Researchershavemadefilmsoftheseminutemolecularmotorsinaction,andseenthem‘walking’around the cell like tiny robots. These motors have ratchet mechanisms, that keep them moving forward, and helpthemavoidbeingknockedoffcoursebyaccidentalcollisionswithothermolecules.
Versionsofthesemolecularmotorsalsocreatetheforcesneededtoseparatechromosomesandcleave dividing cells in half. And although they are each infinitesimally small, by working together in their billions,acrossmanymillionsofmusclecells,thesemolecularmotorsarethethingsthatpowerthewings ofyellowbutterfliesastheyflutterthroughourgardens,allowyoureyestofollowthewordsonthispage, and enable cheetahs to run at extraordinary speeds. Combining the tiny effects of individual proteins, workinginverylargenumbersacrossmanycells,leadstothereal-worldconsequencesweseeallaround us.
At a somewhat larger scale than individual enzymes and molecular machines, groups of proteins can dockwitheachotherphysically,toformasetofcellulardevicesthatorchestratemorecomplexchemical processes.Importantamongthesearetheribosomes,whicharewhereproteinsaremade.Eachribosome ismadefromseveraldozenproteins,togetherwithseverallargemoleculesofRNA,DNA’sclosechemical cousin.Ribosomesarebiggerthanthetypicalenzyme–they’dlineupafewhundred,ratherthanseveral thousand,abreastacrossahair’sbreadth,butarestillfartoosmalltoseedirectly,withouttheaidofan electronmicroscope. Cells that are growing and reproducing have a huge demand for new proteins, so theycaneachcontainseveralmillionribosomes.
To build a new protein molecule, a ribosome must read the genetic code of a specific gene and translate it into the twenty-letter amino acid alphabet of proteins. To do this, the cell first makes a temporary copy of a specific gene. This copy is made from RNA. It acts as a messenger, and is indeed calledmessengerRNA,sinceitisphysicallytransportedfromthegenesinthenucleustotheribosome, takingacopyofthegene’sinformationwithit.TheribosomeusesthemessengerRNAasatemplateto build the protein, by stringing together amino acids in the order dictated by the gene. By forming a separate and highly structured micro-environment, ribosomes ensure this multistage, multi-enzyme processoccursaccuratelyandrapidly:ittakesonlyaboutaminuteforeachribosometobuildanaverage protein,consistingof300orsoaminoacids.
Muchbiggerthanribosomes,althoughstilltrulyminutecomparedtofamiliarhuman-scaleobjects,are the cell’s organelles, each contained within their own lipid membrane wrapper. These provide the next criticallayerofcompartmentationineukaryotecells.Attheheartofeachofthesecellsistheorganelle weknowasthenucleus.Downamicroscopethenucleusisusuallythemostvisibleoftheorganelles.But ifmostcellsaresmall–twoorthreeofyourbody’swhitebloodcellswouldlineupacrossthebreadthof thosefinehairsonyourhands–nucleiaresmaller.Eachoneoccupiesonlyaround10%ofthevolumeofa white blood cell. But remember, packed into that incredibly tiny space is an entire copy of all of your
DNA,includingallofyour22,000genes–2metresofitinallwhenstretchedoutstraight.
All the different chemical activity that keeps cells alive requires energy, in fact lots of energy. Today, the great majority of life forms around us ultimately derive their energy from the sun. This is what the chloroplast, another organelle critical for life, achieves. Unlike the nucleus, these don’t exist in animal cells; they are found only in plants and algae. Chloroplasts are the sites of photosynthesis: the set of chemicalreactionsthatusesenergyfromsunlighttodrivethetransformationofwaterandcarbondioxide intosugarandoxygen.
Theenzymesneededforphotosynthesisarearrangedwithinthetwolayersofmembranethatsurround eachchloroplast.Eachofthecellsinthebladesofgrassinyourlocalparkaccommodatesahundredorso of these roughly spherical organelles, all of which contain high levels of proteins called chlorophylls.
Thesechlorophyllsarethereasongrasslooksgreen:theyabsorbenergyfromtheblueandredpartsof the spectrum of light, using it to power photosynthesis, resulting in them reflecting the green wavelengths.
The plants, algae and some bacteria that can carry out photosynthesis use the simple sugars they produceasanimmediatesourceofenergyandasarawmaterialforbuildingothermoleculestheyneed to survive. They also produce the sugars and carbohydrates that are consumed by so many other organisms:thefungithatfeedondecayingwood,thesheepthatnibbleongrass,thewhalesthathoover up tons of photosynthesizing plankton in the sea, and all the food crops that sustain people on every continent of our world. In fact, the carbon that is so crucial for the construction of every part of our bodiescomesultimatelyfromphotosynthesis.Itstartsascarbondioxide,whichisdrawnoutoftheairby thechemicalreactionsofphotosynthesis.
Thechemistryofphotosynthesishasnotonlyprovidedtheenergyandrawmaterialtobuildmostofthe lifeonEarthtoday,ithasalsoplayedadefinitiveroleinshapingourplanet’shistory.Lifeseemstohave firstappearedaround3.5billionyearsago,whichistheageoftheoldestfossilssofardiscovered.These were single-celled microbes, which probably derived their energy from geothermal sources. Because there was no photosynthesis during the earliest period of life on Earth, there was no major source of oxygen.Asaresult,therewasalmostnooxygenintheatmosphere,andwhentheplanet’searlylifeforms didencounteroxygenitwouldhavecausedthemproblems.
Althoughwethinkofoxygenaslife-sustaining,asindeeditis,itisalsoahighlychemicallyreactivegas whichcandamageotherchemicals,includingthepolymersessentialforlife,suchasDNA.Oncemicrobes evolved the ability to photosynthesize, they multiplied, over the millennia, to such an extent that the amountofoxygenintheatmospherespiked.Whatfollowed,between2and2.4billionyearsago,iscalled theGreatOxygenCatastrophe.Allorganismsthatexistedatthattimeweremicrobes,eitherbacteriaor archaea,butsomeresearchersthink mostofthemwerewipedoutbytheappearanceofallthatoxygen.It is ironic that life created conditions that nearly ended life as a whole. The minority of life forms that survivedwouldhaveeitherretreatedtoplaceswheretheywerelessexposedtooxygen,perhapsatthe bottom of the sea or deep underground, for example, or they had to adapt and evolve new chemistries neededtothriveinanoxygenatedworld.
Today,organismslikeushumansstillhandleoxygenwithcare,butweentirelydependonitbecausewe needittoreleaseenergyfromthesugars,fatsandproteinsthatourbodieseat,makeorabsorb.Thisis broughtaboutbyachemicalprocesscalled cellularrespiration. The final stages of this set of reactions take place within mitochondria: another organelle compartment that is critically important for all eukaryotecells.
The principal role of mitochondria is to generate the energy that cells need to power the chemical reactions of life. That’s why cells that need a lot of energy contain a lot of mitochondria: to keep your heartbeating,eachofthecellsinthemusclesofyourheartmustemployseveralthousandmitochondria.
Alltogethertheyoccupyabout40%ofthespaceavailableinthoseheartcells.Instrictlychemicalterms, cellularrespirationreversesthereactionatthecoreofphotosynthesis.Sugarandoxygenreactwitheach other to make water and carbon dioxide, releasing a lot of energy, which is captured for later use. The mitochondriaensurethismulti-stepchemicalreactionishighlycontrolledandtakesplaceinanorderly, stepwise way, without too much energy being lost, and without reactive oxygen and electrons escaping anddamagingtherestofthecell
.
Thekeyenergy-capturingstepincellularrespirationisbasedonthemovementofprotons,whichare singleatomsofhydrogenthathavebeenstrippedofanelectrontogivethemanelectricalcharge.These protonsarepushedoutfromthecentreofthemitochondrion,intothegapbetweenthetwomembranes thatencloseeachmitochondrion.Thisresultsinthebuild-upofmanymorechargedprotonsoutsidethe inner mitochondrial membrane than inside. Although based on chemistry, this is essentially a physical process. You can think of it as being rather like pumping water uphill to fill a dam. In a hydroelectric power station, water from the dam is allowed to rush downhill, through turbines that turn the water’s kinetic energy into electric energy. In the case of the mitochondria, protons pumped beyond the membrane‘dam’rushbackintothecentreoftheorganelle,viachannelsmadeofprotein,whichcapture the force created by the cascade of charged particles and store it in the form of high-energy chemical bonds.
Thepersonwhofirstimaginedthatcellsmightproducetheirenergyinsuchanunexpectedwaywas theBritishbiochemistandNobellaureatePeterMitchell.HeusedtobeintheZoologyDepartmentofthe UniversityofEdinburgh,whereIlaterworkedontheyeastcellcycle,butbythetimeIgotthere,hehad lefttosetuphisownprivatelaboratoryonthemoorsofsouth-westEngland.Thiswasquiteanunusual thingtodo,andhewasconsideredbysometobeatrueBritisheccentric.Imethimwhenhewasinhis
lateseventiesandwasimpressedbyhisunabatedcuriosityandpassionforknowledge.Ourconversations wenteverywhere.Iwasstruckbythecreativityofhisthinking,andimpressedbythewayheignoredhis doubtersandwentontoprovethathisunusualideawas,infact,correct.
The tiny protein structures that act as the ‘turbines’ in the mitochondria even look a bit like the turbinesinelectricpowerstations,althoughtheyareminiaturizedbyafactorofseveralbillion-fold!As protons rush through the molecular turbine, which has a channel only 10 thousandths of a millimetre wide,theyturnanequallysmallmolecular-scalerotor.Thatturningrotordrivesthegenerationofanall-importantchemicalbond,creatinganewmoleculeofasubstancecalledadenosinetriphosphate,orATP
forshort.Thishappensattherapidrateof150reactionspersecond.
ATP is life’s universal energy source. Each molecule of ATP stores energy, acting like a minuscule battery. When a chemical reaction within a cell needs energy the cell breaks ATP’s high-energy bond, turning ATP into adenosine diphosphate (ADP), a process that releases energy that the cell can use to triggerachemicalreactionoraphysicalprocess,suchaseachofthestepstakenbyamolecularmotor.
Mostofthefoodyoueateventuallyendsupbeingprocessedinyourcells’mitochondria,whichusethe chemical energy it contains to make a prodigious quantity of ATP. To fuel all of the chemical reactions needed to support your body’s trillions of cells, your mitochondria together produce, amazingly, the equivalentofyourentirebodyweightinATPeveryday!Feelthepulsebeatinginyourwrist,theheatof yourskin,andtheriseandfallofyourchestasyoubreathe:it’sallfuelledbyATP.LifeispoweredbyATP.
All living things need a constant and reliable supply of energy and, ultimately, they all make their energythroughthesameprocess:controllingtheflowofprotonsacrossamembranebarriertomakeATP.
If there is anything remotely like a ‘vital spark’ that sustains life, it is perhaps this tiny flow of electric charge across a membrane. But there is nothing mystical about it: it is a well-understood physical process. Bacteria do this by actively pumping protons across their outer membrane, while the more complexcellsofeukaryotesdoitwithinaspecializedcompartment:themitochondrion.
Together,allofthesedifferentlevelsofspatialorganizationwithincells–fromtheunimaginablysmall docking sites within individual enzymes, to the comparatively large nucleus that contains the chromosomes–pointtoanewwayofthinkingaboutthecell.Whenwelookatthebeautifulandhighly elaborate pictures produced by the powerful microscopes of today, we are looking at a complex and constantlychangingnetworkoforganizedandinterconnectedchemicalmicro-environments.Thisviewof thecellisworldsawayfromthatofcellsasmereLego-likebuildingblocksforthemorecomplextissues andorgansofplantsandanimals.Eachcellisacompleteandhighlysophisticatedlivingworldinitsown right.
Gradually, since Lavoisier started to ask how fermentation worked more than two centuries ago, biologists have come to recognize that even the most complex behaviours of cells and of multicellular bodiescanbeunderstoodintermsofchemistryandphysics.Thiswayofthinkingwasveryimportantto meandmylabcolleaguesaswesoughttounderstandhowthecellcycleiscontrolled.Wehaddiscovered the cdc2 gene as a cell cycle controller, but we then wanted to know what the gene actually did. What chemicalorphysicalprocessesdoestheCdc2proteinitmakesactuallycarryout?
Toworkthisoutweneededtomovefromtheratherabstractworldofgeneticstothemoreconcrete, mechanistic world of cellular chemistry. That meant we had to do biochemistry. Biochemistry tends to takeamorereductionistapproach,describingchemicalmechanismsingreatdetail,whilstgeneticstakes amoreholisticapproach,lookingatthebehaviourofthelivingsystemasawhole.Inourcase,genetics and cell biology had shown us that cdc2 was an important controller of the cell cycle, but we needed biochemistry to show how the protein made by the cdc2 gene worked in molecular terms. Both approaches provide different kinds of explanations; when they agree with each other it gives you confidencethatyouareontherighttrack.
ItturnedoutthattheCdc2proteinwasanenzymecalledaproteinkinase.Theseenzymescatalyzea reaction called phosphorylation that adds a small phosphate molecule, which has a strong negative charge,tootherproteins.ForCdc2tofunctionasaproteinkinaseitmustfirstbindtoanotherprotein calledcyclin,whichactivatesit.Together,Cdc2andcyclinformanactiveproteincomplexcalledCyclin DependentKinase,orCDKforshort.CyclinwasdiscoveredandnamedbymyfriendandcolleagueTim Hunt,asaproteinthat‘cycled’upanddowninlevelthroughthecellcycle,withthosechangesbeingpart of the mechanism the cell uses to ensure the CDK complex is turned ‘on’ and ‘off’ at the correct time.
Cyclin,incidentally,isamuchbetternamethan cdc2!
When the active CDK complex phosphorylates other proteins, the negatively charged phosphate moleculethatitaddschangestheshapeandchemicalpropertiesofthosetargetproteins.That,inturn, changesthewaytheywork.Itcan,forexample,activateotherenzymes,justasaddingcyclintotheCdc2
protein makes active CDK. Because protein kinases like CDK can rapidly phosphorylate many different proteinssimultaneously,theseenzymesareoftenusedasswitchesincells.Thatiswhathappensinthe cell cycle. Processes such as copying the DNA in S-phase, early in the cell cycle, and separating the copied chromosomes during mitosis, late in the cell cycle, demand the co-ordinated action of many different enzymes. By phosphorylating large numbers of these different proteins all at once, CDK can exertcontrolovercomplexcellularprocesses.Understandingproteinphosphorylationis,therefore,keyto understandingcellcyclecontrol.
Icannotstressenoughhowsatisfyingitwastoworkallofthisoutandreallyseehow cdc2exertedits great influence over the cell cycle. It really did feel like one of those rare eureka moments. The programme of research in my lab had moved from identifying genes in yeast, such as cdc2, which controlledthecellcycleandthereforecellreproduction,throughtoshowingthisc
ontrolwasthesamein
alleukaryotesfromyeasttohumans,tofinallyworkingoutthemolecularmechanismbywhichitacted.
This took quite a long time though, a total of about fifteen years, with about ten colleagues working togetherinmylab.And,asisusuallythecaseinscience,itwasalsobasedoncontributionsfrommany otherlabsaroundtheworld,workingonthecellcycleincellsfromanexoticrangeoflivingorganisms, includingstarfish,seaurchins,fruitflies,frogs,miceand,eventually,humans.
Ultimately,lifeemergesfromtherelativelysimpleandwell-understoodrulesofchemicalattractionand repulsion, and the making and breaking of molecular bonds. Somehow these foundational processes, operating en masse at a minuscule molecular scale, combine to create bacteria that can swim, lichens thatgrowonrocks,theflowerswetendinourgardens,flittingbutterflies,andyouandme,whoareable towriteandreadthesepages.
The notion that cells, and therefore living organisms, are astoundingly complicated, but ultimately comprehensible, chemical and physical machines is now the accepted way to think about life. Today, biologistsbuildonthisinsightbyattemptingtocharacterizeandcatalogueallthecomponentsofthese astonishingly complex living machines. To do this, we now have access to powerful technologies that allow deep study of the extreme complexity of living cells. We can take a cell or a group of cells and sequencealltheDNAandRNAmoleculestheycontain,andidentifyandcountthethousandsofdifferent typesofproteinspresent.Wecanalsodescribeindetailallthefats,sugarsandothermoleculesthatare foundinthecells.Thesetechnologieshugelyextendthereachofoursenses,givingusanewandhighly comprehensiveviewofcells’invisibleandever-changingcomponentry.
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