Table Of ContentThe Philosophy of
Biology
Mechanisms in
Molecular Biology
Tudor M. Baetu
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ElementsinthePhilosophyofBiology
editedby
GrantRamsey
KULeuven
MichaelRuse
FloridaStateUniversity
MECHANISMS IN
MOLECULAR BIOLOGY
Tudor M. Baetu
Université du Québec à Trois-Rivières
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Mechanisms in Molecular Biology
ElementsinthePhilosophyofBiology
DOI:10.1017/9781108592925
Firstpublishedonline:September2019
TudorM.Baetu
UniversitéduQuébecàTrois-Rivières
Authorforcorrespondence:TudorM.Baetu,[email protected]
Abstract:Thenewmechanisticphilosophyisdividedintotwolargely
disconnectedprojects.Onedealswithametaphysicalinquiryintohow
mechanismsrelatetoissuessuchascausation,capacities,andlevelsof
organization,whiletheotherdealswithepistemicissuesrelatedtothe
discoveryofmechanismsandtheintelligibilityofmechanistic
representations.TudorM.Baetuexploresandexplainstheseprojects,
andshowshowthegapbetweenthemcanbebridged.Hisproposed
accountiscompatiblebothwiththeassumptionsandpracticesof
experimentaldesigninbiologicalresearch,andwithscientifically
acceptedinterpretationsofexperimentalresults.
Keywords:mechanism,newmechanisticphilosophy,biology,philosophyof
science,philosophyofbiology
©TudorM.Baetu2019
ISBNs:9781108742306(PB),9781108592925(OC)
ISSNs:2515-1126(online),2515-1118(print)
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Contents
1 MechanismsandTheirDiscovery 1
2 WhatIsaPhenomenon? 7
3 HowDoMechanismsandPhenomenaRelatetoOne
Another? 22
4 WhatIsthePhysicalNatureofBiologicalMechanisms? 39
ARecapitulationandSomeClarifications 62
References 66
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MechanismsinMolecularBiology 1
1MechanismsandTheirDiscovery
1.1MechanismsandMechanisticExplanations
Manyexplanationsinbiologytellushowphenomenaareproducedasaresult
ofchangesandinteractionsamongthevariouspartsofaphysicalsystem.Such
systems of parts changing over time are commonly known as ‘mechanisms’,
whilethemore-or-lessdetaileddescriptionsofthesesystemsandtheseriesof
changestheyundergoarereferredtoas‘mechanisticexplanations’.
Ifthereaderisleftwonderingwhataphenomenonisandhowamechanism
explains it, a concrete example may help. Biologists take reproducible
sequencesofevents,wherebyexposureofabiologicalsystemtoastimulusis
consistentlyfollowedbyasimilarkindofresponse,tobephenomenainneedof
anexplanation(Figure1).Takesunburns,forexample.Prolongedexposureto
ultravioletradiationconsistentlyresultsinapronouncedrednessandswelling
of the skin. Since this sequence of events can be consistently reproduced in
humans and many other animals, it is unlikely to be just a coincidence. It is
somethingthatdemandsanexplanation.
Sunburns belong to a family of related phenomena of great clinical impor-
tance known as inflammatory responses. These responses are triggered by
a wide variety of harmful stimuli, including radiation, tissue damage, patho-
gens,andantigens,andtypicallyconsistoffivedirectlyobservablesymptoms:
erythema (redness), edema (swelling), pain, heat, and loss of function (e.g.,
immobility).Inmostcases,inflammatoryresponsesshutdownafterthethreat
has been eliminated or the harmful stimulation has subsided, which is highly
desirablesince aprolongedorchronicinflammatoryresponsehasdetrimental
consequencesfortheorganism.
Much research in immunology and medicine has been devoted to finding
out how – that is, by means of which mechanisms – inflammatory responses
are produced. Since my goal is simply to give the reader an idea of what a
mechanisticexplanationmaylooklike,Iwillfocusononeofthebetterunder-
stoodmechanismsinvolvingatypeofwhitebloodcellsknownasT-cells.By
theendofthe1980s,ithadbeenestablishedthat,whenanorganismisexposed
toharmfulstimuli,T-cellsbeginsecretingavarietyofmoleculesnecessaryfor
mountinginflammatoryresponses.Thus,onekeyresearchquestionwastofind
outhowT-cellsareactivated.ThemolecularunderpinningsofT-cellactivation
turned out to revolve around a couple of regulatory DNA-binding proteins,
oneofwhichisthetranscriptionalfactornuclearfactorκB,orNF-κBinshort
(Sun et al. 1993). In resting T-cells, NF-κB is trapped in the cytoplasm by
a protein known as inhibitor of NF-κB, or IκB. When cells are exposed to
harmful stimuli (Figure 2A), however, a chain of protein–protein interactions
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2 ElementsinthePhilosophyofBiology
Figure1Inflammatoryresponsesasphenomenatobeexplained
leadstothedissociationofinactiveIκB/NF-κBcomplexes(B).NF-κBisfreed
(C)andcannowmovetothenucleus,whereitbindsspecificDNAsequences
andenhancestheexpressionofanumberofgenes,manyinvolvedinimmune
responses(D).Thisresultsinavarietyofnewproteinsbeingmanufacturedin
the cell, such as the cyclooxygenase-2 (COX-2) enzyme, which catalyzes the
synthesis of prostaglandins. Once secreted in the bloodstream, prostaglandins
promote vasodilation, which is responsible for erythema and edema (redness
and swelling of the skin); sensitize spinal neurons to pain; and act on the
thermoregulatorycenterofthehypothalamustoproducefever(E).
We can now form a general idea about how inflammatory responses are
initiated when organisms are exposed to harmful stimuli. What is missing is
an explanation of how the responses shut down. It was eventually discovered
thatNF-κBalsoenhancestheproductionofitsowninhibitor,IκB.Thenewly
synthesized IκB binds NF-κB, trapping it back in the cytoplasm (F).
ProstaglandinstoocurbNF-κBactivitybyinterferingwiththesignalingpath-
wayleadingtothedegradationoftheinhibitoryproteinIκB(G).Thus,follow-
ing stimulation, T-cells are initially activated, resulting in an inflammatory
response, then are automatically turned off by means of a negative feedback
loop molecular mechanism, which performs a function analogous to that of
acommonthermostat.
The above explanation is in many respects incomplete. For instance, it is
not specified how prostaglandins cause the symptoms of inflammation.
Quantitative-dynamic details are also missing. The explanation doesn’t say
anything about the duration of the inflammatory response or whether cyclical
inflammatory responses are generated in response to persistent stimulation.
Finally,somefamiliaritywithchemistryistacitlyassumed,suchasthenotion
thatprotein–proteinandprotein–DNAinteractionsareweakerformsofbinding
incomparisontothecovalentbondsholdingmoleculestogether.Nevertheless,
despiteassumed,abstracted,andunknowndetails,theabovenarrativeandthe
accompanying diagram should help the reader imagine how inflammatory
responses are produced as a result of a sequence of changes and interactions
involvingvariouscellularandmolecularcomponentsofanorganism.
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MechanismsinMolecularBiology 3
Figure2AsimplifiedrepresentationoftheNF-κBmechanismanditsrolein
regulatinginflammatoryresponses
1.2TheDiscoveryofBiologicalMechanisms
Theelucidationofbiologicalmechanismsoftenbeginswiththeformulationof
hypotheses sketching out possible mechanisms.1 For instance, experimental
results indicating that protein synthesis inhibitors block T-cell activation led
someresearcherstohypothesizethatinflammatoryresponsesrelyonamechan-
ism of genome expression regulation. Initial speculative work is followed by
whatLindleyDarden(2006b,Ch.4)describesasagradualfillinginofmissing
mechanisticdetails.Thisusuallyrequiresasignificantamountofexperimental
research.
Inafirststep,asystemresponsibleforproducingthephenomenonofinterest,
orwhatWilliamBechtelandRobertRichardson(2010,Ch.3)callthe‘locusof
control’, is identified. In practice, this amounts to the characterization of an
experimentalsetupinthecontextofwhichaphenomenoncanbeconsistently
reproduced. Forinstance, the experimental setupused to elucidate theNF-κB
regulatory mechanism consisted mainly of a cell model of T-cell activation.
Normal T-cells extracted from the blood of a healthy donor or precancerous
(‘immortalized’)T-celllinesweregrowninanartificialmediumandstimulated
1 PeterMachamer,LindleyDarden,andCarlCraver(2000,18)defineamechanismsketchas“an
abstractionforwhichbottomoutentitiesandactivitiescannot(yet)besuppliedorwhichcontains
gapsinitsstages.Theproductivecontinuityfromonestagetothenexthasmissingpieces,black
boxes,whichwedonotyetknowhowtofillin.Asketchthusservestoindicatewhatfurtherwork
needstobedoneinordertohaveamechanismschema.”Incontrast,amoredetailedmechanism
schema,suchastheonedepictedinFigure2,isa“truncatedabstractdescriptionofamechanism
thatcanbefilledwithdescriptionsofknowncomponentpartsandactivities...Wheninstantiated,
mechanism schemata yield mechanistic explanations of the phenomenon that the mechanism
produces”(2000,15,17).
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4 ElementsinthePhilosophyofBiology
by the addition of a chemical inducer, such as lipopolysaccharides, a toxin
releasedwhenthecellwallsofcertainbacteriaaredestroyed,andwhichcauses
septicshockunderphysiologicalconditions.
Inasecondstep,variablesdescribingtheexperimentalsetuparetargetedby
experimentalinterventionsinthehopeofdemonstratingthatspecificchangesin
theexperimentalsetupandthephysicalsystemsofwhichitiscomposedresult
in changes in the phenomenon under investigation. For example, the IκB
inhibitor was shown to be part of the regulatory mechanism of T-cell activity
basedonexperimentalevidencedemonstratingthatmutationsinthesequence
of IκB result in a prolonged activation of T-cells following stimulation. Carl
Craver (2007, Chs. 2–3) gives an excellent analysis of the role that causal
relevance plays in the identification of putative mechanistic components. In
particular, he points out that causal relevance is demonstrated by means of
controlled experiments, thus establishing a connection between the scientific
practices involved in the elucidation of mechanisms and James Woodward’s
(2003)interventionistaccountofcausation.
Finally,amechanismmusteventuallybe‘recomposed’inordertoshowhow
itgeneratesthephenomenon(Bechtel2011).Amechanism’srecompositioncan
bephysical,forinstance,aninvitroreconstitution experiment,orconceptual,
such asacomputer simulationorsimply a narrative ordiagramsuch asthose
illustratedearlier.Onewayoranother,thegoalistodemonstratethatcompo-
nentsorganized,acting,andhavingthepropertiesdescribedinthemechanistic
explanationcanproduce,andideallyaresufficienttoproducethephenomenon
underinvestigation.
1.3ExperimentalMethodologyFirst
Inscientificpractice,hypothesisandexperimentation proceed intandem. The
initial characterization of an experimental setup and the choice of variables
targeted for intervention are motivated by existing hypotheses about the
mechanism responsible for a phenomenon. Conversely, experimental results,
suchastheabilityorfailuretoconsistentlyreproducethephenomenon,aswell
as the fortuitous discovery of causally relevant factors, play a key role in the
formulationofnewmechanistichypotheses.
This Element, however, focuses almost entirely on experimental inquiry.2
Therearetworeasonsforthisunusualchoice.Thefirsthastodowiththefact
thatmostphilosophersapproachexperimentalpracticefromtheperspectiveof
2 Perhapsaclarificationisneededhere.WhatImeanby‘experimental’or‘empiricalinquiry’is
experimentalresearchinscience.Experimentalistsapproachhypotheticalexplanationswithan
attitudeof‘suspendedbelief’untiladequatesupportingevidenceisproduced.Beingcautious,
however,isnotthesameasbeingskeptical.Experimentalresearchisasustainedefforttoproduce
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