Re-defining the human embryo: A legal perspective on the creation of embryos in research

Science & Socie y Re-defining he human emb yo A legal pe spec i e on he c ea ion o emb yos in esea ch Iñigo De Miguel Be iain 1,2,JonRueda 3,4 ✉& Ad ian Villalba 4,5 The no ion o he human emb yo is no immu able. Va ious scien ificand echnological b eak h oughs in ep o- duc i e biology ha e compelled us o e isi he defini ion o he human emb yo du ing he pas 2 decades. Soma ic cell nuclea ans e , oocy e haploidisa ion and, mo e ecen ly, human s em cell-de i ed emb yo models ha e challenged his scien ific e m, which has bo h e hical and legal epe cus- sions. He e, we o e a legal pe spec i e o iden i y a uni e sally accep ed defini ion o ‘emb yo’which could help o ease and uni y he egula ion o such en i ies in di e en coun ies. His o ical pe spec i e Scien ific ad ances in ep oduc i e biology ha e made imp essi e achie emen s ha seemed impossible hi y yea s ago (Vil- lalba e al, 2023). The c ea ion o emb yos h ough echniques such as soma ic cell nuclea ans e (SCNT) in he 1990s was only he fi s s epinag ea chaino miles ones. SCNT challenged con en ional no ions o de elopmen , demons a ing he possibili y o emb yogenesis wi hou e iliza ion in ol ing wo opposi e-sex game es. Nuclea ans e me hods ha e since demons a ed hei e ficacy ac oss a wide ange o mammalian species, including non-human p ima es, p omp ing specula ion abou hei applicabili y o human cells. ......................................................... SCNT challenged con en ional no ions o de elopmen , demons a ing he possibili y o emb yogenesis wi hou e iliza ion in ol ing wo opposi e-sex game es. ......................................................... La ely, o he echnologies ha e eme ged, as exemplified by he success ul gene a ion o mice h ough he me ging o wo oocy es in he absence o spe m. To do ha , esea che s combined haploidiza ion o educe he gene ic dosage o each oocy e wi h gene ic manipula ion o one o he eggs o mimic male gene ic imp in ing. Mo e ecen ly, a ious g oups ha e de eloped human emb yo models om plu ipo en s em cells o eplica e ea ly human emb yo- nic s uc u es in i o (Villalba e al, 2023). These models hemsel es con ain di e en plu ipo en s em cell lines, leading o bo h emb yonic and ex aemb yonic cell a es and ecapi ula ing key his ological ea u es o p eimplan a ion emb yos. ......................................................... … he p ecise delinea ion o wha a human emb yo is and i s dis inc ion om o he , simila en i ies has assumed pa amoun significance. ......................................................... We a e, he e o e, a a momen in which bio echnology can make a decisi e con i- bu ion o imp o ing ou knowledge and con ol o he ea ly s ages o human li e. Howe e , his scena io gene a es challen- ging con o e sies om an e hical and legal poin o iew. This is no su p ising a all— ew bio echnological opics a e mo e con- o e sial han hose in ol ing human emb yos. Howe e , he e is one aspec ha emains unexplo ed in ecen deba es. E en hough he mo al s a us o he emb yo has been a c ucial issue in public discussions, he p ecise delinea ion o wha a human emb yo is and i s dis inc ion om o he , simila en i ies has assumed pa amoun significance. This is no a me ely a seman ic p oblem, bu a no ma i e one, which has impo an p ac ical consequences o esea ch. As a ecen commen in Na u e on an a icle published in Cell by Ri on e al (Ri on e al, 2023)s a ed,“i is ime o a edefini ion o he human emb yo”(Ball, 2023). The p oblem is ha he defini ion p oposed by hese au ho s—“ag oupo human cells suppo ed by elemen s ulfilling ex aemb yonic and u e ine unc ions ha , combined, ha e he po en ial o o m a e us”(Ri on e al, 2023, p. 3548)—is no a sound defini ion, a leas om he poin o iew o he law. ......................................................... A uni e sal and gene ally accep ed legal defini ion o an emb yo a ound a mo e a ional in e p e a ions would he e o e help o alle ia e legal unce ain ies and ha monize egula ions. ......................................................... In his b ie commen a y, we will explain why hisisno anop imallegaldefini ion o an emb yo and p opose an al e na i e. This is a ma e o pa icula impo ance because he di e en legal defini ions o an emb yo in di e en coun ies is p oblema ic o esea ch in pa icula o in e na ional collabo a ions among esea ch g oups. Legally, an emb yo is no he same in Ge many—whe e only he e ilized o um is conside ed as such a e he e iliza ion p ocess has been comple ed—as i is in Spain—whe e a dis inc ion is being made be ween emb yo and p e-emb yo—o in he Ne he lands whe e i is a cell o g oup o cells wi h he po en ial o de elop in o an emb yo. These di e se defini ions no only ep esen a ailu e in axiological e ms bu also gene a e se ious di ficul ies o esea ch as he legal concep o he emb yo in o ms 1UPV/EHU, Leioa, Spain. 2Basque Founda ion o Science, Bilbao, Spain. 3Uni e si y o Cali o nia-San Diego, Ins i u e o P ac ical E hics, San Diego, Cali o nia 92109, USA. 4Uni e si y o G anada, G anada, Spain. 5Uni e si é Pa is Ci é, Pa is, F ance. ✉E-mail: [email p o ec ed]m h ps://doi.o g/10.1038/s44319-023-00034-0 | 1234567890();,: © The Au ho (s) EMBO epo s 1 Downloaded om h ps://www.embop ess.o g on Janua y 22, 2024 om IP 88.9.230.164. na ional egula ions on esea ch wi h human emb yos o emb yonic s em cells. I does no only a ec in e na ional esea ch eams bu also esea che s who mo e om one coun y o ano he whe e hey may no longe be pe mi ed o con inue hei wo k. A uni e sal and gene ally accep ed legal defini ion o an emb yo a ound a mo e a ional in e p e a ions would he e o e help o alle ia e legal unce ain ies and ha monize egula ions. Two compe ing defini ions o human emb yo B oadly speaking, he e a e wo main pe spec i es ha in o m he defini ion o an emb yo. The fi s and olde one con- side s he emb yo as he esul o he e iliza ion p ocess: “a g oup o cells esul ing om e iliza ion whose comple- ion was signalled by he fi s cell di ision o he expulsion o he pola bodies”(Ri on e al, 2023,p.3550).This ypeo defini ion is no e y p ac ical o ealis ic since i in ol es bo h s uc u es ha could de elop in o a oe us and o he s ha could no , owing o, o example, mu a ions o he cellula o mi ochond ial DNA. Indeed, om a legal poin o iew, bo h ypes o en i ies do no ha e he same impo ance. None heless, his pe spec i e held p omi- nen ly o decades un il he eme gence o SCNT echniques in he 1990s and he bi h o Dolly, he cloned sheep. SNCT made i possible o ‘concei e’an adul mammal wi hou eso ing o he mixing o gene ic ma e ial ha occu s du ing e iliza ion. This achie emen aised wo possibili- ies: ei he main aining he adi ional defini ion, he eby holding ha Dolly ne e a ose om an emb yo, o expanding he concep o emb yoso ha i couldno only be p oduced by e iliza ion bu also h ough o he echniques. The la e is wha coun ies such as Aus alia o Ge many did. O he s, such as The Ne he lands o Bel- gium, wen a s ep u he , comple ely ob ia ing he way in which he emb yo was gene a ed o ocus exclusi ely on i s po en iali y. Acco dingly, in he Du ch no m, an emb yo is “a cell o se o cells wi h he capaci y o g ow in o a human” (Emb yowe , 2001). In ou iew, he second s a egy o conside ing he po en iali y o capaci y o de elopmen makes mo e sense as i ob ia es he a ious ways in which a cell o g oup o cells can a ise and ins ead ocus on i s own quali ies. A e all, in legal e ms, an emb yo is only ele an o i s capaci y o gi e ise o a pe son, ha is, o a human being. Fo he law, he only ele an subjec is a pe son. Any o he en i y—emb yo, oe us o co pse—would only be ele an inso a as i ela es o a pe son ha has exis ed o may exis . Thus, i he e is any legally significan cha ac e is ic, i mus be he capaci y o become in o a human being a e de elopmen and bi h. ......................................................... A e all, in legal e ms, an emb yo is only ele an o i s capaci y o gi e ise o a pe son, ha is, o a human being. ......................................................... Wha capaci y? The new defini ion based on po en iali y was no wi hou p oblems ei he . Wha kind o po en iali y o capaci y o de elopmen should be equi ed in o de o conside cells o g oups o cells as emb yos? Tha ques ion p omp ed di e en solu ions. In he USA, he Dickey-Wicke Amendmen , which was passed by Cong ess in 1996 as pa o an app op ia ions bill, s a ed ha “ he e m ‘human emb yo o emb yos’includes any o ganism, no p o ec ed as a human subjec unde 45 CFR 46 as o he da e o he enac men o his Ac , ha is de i ed by e iliza ion, pa henogenesis, cloning, o any o he means om one o mo e human game eso humandiploidcells”(Dickey- Wicke Amendmen , 1996). Consequen ly, pa heno es ha e been conside ed as emb yos unde his ule in he USA (Rod iguez e al, 2011). The EU adop ed a simila defini ion. In 2011, in he con ex o Case C-34/10, Oli e B üs le G eenpeace e.V., he Cou o Jus ice o he Eu opean Union (CJUE) uled ha “any human o um a e e ilisa ion, any non- e ilised human o um in o which he cell nucleus om a ma u e human cell has been ansplan ed, and any non- e ilised human o um whose di ision and u he de elopmen ha e been s imula ed by pa henogenesis cons i u e a “human emb yo”’ (poin 39). The easoning behind his conclusion was shown in poin s 35 and 36 o he uling: poin 35 s a ed ha “any human o um mus , as soon as e ilised, be ega ded as a ‘human emb yo’ wi hin he meaning and o he pu poses o he applica ion o A icle 6(2)(c) o he Di ec i e, since ha e ilisa ion is such as o commence he p ocess o de elopmen o a human being”. The same conside a ion should “also apply o a non- e ilised human o um in o which he cell nucleus om a ma u e human cell has been ansplan ed and a non- e ilised human o um whose di ision and u he de elopmen ha e been s imula ed by pa henogenesis”(poin 36). This posi ion was due o a scien ific con ic ion by he Cou ha “…al hough hose o ganisms ha e no , s ic ly speaking, been he objec o e ilisa ion, due o he e ec o he echnique used o ob ain hem hey a e, as is appa en om he w i en obse a ions p e- sen ed o he Cou , capable o commencing he p ocess o de elopmen o a human being jus as an emb yo c ea ed by e ilisa ion o an o um can do so”(poin 36). A ha ime, he a gumen wen ha he possibili y ha a cell o g oup o cells begins de elopmen simila o ha o an emb yo c ea ed by e iliza ion was su ficien o equa e ei he . In he case o he EU, howe e , he Cou did no ake long o change i s posi ion. In Case C-364/13, he Cou s a ed ha “in o de o be classified as a‘human emb yo’, a non- e ilised human o um mus necessa ily ha e he inhe en capaci y o de eloping in o a human being” (poin 28) and “consequen ly, whe e a non- e ilised human o um does no ulfil ha condi ion, he me e ac ha ha o ganism commences a p ocess o de elopmen is no su ficien o i o be ega ded as a ‘human emb yo’, wi hin he meaning and o he pu poses o he applica ion o Di ec i e 98/ 44”(poin 29). Ex ending he c i e ion se by he CJEU o e ilized eggs One may hink ha he CJEU ook a sensible s ep in modi ying i s own posi ion by equi ing ha only en i ies ha “ha e he inhe en capaci y o de eloping in o a human being”should be conside ed human emb yos. Howe e , he e was one s ep ha he cou did no ake: why should we limi he equi emen o possessing ha inhe en capaci y o only non- e ilised human en i ies and no o e ilized ones? This only makes sense i one assumes ha e e y e ilized egg possesses he inhe en capaci y o become a pe son, ha is, a bo n human being. Bu i his is no he case, i does no seem a ional o pu in o he same ca ego y human emb yo s uc u es ha do and do no ha e his capaci y jus because some o EMBO epo s Iñigo De Miguel Be iain e al 2EMBO epo s © The Au ho (s) Downloaded om h ps://www.embop ess.o g on Janua y 22, 2024 om IP 88.9.230.164. hem come om e iliza ion. I wha ma e sispo en iali y, heo iginshouldbe i ele an . And i so, he defini ion o an emb yo should be: a cell o g oup o cells ha ha e he inhe en capaci y o de elop in o a human being, which is simila o he one cu en ly in o ce in he Ne he lands and Belgium. None heless, he Ne he lands is cu en ly e o ming i s Emb yos Ac , and an impo an eason o e isi he defini ion o he human emb yo was p ecisely ha defining i in e ms o po en ial o de elop in o human beings would p esen an epis emological challenge in ela ion o no el s em-cell de i ed en i ies, such as human emb yo models (de We and Dondo p, 2022). ......................................................... I wha ma e s is po en iali y, he o igin should be i ele an . ......................................................... While his sounds p ecisely wha Ri on and colleagues p opose, i is no he case because o one c ucial de ail. No because hey in oduce he addi ional equi emen ha he g oup o human cells mus be “suppo ed by elemen s ulfilling ex aem- b yonicandu e ine unc ions”, bu because hey s a e ha he po en ial mus be su ficien “ o o m a e us”(Ri on e al, 2023). F om a legal poin o iew, howe e , he oe us is a ca ego y ha has li le impo ance by i sel . The ac ha a g oup o cells can de elop up o wen y weeks in o p egnancy does no endow i wi h pa icula impo ance in ega d o he law. Wha is impo an is ha i can be bo n as a human being, ha is, ha i will e en ually be capable o su i ing ou side he womb, i i is gi en he oppo uni y o de elop, o example, by ans e ing i o a u e us. Thus, po en iali y mus e e o he emb yo’s capaci y o de elop in o a human being. I i canno each ha s age, i should no be conside ed an emb yo, bu an emb yoid (Il is e al, 2023). O cou se, ou a gumen does no imply ha an en i y ha has he capaci y o de elop o he oe al s age o e en a oe us incapable o eaching iabili y has no mo al significance. Indeed, i seems pe ec ly easonable ha a po en ial o ( oe al) sen ience as an unde lying and in i sel ele an ea u e a o ds said en i y a leas some mo al and legal s a us. Simila ly, one can a gue ha emb yos ha canno de elop in o pe sons o emb y- oids, as p e iously men ioned could s ill ha e ‘symbolic’ alue as ea ly o ms o human li e, and hei use should he e o e no be allowed o commodi y easons. This would lead us o he conclusion ha legisla ion ough o es ablish egula ions aimed a sa egua ding he well-being o such emb yoids in o de o p e en any ha m. Ne e heless, i is impo an o no e ha his does no sugges any o m o equi alence be ween emb yoids and ac ual human emb yos. The p oposed ac ion would necessi a e he c ea ion o a dis inc legal amewo k o emb yoids, which is cu en ly lacking in he majo i y o legisla- i e sys ems, al hough ce ain egula ions pe aining o specific scena ios do exis (Il is e al., 2023). ......................................................... The p oposed ac ion would necessi a e he c ea ion o a dis inc legal amewo k o emb yoids, which is cu en ly lacking in he majo i y o legisla i e sys ems ......................................................... Las , we would like o s ess ha accep ing such a defini ion would ha e impo an p ac ical consequences. Indeed, i s adop ion by he CJEU allowed he c ea ion o pa heno es o esea ch on cell lines. Accep ing ha only a cell o g oup o cells ha ha e he inhe en capaci y o de elop in o a human being is an emb yo and he de elopmen o a di e en legal amewo k o non-emb yonic en i ies, ha is, emb yoids, would pa e he way o he c ea ion o human-animal chime as incap- able o de eloping in o a li ing c ea u e. I wouldalsohelp ocla i y helegals a us o cell lines de i ed om impe ec nuclea ans e s, ha is, gene a ing emb yoids, a he han emb yos, because o hei inabili y o de elop in o a li ing c ea u e. And, o cou se, i would help o cla i y he legal s a us o mi ochond ial ansplan a- ion i he in ol ed m DNA is damaged. Thus, he e a e significan easons, no only om a heo e ical poin o iew bu also om a p agma ic pe spec i e, o adop a single defini ion as we p opose he e. Conclusion The conclusion is ha , om a legal poin o iew, he mos obus defini ion o human emb yo eads as ollows: a cell o g oup o cells ha ha e he inhe en capaci y o de elop in o a human being. This way, we will be able o disc imina e be ween en i ies ha eally dese e he p o ec ion we g an o emb yos and hose ha do no . This, o cou se, will no se le all deba es. Ac ually, he ac ha anen i yisno anemb yo,bu an emb yoid, does no mean ha i does no dese e any legal p o ec ion. As we ha e a gued, he e a e s ong easons o suppo such p o ec ion. We will also ha e o discuss whe he i is law ul o al e a p ocess so ha he esul ing en i y does no ha e he capaci y o an emb yo (de Miguel Be iain, 2007); whe he a chime ic emb yo is eally an emb yo (de Miguel Be iain, 2011); o whe he he esul o gene ic modifica ion o mi ochon- d ial DNA o a mi ochond ial ansplan is an emb yo (de Miguel Be iain e al, 2016). And, o cou se, de e mining wha exac ly ‘inhe en capaci y’is a any gi en ime is no easy a all. To esol e his issue, we will need o unde s and he biological basis o ‘po en ial’and a wha poin i exac ly eme ges. On his basis, a cell o g oup o cells would possess inhe en capaci y i i we e capable o gi ing ise o a human being wi hou he need o al e i s biological p og amme, jus by being in he igh en i onmen . Thus, a g oup o cells cul- u ed in i o bu capable o g owing un il bi h would be an emb yo—i would be enough o ans e hem o a u e us o hem o gi e ise o a pe son, ba ing an acciden —bu a cell ha would equi e, o example, modifica ion o i genomic o mi ochond ial DNA would no . These a e s ill challenging ques ions ha equi e u he esea ch. Finally, in a wo ld whe e bio echnology is ad ancing apidly o he poin ha ec oges a ion is becoming easible, as well as human-animal chime ic, hese ypes o challenges will inc ease. None heless, a clea and uni e sally accep ed defini ion o an emb yo as we a gued abo e, will help o cla i y some undamen al legal ques ions and o ad ance legal ce ain y o esea ch and ep oduc i e biomedicine. A pee e iew file is a ailable a h ps:// doi.o g/10.1038/s44319-023-00034-0. Re e ences Ball P (2023) Wha is an emb yo? Scien is s say defini ion needs o change. Na u e 620(7976):928–929. h ps://doi.o g/10.1038/ d41586-023-02641-2 Iñigo De Miguel Be iain e al EMBO epo s © The Au ho (s) EMBO epo s 3 Downloaded om h ps://www.embop ess.o g on Janua y 22, 2024 om IP 88.9.230.164. Dickey-Wicke Amendmen , 1996, (1996) ( es imony o US Cong ess). h ps://emb yo.asu.edu/pages/ dickey-wicke -amendmen -1996 de Miguel Be iain I (2007) La clonación, diez años después: luces y somb as de una apo ación cien ífica de p ime o den. Cuade nos de Realidades Sociales 69:107–124 de Miguel Be iain I (2011) Quime as e híb idos:¿ P oblema é ico o p oblema pa a la é ica? Dilema a 6:101–122 de Miguel Be iain I, A ienza Macías E, A maza A maza EJ (2016) Algunas conside aciones sob e la ans e encia mi ocond ial:¿ un nue o p oblema pa a la bioé ica? Ac a Bioe hica 22(2):203–211 de We G, Dondo p W (2022). Du ch Emb yo Ac unde e ision. BioNews. h ps://www.p og ess. o g.uk/du ch-emb yos-ac -unde - e ision/ Emb yowe , (2001) ( es imony o Du ch Pa liamen ). h ps://we en.o e heid.nl/BWBR0013797/2021- 07-01 Il is AS, Kos e G, Ree es E, Ma hews KRW (2023) E hical, legal, egula o y, and policy issues conce ning emb yoids: a sys ema ic e iew o he li e a u e. S em Cell Res The apy 14(1):209 Ri on NC, A ias AM, Pe a MF, Mo is N, M’hamdi HI (2023) An e hical amewo k o human emb yology wi h emb yo models. Cell 186(17):3548–3557 Rod iguez S, Campo-Engels ein L, Tingen C, Wood u T (2011) An obscu e ide obs uc ing science: he confla ion o pa heno es wi h emb yos in he Dickey–Wicke Amendmen . Am J Bioe hics 11(3):20–28 Villalba A, Rueda J, de Miguel Be iain Í (2023) Syn he ic emb yos: a new enue in e hical esea ch. Rep oduc ion 165(4):V1–V3 Acknowledgemen s IDM acknowledges he suppo o he Basque Go e nmen , Ayudas a g upos de in es igación, G upo de In es igación IT 1541-22, and esea ch p ojec GODAS, PID2022-137140OB-I00, unded by MCIN/AEI/10.13039/501100011033/FEDER, UE. JR hanks he US-Spain Fulb igh g an . AV acknowledges he unding om he Fundació Víc o G í ols i Lucas (BEC-2022-05). Au ho con ibu ions Iñigo De Miguel Be iain: Concep ualiza ion; In es iga ion; W i ing—o iginal d a ; W i ing— e iew and edi ing. Jon Rueda: In es iga ion; W i ing— e iew and edi ing. Ad ián Villalba: In es iga ion; W i ing— e iew and edi ing. Disclosu e and compe ing in e es s a emen The au ho s decla e no compe ing in e es s. 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