From: Subject: NWO - De kunst om klein te bouwen Date: Sun, 6 Apr 2008 21:49:27 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C89830.1627FA30" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3198 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C89830.1627FA30 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nwo.nl/nwohome.nsf/pages/NWOP_66cbrt NWO - De kunst om klein te bouwen
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De kunst om klein te bouwen

Prof. dr. B.L. (Ben) Feringa

'Men stelle zich een tuin voor,met honderd soorten bomen, met = duizend=20 soorten bloemen, met honderd soorten vruchten, met honderd soorten = kruiden. Als=20 nu de tuinman van die tuin geen ander onderscheid kent als eetbaar en = onkruid,=20 dan zal hij met negentiende van zijn tuin niets weten te beginnen, hij = zal de=20 verrukkelijkste bloemen uitrukken, de edelste bomen omhakken'.=20
Herman Hesse in zijn befaamde boek De Steppewolf.=20

Verwondering voor de natuur, maar vooral toevoegen wat niet = vanzelfsprekend=20 voorhanden is in die natuur, is onze drijfveer. Onze tuin is die van de=20 moleculen. We bewonderen ze om hun prachtige structuur of hun heilzame = werking.=20 Moleculen die we verfoeien omdat ze zo giftig zijn. Na het ontrafelen = van het=20 menselijk genoom en na de technologische successen van de micro- = elektronica=20 dringen we nu dieper door in de moleculaire basis van de natuur en = beginnen we=20 ons te realiseren dat de eeuw van de moleculaire wetenschappen voor ons = ligt.=20 Inzicht willen verwerven in structuur, eigenschappen en werking op = moleculair=20 niveau speelt een essenti=EBle rol bij het snel vervagen van de grenzen = tussen=20 chemie en biologie. De uitdaging om uit moleculaire bouwstenen met = nanoprecisie=20 de materialen van de toekomst te construeren, brengt fysici en chemici = bij=20 elkaar.=20

Het bouwen met moleculen, maar vooral het bedenken van niet bestaande = moleculen, is mijn passie.=20

Ontwerp en Synthese

Met een groot aantal ingredi=EBnten zoals elementen en kleine = moleculen=20 construeert de chemicus de meest verfijnde moleculen. Dit kunnen = fascinerende=20 stoffen uit de natuur zijn, die slechts in minuscule hoeveelheden, = moeizaam, en=20 met grote ecologische gevolgen te isoleren zijn (figuur 1a ). Of = natuurlijke=20 moleculen die we met grote precisie aanpassen om aldus de = geneeskrachtige=20 werking te verbeteren, zoals bij het antibioticum in figuur 1b. Maar = misschien=20 wel het meest avontuurlijk is dat de synthetisch- chemicus letterlijk = zijn eigen=20 wereld kan bouwen (figuur 1c ).=20

3D"Figuur=20

Figuur 1:
a.(-)-Pumiliotoxine C,een=20 nicotine-acetylcholine-receptorblokker uit de huid van een = amazonekikker.
b.=20 Meropenem=AE,een synthetisch antibioticum.
c. Een moleculaire = bouwsteen voor=20 'liquid crystal display'- materialen.
=20

Synthese is in dit opzicht ook te vergelijken met kunst. Je ontwerpt = en=20 cre=EBert je eigen object op moleculair niveau. Soms omdat het heel mooi = is, vaak=20 om een fundamentele vraag te beantwoorden of omdat je er een hele nieuwe = toepassing van verwacht. Een dagelijks leven zonder de brandstoffen,=20 voedingsmiddelen, elektronische materialen en medicijnen, die in het=20 laboratorium zijn ontworpen, is bijna niet voor te stellen.=20

Bij het bouwen van moleculen kijken we graag af van de prachtige = ontwerpen in=20 moeder natuur. Er is echter een groot verschil. Daar waar de evolutie = een zeer=20 beperkt aantal bouwstenen heeft geselecteerd voor alle essenti=EBle = functies,=20 kennen wij die beperkingen helemaal niet. Onze moleculaire legodoos is = heel=20 groot en het speelveld oneindig. Het is opmerkelijk dat Leonardo da = Vinci=20 vijfhonderd jaar geleden al voorspelde: 'where Nature finishes = producing its=20 own species man begins, with the help of Nature, to create an infinity = of=20 species'.=20

In dit speelveld van de synthese is onze specialisatie de = stereochemie. Dat=20 is de precieze controle over de ruimtelijke structuur van moleculen. De=20 driedimensionale structuur is doorgaans cruciaal voor de eigenschap van = een=20 molecuul bijvoorbeeld als medicijn.=20

Spiegeltje, spiegeltje...

Symmetrie wordt vaak geassocieerd met schoonheid. De ogenschijnlijk = perfecte=20 symmetrie van een gelaat wordt in de wereld van de glamour vaak zeer=20 gewaardeerd. Hoe anders is het in het menselijk lichaam op moleculair = niveau.=20 Daar is asymmetrie, het uitsluitend voorkomen van een spiegelbeeldvorm = van de=20 essenti=EBle moleculen, een kenmerkende eigenschap. Het feit dat we = kunnen zien,=20 voedsel verteren, ons voortplanten, komt onder andere doordat alle = aminozuren=20 linkshandig en alle suikers rechtshandig zijn. Dit verschijnsel van=20 spiegelbeeldsymmetrie staat bekend als chiraliteit, van het Griekse = 'cheir' wat=20 hand betekent (figuur 2a ).=20

3D"Figuur=20

Figuur 2a: Spiegelbeeldsymmetrie of chiraliteit: vanaf linksonder = (met=20 klok mee): linkshandig aminozuur, rechtshandige DNA helix en een enzym = opgebouwd=20 uit aminozuren.=20

Met ons onderzoek in de stereochemie, treden we in de voetsporen van = Jacobus=20 van 't Hoff. Hij was de eerste Nobelprijswinnaar in de chemie en degene = die het=20 tetra=EBdermodel van koolstof heeft bedacht. Hierdoor wordt onmiddellijk = duidelijk=20 waarom moleculen chiraal kunnen zijn, dus waarom ze in een linker en = rechter=20 spiegelbeeldvorm kunnen voorkomen (figuur 2b ).=20

3DFiguur=20=20

Figuur 2b: Jacobus van 't Hoff, eerste Nobelprijswinnaar in de=20 scheikunde, en zijn molecuulmodellen.=20

Wat zijn de consequenties voor het ontwerp van een nieuw = geneesmiddel? Alleen=20 de linkshandige vorm wordt door ons lichaam herkend en de rechtshandige = kan in=20 het uiterste geval zelfs dodelijk zijn (figuur 3). De synthese van = uitsluitend=20 een spiegelbeeldvorm van moleculen, de asymmetrische synthese, is een=20 fundamenteel wetenschappelijke uitdaging met grote economische = betekenis.=20 Illustratief is dat acht van de tien meest verkochte geneesmiddelen uit = =E9=E9n=20 spiegelbeeldvorm bestaan. Het kernprobleem bij het bouwen, is dat de = moleculen=20 identiek zijn, afgezien van de spiegelbeeldrelatie. Kortom, hoe moeten = we=20 onderscheid maken tussen links en rechts?=20

3D"Figuur=20

Figuur 3: L-Dopamine is een anti-Parkinson geneesmiddel, de=20 spiegelbeeldvorm veroorzaakt ernstige nevenverschijnselen.=20

Asymmetrische katalyse

De oplossing ligt in het ontwerp van selectieve katalysatoren. Een=20 katalysator is de motor van bijna elk chemisch proces en zonder deze=20 'moleculaire robots' zou niet alleen onze chemische industrie maar ook = het leven=20 zelf knarsend tot stilstand komen. De ontwikkeling van nieuwe selectieve = katalysatoren zal ten grondslag liggen aan de productieprocessen van de = toekomst=20 zonder afval en met effici=EBnter gebruik van grondstoffen en energie.=20

We ontwerpen katalysatoren die zelf uit =E9=E9n spiegelbeeldvorm = bestaan. Zoals=20 een rechterhand onderscheid maakt tussen een linker en rechter = handschoen zo=20 weet de asymmetrische katalysator precies te herkennen wat de linker-of=20 rechterkant van een molecuul is. Figuur 4 illustreert dit voor de = additie van=20 waterstof.=20

3D"Figuur=20

Figuur 4: Een asymmetrische katalysator voor de waterstof- = additie=20 waarbij uitsluitend linkshandige aminozuurmoleculen geproduceerd = worden.=20

Stelt u zich voor: een minuscule machine, een miljardste meter (een=20 nanometer) groot, die duizenden keren per minuut met grote precisie uit = een vlak=20 lapje stof uitsluitend linker handschoenen maakt. Tot nu zijn vooral=20 katalysatoren gebouwd bestaande uit een metaalion met daar omheen = chirale=20 organische moleculen, liganden genaamd. Die liganden zijn heel star en = bepalen=20 precies van te voren hoe de ruimtelijke structuur van de katalysator er = uit gaat=20 zien. Vaak is zo'n katalysator heel ingewikkeld en duur.=20

Hoe werkt de natuur? De componenten zijn zodanig ontworpen dat ze = zichzelf=20 organiseren tot de juiste asymmetrische katalysator. We zijn erin = geslaagd dit=20 natuurlijk proces en beetje na te bootsen; een paradigmaverschuiving in=20 katalysatorontwerp. We hebben heel simpele chirale liganden bedacht,=20 fosforamidieten genaamd. Die assembleren met een geschikt metaalzout = spontaan=20 tot de correcte driedimensionale structuur. Zo kunnen we heel eenvoudig = op maat=20 gesneden katalysatoren maken. En het allerbelangrijkste, zo kunnen we = zeer hoge=20 selectiviteit bereiken voor het juiste spiegelbeeld van een gewenst = product.=20

Inmiddels wordt met =E9=E9n van onze katalysatoren op grote schaal = een nieuw=20 geneesmiddel geproduceerd. Een mooi voorbeeld van het belang van een = vruchtbare=20 academisch-industri=EBle samenwerking. Bovendien betekent het een = geweldige=20 stimulans voor de studenten die hieraan hebben meegewerkt.=20

Moleculaire motor

De 'kunst om klein te bouwen' vormt ook de kern van ons onderzoek in = de=20 nanotechnologie. Technologie met dimensies duizend keer kleiner dan de = huidige=20 microtechnologie. Het doel is schakelaars,motoren en uiteindelijk = machines via=20 een 'bottom-up'-benadering uit moleculaire bouwstenen te maken. = Biologische=20 systemen vormen wederom onze grootste inspiratiebron. Fascinerende = voorbeelden=20 van nanomachines in ons lichaam zijn de optische retinalschakelaar in = ons oog,=20 de ATP-ase-rotatiemotor in onze celwand en het ribosoom dat zorgt voor = de=20 eiwitsynthese in de cel (figuur 5).=20

3D"Figuur=20

Figuur 5: Biologische nanosystemen.
a. De retinal-schakelaar = in ons=20 oog.
b. Een ATP-ase-rotatiemotor in het celmembraan.
c. Het = ribosoom, de=20 eiwitproducerende 'machine' in de cel.
=20

Ik zal kort de constructie van de eerste kunstmatige, door licht=20 aangedreven,moleculaire motor toelichten. Ook hier speelt = spiegelbeeldsymmetrie=20 een cruciale rol. Stel, u bouwt een motor die inderdaad ronddraait maar = de=20 waarschijnlijkheid dat deze linksom of rechtsom draait is even groot. = Een auto=20 met deze motor komt netto geen stap vooruit.=20

Door een spiegelbeeldvorm van een motormolecuul te bouwen (figuur 6) = slaagden=20 we erin deze uitsluitend linksom te laten draaien met licht als = energiebron. De=20 motor is een nanometer groot. Gelijktijdig bouwden we een miljard maal = een=20 miljard identieke exemplaren. Het mooie van de chemische synthese is dat = je aan=20 zo =92n motor letterlijk kunt sleutelen. Zo lukte het ons om de motor=20 twintigduizend keer sneller te laten draaien.=20

3D"Figuur=20

Figuur 6: De licht-aangedreven synthetische moleculaire = motor.=20

Deze motor is nog heel primitief en het ontwerp toont weinig = gelijkenis met=20 bekende motoren. Maar een computerchip is ook geen kopie van een = hersencel. Laat=20 staan dat een Boeing 747 een vergrote versie van een duif is.=20

Het is verleidelijk terug te gaan naar het begin van de industri=EBle = revolutie=20 met de ontdekking van de stoommachine. Het gebruik van een motor voor=20 gecontroleerde beweging en het verrichten van arbeid is een gigantische = stap=20 vooruit geweest naar de gemechaniseerde maatschappij van vandaag. Het is = niet=20 moeilijk voor te stellen dat moleculaire motors en machines een = belangrijke rol=20 gaan spelen wil de huidige nanoscience de hooggespannen verwachtingen = van de=20 nanotechnologie waarmaken.=20

Van de oorsprong naar ...

In de ban van de stereochemie en gestimuleerd door de Spinozapremie = willen we=20 een deel van ons onderzoek in de katalyse richten op =E9=E9n van de = grootste=20 mysteries in de natuurwetenschappen: de oorsprong van chiraliteit.=20

Waar komt de extreme voorkeur voor onder andere L-aminozuren en = D-suikers in=20 de natuur vandaan? Is het toeval? Ligt de oorsprong in de ruimte? Of is = er een=20 verschijnsel dat we nog niet ontdekt hebben?=20

Zo gaan we deelnemen in de ontwikkeling van een uiterst gevoelig=20 detectiesysteem voor L-aminozuren voor een toekomstige ruimtemissie. Een = kleine=20 voorkeur voor een spiegelbeeldvorm moet ook worden versterkt en = doorgegeven op=20 moleculair niveau. Met de kennis opgedaan bij de katalysatoren die = zichzelf=20 assembleren is de volgende stap het bouwen van kunstmatige = zelfreplicerende=20 systemen. Zo hopen we een tipje van de sluier op te lichten van de = chemische=20 evolutie die wellicht resulteerde in de unieke spiegelbeeldsymmetrie in = de cel.=20

Een nanoauto

De moleculaire motor vormt een fantastische basis voor het ontwerp = van=20 nanomachines. Momenteel worden een krukas en tandwieltjes gebouwd. Het = hechten=20 van een draaiend motortje op een nanobolletje is net gelukt.De volgende = stap is=20 een 'Hollands lichtmolenpark' waarbij alle propellers dezelfde kant op = draaien.=20 Dit is wellicht de basis voor intelligente materialen. Maar het uiterste = van=20 onze synthetische vaardigheden vergt de constructie van de moleculaire = auto=20 (figuur 7). Door zonlicht voortgestuwd moet deze auto van twee nanometer = uiteindelijk over een weggetje van goud gaan rijden.=20

3D"Figuur=20

Figuur 7: Twee door zonlicht aangedreven auto's, de Nuna II en = een=20 nanoauto op een goudweg.=20

Systeemchemie

Een opmerkelijke evolutie heeft plaatsgevonden in de chemische = synthese. Van=20 stoichiometrische methoden en relatief eenvoudige moleculen naar = katalytische=20 methoden en grote complexiteit. Daarnaast heeft de supramoleculaire = chemie een=20 spectaculaire vlucht genomen. De toekomst lijkt aan moleculaire = systemen.Het=20 integreren van moleculen met heel uiteenlopende structuren en functies = in een=20 werkzaam systeem is namelijk een uitdaging van een heel andere orde. = Laat staan=20 dat deze moleculaire systemen zichzelf spontaan kunnen organiseren, = repareren of=20 aanpassen aan hun omgeving; de manier waarop dit in de levende natuur = gebeurt.=20

Hoe ver de grenzen van ons vakgebied in de nabije toekomst zullen = opschuiven,=20 is moeilijk te voorspellen, maar voor de molecuulbouwer is zeker de = uitspraak=20 van Alan Kay van toepassing: 'The best way to predict the future is = to=20 invent it'.=20

Een toekomst die hoge eisen zal stellen aan de moleculaire = wetenschapper. Bij=20 het aandragen van fundamentele oplossingen voor veel van de problemen op = het=20 gebied van energie, gezondheid, grondstoffen en milieu zal het maken en=20 veranderen van moleculen vaak centraal staan. Dit avontuur heet = 'ontdekking door=20 creatie' en is voor mij de stimulans de intellectuele creativiteit van = het jong=20 talent aan de universiteit tot bloei te laten komen.=20

Hierbij moet niet het leren vragen beantwoorden maar juist het leren = vragen=20 stellen, wat vaak veel lastiger is, weer tot de kern van ons academisch=20 onderwijs gaan behoren. Voor de ontwerper van moleculen is niet de vraag = 'Waarom?' maar juist de vraag 'Waarom niet?' de belangrijkste. =

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VERTICAL-ALIGN: top } TH { VERTICAL-ALIGN: top } SUP { LINE-HEIGHT: 13pt } A { COLOR: #eb2717 } A.redlink { COLOR: #eb2717 } A:hover { TEXT-DECORATION: none } H1 { FONT-WEIGHT: bolder; FONT-SIZE: 13pt; MARGIN: 10pt 0px 3pt; = LINE-HEIGHT: 120% } H2 { FONT-SIZE: 10pt; MARGIN: 3px 0px; LINE-HEIGHT: 120%; FONT-STYLE: italic } H3 { FONT-WEIGHT: bolder; FONT-SIZE: 9pt; MARGIN: 3px 0px; LINE-HEIGHT: 120% } H4 { FONT-SIZE: 9pt; MARGIN: 0px; LINE-HEIGHT: 120%; FONT-STYLE: italic } UL { PADDING-RIGHT: 0px; LIST-STYLE: square url(menu_red.gif) outside; = PADDING-LEFT: 10px; PADDING-BOTTOM: 3pt; MARGIN: 0px 0px 3pt 10px; = PADDING-TOP: 0px } LI A { COLOR: #000000; TEXT-DECORATION: none } LI A:hover { TEXT-DECORATION: underline } SELECT { FONT-SIZE: smaller } #selectform { MARGIN: 3pt 0px 6pt } TABLE.view { =09 } DIV.entry { MARGIN-BOTTOM: 6pt; WIDTH: 98% } .entry DIV.title { FONT-WEIGHT: bold } .entry DIV.summary { PADDING-LEFT: 30px } .entry DIV.more { CLEAR: both; PADDING-LEFT: 30px } .entry H3 { FONT-SIZE: 9pt; MARGIN: 1pt 0px; LINE-HEIGHT: 11pt } .entry A { COLOR: #000000; TEXT-DECORATION: none } .entry .more A { COLOR: #eb2717; TEXT-DECORATION: none } SPAN.tab { PADDING-RIGHT: 2pt; PADDING-LEFT: 2pt; BACKGROUND: #dddddd; = PADDING-BOTTOM: 1pt; COLOR: #999999; MARGIN-RIGHT: 2px; PADDING-TOP: 1pt } A.tab { PADDING-RIGHT: 2pt; PADDING-LEFT: 2pt; FONT-WEIGHT: bold; BACKGROUND: = #eb2717; PADDING-BOTTOM: 1pt; COLOR: #ffffff; MARGIN-RIGHT: 2px; = PADDING-TOP: 1pt; TEXT-DECORATION: none } A.tab:hover { BACKGROUND: #e92717; TEXT-DECORATION: none } DIV.totop { TEXT-ALIGN: right } .totop A { FONT-WEIGHT: normal; FONT-SIZE: smaller; COLOR: #000000; = TEXT-DECORATION: none } DIV.label { PADDING-LEFT: 3px; FLOAT: left; VERTICAL-ALIGN: top; WIDTH: 140px; = FONT-STYLE: italic } DIV.value { WIDTH: 380px } INPUT.resultsel { BORDER-RIGHT: #eb2717 1px solid; BORDER-TOP: #eb2717 1px solid; = FONT-SIZE: smaller; BACKGROUND: white; BORDER-LEFT: #eb2717 1px solid; = COLOR: #eb2717; BORDER-BOTTOM: #eb2717 1px solid } INPUT.resultnav { BORDER-RIGHT: #eb2717 1px solid; BORDER-TOP: #eb2717 1px solid; = FONT-SIZE: smaller; BACKGROUND: #eb2717; BORDER-LEFT: #eb2717 1px solid; = COLOR: white; BORDER-BOTTOM: #eb2717 1px solid } SPAN.open { FONT-WEIGHT: bold; FONT-SIZE: smaller; COLOR: #eb2717 } IMG.floatleft { FLOAT: left; MARGIN: 0px 5px 3pt 0px } DIV.floatleft { FLOAT: left; MARGIN: 0px 5px 3pt 0px } TABLE.floatleft { FLOAT: left; MARGIN: 0px 5px 3pt 0px } IMG.floatright { FLOAT: right; MARGIN: 0px 0px 3pt 5px } DIV.floatright { FLOAT: right; MARGIN: 0px 0px 3pt 5px } TABLE.floatright { FLOAT: right; MARGIN: 0px 0px 3pt 5px } A.basecolor { COLOR: red; TEXT-DECORATION: underline } A SPAN.basecolor { COLOR: red; TEXT-DECORATION: underline } A.basecolor:hover { TEXT-DECORATION: none } A SPAN.basecolor:hover { TEXT-DECORATION: none } A.more { PADDING-LEFT: 15px; BACKGROUND: url(menu_red.gif) no-repeat left = center; COLOR: #eb2717 } TABLE.nwo { BORDER-COLLAPSE: collapse } 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white } #menu A { PADDING-RIGHT: 0px; PADDING-LEFT: 15px; FONT-SIZE: 8pt; BACKGROUND: = url(menu_white.gif) no-repeat left center; PADDING-BOTTOM: 0px; COLOR: = white; PADDING-TOP: 0px; TEXT-DECORATION: none } #menu UL { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; LIST-STYLE-POSITION: outside; = PADDING-BOTTOM: 0px; MARGIN: 10px 0px; COLOR: white; PADDING-TOP: 0px; = LIST-STYLE-TYPE: none } #menu LI { PADDING-RIGHT: 5px; PADDING-LEFT: 4px; FONT-WEIGHT: bold; FONT-SIZE: = 8pt; BACKGROUND-IMAGE: url(dash_white.gif); PADDING-BOTTOM: 3pt; = PADDING-TOP: 3pt; BACKGROUND-REPEAT: repeat-x } #menu LI.active { BACKGROUND-COLOR: #fb2717 } #menu LI.sub { PADDING-RIGHT: 5px; PADDING-LEFT: 10px; FONT-WEIGHT: normal; = BACKGROUND-IMAGE: none; PADDING-BOTTOM: 3px; PADDING-TOP: 1px } #menu LI.sub A { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; BACKGROUND: none transparent = scroll repeat 0% 0%; PADDING-BOTTOM: 0px; PADDING-TOP: 0px } #main { LEFT: 199px; MARGIN-LEFT: 1px; WIDTH: 799px; POSITION: absolute; TOP: 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