24 maart 2009 Martine Segers 25 reacties 1924x gelezen
Op zoek naar kenmerkende verschillen in de concentraties van duizenden metabolieten in bloed- of urinemonsters van gezonde vrijwilligers en zieke patiënten? Verbeteringen in de robuustheid van FTMS-apparatuur maken zo’n onbevooroordeelde zoektocht steeds beter mogelijk. Het moet biomarkers opleveren die de aanwezigheid van een sluipende ziekte verraden.
“Allerlei verschillende metabolieten meten in een cel of in lichaamsvloeistoffen is analytisch extreem uitdagend”, stelt Jan van der Greef, hoogleraar Analytische biowetenschappen in Leiden bij het Centrum for Medical Systems Biology (CMSB) en wetenschappelijk directeur van TNO Systems Biology Research. Allereerst is het aantal groot. Naast cellen en eiwitten bevatten lichaamsvloeistoffen ook nog tien tot dertigduizend laagmoleculaire stofwisselingsproducten, de zogenaamde metabolieten. Ze zijn essentieel voor het onderhoud, de energieproductie en de structuur van het lichaam.
Daarnaast is de chemische variëteit tussen de metabolieten enorm, licht Van der Greef toe. Zo is er een groot verschil in polariteit, waardoor het lastig is om veel metabolieten op dezelfde kolom te scheiden. En de verschillen in concentraties zijn ook nog eens gigagroot. De concentratie van de meest voorkomende metaboliet kan tot 109 zo hoog zijn als de concentratie van de metaboliet waar het minst van aanwezig is.
Die grote variëteit heeft ook voordelen. Het ontrafelen van de metabolietensamenstelling van een cel of lichaamsvloeistof levert enorm veel fysiologische informatie. Verandert de concentratie van een setje metabolieten sterk, dan is dat vaak een teken aan de wand. Met deze setjes van biomarkers zijn allerlei ontsporingen in het lichaam vroegtijdig op te sporen, is de hoop van Van der Greef, nog voordat ziektes zich uiten via lichamelijke symptomen.
Onbekende stoffen
Verbeteringen in massaspectrometrische technieken maken het mogelijk om steeds gedetailleerdere kennis over metabolieten te verzamelen. De laatste jaren nam de robuustheid van met name de FTMS-apparaten flink toe, volgens Van der Greef, die in Leiden door een subsidie van het Nationaal Regieorgaan Genomics de beschikking kreeg over de meest geavanceerde FTMS-apparatuur. “We kunnen nu duizenden monsters meten zonder steeds het apparaat opnieuw in te stellen. Voor een goede vergelijking tussen grote hoeveelheden monsters is zo’n geautomatiseerd systeem een must.”
Daarnaast is de resolutie van de MS-apparaten verbeterd. Door de data voor te bewerken, bijvoorbeeld door bekende grote pieken soms iets op te schuiven naar hun vaste plek in het spectrum, zijn steeds meer pieken goed van elkaar te scheiden. “Hierdoor kunnen we steeds lagere concentraties metabolieten meten, waardoor we vaker pieken van nog onbekende stoffen tegenkomen.” Die onbekende stoffen zijn lastig meteen te identificeren. Om grote hoeveelheden metabolieten in één spectrum uit elkaar te kunnen houden, kiezen de onderzoekers er namelijk voor om tijdens de eerste MS-meting al die metabolieten niet afzonderlijk te fragmenteren. Ze kiezen dan dus voor zachte ionisatie.
Als je geluk hebt kun je op basis van het nauwkeurige molecuulgewicht, de kracht van FTMS, al ontrafelen met welke stof je te maken hebt. Meestal lukt dit niet. Dan is een MS/MS-aanpak nodig, waarin geselecteerde stoffen met een bepaald molecuulgewicht na fragmentatie wederom geanalyseerd worden, wat in een FTMS instrument uiterst efficiënt kan plaatsvinden. En dan is het te hopen dat op basis van het nieuwe spectrum de structuurformule wel in elkaar te puzzelen is.
Met een FTMS-apparaat zijn monsters overigens ook zonder of met geringe voorbewerking direct te meten. Die aanpak wordt steeds populairder, volgens Van der Greef. “Het aantrekkelijke hiervan is dat je snel veel kunt meten. Dat levert aardig wat interessante meetresultaten tegen een relatief lage prijs. Als je geluk hebt, vind je meteen bekende metabolieten waarvan de concentratie tussen een gezonde en zieke cel groot is. Dan heb je snel een biomarkerpatroon te pakken.”
Humane genoomproject
De geneesmiddelenindustrie had lange tijd weinig interesse in het analyseren van metabolieten met massaspectra. Dat er met massaspectrometrie grote ontsporingen te zien zijn in het urineprofiel van de metabolieten van patiënten met een stofwisselingsziekte was allang bekend. Met massaspectra was in die tijd ook al het voorkomen van afbraakproducten van geneesmiddelen in bloed te bepalen. Je ziet dan ook andere lastig te verklaren piekjes in het spectrum omhoog of omlaag gaan. En dat was vervelend, want de Amerikaanse FDA voerde bij medicijnenregistratie lang het beleid dat alles wat afweek verklaard moest worden. “Dat betekende dat een medicijnenfabrikant zich veel meer werk op zijn nek haalde als hij een breed profiel met massaspectrometrie bepaalde.”
“Gelukkig heeft de FDA zijn filosofie nu omgedraaid.” De omslag in het denken van de FDA en vele andere onderzoekers kwam vooral na de voltooiing van het humane genoomproject, analyseert Van der Greef. Daarna gingen onderzoekers met DNA-chips ook via brede screeningsprocedures op zoek naar verschillen tussen zieke en gezonde cellen.
Onderzoekers zien nu legio toepassingen voor via massaspectrometrie opgespoorde metabolieten als biomarkers. Genees middelenonderzoekers kunnen hiermee sneller uitvinden of hun kandidaatgeneesmiddel wel echt het gewenste positieve effect heeft en zo beter inschatten of het het waard is kostbaar vervolgonderzoek te starten. Ook de diagnose van ziektes kan verbeteren met nieuwe MS-technologie, denkt Van der Greef. “Als je iemand wilt helpen, moet eerst de diagnose goed zijn. Nu krijgen veel mensen geneesmiddelen die bij anderen wel, maar bij hen helemaal niet werken.”
Ook in het voedingsonderzoek zijn de biomarkers interessant. Als je goede biomarkers voor het ontstaan van suikerziekte vindt, kun je bij proefpersonen sneller uittesten of een verwacht positief effect van een voedingsstof ook echt dat positieve effect heeft. “Daar zijn vroege biomarkers voor nodig, omdat ontsporing van het glucosemetabolisme een heel laat signaal is. Je wilt graag eerder weten of er wat aan de hand is”, vertelt Van der Greef.
Dit is wel tijdrovend onderzoek. Om zulke vroege biomarkers te vinden, moet je bloed verzamelen van gezonde vrijwilligers en tien jaar later bekijken of er karakteristieke verschillen zijn in de metabolietconcentraties tussen mensen die gezond bleven en mensen die in de tussentijd bijvoorbeeld diabetes hebben gekregen. De levensmiddelenindustrie zou met dergelijke biomarkers graag op zoek gaan naar voedingsstoffen die de ontregeling van het lichaam door beginnende suikerziekte ongedaan kunnen maken.
***Kader***
Ronddraaiende ionen
Met een hoge resolutie duizend ionen tegelijk analyseren. Dat is de kracht van Fourier Transform massaspectrometrie (FTMS). In een FTMS-apparaat zitten ionen gevangen in een magnetisch veld. Laat je ze vervolgens interfereren in een radiofrequent veld, dan gaan ze in steeds grotere banen ronddraaien tot ze dicht in de buurt komen van de elektrodes aan de rand van het magnetische veld. In die elektrodeplaten induceren ze vervolgens een stroompje; het signaal. Elk ion met een andere verhouding tussen massa en lading heeft zijn eigen radiofrequentie nodig om in een grote baan te geraken. Via fouriertransformatie is vervolgens te achterhalen welke verhouding tussen massa en lading (m/z-waarden) een signaal opleverde. Doordat de frequenties zeer nauwkeurig te meten zijn, levert FTMS heeft een hoge resolutie op.
Bron: C2W3, 2005
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