KEMAL ATLAY

Bri­tain has ap­proved an ex­per­i­men­tal IVF tech­nique to pre­vent mi­to­chon­drial dis­ease from be­ing passed on to chil­dren. The re­sult will be ba­bies with three bi­o­log­i­cal par­ents, writes Kemal Atlay.

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In De­cem­ber, Bri­tain be­came the first coun­try in the world to of­fi­cially give the green light for the con­tro­ver­sial three-per­son in vitro fer­til­i­sa­tion (IVF) tech­nique. Al­though the Bri­tish par­lia­ment had al­ready voted for reg­u­la­tions on its use in early 2015, the power to give fi­nal ap­proval was given to the Hu­man Fer­til­i­sa­tion and Em­bry­ol­ogy Author­ity (HFEA), the reg­u­la­tory body in charge of the coun­try’s fer­til­ity clin­ics and hu­man em­bry­onic re­search. Al­most a decade in the mak­ing, with count­less stud­ies, re­views and pub­lic con­sul­ta­tions to gauge both the sci­en­tific and eth­i­cal ar­gu­ments around this is­sue, the tech­nique was fi­nally given the go-ahead.

Three-per­son IVF, also known as mi­to­chon­drial re­place­ment ther­apy (MRT), was de­vel­oped to give fam­i­lies suf­fer­ing from or with a his­tory of mi­to­chon­drial DNA dis­ease the op­tion to have chil­dren free of any re­lated com­pli­ca­tions. Al­most all hu­man cells con­tain or­ganelles called mi­to­chon­dria that are largely re­spon­si­ble for pro­duc­ing en­ergy, but they also house a small set of 37 genes – 0.1 per cent of the en­tire hu­man genome, with the rest con­tained in the cell nu­cleus – that can cause se­vere com­pli­ca­tions if mu­tated.

Professor David Thor­burn, who leads the mi­to­chon­drial re­search team at the Mur­doch Chil­drens Re­search In­sti­tute, says HFEA ap­proval would give fresh hope for fam­i­lies with a his­tory of mi­to­chon­drial DNA dis­ease. “It’s an ex­per­i­men­tal tech­nique, so there’s is­sues around that, like in­tro­duc­ing any new tech­nique to medicine,” he says. “And this has been, I think, an ex­em­plary process.”

Mi­to­chon­drial dis­ease can some­times be dif­fi­cult to di­ag­nose, but ac­cord­ing to a study Thor­burn was in­volved in, it af­fects about one in 5000 peo­ple. “About 60 births in Aus­tralia each year will re­sult in a child who will de­velop mi­to­chon­drial dis­ease at some stage dur­ing their life, and about half of those are mi­to­chon­drial DNA dis­ease,” he says. Treatment op­tions are lim­ited, with an ex­ten­sive re­view of lit­er­a­ture in 2012 con­clud­ing there was no ev­i­dence to sup­port that any of the avail­able treat­ments were ben­e­fi­cial to pa­tients, leav­ing some at the mercy of life-threat­en­ing con­di­tions. For ex­am­ple, in a de­bil­i­tat­ing neu­ro­log­i­cal dis­or­der called Leigh syn­drome, where about one in five cases are linked to mu­ta­tions in mi­to­chon­drial DNA, the av­er­age life ex­pectancy is about two to three years.

Sean Mur­ray, chief ex­ec­u­tive of the Aus­tralian Mi­to­chon­drial Dis­ease Foun­da­tion, says MRT pro­vides gen­uine hope. “Pa­tients or peo­ple who have fam­ily mem­bers with mi­to­chon­drial dis­ease have seen first­hand the devastation that this dis­ease can cause,” he says. “This is one of the first op­por­tu­ni­ties or ther­a­pies that will have a very high like­li­hood of pre­vent­ing the transmission of mi­to­chon­drial dis­ease.”

How­ever, one of the main rea­sons MRT has been so con­tro­ver­sial and the ap­proval process so ar­du­ous is that the re­sult­ing em­bryo – and even­tu­ally child – will have not two but three ge­netic par­ents. The process works by tak­ing the nu­cleus out of the egg that con­tains the faulty mi­to­chon­drial DNA and in­sert­ing it into a donor egg, which has no faulty mi­to­chon­drial DNA and has also had its nu­cleus re­moved. There are vari­a­tions on this tech­nique that in­volve the trans­fer tak­ing place be­fore fer­til­i­sa­tion and after, but the re­sult­ing em­bryo es­sen­tially has 99.9 per cent of their DNA from the mother and fa­ther cou­ple, with the re­main­ing 0.1 per cent com­ing from the donor mother’s mi­to­chon­dria. How­ever small the donor’s DNA con­tri­bu­tion, the re­cip­i­ent will have three bi­o­log­i­cal par­ents.

Dr Ains­ley New­son, as­so­ciate professor of bioethics at the Univer­sity of Syd­ney, says MRT “is not an eth­i­cally neu­tral tech­nol­ogy” and that there will in­evitably be dis­agree­ments about is­sues such as al­ter­na­tive routes to par­ent­hood and whether it will cause changes in the hu­man germline – the gen­er­a­tional suc­ces­sion of de­scen­dants. That is, any defects in­ad­ver­tently caused by the pro­ce­dure would af­fect not just the re­sult­ing child but could be passed on to their chil­dren.

MRT may also raise such eth­i­cal con­sid­er­a­tions with­out ad­dress­ing the dis­ease. “We know that even with the best tech­niques, there can be no ab­so­lute guar­an­tee that a child born of MRT will re­main free of dis­ease,” she says. “But then no re­pro­duc­tive tech­nol­ogy is per­fect. Who gets to make that call? And as to ex­pe­ri­ence, what will life be like for those born of MRT?”

Th­ese ques­tions are of par­tic­u­lar im­por­tance when con­sid­er­ing the case of the first baby to be born from MRT, who was five months old when the news broke in Septem­ber last year. A team of United States re­searchers took the un­prece­dented step of trav­el­ling to Mex­ico, which has no reg­u­la­tions around the use of this tech­nol­ogy, to help a Jor­da­nian fam­ily in which the mother had a his­tory of mi­to­chon­drial DNA dis­ease and had al­ready ex­pe­ri­enced four mis­car­riages and the deaths of two chil­dren.

How­ever, the US doc­tors have faced fierce crit­i­cism for their brazen ef­forts to dodge the law at home and a lack of trans­parency. “This group has just gone and done it,” David Thor­burn says. “They’ve not been sub­ject to any peer re­view in their meth­ods and in fact the Amer­i­can group have no real ev­i­dence of any ex­per­tise with mi­to­chon­drial DNA.” He also says the fam­ily wouldn’t have even been el­i­gi­ble for MRT if the case had been pre­sented in Bri­tain, as the mother had a rel­a­tively small amount of mi­to­chon­drial DNA mu­ta­tions.

Thor­burn fur­ther raises the is­sue of pos­si­ble car­ry­over of ab­nor­mal mi­to­chon­drial DNA – the MRT tech­nique is in­cred­i­bly pre­cise but some mi­to­chon­dria can end up be­ing trans­ported from the mother’s egg to the donor egg along­side the nu­cleus. Could it ex­pand in the em­bryo and end up caus­ing dis­ease? Re­ports from the Univer­sity of New­cas­tle in Bri­tain, where re­searchers have been per­fect­ing the tech­nique, sug­gest this is un­likely to oc­cur if there is a car­ry­over of less than 2 per cent, but Thor­burn says it re­mains a sig­nif­i­cant con­cern.

There are other com­pli­cat­ing fac­tors. Some sci­en­tists have ques­tioned whether com­pli­ca­tions can arise from po­ten­tial mis­match­ing of nu­clear and mi­to­chon­drial DNA. As gen­er­a­tions of hu­mans dis­persed fur­ther around the world, their nu­clear genomes have evolved along­side their mi­to­chon­drial genomes to en­sure they work well to­gether – some hu­man pop­u­la­tions are more closely re­lated to each other than oth­ers. The­o­ret­i­cally, the closer the an­ces­tral link be­tween the genomes the bet­ter chance of de­vel­op­ing well to­gether to cre­ate a healthy spec­i­men. Hence, to en­sure a suc­cess­ful MRT, it’s bet­ter to get mi­to­chon­dria from a donor more closely re­lated in evo­lu­tion­ary terms to the re­cip­i­ent mother so that the mi­to­chon­drial and nu­clear DNA are op­ti­mally matched. Professor Ste­fan Hien­dleder, an ex­pert in epi­ge­net­ics from the Univer­sity of Ade­laide, says, “If there’s no match­ing here, you can cre­ate a con­di­tion that’s called het­ero­plasmy, and an­i­mal mod­els have shown that het­ero­plasmy can be detri­men­tal and af­fect var­i­ous phe­no­typic as­pects in­clud­ing be­hav­iour and cog­ni­tion.” How­ever, stud­ies in mice have shown that such a DNA mis­match might not be so detri­men­tal and could in fact be ben­e­fi­cial to health and longevity, but fur­ther re­search is needed.

Hien­dleder also notes that some have pro­posed to re­strict MRT to hav­ing male chil­dren, as only fe­males can pass on mi­to­chon­drial DNA.

Op­po­nents of the tech­nique have ac­cused re­searchers of play­ing God, and fear that MRT will lead to the cre­ation of de­signer ba­bies. Dr Alexan­dra Har­vey, a re­pro­duc­tive bi­ol­ogy ex­pert from the Univer­sity of Mel­bourne, coun­ters that we need to look at it from a risk-ben­e­fit per­spec­tive. “At the end of the day, any time we do any med­i­cal in­ter­ven­tion, we’re ba­si­cally play­ing God in a sense,” she says. “The main pur­pose be­hind this tech­nique is so that eth­i­cally we can’t con­demn chil­dren to be dis­eased and have a de­te­ri­o­rated life and po­ten­tially not live long enough to re­ally have a life.”

It is cur­rently il­le­gal to of­fer MRT in Aus­tralia, thanks to both the Pro­hi­bi­tion of Hu­man Cloning for Re­pro­duc­tion Act and the Re­search In­volv­ing Hu­man Em­bryos Act. The Univer­sity of Syd­ney’s Ains­ley New­son ex­plains that th­ese laws were de­vel­oped in re­sponse to re­pro­duc­tive hu­man cloning back in 2002. “Leg­is­la­tion can be cum­ber­some to cre­ate and ex­pen­sive and slow to change,” she says. “The UK has re­sponded by us­ing spe­cific reg­u­la­tions [for MRT] to com­ple­ment leg­is­la­tion, as th­ese are faster and sim­pler to change. Aus­tralia needs a reg­u­la­tory regime that is for­ward­look­ing and more re­spon­sive to the science.”

Sean Mur­ray says the Aus­tralian Mi­to­chon­drial Dis­ease Foun­da­tion stepped up its lob­by­ing ef­forts in the past 12 months in re­sponse to Bri­tish de­vel­op­ments, in an ef­fort to bring about a re­view of the cur­rent leg­is­la­tion. “I think that it would only be fair and rea­son­able to the Aus­tralian peo­ple to progress and to make sure that that ther­apy is avail­able to women at risk of pass­ing on mi­to­chon­drial dis­ease to their chil­dren,” he says.

“This ther­apy re­ally is one that of­fers hope to a com­mu­nity – the mi­to­chon­drial dis­ease com­mu­nity – that’s re­ally been lack­ing hope up un­til this point.

And for that rea­son we’re re­ally en­cour­aged that this is

• some­thing that re­ally of­fers us some hope.”

Test tubes be­ing placed in a con­tainer used to freeze hu­man eggs for in vitro fer­til­i­sa­tion.

KEMAL ATLAY is a free­lance science jour­nal­ist based in Mel­bourne.

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