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n an episodeof the classic1950stelevisioncomedyThe Honeymooners,
I
Brooklyn bus driver Ralph Kramdenloudly explainsto his wife, Alice,
I "You
know that I knorv holv easyyou getthe virus.' Half a centuryago
|
euen
regular
folkslike the Kramdenshadsomeknorvledge
of viruses-as
I
I microscopicbringersof disease.
Yer it is almostcertainthat theydid not
knorv exactlywhat a virus was.They were,and are,not alone.
For about 100 years,the scientificcommunityhasrepeatedlychangedits
collectivemind overwhat virusesare.Firstseenaspoisons,thenaslife-forms,
thenbiologicalchemicals,virusestoday arethoughtof as beingin a grayarea
betweenliving and nonliving: they cannot replicateon their own but can do so
in truly living cellsand can also affect the behaviorof their hostsprofoundly.
The categorizationof virusesasnonliving during muchof the moderneraof biologicalsciencehashad an unintendedconsequence:
it hasled mostresearchersto ignore virusesin the study of evolution.Finally,however,scientistsare
beginningto appreciatevirusesas fundamentalplayersin the history of life.
o u rc o n c e p t
o fw h a t
" l i v i ng "
m e an s ,t h e u
ar e v i t aI
members
o f t h ew e b
oflife
C o m i ntgo T e r m s
I r I S E A S y r o s E Ew H y v r R U s E s h a v e b e e n d i f f i c u l t t o p i g e o n h o l e . T h e y
seemto vary with each lens applied to examine them. The initial interestin
virusesstemmedfrom their associationrvith diseases-the word "virus' has
its roots in the Latin term for "poison.' In the late 19th century researchers
realizedthat certain diseases,including rabiesand foot-and-mouth,were
causedby particlesthat seemedto behavelike bacteriabut were muchsmaller.
Becausethey wereclearlybiologicalthemselvesand could be spreadfrom one
victim to another with obvious biological effects,viruseswere then thought
to be the simplestof all living, gene-bearinglife-forms.
=
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w w w ,s c r am .c o m
s c r E N T r F r c l u E n1t c0 l1H
baresits genesand inducesthe cell'sown replication machintheintruder'sDNA or RNA and manufacture
eryto reproduce
moreviral proteinbasedon the instructions in the-viral nucleic
acid.The nervlycreatedviral bits assembleand, voili, more
virus arises,which also may infect other cells.
Thesebehaviorsare what led many to think cif viruses as
existingat theborderbetweenchemistry and life- More poetically,virologistsMarc H. V. van Regenmortelof the University
of Strasbourgin Franceand Brian W. J. Mahy of the Centers
for DiseaseConrol and Preventionhaverecentlysaid that with
"a
on hostcells,viruseslead kind of borrowed
theirdependence
life." Interestinglneventhough biologists long favored the view
mereboxesof chemicals,they took advantage
that virusesrvere
of viial activiryin host cells to determine how nucleic acids
codefor proteins:indeed,modern molecular biology rests on
a foundationof information gainedthrough viruses.
Molecularbiologistswent on to crystallize most of the esof cellsand aretoday accustomedto thinksentialcomponents
example, ribosomes, miconstituents-for
cellular
about
ing
either chemiproteins-as
and
DNA
membranes,
tochondria,
or produces.
uses
machineiy
that
the
the
stuff
or
calmachinery
that
structures
chemical
multiple
complex
to
This exposure
most
that
a
reason
probably
is
processes
of
life
carry out the
molecularbiologistsdo not spenda lot of time puzzling over
whethervirusesare alive. For them, that exercisemight seem
equivalentto ponderingwhether those individual subcellular
constituentsarealive on their own. This myopic view allows
themto seeonlyhow virusesco-opt cellsor causedisease.The
more sweepingquestionof viral contributions to the history
of life on eanh, which I will addressshortly, remains for the
and evenunasked.
most part unansrvered
Their demotion to inert chemicalscameafter 1935,when
at rvhatis now the
Vendell M. Stanleyand his colleagues,
RockefellerUniversityin New York City, crystallizeda virus-tobacco mosaicvirus-for the first time.Theysawthat it
But it lacked
consistedof a packageof complexbiochemicals.
essentialsystemsnecessary
for metabolicfunctions,the biochemicalactivityof life.Stanleysharedthe1945NobelPrizein chemistry,not in physiologyor medicine-for this work.
that a
Further researchby Stanleyand othersestablished
virus consistsof nucleicacids(DNA or RNA) enclosedin a
proreincoatthar mayalsoshelterviralproteinsinvolvedin infection.By that description,
a virusseemsmorelike a chemistry setthan an organism.But whena virusentersa cell(called
a host after infection),it is far from inactive.k shedsits coat,
1 0 2 s c r e x r r FA
l cM E R t c A N
T oB eo r N o t o B e
T H E s E E l l t I N G LsYI M P L E Q U E S T I o No f w h e t h e r o r n o t
virusesarealive,which my studentsoften ask, has probably
defieda simpleanswerall theseyears becauseit raisesa fun'life?' A precisesciendamentalissue:What exactlydefines
ti6c definitionof life is an elusivething, but most observers
would agreethat life includescertain qualities in addition
to an ability to replicate.For example, a living entity is in a
stateboundedby birth and death. Living organisms also are
thought to requirea degreeof biochemicalautonomy, carrying on the metabolicactivities that produce the molecules
and energyneededto sustain the organism- This level of autonomy is essentialto most deEnitions.
Viruses,however,parasitizeessentiallyall biomolecular
aspectsof life. That is, they depend on the host cell for the
raw materialsandenergynecessaryfor nucleic acid synthesis,
processingand transport, and all other bioproteinsynthesis,
chemicalactividesthar allow the virus to multiply and spread'
One might then conclude that even though these processes
comeunderviraldirection, virusesare simply nonliving parasitesof living metabolic systems.But a spectrum may exist
betweenwhat is certainly alive and what is not.
A rock is not alive. A metabolically active sack, devoid of
OO4
O E C E M B E2 R
z
2
g e n e t i cn . r a r e r i a n
l dr h ep o r e n r i aflo r p r o p a g a r i o ni s, a l s on o t
building blocksrhar consrirurea r.inrs.Approachedfrom this
a l i v e .A b i r c r e r i u mt h, o u g h ,i s a l i v eA
. l ; h o ; g h i r i s a s i n g l ec e l l , perspective,
viruses,thoughnor fully.alive,ma1.be thoughtof
it cangenerare
energyandthemolecules
n."j.d to susrainirself, a s b e i n gn r o r er h a n i n e r tm a r t e r t: h e r . v e r goen l i f e .
and ir can reproduce.
Br.rr
u,harabouta seed? A seedmighrnot
In fact, in Ocrober, Frenchresearchers
announcedfindb ec o n s i d e r eadl i v e y. e t i r h a sa p o r e n t i aflo r I i f e ,a n c il r m a y
b e i n g st h a t i l l u s t r a r ea f r e s hj u s rh o l r , c l o s es o m ev i r u s e sm i g h t
destroyed.
In thisregard,virusesresemble
seedsmorethanthey come. Didier Raor.rltand his colleaguesar the Universit/
of
do livecells.Ther.have
a cerrainporenrial,
rvhichcanbesnuffed t h e M e d i t e r r a n e a ni n M a r s e i l l ea n n o u n c e dt h a t t h e y i r a d
o u t , b u t t h e yd o n o r a t t a i nt h e m o r ea u l o n o m o u s r a t e
o f l i f e . sequencedthe genome of rhe largesrknorvn virus, MimiAnotheru'avro think abourlifeisasan emergenr
propertyof virus, rvhich u.as discoveredin 1992. The virus. about the
a collectionoicerrainnonlivingthings.Borh rifelnd conscioLrss a m es i z ea s a s m a l l b a c t e r i t r mi.n f e c t sa m o e b a eS
. eouence
n e s sa r e e x a m p l e so f e m e r g e ncr o m p l e xs y s r e m s .
Theyeach
requrrea crirical levelof complexityor inreraction
to achieve
L U I SP .V I L L A R R 8 A
i sId i r e c t o o
r f t h e C e n t e r f o r V i r uRse s e a r c h
their respective
srates.
A neuronby itself,or e\.enrn a netlvork
a t t h e U n i v e r s i t go f C a l i f o r n i al r, v i n e H
. ew a s b o r ni n E a s tL o s
of nerves,is not conscious-rvho[e
braincomplexrtyis needed.
A n g e l e sH. er e c e i v e dh i sd o c t o r a t ei n b i o l o g gf r o mt h e U n i v e r Yet evenan intacr human brain can be biologicallyalive
but
s i t g o f C a l i f o r n i aS, a n0 i e g o ,a n dd i dp o s t d o c t o r ar le s e a r c hi n
incapable
of consciousness,
Similarly,neirher
or ,.brain-dead.',
v i r o l o g ga t S t a n f o r dU n i v e r s i t w
g i t h N o b e l a u r e a t eP a u lB e r g .
cellularnor viral individualgenes
or proteinsareb1.rhemselves
H ei s a c t i v ei n s c i e n c e d u c a t i oann dh a sr e c e i v e ad N a t i o n a l
a l i v e .T h e e n u c l e a r ecde l l i s a k i n r o t h e s t a r eo f b e i n gb r a i n _
S c i e n cF
e o u n d a t i oPn r e s i d e n t iA
aw
l a r df o rm e n t o r i n gl n. h i sc u r dead,in thar it lacksn fullcriticalcomplexir;-.
A virus,too, fails
r e n tp o s i t i o nV, i l l a r r e a
h la se s t a b l i s h epdr o g r a mfso r t h er a p i d
to reacha criticalcorrrplexiry.
Solifeitselfis an emergenr,
comd e v e l o p m e notf d e f e n s e a
s gainsb
t ioterrorism
t h r e a t sH
. eh a s
state'Dutrt ls nt;rdefrom rhesamefundamenral,physical
Ple.Y
t w o s o n sa n de n j o g sm o t o r c g c l easn dL a t i nm u s i c .
www.sciam.com
s c l E N T r Fl ur ce n r c l H 1 0 3
"Attentionof biologistswa-g
.
establishedfrontier betrveenvirusesand parasiticcellular
organisms."
q.c6itlltg
distractedfor n.eQrlU
b q a r q u m e n tos v e rw h e t h e r
".rr.:
l m p a cot n E v o l u t i o n
_
virusesareoiganisms:
The.."
disagreement
stemstarge!g
;
fromthegeneralization
piit
.
f o r t hi n t h el a t t e rh a l fo f t h en i n e t e e nct he n t u f g
t h a tc e l l sa r et h e b u i l d i nbgl o c k o
s f a l ll i f e V
. iruses
''
a r es i m p l etrh a nc e l l ss, o ,t h el o g i cg o e sv,i r u s b s'
c a n n obt el i v i n go r g a n i s mTsh. i sv i e w p o i ns te e m s
b e s td i s m i s s eads s e m a n t idco gw a g g i nbgg
t h et a i l so f d o g m a . "
, ; : : .,
-Am eri con evolutionorgbiologist PoulEwaId, 2000
analysisof the virr.rsrevealednumerousgenespreviously
thought to exist only in cellularorganisms.Someof these
genesare involved in making the proteinsencodedby the
viral DNA and may make it easierfor N{imivirusto co-opr
host cell replicationsystems.As the researchteam notedin
i t s r e p o r t i n t h e j o u r n a l S c i e n c et,h e e n o r m o u sc o m p l e x ity of the Mimivims's geneticcomplement"challengesthe
D E B A T E So v E R w H E T H E Rt o l a b evl i r u s e as sl i v i n gl e a d
naturallyto anotherquestion:Is ponderingthe sta'tusof virusesas living or noniivingmorethan a philosophicalexercise,thebasisof a livelyand heatedrhetoricaldebatebut rvith
I think theissueis important,because
little realconsequence?
regardthis questioninfluences
their thinking
horv scientists
of evolution.
aboutthe mechanisms
history,datViruseshavetheirorvn,ancientevolutionary
ing to the very origin of cellularlife. For example,somevidamaged
ral-repairenzymes-whichexciseand resynthesize
DNA, mendoxygenradicaldamage,and so on lseebox be'
low)-are uniqueto certainvirusesand haveexistedalmost
unchangedprobablyfor billionsof years.
mostevolutionarybiologistshold that beNevertheless,
causevirusesarenot alive,theyareunrvorthyof seriousconsiderationwhen trying to understandevolution.They also
look on virusesas coming from host genesthat sorirehorv
the hostandacquireda proteincoat.In this view,viescaped
into pararusesarefugitivehostgenesthat havedegenerated
sites.And with virusesthus dismissedfrom the web of life,
i m p o r t a n tc o n t r i b u t i o n st h e ym a 1h' a v em a d et o t h e o r i g i n
of life may go unrecognized.
and the maintenance
of species
f r o mt h e
1 0 4 s c r e H r r FAt cM E R t c A N
O E C E M E 2EO
RO 4
(Indeed,only four of the 1,205pagesof the 2002volumeThe
Encyclopediaof Euolutionaredevotedto viruses.)
Of course,evolutionary
biologists
do not denythar viruses
havehad somerolein evolution.But by viewingvirusesasinanimate,theseinvestigators
placethem in the samecaregory
of influences
as,say,climatechange.Suchexrernalinfluences
selectamongindividualshavingvlried, genetically
controlled
trairs;thoseindividualsmostableto surviveand thrive lvhen
facedwith thesechallenges
go on to reproducemosr successfully and hencespreadtheir genesto fr'rturegenerations.
But virusesdirectlyexchangegeneticinformation with living organisms-thatis,rvithintheweb of life itself.A possible
surpriseto mostphysicians,
andperhapsto mostevolutionary
biologistsas well, is that mostknown virusesare persistent
and innocuous,not pathogenic.They take up residencein
cells,wherethey may remaindormantfor longperiodsor take
advantageof the cells'replicationapparatusto reproduceat
a slorvand steadyrate.Theseviruseshavedevelopedmany
cleverwaysto avoiddetectionby the hosr immune sysremessentially
everystepin the immuneprocesscan be alteredor
controlled by variousgenesfound in one virus or anorher.
Furthermore,a virus genome(the entirecomplementof
DNA or RNA) canpermanentlycolonizeirs host, adding viral genesto host lineagesand ultimatelybecominga crirical
part of the host species'genome.Virusesthereforesurelyhave
effectsthat are fasterand more direct than those of external forcesthat simplyselecramongmore slowly generated,
internalgeneticvariations.The hugepopulationof viruses,
combinedrvith their rapid ratesof replicarionand muration,
makesthemthe rvorld'sleadingsourceof geneticinnovation:
they constantly"invent" new genes.And uniquegenesof viral
origin may travel,6ndingtheirway into otherorganismsand
contributingto evolutionarychange.
Data publis[edby the InternationalHuman GenomeSequencingConsortiumindicatethat somelvhere
betrveen113
and223 genespresenrin bacteriaand in the human genome
are absentin well-studiedorganisms-suchas the yeastSaccharomycescereuisiae,the fruit fly Drosophila melanogaster and the nematode Caenorbabditiselegans-that lie in
betrveenthosetwo evolutionaryextremes.Someresearchersthoughrthat theseorganisms,which aroseafter bacteria
but beforeverrebrates,
simplylost the genesin questionat
somepoint in their evolutionaryhistory. Others suggested
that thesegeneshad beentransferreddirectly to the human
lineageby invadingbacteria.
My colleagueVictor DeFilippisof the Vaccineand Gene
Therapy Institute of the OregonHealth and ScienceUniversity and I suggested
a third alternative:virusesmay originate
genes,then colonizetwo differentlineages-for example,bacteria and vertebrates.
A geneapparentlybestowedon humaniry by bacteriamay havebeengivento both by a virus.
philip Bell of MacIn fact, along with other researchers,
quarieUniversityin SydnenAustralia,and I contendthat the
cell nucleusitself is of viral origin. The adventof the nucleus-which differentiateseukaryotes(organismswhose cells
w w r Y . sc i a m . c o m
containa true nucleus),includinghumans,from prokaryotes,
suchas bacteria-cannotbe satisfacrorily
explainedsolelyby
thegradualadaptationofprokaryoticcellsuntil they became
eukaryotic.Rather the nucleusmay have evolvgdfrom a persistinglargeDNA virus that madea permanenrhome rvirhin
prokaryotes.
Somesupportfor this ideacomesfrom sequence
data showingthat the genefor a DNA polymerase(a DNAcopyi_ng
enzyme)in the viruscalledT4, which infectsbacteria,
is closelyrelatedto other DNA polymerasegenesin both eukaryotesand the virusesthar infectrhem. PatrickForrerreof
theUniversityof Paris-Sudhasalsoanalyzedenzymesresponsiblefor DNA replicationandhasconcludedthat the genesfor
suchenzymesin eukaryotesprobablyhavea viral origin.
From single-celled
organismsro human populations,virusesaffectall life on earth,oftenderern'rining
rvhatrvill survive.But virusesthemselves
alsoevolve.Nerv viruses,suchas
the AIDS-causingHIV-1, may be the only biologicalentities
that researchers
can actuallyrvitnesscomeinro being,providing a real-timeexampleof evolurionin action.
Virusesmatter to life. They are the consrantll'changing
boundaryberrveenthe rvorldsof biology and biochemistry.As
we continueto unravelthegenomes
of more and more organisms,the contributionsfrom rhis dynamic and ancienrgene
pool shouldbecomeapparenr.Nobel laureateSalvadorLuria
musedabout the viral influenceon evolurionin 1959. "May
we not feel,"helvrote,"that in thevirrrs,in theirmergingwith
the cellulargenomeand reemergingfrom them, lve observe
the units and processwhich, in the courseof evolution,have
createdthe successful
geneticparternsthat underlieall living
cells?" Regardless
of whetheror not we considervirusesto be
alive,it is time to acknowledgeand study them in their natural
context-within the web of life.
sr
V i r a l Q u a s i s p e c i c s .M a n f r e d E i g e ni n S c i e n t r y ' cA m e r i c o n ,V o l . 2 6 9 ,
N o .1 , p a g e s4 2 - 4 9 ; J u l g 1 9 9 3 .
D N A Y i r u sC o n t r i b u t i o nt o H o s t E v o l u t i o n L. .P .V i l l a r r e ailn 0 r i g i n o n d
t v o l u t i o no f V i r u s a sE
. d i t e db g E .O o m i n g oe t a l .A c a d e m i cP r e s s ,1 9 9 9 .
L a t e r a l6 e n e T r a n s f e ro r V l r a l C o l o n i z a t i no ? V i c t o rD e F i l i D o ai sn dL o u i s
V i l l a r r e ailn S c i e n c eV, o l . 2 9 3 ,p a g e1 0 4 8 ;A u g u s t1 0 , 2 0 0 1 .
V i r u s e sa n d t h e E v o l u t i o no f L i f e .L u i sV i l l ar r e a l .A SM P r e s s( i n p r e s s l .
A l l t h eV i r o l o g go n t h e W W Wi s a t w w w . v i r o l o g g . n e t
s c r E N T r r r c l v e n r1c0l 5N