Paul Nurse - What Is Life

by Understand Biology In Five Steps (pdf)

  Gatheringdatalikethisisimportant,butonlyasafirststeptowardsthecrucial,andmorechallenging, aimofunderstandinghowitallworkstogether.Withthisobjectiveinmind,Ithinkmostprogresswillbe made by looking at the cell as being made up of a series of individual modules that work together to achievelife’smorecomplexproperties.Iusethewordmoduleheretodescribeasetofcomponentsthat functionasaunitinordertoexecuteaparticularinformation-processingfunction.

  By this definition, Watt’s governor would be a ‘module’, one with the clearly defined purpose of controlling the speed of an engine. The gene regulatory system Jacob and Monod discovered for controlling sugar usage in bacteria is another example. In terms of information, they both work in a similar way: they are examples of information-processing modules called negative feedback loops. This kind of module can be used to maintain a steady state, and they are employed widely in bio-logy. They work to keep your blood sugar levels relatively constant, even after you consume a sweet snack like a

  sugar-coateddoughnut,forexample.Cellsinyourpancreascandetectanexcessofsugarinyourblood and respond by releasing the hormone insulin into your bloodstream. Insulin, in turn, triggers cells in your liver, muscles and fatty tissues to absorb sugar out of your blood, reducing your blood sugar, and convertingitintoeitherinsolubleglycogenorfat,whichisthenstoredforlateruse.

  Adifferenttypeofmoduleisthepositivefeedbackloop,whichcanformirreversibleswitchesthatonce turnedonareneverturnedoff.Apositivefeedbackloopworksinthiswaytocontrolthewayapplesripen.

  Ripeningapplecellsproduceagascalledethylene,whichactstobothaccelerateripeningandtoincrease theproductionofethylene.Asaresult,applescannevergetlessripe,andneighbouringapplescanhelp eachothertoripenmorequickly.

  When different modules are joined together, they can produce more sophisticated outcomes. For example, there are mechanisms that produce switches that can flip reversibly between ‘on’ and ‘off’

  states, or oscillators that rhythmically and continuously pulse ‘on’ and ‘off’. Biologists have identified oscillatorsthatworkatthelevelofgeneactivitiesandproteinlevels–theseareusedformanydifferent purposes,forexampletodifferentiatebetweendayandnight.Plantshavecellsintheirleavesthatusean oscillatingnetworkofgenesandproteinstomeasurethepassingoftime,andtherebyallowtheplantto anticipatethestartofanewday,turningonthegenesneededforphotosynthesisjustbeforeitgetslight.

  Otheroscillatorspulseonandoffasaresultofcommunicationbetweencells.Oneexampleistheheart thatisbeatinginyourchestrightnow.Anotheristheoscillatingcircuitofneuronsthatticksawayinyour spinalcord,whichactivatesthespecificpatternofrepeatedcontractionsandrelaxationsoflegmuscles thatallowsyoutowalkataconstantpace.Allwithoutyouhavingtogiveitanyconsciousthought.

  Differentmoduleslinktogetherinlivingorganismstogeneratemorecomplexbehaviours.Ametaphor for this is the way the different functions of a smartphone work. Each of those functions – the phone’s abilitytomakecalls,accesstheinternet,takephotographs,playmusic,sendemailsandsoon–canbe consideredlikethemodulesoperatingincells.Anengineerdesigningasmartphonehastomakesureall thesedifferentmodulesworktogethersothephonecandoeverythingitneedstodo.Toachievethis,they createlogicalmapsthatshowhowinformationflowsbetweenthedifferentmodules.Thegreatpowerof starting the design of a new phone at the level of modules is that engineers can make sure their plans make functional sense, without getting lost in the details of individual parts. That way, they need not initially give too much thought to the huge number of individual transistors, capacitors, resistors and countlessotherelectroniccomponentsthatmakeupeachmodule.

  Adoptingthesameapproachprovidesapowerfulwaytocomprehendcells.Ifwecanunderstandthe cell’sdifferentmodulesandseehowcellslinkthemtogethertomanageinformation,wedon’tnecessarily needtoknowalltheminutemoleculardetailsofhoweachmoduleworks.Theoverridingambitionshould be to capture meaning, rather than simply catalogue complexity. I could, for example, give you a list containing all the different words printed in this book, together with how frequently they occur. This catalogue would be like having a parts list without an instruction manual. It would give a sense of the complexity of the text, but almost all of its meaning would be lost. To grasp that meaning, you need to read the words in the correct order and develop an understanding of how they convey information at higherlevels,intheformofsentences,paragraphsandchapters.Theseworktogethertotellstories,give accounts,connectideasandmakeexplanations.Exactlythesameistruewhenabiologistcataloguesall the genes, proteins or lipids in a cell. It is an important starting point, but what we really want is an understandingofhowthosepartsworktogethertoformthemodulesthatkeepthecellaliveandableto reproduce.

  Analogies derived from electronics and computing, like the smartphone example I used just now, are helpful in understanding cells and organisms, but we must use them with care. The information-processing modules used by living things and those used in human-made electronic circuitries are in somerespectsverydifferent.Digitalcomputerhardwareisgenerallystaticandinflexible,whichiswhy wecallit‘ hardware’.Bycontrast,the‘wiring’ofcellsandorganismsisfluidanddynamicbecauseitis based on biochemicals that can diffuse through water in the cells, moving between different cellular compartments and also between cells. Components can be reconnected, repositioned and repurposed much more freely in a cell, effectively ‘rewiring’ the whole system. Soon, our helpful hardware and software metaphors begin to break down, which is why the systems biologist Dennis Bray coined the insightful term ‘wetware’ to describe the more flexible computational material of life. Cells create connectionsbetweentheirdifferentcomponentsthroughthemediumofwetchemistry.

  Thisisalsotrueinthebrain,thearchetypalandhighlycomplexbiologicalcomputer.Throughoutyour life,nervecellsaregrowing,retractingandmakingandbreakingconnectionswithothernervecells.

  Foranycomplexsystemtobehaveasapurposefulwhole,thereneedstobeeffectivecommunication between both the different components of the system and with the outside environment. In biology, we call the set of modules that carry out this communication signalling pathways. Hormones released into yourblood,liketheinsulinthatregulatesyourbloodsugar,areoneexampleofasignallingpathway,but therearemanyotherstoo.Signallingpathwaystransmitinformationwithincells,betweencells,between organs,betweenwholeorganisms,betweenpopulationsoforganismsandevenbetweendifferentspecies acrosswholeecosystems.

  Thewaysignallingpathwaystransmitinformationcanbeadjustedtoachievemanydifferentoutcomes.

  They can send signals that simply turn an output on or off, like a light switch, but signals can work in more subtle ways too. In some situations, for example, a weak signal switches on one output and a strongersignalswitchesonasecondoutput.Inasimilarwayawhispergetsyourimmediateneighbour’s attention, but a shout is needed to evacuate a whole room in an emergency. Cells can also exploit the

  dynamic behaviour of signalling pathways to transmit a far richer stream of information. Even if the signal itself can only be ‘on’ or ‘off’, more information can be transmitted by varying the time spent in each of those two states. A good an
alogy is Morse code. Through simple variations in the duration and order of signal pulses, the ‘dots’ and ‘dashes’ of Morse code can convey streams of information that overflow with meaning, be it an SOS call or the text of Darwin’s On the Origin of Species. Biological signalling pathways that behave in this way can generate information-rich properties that carry more meaningthansignallingsequencesconveyingasimple‘yes/no’or‘on/off’message.

  Aswellassignallingthroughspace,cellsneedwaystosignalthroughtime.Toachievethis,biological systemsmustbeabletostoreinformation.Thismeansthatcellscancarrywiththemchemicalimprintsof theirpastexperiences,whichwecanthinkofasworkingabitlikethememoriesweforminourbrains.

  Thesecellularmemoriesrangewidely,fromtransientimpressionsofwhathappenedjustamomentago, to the extremely long-term and stable memories held by DNA. The cell uses short-term historical information during the cell cycle, when the status of events that occur early in the cycle are

  ‘remembered’andsignalledforwardtolatereventsinthecycle.Forexample,iftheprocessofcopying DNAhasnotyetbeencompletedorhasgonewrong,thisfactneedstoberegisteredandrelayedtothe mechanisms which bring about cell division. If not, the cell could attempt to divide before its entire genomehasbeenproperlycopied,whichcouldresultinthelossofgeneticinformationandthedeathof thecell.

  Theprocessesinvolvedingeneregulationallowcellstostoreinformationoverlongertimescales.This wasaparticularinterestoftheBritishbiologistConradWaddingtonduringthemid-twentiethcentury.I metWaddingtonatEdinburghUniversitywhenIstartedmypostdoctoralresearchtherein1974.Hewas a striking character, with wide interests in art, poetry and left-wing politics, but he is best known for coining the word epigenetics. He used it to describe the way cells gradually take on more specialized rolesduringthedevelopmentofanembryo.Oncethegrowingembryoinstructscellstocommittothese roles,theyrememberthatinformationandrarelychangetrack.Thatway,onceacellhascommittedto formingpartofthekidney,itwillremainpartofthekidney.

  Today,thewaymostbiologistsusethewordepigeneticsisbasedonWaddington’sideas.Itdescribes thesetofchemicalreactionsthatcellsusetoturngeneseitheronoroffinfairlyenduringways.These epigeneticprocessesdonotchangetheDNAsequenceofthegenesthemselves;instead,theyoftenwork byaddingchemical‘tags’totheDNA,ortoproteinsthatbindtothatDNA.Thiscreatespatternsofgene activity that can persist through the lifespan of a cell and sometimes even longer, through many cell divisions. Occasionally, although far less commonly, they can persist from one generation to the next, potentially carrying information about an individual organism’s life history and experience directly, in chemicalform,fromparentstotheiroffspringandontosubsequentgenerations.Somehavearguedthat the cross-generational persistence of these patterns of gene expression poses a major challenge to the ideathatinheritanceisbasedonlyontheDNAsequencesencodedingenes.However,presentevidence indicates that cross-generational epigenetic inheritance only occurs in a few instances and seems to be veryrareinhumansandothermammals.

  In addition to gene regulation, information processing is important for the ways living beings create ordered structures in space. Take my brimstone butterfly. It is an exquisitely complex construction: the wingsarecarefullyshapedtoallowittofly;therearespotsandveinsplacedonthosewingswithgreat precision.Moreover,allindividualbutterfliesarebuilttothesameplan:theyallhaveahead,thoraxand abdomen, six legs and two antennae, for example. These structures all form and grow in the same predictable proportion to the rest of their bodies. How is all this extraordinary spatial structure generated?Howdoesitallemergefromasingleuniformeggcell?

  Evencellscantakeonarangeofhighlyelaboratestructuresandshapesthatarequitedistinctfrom the regular, box-like cork cells that Robert Hooke described in the seventeenth century and that I observed in onion roots as a schoolboy – there are the comb-like hairs on lung cells, whose constant beating pushes mucus and infections out of your lungs; cube-shaped cells that live in and manufacture your bones; and neurons whose long, branching connections reach all parts of your body; among very manyothers.Andwithinthosecells,theirorganellescanbepreciselylocatedandgrowandadjusttheir positionasthecellchanges.

  Howallofthisspatialorderdevelopsisoneofthemorechallengingquestionsinbiology.Satisfactory answers will depend on understanding how information is signalled through both space and time. At present,weonlyreallyunderstandfullythestructureofbiologicalobjectsthataredirectassembliesof molecules.Theribosomeisagoodexample.Theshapesoftheserelativelysmallobjectsaredetermined bythechemicalbondsthatformbetweentheirmolecularcomponents.Youcanthinkofthesestructures as if they are built up by adding pieces to a three-dimensional jigsaw, a bit like Lego. That means the informationneededtoassemblethesestructuresisembodiedintheshapeoftheribosomecomponents themselves–theproteinsandRNAs.Thoseshapes,inturn,areultimatelyspecifiedverypreciselybythe informationheldinthegenes.

  Understanding how structures form at larger scales, in objects such as organelles, cells, organs and wholeorganismsismoredifficult.Directmolecularinteractionsbetweencomponentscannotexplainhow these structures form. That’s partly because they are larger, sometimes much larger, than objects like ribosomes. But it is also because they can produce and maintain perfect structures over a range of differentsizes,evenwhencellsorbodiesgroworshrink.Thatissimplynotpossiblewithfixed,Lego-like molecular interactions. Take the division of a cell for example. A cell has a well-organized overall structure,andwhenthecelldividesitgeneratestwocellsofapproximatelyhalfthesizeandyeteachof

  themhasthesameoverallstructureastheoriginal‘mother’cell.

  Asimilarphenomenonisseenwiththedevelopmentofanembryo,suchasaseaurchin.Afertilizedsea urchin egg undergoes repeated cell divisions and generates an elaborate and rather beautiful little organism.Ifthetwocellsformedaftertheveryfirstdivisionoftheeggaresplitapart,theneachcellwill generatetwoperfectlyformedseaurchins,but,amazingly,eachonewillbejusthalfthesizeofanormal urchin of that age. This self-regulation of size and form is extraordinary and has puzzled biologists for morethanacentury.

  However, by thinking about information, biologists are beginning to make sense of how these things takeshape.Onewaythatdevelopingembryosgeneratetheinformationtheyneedtotransformauniform cellorgroupofcellsintoahighlypatternedstructureisbymakingchemicalgradients.Ifyouputasmall drop of ink into a bowl of water, it will slowly diffuse away from the location of the original drop. The intensity of the ink colour gets lower further away from the drop, making a chemical gradient. That gradient can be used as a source of information: for example, if the concentration of ink molecules is high,weknowweareclosetothecentreofthebowl,wheretheinkwasdrippedin.

  Let’snowreplacethebowlwithaballofidenticalcellsand,insteadofink,weinjectonesideofthe ballwithadoseofaparticularproteinthatcanchangethepropertiesofcells.Whatthisprovidesisaway to add spatial information to those cells so they can begin to build a pattern. The protein will diffuse throughthecells,formingagradientofhighconcentrationatonesideoftheballandlowconcentration on the other side. If cells react differently to high and low concentration
s, the protein gradient can provide the information needed to start constructing a complex embryo. If, for example, a high protein concentrationmadeheadcells,amediumconcentrationmadethoraxcells,andalowconcentrationmade abdomen cells, then one simple protein gradient could, in principle, lead to the beginnings of a new brimstonebutterfly.Inlife,thingsareusuallynotquiteassimpleasthat,butthereisgoodevidencethat gradientsofsignallingmoleculesacrossthebodiesofdevelopingorganismsdoindeedcontributetothe appearanceofsophisticatedbiologicalforms.

  ThiswasasetofproblemsthatAlanTuring–heofEnigmacode-crackingfameandoneofthefounders of modern computing – turned to during the early 1950s. He came up with an alternative, and imaginative, suggestion for how embryos generate spatial information from within. He devised a set of mathematicalequationsthatpredictedthebehaviourofchemicalsubstancesinteractingwitheachother, and so undergoing specific chemical reactions as they diffuse through a structure. Unexpectedly, his equations, which he called reaction-diffusion models, could arrange chemical substances into elaborate and often rather beautiful spatial patterns. By tweaking the parameters of his equations, the two substances could organize themselves into evenly spaced spots, stripes or blotches, for example. The attractivethingaboutTuring’smodelisthatthepatternsemergespontaneously,accordingtorelatively simplechemicalrulesofinteractionbetweenthetwosubstances.Inotherwords,thisprovidesawayfora developingcellororganismtogeneratetheinformationitneedstotakeshape,entirelyfromwithin;itis self-organizing. Turing died before his theoretical ideas could be tested in real embryos, but developmentalbiologistsnowbelievethatthiscouldbethemechanismthatputsspotsoncheetah’sbacks andstripesonmanyfish;distributesthehairfolliclesonyourhead;andevendivideseachofadeveloping humanbaby’shandsintofivedistinctfingers.