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Molecula Biology Repo s
h ps://doi.o g/10.1007/s11033-021-06594-5
COMMENTARY
Wha isli e?
JaimeGómez‑Má quez1
Recei ed: 5 Ap il 2021 / Accep ed: 24 July 2021
© The Au ho (s) 2021
Abs ac
Backg ound Many adi ional biological concep s con inue o be deba ed by biologis s, scien is s and philosophe s o sci-
ence. The speci ic objec i e o his b ie e lec ion is o o e an al e na i e ision o he de ini ion o li e aking as a s a ing
poin he ai s common o all li ing beings.
Resul s and Conclusions Thus, I de ine li e as a p ocess ha akes place in highly o ganized o ganic s uc u es and is cha ac-
e ized by being p ep og ammed, in e ac i e, adap a i e and e olu iona y. I li e is he p ocess, li ing beings a e he sys em
in which his p ocess akes place. I also wonde whe he i uses can be conside ed li ing hings o no . Taking as a s a ing
poin my de ini ion o li e and, o cou se, on wha o he s ha e hough abou i , I am in a o o conside ing i uses as li ing
beings. I base his conclusion on he ac ha i uses sa is y all he i al cha ac e is ics common o all li ing hings and on
he ole hey ha e played in he e olu ion o species. Finally, I a gue ha i he e we e li e elsewhe e in he uni e se, i would
be e y simila o wha we know on his plane because he laws o physics and he composi ion o ma e a e uni e sal and
because o he p inciple o he inexo abili y o li e.
Keywo ds Li e de ini ion· Li ing i uses· Robo s· Ex a e es ial li e
In oduc ion
Li e is a wonde ul na u al p ocess ha occu s in highly
o ganized dynamic s uc u es ha we call li ing beings.
Today, hanks o he eno mous ad ance o Biology, we
know and unde s and much be e he i al phenomenon,
he molecula biology o he cells, he eno mous biodi e si y
on ou plane , he e olu iona y p ocess, and he complexi y
o ecosys ems. Howe e , despi e hese eno mous ad ances,
biology s ill lacks a solid heo e ical amewo k necessa y
o unde s and he i al phenomenon and o answe ques ions
such as wha is li e? o a e i uses li ing en i ies? To answe
hese and o he undamen al ques ions ela ed o li e, in addi-
ion o he uni e sal laws o physics, biology needs i s own
p inciples o help us ind answe s o majo heo e ical chal-
lenges such as he o igin o li e, he cons uc ion and main-
enance o genomes, o he concep o li e i sel . Rega d-
ing he p inciples go e ning li e, he e ha e been se e al
con ibu ions om di e en pe spec i es (e.g. [1–5]) and I
mysel ha e p oposed a se ies o p inciples (named as he
commandmen s o li e) o explain and unde s and he i al
phenomenon om an e olu iona y pe spec i e, a om any
i alis , pseudo-scien i ic o supe na u al conside a ions [6].
In he wo ds o B. Cla k, a de ini ion o li e is needed
mo e han e e be o e o p o ide de endable objec i e c i e-
ia o sea ches o li e on o he plane s, o ecognize c i i-
cal dis inc ions be ween machine li e and obo s, o p o ide
insigh in o labo a o y app oaches o c ea ing es - ube li e,
o unde s and he p o ound changes ha occu ed du ing
he o igin o li e, and o cla i y he cen al p ocess o he
discipline o biology [7]. I is wo h no ing wha E. Koonin
w o e abou he complexi y o de ining li e: “In my iew,
al hough li e de ini ions a e me aphysical a he han s ic ly
scien i ic p oposi ions, hey a e a om being poin less
and ha e po en ial o yield genuine biological insigh s” [8].
Howe e , despi e i s impo ance he e is no widely accep ed
de ini ion o wha li e is and some o he mos commonly
employed de ini ions (see below) ace p oblems, o en in he
o m o obus coun e -examples [5, 9]. E en some scien is s
and philosophe s o science sugges ha i is no possible o
de ine li e [5, 8].
* Jaime Gómez-Má quez
jaime.gomez.ma q[email p o ec ed]
1 Depa men o Biochemis y andMolecula Biology, Facul y
o Biology - CIBUS, Uni e si y o San iago de Compos ela,
15782San iagodeCompos ela, Galicia, Spain
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Wha isli e?
We can de ine li e in e y di e en ways depending on
he con ex and he ocus we wan o gi e o he de ini-
ion. Fo example, we can de ine li e as he pe iod om
bi h o dea h o as he condi ion ha occu s only in li -
ing o ganisms. We can also say ha li e is a wonde ul
and e e -changing p ocess ha occu s in highly o gan-
ized ecep acles ha we iden i y as li ing en i ies. Like-
wise, he popula encyclopedia Wikipedia de ine li e as
“a cha ac e is ic ha dis inguishes physical en i ies ha
ha ebiological p ocesses ….. om hose ha do no …”
[10]. Howe e , wi h hese exp essions we a e no de in-
ing p ecisely wha li e is and he e o e we need o c ea e
a de ini ion ha concisely bu in o ma i ely e lec s ou
scien i ic knowledge o he i al phenomenon. We ha e
o dis inguish be ween li e and li ing ma e , which is he
place whe e li e li es, and be ween li ing beings and non-
li ing ma e . In eali y, when we ask ou sel es “wha is
li e?” we a e asking “wha a e he cha ac e is ics ha dis-
inguish a li ing o ganism om a non-li ing en i y?
The e a e nume ous de ini ions o li e o mula ed
om di e en cha ac e is ics o li ing beings ( eplica-
ion, me abolism, e olu ion, ene gy, au opoiesis, e c.)
and om di e en app oaches ( he modynamic, chemi-
cal, philosophical, e olu iona y, e c.). O en, de ini ions
o li e a e biased by he esea ch ocus o he pe son mak-
ing he de ini ion; as a esul , people s udying di e en
aspec s o biology, physics, chemis y, o philosophy will
d aw he line be ween li e and non-li e a di e en posi-
ions [11]. These s a egies c ea e a panoply o al e na i e
de ini ions ha makes i e y di icul o each a consensus
on he bes de ini ion o li e because hey all ha e p os and
cons. [12, 13]. Le me b ie ly discuss some o he mos
ep esen a i e de ini ions o li e. The e is a sho de ini-
ion “Li e is sel - ep oduc ion wi h a ia ions” [14] ha
is in e es ing o i s b e i y and because i includes wo
undamen al cha ac e is ics o li ing o ganisms: ep oduc-
ion and e olu ion. Howe e , his minimalis de ini ion is
clea ly insu icien [8] and i does no include some o he
mos impo an ai s we see in li ing hings. Along hese
lines, he e is also he de ini ion coined by NASA: “Li e
is a sel -sus aining chemical sys em capable o Da winian
e olu ion” [15, 16]. This is a mo e comple e and, I belie e,
be e de ini ion han he p e ious one, as i inco po a es,
in addi ion o ep oduc ion and e olu ion, me abolism.
Howe e , bo h de ini ions a e unsa is ac o y because nei-
he cell no mul icellula o ganisms a e sel -su icien
as he e is always a dependence on o he o ganisms and
ex e nal ac o s o li e and ep oduce. Fu he mo e, hese
de ini ions say no hing abou he chemical na u e o li ing
ma e , he in e ac ions wi h he en i onmen o he low
en opy o li ing hings. Apa om ha , ep oduc ion
being essen ial o he pe pe ua ion o species and e olu-
ion, no all li ing beings a e able o ep oduce (e.g. he
mule, mos bees, e c.) and do no he eby lose hei li ing
s a us. A mo e ecen de ini ion o li e s a es: “Li e is a
sel -su icien chemical sys em a om equilib ium, capa-
ble o p ocessing, ans o ming and accumula ing in o ma-
ion acqui ed om he en i onmen ” [17]. Al hough his
de ini ion is mo e comp ehensi e han he p e ious ones
and includes a e e ence o he modynamics, in my opin-
ion i has ou d awbacks: (i) he e m “sel -su icien ” is
no adequa e because he quali y o li e does no p o ide
sel -su iciency; (ii) he he modynamic componen does
no highligh how undamen al low en opy o high o de
is o any li ing being; (iii) in o ma ion can be acqui ed
om “wi hin” and no only om he en i onmen ; (i )
li e is no a sys em is a p ocess and li ing beings a e he
sys em whe e ha p ocess occu s (I discuss his poin
below). F om a e y di e en pe spec i e i was de ined
li e as “ma e wi h he con igu a ion o an ope a o , and
ha possesses a complexi y equal o, o e en highe han
he cellula ope a o ” [18]. This p oposal in oduces a
new e m, he ope a o , which is somewha con using,
excludes i uses and makes a s ange classi ica ion o li -
ing sys ems. On he o he hand, some scien is s ha e also
a emp ed o de ine li e om a hand ul o key ea u es.
Thus, se en “pilla s” ( he essen ial p inciples by which a
li ing sys em unc ions) ha e been p oposed on which li e
as we know i can be de ined [19], bu no de ini ion was
p o ided. Li e has also been conside ed as any sys em ha
om i s own inhe en se o biological ins uc ions and he
algo i hmic p ocessing o ha "p esc ip i e in o ma ion"
can pe o m he nine bio unc ions [20] which a e basically
he same as he "pilla s" men ioned abo e. Howe e , no
de ini ion o li e was p oposed, and again i was conside ed
as a sys em a he han a p ocess. Bo h de ini ions exclude
i uses as li ing beings, mainly because he exis ence o
a memb ane, a me abolic ne wo k and sel - eplica ion a e
se as condi ions o li e. In sho , he e a e many mo e
de ini ions o li e bu as R. Popa says “We may ne e ag ee
on a de ini ion o li e, which will emain o e e subjec o
a pe sonal pe spec i e” [21].
My de ini ion o li e
T ai s a e measu able a ibu es o cha ac e is ics o o gan-
isms and ai -based app oaches ha e been widely used in
sys ema ics and e olu iona y s udies [22]. Since any de ini-
ion o li e mus connec wi h wha we obse e in na u e,
my s a egy o inding a de ini ion o li e was o es ablish
wha a e he key a ibu es o ai s common o all li ing
hings. Wha do bac e ia, yeas s, lichens, ees, bee les,
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bi ds, whales, e c. ha e in common ha clea ly di e en i-
a es hem om non-li ing sys ems? In my opinion, li ing
o ganisms sha e se en ai s: o ganic na u e, high deg ee o
o ganiza ion, p e-p og amming, in e ac ion (o collabo a-
ion), adap a ion, ep oduc ion and e olu ion, he las wo
being acul a i e as hey a e no p esen in all li ing beings.
O ganic na u e and highly o ganized s uc u es. Li ing
ma e is o ganic because i is based on ca bon chemis y
and molecula in e ac ions ake place ollowing he laws o
chemis y. As R. Hazen w o e “Ca bon chemis y pe ades
ou li es. Almos e e y objec we see, e e y ma e ial good
we buy, e e y bi e o ood we consume, is based on ele-
men six. E e y ac i i y is in luenced by ca bon—wo k and
spo s, sleeping and waking, bi hing and dying.” [23]. Li -
ing o ganisms a e highly o ganized s uc u es ha main ain
low en opy ( he i al o de ) by gene a ing g ea e diso de
in he en i onmen , hus ul illing he pos ula es o he mo-
dynamics [24, 25]; when his i al o de is los , li e disap-
pea s and he only way o es o e li e is o gene a e a new
i al o ganized s uc u e h ough ep oduc ion [6]. Li ing
o ganisms esis en opy hanks o biochemical p ocesses
ha ans o m he ene gy hey ob ain om nu ien s, sun o
edox eac ions. I could be said ha i al o de and ene gy
a e wo sides o he same coin.
P e-p og amming. E e y li ing en i y has a so wa e (a
p e-p og amme) in i s gene ic ma e ial ha con ains he
ins uc ion manual necessa y o bo h i s cons uc ion (mo -
phology) and i s unc ioning (physiology). This p og amme
has been modi ied in he cou se o e olu ion, as a conse-
quence o con ingency and causali y, so i is no a s a ic o
immu able p og am bu a dynamic one. Fu he mo e, he e
is also ano he p ees ablished p og am ha condi ions he
i al phenomenon and ha I ha e called he p inciple o
inexo abili y [6]. Le me gi e ew examples o he p inciple
o inexo abili y a di e en le els o complexi y. The shape
o ibosome is de e mined (p e-p og ammed) by he chemi-
cal bonds ha a e es ablished be ween ibosomal p o eins
and RNA. A simila example is he λ phage mo phogenesis
ha depends only on in e ac ions p o ein–p o ein and p o-
ein-DNA. E olu iona y con e gence o he need o wings
o ly a e o he examples o his inexo abili y guided by he
laws o na u e.
In e ac ion and adap a ion. I we look a na u e in i s
pu es s a e o a he complex human socie y, we can see
coun less in e ac ions be ween li ing beings and wi h hei
en i onmen necessa y o su i al and ep oduc ion. We
can see in e ac ions a he molecula le el (e.g., allos e ic
in e ac ions, me abolic pa hways, cellula signaling, quo-
um sensing), in he ela ionships be ween o ganisms o he
same o di e en species (e.g., sexual ep oduc ion, sym-
biosis, in ec ion, pa asi ism, p eda o –p ey, o sound lan-
guage), o be ween li ing o ms and he en i onmen (e.g.,
pho osyn hesis o physiological/ana omical in e ac ions
o swimming o lying). In e ac ion is collabo a ion, i is
coope a ion a all le els [6], he ecosys em being he bes
example o mul iple collabo a i e in e ac ions be ween e y
di e en o ganisms. In e ms o adap a ion, li ing o ganisms
show a g ea capaci y o adap bo h o hei su oundings
and o en i onmen al ci cums ances; u he mo e, adap a-
ions in ol ing new biological cha ac e is ics can be seen
as an oppo uni y o ind a di e en way o e ol e. In his
sense, he e olu iona y p ocess e lec s his con inuous adap-
a ion and ana omy, physiology and genome bea wi ness
o his. Li e is adap a i e because species adap o en i on-
men al changes modi ying hei physiology o me abolism,
o ins ance educing hea bea du ing hibe na ion (e.g. he
g izzly bea U sus a c os ho ibilis) o syn hesizing a om
excess suga o inc ease he ene gy ese es o he body
(e.g. Homo sapiens). In addi ion o hese empo al adap a-
ions in esponse o en i onmen al changes [26], he e a e
also changes in geno ype o pheno ype since he adap a-
ion p ocess is he esul o na u al selec ion ac ing upon
he i able a ia ions [27]; a well-known example o his is
he peppe ed mo h Bis on be ula ia whose allele equen-
cies o he locus ha con ols he dis ibu ion o melanin in
he wings changed wi h he indus ial e olu ion in England
[28]. Epigene ic a ia ions also con ibu e o apid adap a-
i e esponses [29, 30].
Rep oduc ion and E olu ion. Ano he p ope y o li -
ing beings is hei abili y o pe pe ua e hemsel es and
hus make i possible o he species no o disappea and
o e ol e. Rep oduc ion can be obse ed a he molecula
(DNA eplica ion), cellula (mi osis, meiosis, bina y di i-
sion), and o ganismal (sexual and asexual) le els. F om a
di e en pe spec i e, ep oduc ion is also he way o o e -
come he second law o he modynamics and he y anny
o ime because when we ep oduce, we a e c ea ing a new
o de and ese ing he i al clock o ze o [6]. Wha abou
indi iduals such as he mule o he male and emale o a
species, o he he maph odi e ha canno sel - e ilize, who
canno ep oduce because hey a e s e ile o because hey
need ano he membe o hei species o ep oduce? A e
no hese o ganisms li ing beings? O cou se, hey a e! In
his con ex , ep oduc ion mus be conside ed as a acul-
a i e ai because no all li ing o ganisms a e e ile o
can p oduce o sp ing on hei own bu main ain all o he
ai s necessa y o he li e p ocess. I an indi idual is s e -
ile, he species will con inue o exis because he e olu ion-
a y p ocess mus be analyzed a he popula ion le el, no a
he le el o indi idual o ganisms; ob iously, i he en i e
popula ion we e s e ile, hen he species would disappea
and he e would be no li e. All species ha e he capaci y o
e ol e, and his p ope y is unique o li e. E olu ion allows
li ing beings o adap o new ci cums ances and he bes
genomes a e selec ed and ansmi ed o he nex gene a-
ions. The concep o e olu ion ( ep oduc ion wi h a ia ions
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and pe manence in ime) allows us o in e p e he eali y o
he li e we obse e now and o guess wha i has been like in
he pas . We canno p edic he u u e because e olu ion is
no a inalis ic p ocess, i is, o use he wo ds o J. Monod,
he ui o chance and necessi y.
The e is no hing on his plane , apa om a li ing being,
ha complies wi h all hese cha ac e is ic ea u es o li ing
beings. I should he e o e be possible o de ine li e by logi-
cally combining hem. Consequen ly, I de ine li e as a p o-
cess ha akes place in highly o ganized o ganic s uc u es
and is cha ac e ized by being p ep og ammed, in e ac i e,
adap a i e and e olu iona y. I li e is he p ocess, a li ing
o ganism is he sys em in which ha p ocess akes place
and which is cha ac e ized as o ganic, highly o ganized, p e-
p og ammed, in e ac i e, adap a i e, and e olu iona y. Why
do I say ha li e is a p ocess and no a sys em? Acco ding o
he Me iam-Webs e dic iona y, a p ocess is a na u al phe-
nomenon cha ac e ized by g adual changes ha lead owa ds
a ce ain esul . A second meaning de ines i as a con inuous
na u al o biological ac i i y o unc ion; and a hi d one as
a se ies o ac ions o ope a ions conducing o an end. These
h ee meanings o wha a p ocess is i e y well wi h wha
we obse e happening in li ing beings, which is none o he
han he i al p ocess o li e. The dic iona y i sel de ines a
sys em as a egula ly in e ac ing o in e dependen g oup
o i ems o ming a uni ied whole, and as an assemblage o
subs ances ha is in o ends o equilib ium o a g oup o
body o gans ha oge he pe o m one o mo e i al unc-
ions. Once again, hese de ini ions i e y well wi h wha a
li ing being ep esen s.
Wha is he di e ence be ween li e, li ing being and a
obo ? [31] Li e is he i al p ocess and he li ing being is
he sys em, he “con aine ” in a me apho ical way, whe e
he i al p ocess akes place. Following his easoning, a
obo would be an a i icially o ganized, p e-p og ammed
and in e ac i e sys em, bu unlike a li ing being i is no
ali e because i is nei he o ganic, no does i ep oduce,
adap , o e ol e. A obo o a popula ion o obo s canno
“ ep oduce and e ol e” on i s own, wi hou he in e en ion
o i s "c ea o " ( he human being), i will always need o be
buil o p og ammed by an enginee o do so. I do no dis-
pu e ha he obo can adap , especially hanks o ad ances
in a i icial in elligence, al hough I am no su e ha i can do
so in he biological sense o he e m. Biological adap a ion
is a p ocess by which a species e en ually adap s o i s en i-
onmen as a esul o he ac ion o na u al selec ion on phe-
no ypic cha ac e is ics [32]. A obo may be able o adap o
i s en i onmen , bu wha i canno do is adap i sel h ough
a selec i e p ocess (wi hou in e en ion om i s c ea o )
and change in o a new ype o obo (e ol e). On he o he
hand, ega ding he syn he ic li e o ms named as xenobo s
[33], I hink hey canno be conside ed as pu e obo s, bu
as an in e ace be ween li ing beings and a i icial obo s,
as hey a e made om cells. In he u u e we will p obably
build obo s so pe ec ha we can conside hem as almos
li ing beings and as he esul o he in e en ion o a c ea o
( hei enginee ), some hing ha we canno say abou li ing
beings unless we a e c ea ionis s.
A e i uses ali e?
A. Tu ing, one o he pionee s in he de elopmen o
compu e sciences, w o e: “Can machines hink? This
should begin wi h de ini ions o he meaning o he e ms
“machine” and “ hink” [34]. To pa aph ase Tu ing, we could
ask ou sel es: can i uses be conside ed li ing en i ies? And
he answe o his ques ion, so impo an o biology and s ill
con o e sial [35], is o de ine wha a i us is and wha li e
is. A leas om a heo e ical poin o iew, biology should
seek a clea and de ini i e answe o his ques ion ins ead o
adop ing a skep ical a i ude and assuming wha K. Smi h
w o e in his classic book on i uses, “As o he ques ion
asked mos equen ly o all, a e i uses li ing o ganisms?
ha mus be le o he ques ione himsel o answe ” [36].
Vi uses a e en i ies ha s addle he bounda y be ween
li ing and non-li ing and he e o e hei biological s a us is
con o e sial. A i us can be de ined as an acellula in ec-
ious agen whose s uc u e consis s o a mac omolecula
complex o p o eins and nucleic acids. Vi uses a e no cells,
hey do no me abolize subs ances, no can hey ep oduce
by hemsel es, g ow, o b ea he. Ye , ega dless o whe he
we conside i uses o be li ing beings o no , hey a e an
inescapable pa o li e and he e is an undeniable biological
connec ion be ween he i us and he o ganism i in ec s.
Gi en he close in e connec ion be ween i uses and hei
hos s, i seems plausible ha i uses play essen ial oles in
hei hos s [37]. Fo example, endogenous e o i al ele-
men s ha e shaped e eb a e genome e olu ion, no only
by ac ing as gene ic pa asi es, bu also by in oducing use-
ul gene ic no el y [38]. Mo e ecen ly, i was ound in he
human genome a gene egula o y ne wo k based on endog-
enous e o i us ha is impo an o b ain de elopmen [39]
and a new amed e o i al en elope ha is p oduced by
he e us and hen shed in he blood o he mo he du ing
p egnancy [40].
Vi uses a e capsid-encoding pa icles ha in ec all kind
o cells and sha e hallma k genes wi h capsidless sel ish
gene ic elemen s, such as plasmids and ansposons [41].
T adi ionally, hey ha e been ega ded as li eless agen s
because hey ha e no me abolism o hei own and need a
cell o eplica e and gene a e new i uses [42]. Howe e ,
while his is ue, I belie e ha his is no a de ini i e c i-
e ion o excluding hem om he ee o li e (mo e on
his below). The e a e scien is s in he opposi e side ha
conside i uses as li ing beings ha can e ol e [43] and
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classi y hem as capsid-encoding o ganisms as opposed o
he ibosome-encoding o ganisms ha include all cellula
li e o ms [37, 44]. Vi uses ha e played a key ole in he
e olu ion o species [35] because hey a e he mos abundan
sou ce o gene ic ma e ial on Ea h, a e ubiqui ous in all
en i onmen s, and ha e ac i ely pa icipa ed in he exchange
o genes o DNA agmen s wi h hei hos s [41, 45, 46].
We canno say whe he a i us is a li ing hing o no
wi hou de ining wha is li e and wha is a li ing hing. Ob i-
ously, i we ake he cell as he minimum i al uni , we can-
no conside i uses as li ing en i ies, and any discussion o
his is supe luous. As a as I am conce ned, conside ing
i uses as non-li ing c ea u es because hey need a cell o
ep oduce is no a e y s ong a gumen o wo easons.
Fi s , i uses a e obliga e in acellula pa asi es, and, like all
pa asi es, hey use he hos o hei own bene i , and his is
hei su i al s a egy. Vi uses need no hing else o pu sue
he same goal as all species on his plane , which is o gen-
e a e mo e i uses be e adap ed o in ec new o ganisms.
They apply he “law o leas e o ” o achie e his goal and
may e en decide o emain inside he hos cell in a lysogenic
manne , as in he case o bac e iophage lambda [47], o by
es ablishing la ency as he pes i uses do [48]. Second, as I
said be o e no cell o o ganism is sel -su icien , as i needs
a leas a supply o ood/ene gy o su i e and ep oduce.
We know ha li e is absolu ely in e dependen . Fo example,
we depend di ec ly on ou in es inal bac e ial lo a o ou
su i al, and indi ec ly on ni ogen- ixing bac e ia o pho-
osyn hesis. We could ake o absu di y he a gumen ha
because i uses need a cell o ep oduce, hey a e no ali e
and say ha a man o a woman is no a li ing being because
hey canno ep oduce by hemsel es. The a gumen ha a
i us is no a li ing hing because i is an ine en i y ou side
he cell is also no alid because such a i us could s ill ha e
he abili y o in ec cells. Simila ly, a spo e o a seed canno
be conside ed li eless because i is ine , as i is only wai ing
o he igh en i onmen al condi ions o ge mina e, and ha
wai can las o housands o yea s.
To answe he ques ion o whe he i uses a e ali e o
no , I base my a gumen in suppo o conside ing i uses
as li ing en i ies ob iously on my own de ini ion o li e
( his pape ), as well as on wha we know abou he biology
o i uses. Fi s , i uses, like all cellula en i ies in na u e,
a e composed o o ganic molecules; a i us consis s o a
nucleic acid (DNA o RNA), which is i s gene ic ma e-
ial as in all li ing hings, and a p o ein capsid encoded
by he i al genome ha p o ec s he i al gene ic ma e-
ial and pa icipa es in he p opaga ion o he i us in he
hos ; i al capsids show ascina ing dynamics du ing he
i al li e cycle [49]. Secondly, i uses a e highly o ganized
s uc u es. The e is an as onishing di e si y o o ganiza-
ion and geome ic design o i uses, equi ing only a ew
di e en s uc u al subuni s o he capsid o cons uc an
in ec ious pa icle. Many i uses ha e de eloped e y suc-
cess ul sel -assembly sys ems; so much so ha he i al
capsid can sel -assemble e en ou side he hos cell [50].
The hi d ea u e common o all li ing hings is ha hey
a e p e-p og ammed, and i uses also ul ill his cha ac-
e is ic because in hei gene ic ma e ial a e w i en he
ins uc ions o make new i uses capable o in ec ing
new cells o o ganisms. Vi uses in hei genome ha e he
necessa y ( hough no su icien because hey need ele-
men s p o ided by he hos cell) ins uc ions o make new
i uses, and in his hey a e he same as any o he li ing
hing. In addi ion, he p ocess o sel -assembly o gene a e
new i uses occu s spon aneously because he ins uc ions
o do i au onomously a e bo h in he capsid- o ming mol-
ecules hemsel es and in he nucleic acid, ei he DNA o
RNA [49].
Two o he cha ac e is ics o li ing o ganisms a e he
abili y o in e ac wi h o he li ing o ganisms (in e ac ion)
and o adap gene ically o new ci cums ances (adap a ion).
Vi uses in e ac wi h hei hos in mul iple ways: du ing
in ec ion, when hei genes a e exp essed and hei genome
eplica ed, when i ions a e o med, when hey in eg a e
in o he genome o he hos cell, o when hey engage in
ho izon al gene ans e p ocesses. Vi uses no only in e -
ac wi h hei hos , bu also adap by gene a ing new a i-
an s ha inc ease hei abili y o in ec o he cells, o by
aking con ol o cell me abolism o hei own bene i , o
e en o escape he immune esponse [51]. In e ms o ep o-
duc ion and e olu ion, which a e wo closely ela ed p o-
cesses, i uses ep oduce in he hos cell and e ol e h ough
changes in hei genome. Vi al e olu ion, like ha o all
li ing hings, e e s o he he i able gene ic changes ha a
i us accumula es du ing i s li e cycle, which may a ise om
adap a ions in esponse o en i onmen al changes o hos
immune esponse. Because o hei sho gene a ion imes
and la ge popula ion sizes, i uses can e ol e apidly [52].
Mic obiologis and Nobel lau ea e J. Lede be g said
ha “The e y essence o he i us is i s undamen al
en anglemen wi h he gene ic and me abolic machine y
o he hos ”. As a as I am conce ned, his s a emen is
essen ially ue and i s p o ound meaning is, a leas o
me, u he p oo ha i uses a e li ing hings. Vi uses
o m pa o many in eg a ed biological sys ems, and
hey played an impo an ole in he e olu ion o species
[53]. They can exchange gene ic ma e ial and pa icipa e
in ho izon al gene ans e [43] e en be ween indi iduals
om di e en species [54]. Due o hei high equency
o mu a ion [55], i uses a e so abundan in na u e and
p esen such a high deg ee o di e si y ha hey cons i u e
by hemsel es he i osphe e [46]. This g ea i al biodi-
e si y is p oo ha hese li ing en i ies pe o m unda-
men al e olu iona y and ecological unc ions [56, 57]. In
conclusion, I belie e ha i uses should be conside ed as

Molecula Biology Repo s
1 3
li ing en i ies ha can pa icipa e in e en s as di e se as
causing pandemics, des oying bac e ia, causing cance ,
o pa icipa ing in ho izon al gene ans e .
Following he me apho o he “con aine ” as he es-
sel o sys em ( he li ing being) in which he li e p ocess
akes place, he ac ha i uses a e obliga ed in acellula
pa asi es and do no ha e a cellula s uc u e and me abo-
lism o hei own does no seem o i his me apho . I is
ob ious ha he i us canno be he “con aine ” whe e he
li e p ocess akes place, since he i us, when ou side he
cell, is in a “do man ” s a e wai ing o ind a sui able hos
o in ec and comple e i s li e cycle; we could say ha i
is ine bu no ye dead. The e o e, in he special case o
i uses, he “con aine ” is he cell. Once he i us inds
i s speci ic “con aine ”, i can hen ep oduce, o in eg a e
in o he genome o he hos cell, o emain as an episome,
o in e ene in he e olu iona y p ocess h ough exchange
o gene ic ma e ial. F om genomic and me agenomic da a,
we know ha co-e olu ion be ween i al and hos genomes
in ol es equen ho izon al gene ans e and he occasional
co-op ion o no el unc ions o e e olu iona y ime. We can
say ha i uses and hei cellula hos s a e ecologically and
e olu iona y in e wined [58].
I would like o e e o an in e es ing e lec ion on he
de ining cha ac e is ics o li e and how i uses i in o his
concep ual amewo k [59]. Thus, Dup é and O’Malley con-
side collabo a ion as a common c i e ion o li e and I can
only ag ee wi h his assessmen ; in his sense, in a p e i-
ous pape on he p inciples ha go e n li e [6], I use he
exp ession “coope a i e h us ” o e e o he impo ance
o collabo a ion in he o igin and e olu ion o li ing beings.
Wi hou conside ing collabo a ion o coope a ion as a key
in e ac ion, we could no explain endosymbiosis, euka yo-
genesis, me abolism, mul icellula i y, e c. In he p esen
pape , collabo a ion is implici in wha I call in e ac ion as a
common and undamen al ea u e o all li ing hings. In e -
es ingly, hese au ho s poin ou ha “lea ing i uses ou o
e olu iona y, ecological, physiological o concep ual s udies
o li ing en i ies, would allow only an incomple e unde -
s anding o li e a any le el” [59]. Conside ing his emphasis
on collabo a ion as a sine qua non condi ion o li e, how
does he wo ld o i uses i in? Dup é and O’Malley p o-
pose, and I ag ee, ha i uses can be unde s ood as ali e
when hey ac i ely collabo a e (I mean when hey a e in ec -
ing he a ge cell) and when hey do no collabo a e (I would
say hey a e inac i e), hey ha e a mos a po en ial o li e.
Finally, I would like o add ha I am awa e ha he e
a e many scien is s who conside ha i uses a e no li ing
beings basically because hey do no ha e a cellula s uc u e
wi h all ha his means. The e o e, his biological dilemma
will p obably be wi h us o a long ime o come. I hink i
will only be esol ed when we each a consensus on wha
li e is because only hen will we be able o say ca ego ically
whe he some hing is ali e o no . This is wha I ha e mod-
es ly ied o do in his pape .
Wha would li e be likeelsewhe e
in heuni e se?
The massi e numbe o exoplane s s ongly sugges s ha
he e is a high p obabili y ha li e e ol ed elsewhe e in he
uni e se. As obiologis s a e commi ed o he sea ch o
li e in he cosmos and o ha pu pose i is e y con enien
o ha e a c i e ion abou wha li e is [16]. How can we be
su e ha he e is li e on a dis an plane ? To do so, we need
o de ine some biosigna u es ha can es ablish he possible
exis ence o li ing hings elsewhe e in he uni e se [60],
o he wise wha a e we looking o ? In addi ion o his, i
would also help a lo in his sea ch o li e on o he plane s,
inding ou how li e began on Ea h.
Some scien is s and philosophe s o science hink ha
his p econcep ion o wha li e is may be a p oblem a he
han a solu ion in he sea ch o li e in o he plane s. C. Cle-
land in he book abou he na u e o li e s a es, “Li e is no
he so o hing ha can be success ully de ined. In u h, a
de ini ion o li e is mo e likely o hinde han acili a e he
disco e y o no el o ms o li e” [5]. I do no en i ely ag ee
wi h his double s a emen because al hough we mus be
open-minded in he sea ch o li e ou side ou galac ic home,
a he same ime I hink i is a good idea o ha e a hypo hesis
based on he only ce ain y we ha e abou i al phenomena,
which is li e on Ea h, ha will help in he design o he
sea ch o ex a e es ial li e.
Is he e li e elsewhe e in he uni e se? We don’ know
ye and i is p obably only a ma e o ime be o e we ind
li e on o he plane s o aliens ind us. In my opinion i he e
is li e elsewhe e in he uni e se, i will mos likely be simi-
la o wha exis ed, exis s o will exis on ou plane . Le
us see why. Fi s o all, he laws o physics and chemis y
a e uni e sal and hese laws, di ec ly o indi ec ly, go e n
e e y hing ha happens wi h he ma e o he uni e se.
Acco ding o he cosmological p inciple, he same physical
laws and models ha applies he e on Ea h also wo ks in all
pa s o he uni e se [61]; i is also assumed ha physical
cons an s (g a i a ional cons an , speed o ligh , e c.) emain
he same e e ywhe e in he uni e se. Second, he elemen s
ha make up he ma e o he s a s a e he same e e ywhe e
in he uni e se al hough in di e en p opo ions; he “pe i-
odic able” is he same o he whole uni e se. Whe he li e
exis s elsewhe e in he uni e se based on a chemis y o he
han ca bon we do no know and can only specula e, bu
wha we do know o su e is ha li e on Ea h is based on
ca bon chemis y, pe haps because i canno be o he wise.
Thi d, he e is he a o emen ioned p inciple o inexo abil-
i y [6]. In his con ex , wha does his p inciple mean? I
Molecula Biology Repo s
1 3
means ha i he en i onmen al condi ions a e sui able, glu-
cose will be con e ed in o py u a e in an aqueous medium,
chemiosmo ic p ocesses will be an impo an mechanism
o gene a ing chemical ene gy, lying o ganisms will ha e
wings, o gene ic in o ma ion will be encoded in a language
analogous o iden ical o wha we know on Ea h. Acco d-
ing o his, he di e ences be ween he Ea h li ing o ms
and he “space c ea u es” could be a ibu ed o a di e en
e olu iona y s age o o speci ic en i onmen al condi ions.
This hypo he ical p emise could be e y impo an when
de eloping p ojec s ha seek li e elsewhe e in he uni e se.
Acknowledgemen s I would like o hank my colleagues M. L.
González Caamaño and R. Anadón o hei use ul discussions. This
wo k is dedica ed o my pa en s.
Funding The au ho did no ecei e suppo om any o ganiza ion o
he submi ed wo k.
Decla a ions
Con lic o in e es The au ho has no con lic o in e es o decla e ha
a e ele an o he con en o his a icle.
Open Access This a icle is licensed unde a C ea i e Commons A i-
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ion, dis ibu ion and ep oduc ion in any medium o o ma , as long
as you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce,
p o ide a link o he C ea i e Commons licence, and indica e i changes
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