Paul Nurse - What Is Life

by Understand Biology In Five Steps (pdf)

  Thescientificstudyoffermentationbeganwiththeeighteenth-centuryFrenchnoblemanandscientist AntoineLavoisier,oneofthefoundersofmodernchemistry.Unfortunatelyforhim,andunfortunatelyfor scienceasawhole,hispart-timeactivitiesasataxcollectormeanthelosthisheadinMay1794,during the French Revolution. The judge of the kangaroo political court that sentenced him declared that the

  ‘Republic has no need for savants and chemists’. We scientists obviously have to treat politicians with caution! There is an unfortunate tendency for politicians, especially those of a populist bent, to ignore

  ‘experts’,particularlywhenthatexpertisecounterstheirpoorlysubstantiatedopinions.

  Beforehisuntimelyencounterwiththeguillotine,Lavoisierhadbecomefascinatedbytheprocessof fermentation.Heconcludedthat‘fermentationwasa chemicalreactioninwhichthesugarofthestarting grape juice was converted into the ethanol of the finished wine’. Nobody had thought about it in quite thatwaybefore.ThenLavoisierwentfurtherandproposedthattherewassomethingcalleda‘ferment’, whichseemedtocomefromthegrapesthemselves,whichplayedakeyroleinthechemicalreaction.He couldn’tsaywhatthis‘ferment’was,however.

  Things became clearer about half a century later, when the makers of industrial alcohol asked the French biologist and chemist Louis Pasteur to help them solve a mystery that kept destroying their products. They wanted to know why their fermentations of sugar beet pulp sometimes went wrong, producingasourandunpleasantacidinsteadofethanol.Pasteurembarkedonthismysteryasadetective might. Using a microscope, he obtained the crucial clue. Sediments in the fermentation vats that produced alcohol contained yeast cells. The yeast were clearly alive because some of them had buds, showing they were actively multiplying. When he looked into the soured vats he couldn’t see any yeast

  cellsatall.Fromthesesimpleobservations,Pasteurproposedthatthemicrobiallifeformyeastwasthe elusiveferment:thekeyagentresponsibleformakingethanol.Someothermicrobe,probablyasmaller bacterium,generatedtheacidthatruinedthefailedbatches.

  The point here was that the growth of living cells was directly responsible for a specific chemical reaction. In this case, the yeast cells were converting glucose into ethanol. The most important thing Pasteurdidwastostepfromthespecifictothegeneral,toreachanimportantnewconclusion.Heargued that chemical reactions were not just an interesting feature of cellular life – they were one of life’s defining features. Pasteur summarized this brilliantly when he said that ‘chemical reactions are an expressionofthelifeofthecell’.

  Wenowknowthatwithinthecellsofalllivingorganismsmanyhundreds,eventhousands,ofchemical reactionsarebeingcarriedoutsimultaneously.Thesereactionsbuildupthemoleculesoflife,whichform thecomponentsandstructuresofcells.Theyalsobreakmoleculesdown,torecyclecellularcomponents andreleaseenergy.Together,thevastarrayofchemicalreactionsoccurringinlivingorganismsiscalled metabolism. It is the basis of everything living things do: maintenance, growth, organization and reproduction, and the source of all the energy needed to fuel these processes. Metabolism is the chemistryoflife.

  Buthowareallthemanyandvariedchemicalreactionsthatmakeupmetabolismbroughtabout?What typeofsubstancewasitinPasteur’syeastthatwascarryingoutthechemicalreactionsoffermentation?

  AnotherFrenchchemist,MarcelinBerthelot,delveddeeperintothismysteryandmadethenextadvance.

  Hepulverizedyeastcells,andfromthecellularremnantsextractedachemicalsubstancewhichbehaved inanintriguingway.Ittriggeredaspecificchemicalreaction–theconversionoftablesugar,sucrose,into itstwosmallercomponentsugars:glucoseandfructose–butitwasnotitselfconsumedbythereaction.

  Itwasaninanimatesubstancebutintegraltoalivingprocessand,notably,itcontinuedtoworkwhenit wasremovedfromthecell.Hecalledthisnewsubstanceinvertase.

  Invertase is an enzyme. Enzymes are catalysts: that means they facilitate and speed up chemical reactions, often dramatically. They are acutely important for life. Without them many of the chemical processesmostvitalforlifewouldsimplynothappen,especiallyattherelativelylowtemperaturesand mild conditions found within most cells. The discovery of enzymes laid the foundations for today’s consensusview–sharedbyallbiologists–thatmostphenomenaoflifecanbebestunderstoodintermsof chemicalreactionsthatarecatalyzedbyenzymes.Tounderstandhowenzymesachievethisweneedto understandwhattheyareandhowtheyaremade.

  Mostenzymesaremadefromproteins,whicharebuiltbythecellaslong,chain-likemoleculescalled polymers.Polymerstructuresarefundamentallyimportantforeveryaspectoflife’schemistry.Aswellas mostenzymesandallotherproteins,allthelipidmoleculesthatmakeupcellmembranes,allthefatsand carbohydrates that store energy, and the nucleic acids responsible for heredity, deoxyribonucleic acid (DNA)andthecloselyrelatedribonucleicacid(RNA),areallpolymers.

  Thesepolymersarebuiltprincipallyfromtheatomsofjustfivechemicalelements:carbon,hydrogen, oxygen,nitrogenandphosphorus.Ofthesefive,carbonplaysaparticularlycentralrole,largelybecauseit is more versatile than the other elements. Whereas hydrogen atoms, for example, make only one connection–thatis,achemicalbond–withotheratoms,eachcarbonatomcanbondtofourotheratoms.

  Thisisthekeytocarbon’spolymer-makingabilities:twoofcarbon’sfourpotentialbondscanbelinkedto twootheratoms,oftenothercarbonatoms,creatingachainoflinkedatoms–thecoreofeachpolymer.

  Thatleaveseachcarbonwithtwofurtherbondsavailabletolinkwithotheratoms.Theseextrabondscan thenbeusedtoaddothermoleculestothesidesofthemainpolymerchain.

  Manyofthepolymersfoundincellsareverylargemolecules,solarge,infact,thattheyaregivena specialname:macromolecules.Togetasenseofquitehowbigthesemoleculescanbe,rememberthat theDNAmacromoleculesatthecoreofeachofyourchromosomescanbeseveralcentimetreslong.That meanstheyincorporatemillionsofcarbonatomsintoanincrediblylong,butincrediblyslender,molecular thread.

  Proteinpolymersarenotsolong,generallybeingbasedonafewhundredtoseveralthousandlinked carbonatoms.However,theyarefarmorechemicallyvariablethanDNA,whichisthemainreasonthey canworkasenzymesandthereforeplayadominantroleinmetabolism.Eachproteinisacarbon-based polymerbuiltbyjoiningsmalleraminoacidmoleculestogether,oneatatime,intoalongchain.Invertase, for example, is a protein molecule made by linking together 512 amino acids in a specific, ordered sequence.

  Lifeusestwentydifferentaminoacids.Eachoftheseaminoacidshavesidemolecules,branchingoff from the main polymer chain, that grant them distinct chemical properties. For example, some amino acidshavepositiveornegativecharges,othersareeitherattractedtoorrepelledbywater,andsomeare capable of easily forming bonds with other molecules. By stringing together different combinations of amino acids, each with different side molecules, cells can create a huge range of different protein polymermolecules.

  Then,oncetheselinearproteinpolymerchainsareassembled,theyfold,twistandcombinetogetherto createcomplexthree-dimensionalstructures.It’sabitlikethewayalengthofstickytapecanwrapitself up into a tangled ball, although the way proteins fold up is a much more repeatable process that generatesaveryprecisestructure.Inacell,thesamestringofaminoacidswillalwaystrytoformthe same specific shape. This leap from the one-dimensional to three-dimensional is crucial, s
ince it means eachproteinhasadistinctivephysicalshapeandauniquesetofchemicalproperties.Asaresultcellscan buildenzymesinsuchawaythattheyfittogetherverypreciselywiththechemicalsubstancestheywork

  on – parts of the invertase and sucrose molecules are a perfect fit, for example. This in turn allows enzymestoprovidetheprecisechemicalconditionsneededtobringaboutspecificchemicalreactions.

  Enzymesexecutealmostallthechemicalreactionsthatformthebasisofcellularmetabolism.Butas wellasbuildingothermoleculesupandbreakingthemdown,theyplaymanyotherrolestoo.Theyactas qualitycontrollers,theyferrycomponentsandmessagesbetweendifferentregionsofthecell,andthey transportothermoleculesinandoutofthecell.Othersstillareonthelookoutforinvaders,activatingthe proteinsthat defend cellsand therefore ourbodies from disease. Andenzymes are notthe only type of protein.Nearlyeverypartofourbodies–fromthehairsonourheadstotheacidinourstomachsandthe lenses in our eyes – are either made from protein, or are constructed by proteins. All these different proteins have been honed by millennia of evolution to fulfil specific functions within the cell. Even a relativelysimplecellcontainsahugenumberofproteinmolecules.Intotal,thereareover40millionof them in a tiny yeast cell; that’s twice as many proteins in a minuscule cell as there are people in a giganticcitylikeBeijing!

  Theoutcomeofallofthisproteindiversityisamaelstromofchemicalreactionsbeingcarriedoutin everycellatalltimes.Ifyoucouldimaginelookinginsidealivingcellwitheyesthatcouldperceivethe molecularworld,yoursenseswouldbeassaultedbyaboilingtumultofchemicalactivities.Someofthe molecules involved are electrically charged, making them either sticky or repellent, while others are passively neutral. Some are acids or bleach-like alkalis. All of these different substances are constantly interacting, either through random collisions or stage-managed meetings. Sometimes molecules come togethertransientlytoreactchemically,throughaquickexchangeofelectronsorprotons.Atothertimes molecules remain chemically connected through the formation of tight and enduring bonds. Altogether, the cell contains many thousands of different chemical reactions that are constantly working away to sustainlife.Thenumberofchemicalreactionsusedineventhelargestindustrialchemicalplantpalesin comparison.Aplasticsfactory,forexample,mightbebasedonafewtensofchemicalreactions.

  Allthisfranticandfastactivityoccupiestheoppositeendofthetimespectrumfromthedeeptimethat was needed for these systems to evolve. But the dizzying timescale of the cellular world is just as challengingforourbrainstocomprehendasevolutionarytime.Someofthecell’senzymesthat control thesereactionsworkatanastonishinglyfastrate,rattlingthroughthousands,evenmillions,ofchemical reactionseverysecond.Theseenzymesarenotonlyextremelyrapid,butcanalsobeextremelyprecise.

  Theycanmanipulateindividualatomswithalevelofaccuracyandreliabilitythatchemicalengineerscan onlydreamof.Butthenevolutionhasbeenworkingtorefinetheseprocessesforbillionsofyears–rather longerthanushumans!

  Making all this work together is an extraordinary achievement. Although the vast array of chemical reactionsthatoccursimultaneouslyincellsmayappearchaotic,itisinfactveryhighlyordered.Forthem tofunctionproperly,eachofthedifferentreactionsrequiresitsownparticularchemicalconditions.Some require more acid or alkaline surroundings; others demand particular chemical ions like calcium, magnesium,ironorpotassium;othersneedoraresloweddownbythepresenceofwater.Yetsomehowall thesedifferentchemistriesmustbecarriedoutbothsimultaneouslyandveryclosetogetherinthenarrow confines of the cell. This is only possible because the various enzymes do not each require different extremetemperatures,pressuresoracidoralkalineconditions,suchasthosefoundinindustrialchemical facilities. If they did, they would not all be able to co-exist in such close proximity. Many of these metabolic reactions still need to be kept separate from one another, however. They must not interrupt eachother,andalltheirspecificchemicalrequirementsmustbemet.Keytoansweringthischallengeis compartmentation.

  Compartmentation is a way to get complex systems of all kinds to work. Take cities. They only work efficiently if they are organized into different compartments with particular functions: railway stations, schools, hospitals, factories, police stations, power stations, sewage disposal plants, and so on. All of theseandmuchmorearerequiredforthecitytoworkasawhole,buteverythingwouldbreakdownif theywere all completelymixed up together.They have to beseparate to workeffectively, but they also needtoberelativelyclosetogetherandconnected.Itisjustthesameforcells,whichneedtocreatea distinctsetofchemicalmicro-environmentsthatareseparatedfromeachother,eitherinphysicalspace or across time, but also connected. Living things achieve this by constructing systems of interacting compartmentsthatexistatarangeofscales,fromtheverylargetotheextremelysmall.

  The biggest of these scales will probably be most familiar: the different tissues and organs of multicellularorganismslikeplants,andanimals–likeyouandme.Thesearedistinctcompartments,each customized for specific chemical and physical processes. Your stomach and intestines digest the chemicals in food; your liver detoxifies chemicals and drugs; your heart uses chemical energy to pump blood,andsoon.Thefunctionsoftheseorgansalldependonthespecializedcellsandtissuestheyare madefrom:cellsinthestomach’sliningsecreteacid,whilethoseintheheartmusclescontract.Allthose cellsare,inturn,compartmentsintheirownright.

  Infact,thecellisthefundamentalexampleofthecompartmentationoflife.Theessentialroleofthe cell’soutermembraneistokeepthecontentsofthecellseparatefromtherestoftheworld.Thanksto theisolatingeffectofthatmembrane,cellscanworktomaintainanislandofchemicalandphysicalorder.

  Cells can only sustain this state temporarily, of course: when they stop working, they die and chaos reassertsitsgrip.

  Thecellitselfcontainssuccessivelayersofcompartmentation.Thelargestofthesecompartmentsare themembrane-boundedorganelles,suchasthenucleusandthemitochondria.Butbeforewecanseehow these work, we need to first zoom down to the simpler level of the carbon polymers, since the bigger

  compartmentsareallbuiltonandaroundthepropertiesoftheseelementarycomponents.

  The smallest chemical compartments within the cell are the surfaces of the enzyme molecules themselves. To get a feeling for quite how small these molecules are, look at the very fine hairs on the backofyourhand.Theyareamongthemostslenderstructuresyoucanseewithyournakedeye,butthey aremassivecomparedtoenzymeproteins.Aroundtwothousandmoleculesofinvertasecouldlineupside bysideacrossthediameterofeachofthosehairs.

  Eachenzymeproteinmoleculeprovidesenclosedspacesanddockingsiteswhichhavespecificshapes thataretailor-made,atthescaleofindividualatoms,forassociatingwiththespecificmoleculesthatthey workwith.Theseexquisitestructuresarefartoosmalltoseedirectly,evenwiththemostpowerfullight-focusingmicroscopes.ResearchersmustinfertheirshapesandpropertiesusingtechniquessuchasX-ray crystallography and cryo-electron microscopy, which extend our senses to an extraordinary degree, allowingustodeterminethepositionsandpropertiesofthehundredsorthousandsofconnectedatoms theyaremadefrom.Researcherscanthenseehowenzymesinteractwiththechemicalstheymanipulate duringareaction.Thesechemicalsarecalled substrates.Enzymesandtheirsubstratesfittogetherlike thepiecesofaminutethree-di
mensionaljigsawpuzzle.Whenelementsofthispuzzlecometogether,the chemicalreactionsareshieldedfromtherestofthecellandpresentedatjusttherightangleandinthe right chemical conditions for the enzymes to undertake their extraordinarily precise acts of atomic surgery,manipulatingindividualatomsandmakingorbreakingparticularmolecularbonds.Invertase,for example,worksbybreakingonespecificbondbetweenanoxygenatomandacarbonatominthemiddle ofamoleculeofsucrose.

  Enzymesareabletoworktogethertoensurethattheproductofonereactionispassedondirectlyto become the substrate for the next. That way, a whole series of chemical reactions needed for complex processes,suchasthoseneededtobuildlipidmembranesorothercomplexchemicalcomponentsfrom simpler constituents, can be co-ordinated. Biologists call these complex interacting series of chemical processesmetabolicpathways,someofwhichinvolvemanydistinctreactions.Theyworkratherlikethe assemblylinesinafactory;eachstagemustbecompletedbeforetheactionmovesontothenext.

  Enzymescanalsoworktogethertocarryoutevenmorecomplexactsofsynthesis,likecopyingDNA with extraordinary precision. The enzymes that work like this are best imagined as absolutely tiny molecular machines which are extremely accurate and reliable in their operation. Some of these molecularmachinesusechemicalenergytodophysicalworkinthecell.Theseincludeproteinsthatact as molecular ‘motors’, powering most movement of cells themselves and of various cargoes and structureswithincells.Somefunctionlikedespatchdrivers,carryingcellularcomponentsandchemicals tothepartofthecellwheretheyareneeded.Theydothisbyfollowingthecomplextrackways,alsomade fromproteins,thatcriss-crossthecellularinteriorratherlikeanelaboratelybranchingrailwaynetwork.