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 |
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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)
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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.
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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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