duc­ing the CRISPR-Cas9 re­pair ma­chin­ery.

The re­sult­ing em­bryos took up the gene-edit­ing pro­gram so ef­fi­ciently and uni­formly that, af­ter five days of in­cu­ba­tion, 72.4% of the 58 em­bryos tested were free of the MYBPC3 mu­ta­tion. By com­par­i­son, when there was no at­tempt at gene edit­ing, just 47.4% of em­bryos were free of the mu­ta­tion re­spon­si­ble for the deadly heart con­di­tion.

The re­searchers be­lieve their method prompted the em­bryos to rely on the healthy ma­ter­nal copy of the gene as a model for fix­ing the MYBPC3 mu­ta­tion, and not a re­pair tem­plate that used DNA from the sperm donor’s nor­mal ver­sion of the gene. Only one of the 42 em­bryos used the in­tro­duced tem­plate for re­pair. The sci­en­tists con­trasted this process to stem cells, which do use re­pair tem­plates.

The em­bryos’ cells di­vided nor­mally as they ma­tured to the blas­to­cyst stage, the point at which they would usu­ally be ready for trans­fer to a woman’s uterus. Af­ter ex­ten­sive test­ing, the em­bryos were used to make em­bry­onic stem­cell lines, which are stored in liq­uid ni­tro­gen and can be used in fu­ture re­search.

MIT’s Hynes said such find­ings offer im­por­tant in­sights into how hu­man em­bryos grow, de­velop and re­spond to ano­ma­lies, and will help fam­i­lies fac­ing in­fer­til­ity and in­her­ited ill­nesses.

At the same time, he down­played fears that em­bry­ol­o­gists would soon tin­ker with such at­tributes as looks, per­son­al­ity traits and in­tel­li­gence in hu­man chil­dren. “We’re not look­ing at de­signed ba­bies around the cor­ner — not for a long time,” he said.

Kristyna Wentz-Graff Ore­gon Health and Sci­ence Univer­sity

HONG MA, left, study leader Shoukhrat Mi­tal­ipov, cen­ter, and Nuria Mar­tiGu­tier­rez helped write a new re­port on the process known as “germ-line edit­ing.”

Ore­gon Health and Sci­ence Univer­sity

SE­QUEN­TIAL im­ages show the de­vel­op­ment of em­bryos un­der­go­ing the gene-al­ter­ing pro­ce­dure.

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