Table Of ContentC H A P T E R
1
Introduction: The Aims
and Structure of This Book
Thisbookisabouttheshapesoflivingtissuesandbodies.Morespecifically,itisabouthow
these shapes are created as organisms develop from simple fertilized eggs into complex
)
animals and plants. The creationof shape is usually called‘morphogenesis’.
The processes that are responsible for the development of animals and plants can be
divided, for convenience, into three main categories: communication, differentiation and
morphogenesis.
Morphogenesisistheonlyoneoftheseactivitiesthatisobvioustoevenacasualobserver
ofembryosandwasthereforethefirsttobestudied.Indeed,thestudyofmorphogenesisis
oneoftheoldestofallthesciences,datingbacktoancientGreecewhereAristotle(384e323
BCE)describeditsbroadfeaturesinbirds,fishandcephalopods.Evenatthisearlystageof
scientificthinking,heunderstoodthatanegghadthe‘potential’fortheanimal’sfinalform
but that it did not contain a miniature version of the adult.2 Since those days, the deepest
questionsofanimalandplantdevelopmenthavecontinuedtoconcernthecreationofshape
and form. Until very recently, however, the molecular revolution in biology has almost
ignored this most fundamental aspect and has instead concentrated on differentiation and
communication.
It is easy to understand why. The immunologist and philosopher Peter Medawar once
definedscienceas‘theartofthesoluble’,3andlaterwroteanentertainingseriesofessaysunder
that title. This series pointed out the futility of researchers devoting their lives to tackling,
head-on, problems that were simply too difficult to solve by brute force when an intelli-
gently-thought-outseriesofstudiesonrelatedbutsolubleproblemsmightprovideanalter-
native line of attack on the original issue.4 The morphogenesis of a tissue is a formidably
difficult problem, being four-dimensional (three space, one time) and involving the inter-
action of thousands of different molecules. This makes it much more complicated to study
at a mechanistic level than either differentiation or communication. Differentiation can be
)
FromtheGreekrootsmorph,meaning‘form’,andgenesis,meaning‘creation’.AsWaddingtonexplained
almosthalfacenturyago,1‘Theword“morphogenesis”isoftenusedinabroadsensetorefertomany
aspectsofdevelopment,butwhenusedstrictlyitshouldmeanthemouldingofcellsandtissuesintodefinite
shapes’.Thisbookusesthetermstrictly.
MechanismsofMorphogenesis,SecondEdition
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4
1. INTRODUCTION:THEAIMSANDSTRUCTUREOFTHISBOOK
studiedusingsimpleassaysforgeneexpressionsuchasNorthernblots,PCRbandsormicro-
arrays,andthecontrolofgeneexpressioncanbeinvestigatedbymutatingaone-dimensional
length of DNA and monitoring the effects; much of this work can even be done in cell-free
systems. Communication can be studied by grafting pieces of embryo to identify the pres-
ence of signalling events, and then testing the ability of candidate signalling molecules to
drive developmental events by removing the candidates or applying them ectopically.
Eventheseexperiments,whichuselimitednumbersofcomponentsandusuallysimpleassay
systems,canbedifficultandtime-consuming.However,whenperformedwell,theyusually
generate clear and unambiguous results. For this reason, study of differentiation and
communication has dominated developmentalbiology in the molecularera.
Theresultofthishasbeenavastlyimprovedknowledgeofhowplantsandanimalsdevelop
aswellasanewunderstandingofthemolecularbasesofhumancongenitaldisease.Thebest
textbooksofthepre-moleculareraweredominatedbydescriptiveembryologyandbyspecu-
lationaboutmechanisms,thisspeculationbeingbasedmainlyonextrapolationfromunusually
tractablebutdangerouslydistantmodels(suchasgenecontrolinviruses).Thesebooks,which
providedthefoundationsonwhichprogramsofmolecularbiologycouldstand,havebeensuc-
ceededinrecentyearsbylargeandsolidworksfullofwell-establishedmechanismsofsignal-
ling,patternformationandgenecontrol.5,6,7,8Readersundertheageofabout45willnodoubt
havebeenguidedintodevelopmentalbiologybyoneoftheseexcellentvolumes.
Whathasbeengainedhasbeenatriumph,butithascreatedatemporaryimbalanceinthe
fieldofdevelopmentalbiology.Thespotlightofdevelopmentalbooksandreviewvolumesis
usuallyfocusedonthemolecularbiologyofgenecontrolandpatternformation.Morphogen-
esis, the deep developmental question that held centre stage of embryological thought for
overtwomillennia,hasbeensomewhateclipsed.Thisshowsupinseveralways.Mostobvi-
ously, it shows up in the proportion of pages that current texts devote to molecular mech-
anisms of morphogenesis, compared with those devoted to other aspects of developmental
biology;inthecurrentlypopularandexcellentgeneraltextbooksofdevelopmentalbiology,
thisproportionisgenerallylessthan10percentandissometimesclosetozero.Thetakingfor
grantedofmorphogenetic mechanismsalsoshows up,moresubtly,in the‘blobandarrow’
diagramsoftenusedtosummarizedevelopmentalpathways.Thesetendtoshownumerous
arrowsbetween genes and promoters and signalling pathways that set up the controllogic
foradevelopmentalevent.Thesearrowsthenpointto‘blackboxes’inwhichtheactualmor-
phogenesisdthe point of all that lies above them in the diagramdactually takes place
(Figure1.1).Thereasonfortheblackboxesisobvious;forthemostpartmorphogenesisstill
is a ‘black box’, the inner workings of which remain mysterious. And, lest I have offended
anyonebythecommentsinthisparagraph,Istressthatmanyofmyownreviewsonorgan
development9,10,11,12,13,14 have been as full of black boxes that stand for morphogenesis as
anyone else’s have been, for the same reason.
The approach to ‘insoluble’ problems that was recommended by Medawar is, however,
starting to pay off. When molecular biological techniques were first applied to embryonic
development, it would have been impossible to solve the problems of morphogenesis
directly. Even where the reasonableness of hypothetical mechanisms could be confirmed
by computer modelling (see Chapter 26), it was generally not possible to verify them in
realdevelopingsystems.Thegreatadvancesinourunderstandingofthemoleculargenetics
of development and of the biochemistry of cell signalling may have unbalanced
I.INTRODUCTORYSECTION
5
1.INTRODUCTION:THEAIMSANDSTRUCTUREOFTHISBOOK
FIGURE 1.1 A typical develop-
GDNF HGF TGFa FGFs TGFb Activin BMPs mental ‘blob and arrow’ diagram, in
whichsignallingeventsaredepictedin
detailbutmorphogenesisistreatedas
ablackbox.Thisparticulardiagramis
Ret Met EGFR FGFR TGFR ActR BMPR adaptedfromoneofmyownsummar-
ies of processes that control renal
development.10
Erk MAPK
Smad2/3 Smad1
Branching
morphogenesis
developmentalbiologytemporarily,buttheyhaveallowedresearcherstocreatetoolsthatare
powerfulenoughtobeappliedfruitfullytomorphogenesisitself.Veryrecently,mainlyinthe
21stcentury,theapplicationofthesetoolshasbeguntotransformourunderstandingofhow
cells can translate a ‘command’ to make a shape into that shape itself. The long-sought
molecular mechanisms of morphogenesis arenow being glimpsedfor the first time.
The purpose of this book is to bring together in one place some of the most significant
advancesthathavebeenmadeinidentifyingmechanismsofmorphogenesisfromavariety
of species, systems and scales. The field is at too young a stage for the book to be able to
present a complete, rounded story. Rather, it provides examples of the mechanisms that
have been found, or are strongly suspected, to drive the types of morphogenetic event
most common in animal and plant development. The order of chapters in the book does
notfollowtheorderofeventsinthedevelopmentofanyparticularorganism,butisinstead
organized approximately by scale. It begins with the self-assembly of supramolecular
complexes, which is the foundation on which everything else rests. It then considers the
morphogenesis of individual cells and works mainly upwards in size towards the scale of
tissues. This order has been chosen carefully, because the morphogenetic mechanisms
describedinlaterchapterstendtoinvoke,and‘takeforgranted’thefine-scale mechanisms
describedinearlierchapters.Cross-referencesbetweenchaptershavebeenprovided,wher-
ever possible,for readerswhoare‘dipping’ratherthan reading cover to cover.
As well as concentrating on the molecular biology of morphogenetic mechanisms, this
book lays some stresson themore abstractprinciples that seem to beemerging from them.
There are two reasons for this. The first is that it is easier for an author to present, and for
areadertounderstand,detailedmolecularinformationwhenthereisaframeworkonwhich
itcanbeorganized.Thesecondisastubbornbeliefonthepartoftheauthorthattheremust
bemoretounderstandingbiologythanalotofdiagramswithblobsandarrows.Theissueof
‘understanding’ morphogenetic mechanisms is discussed further in Chapter 28. The prin-
ciples that run most pervasively through this book are introduced in Chapter 2; readers
intendingonlytodipintothesectionsofthisbookthataremostrelevanttothemareencour-
aged to lookat Chapter2 first,becauseit willdefine terms used in laterchapters.
I.INTRODUCTORYSECTION
6
1. INTRODUCTION:THEAIMSANDSTRUCTUREOFTHISBOOK
This book is absolutely not intended to compete with the general texts on development
mentionedabove.Astheysetouttheprocessesofdifferentiationandsignallingandpattern
formation in greatdetail and take morphogenesis somewhat forgranted, this book concen-
trates solely on mechanisms of actual morphogenesis and takes all of the differentiation
andpatterningmechanismsthatcontrolitforgranted.Thedecisiontofocusonlyonmorpho-
)
genesis itself was made to keep the length of this volume reasonable and its price down,
and because other authors will have already discussed the many aspects of development
far better than I could. Most readers will already have a sophisticated understanding of
the genes and signalling aspects of modern developmental biology anyway; it is my hope
thatthisbookwillhelpthemintheireffortstolinktheseaspectstothemechanismsthatactu-
ally generate shape.
Reference List
1. WaddingtonCH.Principlesofembryology.GeorgeAllen&Unwin;1956.
2. RonanCA.Cambridgehistoryoftheworld’sscience.CambridgeUniversityPress;1983.
3. MedawarPB.Actofcreation.NewStatesman;1964.
4. MedawarPB.Theartofthesoluble.Methuen;1967.
5. GilbertSF.Developmentalbiology.9thed.Sinauer;2010.
6. WolpertL,TickleC.Principlesofdevelopment.4thed.OxfordUniversityPress;2011.
7. AlbertsB,BrayD,LewisJ,RaffM,RobertsK,WatsonJD.Molecularbiologyofthecell.5thed.2008.Garland.
8. SlackJMW.Essentialdevelopmentalbiology.3rded.Wiley-Blackwell;2012.
9. DaviesJ.Intracellularandextracellularregulationofuretericbudmorphogenesis.JAnat2001;198:257e64.
10. Davies JA. Do different branching epithelia use a conserved developmental mechanism? Bioessays 2002;24:
937e48.
11. DaviesJA,BardJB.Thedevelopmentofthekidney.CurrTopDevBiol1998;39:245e301.
12. DaviesJA,FisherCE.Genesandproteinsinrenaldevelopment.ExpNephrol2002;10:102e13.
13. DaviesJA.Branchingmorphogenesis.LandesBiomedical2004.
14. BarnettMW,FisherCE,Perona-WrightG,DaviesJA.Signallingbyglialcellline-derivedneurotrophicfactor
(GDNF)requiresheparansulphateglycosaminoglycan.JCellSci2002;115:4495e503.
)
Awishtomakethisbookaffordableisalsothereasonthatitisillustratedbydrawingsratherthanfull
colourmicrographs.
I.INTRODUCTORYSECTION
C H A P T E R
2
Key Principles of Morphogenesis
The advancement of developmental biology depends on facts about real organisms,
acquired by painstaking experimentand carefulobservation. Noscience, however, consists
offactsalone;onlywhenhard-wonknowledgeissynthesizedintoprinciplescanresearchers
hopetoreachsomethingthatdeservestobecalled‘understanding’.Principlesserveseveral
functions; they unite a body offactual knowledge into something concise enough to grasp,
they assist with the design of insightful experiments, they help to provide a framework for
the presentation and evaluation of new discoveries and, when the principles are not too
vague,they can beused to make testablepredictions.
Therearetwobroadtheoriesabouthowprinciplesariseinscience.Inoneview,tradition-
allyassociatedwithFrancisBaconbutmorefairlyattributabletoacombinationofWilliamof
Ockham and John Stuart Mill,1 experiments come first and principles emerge later from
consideration of their results. In the other view, traditionally associated with Karl Popper,
hypothesesaboutprinciplescomefirstandtheroleofexperimentsistoattempttodisprove
them.2,3 Biology operates in both Baconian and Popperian modes4 and can switch between
the two many times even during the course of a single project. It is common, for example,
for the phenotype of a random mutant to suggest a new idea in the Baconian manner, and
then for that idea to be tested by experiment in the Popperian manner. This dual mode of
thinking, used by almost all biologists whether they are explicitly aware of it or not, poses
adilemmafor theauthorofatextbook:shouldthepresentationofaconceptualframework
followthepresentationofexperimentaldata,orvice-versa?Discussingconceptsonlyafterthe
data have been presented would enable a reader to assess their meaning with an unbiased
mind rather than through the filter of principles that may turn out to be fallacious. Experi-
mentalresultsare,however,mucheasiertopresentandtoreadinthecontextofaconceptual
framework, if only because such a framework can help to explain why there is a point to
discussingaparticularexperimentinthefirstplace.Thisbookthereforeattemptsacompro-
misebetweenthetwostrategies.Thischapterandthenextwillsetoutsomekeyconceptsof
morphogenesisinthebroadesttermsbecausetheseconceptssettheagendafor,andareused
manytimesby,thechaptersthatconstitutetheexperimentalcoreofthebook.Chapter28,at
the end of the book, will then discuss the principles in moredetail, in light of the data that
will by then have been described.
Thekeyconceptsthatareintroducedbrieflyinthischapteraretheideaofa‘mechanism’,
the principle of emergence, the use of feedback, and the differences between self-assembly
and adaptiveself-organization.
MechanismsofMorphogenesis,SecondEdition
http://dx.doi.org/10.1016/B978-0-12-391062-2.00002-4 7 Copyright(cid:1)2013ElsevierLtd.Allrightsreserved.
8
2. KEYPRINCIPLESOFMORPHOGENESIS
THE IDEA OF ‘MECHANISM’
Theword‘mechanism’,asusedthroughoutthisbook,connotesasequenceofeventsthat
take place at a molecular level and that can be explained by interactions of molecules that
followtheordinarylawsofphysicsandchemistry.Mechanism,inthissense,istheantithesis
ofvitalism.Thereisno‘bio-‘prefixtothewords‘physics’and‘chemistry’inthefirstsentence
ofthisparagraphbecausethereisnoneedforone;thebiologicalcharacterofmorphogenetic
mechanismsliesnotintheindividualinteractionsoftheirmolecularcomponentsbutcomes
fromtheelaboratesystemsoffeedbackthatregulatewhereandwhenthoseinteractionstake
place.Thisemergenceofbiologicalcharacterfromsimplephysicsisdiscussedfurther,later
in thischapter.
Oneofthekeyrequirementsofamolecularmechanism,asthetermisusedinthisbook,is
thatitmustinvolveonlylocalinteractions,formoleculescanbeaffectedonlybyeventsthat
)
take place at their surfacesand they cannot, generally, be affected by action-at-a-distance.
This point is stressed here because traditional embryology has often used the concept of
gradients within a ‘morphogenetic field’ to explain particular aspects of development. The
ideas of morphogenetic gradients and fields5e8 are very useful for providing a high-level
viewofeventsbuttheycannotbeapartofamolecular-levelexplanationbecauseagradient
is,bydefinition,non-localandcannotbesenseddirectlybyasinglemolecule.Atagivetime,
a single receptor molecule will either be binding one of the molecules involved in the
gradientorwillnot,thatisall.Agradientmaybeabletobesensedbyasystemofinteracting
molecules but, to explain the mechanism of such a system, one has to focus on the purely
localinfluenceswithinit.Theseareallthatamoleculecansense.Forthisreason,high-level
conceptssuchasclassicalmorphogeneticfieldsareusefulforconsideringlarge-scaleorgan-
ization in the embryo but they do not belong in a molecular-level discussion. The more
mystical definitions of morphogenetic fields that have been offered by writers such as
Sheldrake9 areeven less relevantto the mechanistic explanations being sought here.
The quest for ‘mechanisms’ of morphogenesis therefore aims to account for the shape
changes at the scales of cells and tissues in terms only of events that take place at the scale
of individual molecules. A simple listing of molecular interactions is not enough, though,
becauseanunderstandingofmechanismcanbeobtainedonlywhenthepathwaysofcontrol
that regulate the behaviourof the components have also been identified and characterized.
This book therefore uses the word ‘mechanism’ to refer to a combination of the molecular
interactions that directly result in shape, of other molecular interactions that control them,
and ofthe principlesof controlthat areinvolved.
EMERGENCE
Emergence is one of the most important concepts in the study of morphogenesis, and
indeedindevelopmentalbiologyasawhole.Emergence,whichcropsupinfieldsasdiverse
)
Electricfieldsareanexceptiontothisgeneralizationthatmaybeimportantinmorphogenesis;theirrolein
developmentisdiscussedinChapter10.Gravitationalandmagneticfieldstowhichembryosarenormally
subjectedareveryweakandhaveanegligibleeffectonthebehaviourofindividualmolecules.
I.INTRODUCTORYSECTION
9
EMERGENCE
as cell biology, neuroscience, information theory, robotics, ecology, game theory, economics
andeventownplanning,10,11doesnotyethaveasinglerigorousdefinition.Thevariousdef-
initionsthathavebeenofferedareallconnectedwiththeconceptofsomethingbeing‘more
than the sum of its parts’. The aspect of emergence that is most relevant to understanding
embryonic development is that very complex behaviours can emerge from the action of
very simple operations and, by extension, very complex forms can emerge from the action of
comparatively simple machines.
Anentertainingillustrationoftheseaspectsofemergence,onethatisaccessibletoanyone
withacomputer,isprovidedbyConway’s‘GameofLife’.The‘GameofLife’isacomputer
simulationofacellularautomaton.Itisnotmeanttobeanaccuratemodelofanykindofreal
celldmodels of real systems are discussed in Section 6 (Modelling Morphogenesis) of this
bookdbutratherprovidesanintellectualsandpitinwhichscientistscanplaywithanimpor-
tantidea.The‘playingarea’ofthegameconsistsofasquaregridoflocations,eachofwhich
)
canbeemptyoroccupiedbyonelivingcell. Theinitialpatternofoccupancyissetupmanu-
ally,andthegamethenbegins.Time,intheworldofthegame,isdividedintointervalsthat
areseparatedbytheticksofamasterclock.Ateachtick,thepatternofoccupancyforthenext
timeintervalisdeterminedbythepatternofoccupancyinthepreviousinterval,accordingto
the followingsimple rules:
1. Acell that has fewer than two neighbours dies from lack of trophicsupport.
2. Acell that has fourormoreneighbours diesfromovercrowding (forexample,through
build up oftoxins).
3. Ifexactlythreecellsareneighboursofanemptylocation,oneofthemdividessothatone
daughterstays wherethe mother was and theotheroccupies thepreviouslyempty
location (since mothers and daughtersareinstantly equivalent,it makesno difference
whichof thecellsis considered to have divided).
In each of these rules, a ‘neighbour’ must be in any of the eight locations that border
a given location (Figure2.1).
Thebestwaytogainafeelingforthegameistoplayit,usingoneofthemanyprograms
andappletsthatcanbefoundbysearchingfor‘GameofLife’ontheWeb.Whatisimmedi-
ately apparent is that the three simple rules of the game give rise to very rich behaviour
which, while predictable formally, is far from predictable intuitively. One very simple
exampleofthedevelopmentofasimplefour-cellpatternisshowninFigure2.2:theinitially
asymmetrical pattern acquires symmetry and goes on to develop, via a sequence of inter-
mediatestages,intoanoscillatingarrangementof12cells.Differentstartingconditionsresult
indifferentbehavioursofthesystem.Someinitialpatternsdieout,somesettledownquickly
into stability, while others keep changing for as long as one continues to watch. Fanaticsof
thegamespendmuchtimediscoveringpatternswhosebehaviourisparticularlyinteresting.
One example of interesting behaviour is shown by ‘gliders’, patterns that recreate their
)
Conway’soriginaldescriptionusedtheword‘cell’torefertoalocationonthegridratherthantoits
contents(like‘prisoncell’).Forconsistencywiththerestofthisbook,Ihaveused‘cell’torefertoliving
thingsand‘location’torefertoplaceswhendescribingtherulesofthegame,asmanywebsitesdevotedto
thesubjectalsonowdo.Todescribethegame,Ihavealsotranslatedtherulesintolanguagethatisas
‘biological’aspossible,buthavenotchangedtheiraction.
I.INTRODUCTORYSECTION
10
2. KEYPRINCIPLESOFMORPHOGENESIS
FIGURE2.1 Theconceptof‘neighbours’intheGameofLife.Acellinthelocationmarked‘*’issurroundedby
eightlocations,markedinblue,eachofwhichmightcontainacell.
starting configuration at a location a little displaced from the starting position. Gliders can
therefore move across the playing area forever unless they meet a boundary or collide
with other cells (Figure 2.3). Patterns have even been found that eject streams of gliders,
one after the otherdsuchpatternsarecalled ‘gliderguns’.
TheGameofLifeisobviouslynotmeanttobealiteralsimulationofanyparticularliving
system. Nobody, not even in 1970 when the game was invented, thought that cells really
behavedaccordingtosuchsimplerules.Thegamedoes,however,sharetwoimportantchar-
acteristicswithmostmorphogeneticprocessesinrealbiology.Thefirstisthattheoperationof
the ‘rules’ is strictly local and requires no knowledge of the state of the system as a whole;
each cell senses only the conditions in its immediate neighbourhood. Biological molecules
are affected only by the other molecules with which they make contact and the rules that
govern them are therefore local to the nanometre scale. It is therefore encouraging to see
thatstrictlylocalrulescangeneraterichbehavioureveninartificialsystemsthataresimple
enoughtounderstandcompletely.Thesecondcharacteristicisthatallcellsareequaldinthe
GameofLifethereisnohierarchyandnoonecellisincommandovertheothers.This,again,
is similar to real life; in many systems described in this book, no one cell takes command.
Even in the exceptions, once one drops down to a molecular level, there comes a point
thatallagentsofagiventype(forexample,moleculesofmyosinlightchain)mustbeconsid-
ered as equal in principle so that any special nature of any one molecule emerges from the
behaviourofthesystemasawhole,rather thananin-builtprivilege.Itispreciselybecause
itsharesthesecharacteristicswithrealbiologythat thegameissuchausefulillustration of
I.INTRODUCTORYSECTION
11
EMERGENCE
FIGURE 2.2 Thedevelopmentofasimplefour-cellstartingarrangementintheGameofLife.Thisparticular
arrangementendsinanoscillatingpatternratherthanastablestate.
the power of simple, local processes to create highly complex behaviour. The rules, for
example,saynothingaboutthetranslocationofanythingacrossthefield,yetwiththecorrect
starting conditions, the ‘glider’ in Figure 2.3 moves steadily and forever (or at least until it
reaches a boundary or another group of cells). These observations, which can be made by
anyonewillingtoplayforevenafewminutes,providebothhopeandwarningtoresearchers
who study the development of form in real biological systems. The hope is that, in real
biology as in the Game of Life, the rich variety of shapes may result from mechanisms
they are simple enough to understand. The warning is that underlying mechanisms may
have a structure completely different from that of their result, and identifying these mech-
anisms thereforerequiresbothpersistence and imagination.
FIGURE2.3 A‘glider’:thearrangementoffivecellsappearsagain,fourtickslater,displacedonelocationup
andonelocationtotheright(forthisorientationoftheglider).Inthefigure,theasterisk‘*’marksthesamelocation
inthefirstandlastdiagramstoemphasizethedisplacementofthegliderpattern.
I.INTRODUCTORYSECTION
12
2. KEYPRINCIPLESOFMORPHOGENESIS
EMERGENCE, TRAP-DOOR PROCESSES AND THE DANGERS
OF POST-HOC REASONING
Emergence often involves processes that are analogous to the ‘trap-door’ algorithms
belovedofcryptographers.Trap-dooralgorithmsarethosethatcannotbereversedunambig-
uously.Thisconceptcanbeillustratedwithasimplearithmeticexample:ifoneistoldthatthe
multiplicationproductoftwonumbersis12,onecannotdeducewhatthosenumberswere.
They may have been 1 and12, or 2and6, or 3and 4, or(cid:1)3 and(cid:1)4, or 1/3rdand36, or an
)
infinitenumberofotherpossibilities. Multiplicationisa‘trapdoor’because,onceapairof
numbers has fallen through the process, some information about them is lost. Rule-based
emergent systems such as the Game of Life also involve trap-door functions: knowing that
the result of running a game is a particular arrangement of cells gives no indication of the
original layout of cells (Figure 2.4). This illustrates a very important point in the vastly
more complex emergent systems that constitute real developing embryos: morphogenetic
processes cannot be deduced from final form. Of course hypotheses can be proposed, especially
when a related developmental system is already understood, but these hypotheses must
always be tested by observing and experimenting on the system as it develops. A concrete
exampleofthisisprovidedbytheelongationoftissues,whichisdescribedindetailinlater
chaptersofthisbook.Someelongationeventsaredrivendirectlybyelongationofcellsasthe
tissueelongates,somearedrivenbytherearrangementofcellswithoutanyelongationofthe
cellsthemselves,andsomeinvolveflatteningofcellsbeforetissueelongationtakesplace,fol-
lowedbyareturnofcellstotheirnormalshapeasthetissueelongates.Simplyobservingthat
atissuebecomeslongerdoesnot,therefore,leadonedirectlytothemechanism.Similarambi-
guities areseen atthe molecular level.
This point is stressed because drawing conclusions from post-hoc reasoning has been
a long and dangerous tradition in morphogenetic research. Since the early decades of the
last century, long before the advent of computers, attempts have been to model possible
mechanisms of development mathematically. If the model produced the correct shapes,
the modeller tended to accept the reality of the proposed mechanism. This tendency has
becomemoremarkedascomputershavebecomemoreavailable.Usedproperly,inconjunc-
tionwith experimentalobservation,computermodellingisa veryimportanttool for inves-
tigationofmorphogenesis(and isdiscussedin moredetailin Chapters25and26).Thefact
thatamechanismworksonacomputerisnot,however,itselfstrongevidencethatitworksin
life; usually, many possible mechanisms will produce the ‘correct’ result and only observa-
tion of the real embryo will indicate which is used. Even now, there seem to be far too
many mathematically inclined researchers, usually entering biology from outside, who
miss or ignore thispoint.
FEEDBACK, SELF-ASSEMBLY AND ADAPTIVE SELF-ORGANIZATION
Thedevelopmentofcomplexstructuresisnotuniquetothebiologicalworld.Purelyphys-
icalsystemscangeneraterichpatternsthatrangefromthesub-millimeterscalesofcrystals,
)
Infinitebecause,foranyinteger,n,multiplying12nby1/nwillyieldtheresult12.
I.INTRODUCTORYSECTION
