Grijze Muizen

Grijze Muizen
VPRO Noorderlicht / 25 min / 28-09-1999
In Amerika melden vrijwilligers zich al bij laboratoria aan voor experimentele verjongingskuren. Allemaal onzin? Toch niet. Want sindskort is de basis ontdekt van veroudering op celniveau en is het bovendien gelukt dat proces om te keren. Een dergelijk verjongingsmiddel is echter niet zonder risico’s…

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VPRO NOORDERLICHT – TRANSCRIPT
AFL. ‘GRIJZE MUIZEN’
DOOR JOS WASSINK

00:00

LEADER NOORDERLICHT

00:20

DR. RON DEPINHO,
DANA FARBER CANCER INSTITUTE, BOSTON
These are the mice that we have genetically engineered and they show signs of accelerated aging. Let’s take a look.
There are two features here that are readily apparent: in one case we have a mouse with hair loss and in another we have hair greying.

01:00

MUZIEK ‘WHEN I’M SIXTY-FOUR’, THE BEATLES

TITEL GRIJZE MUIZEN

BEJAARDE BOKSERS
portretten met foto’s van vroeger

GERRY SPAAY (63):
Ik had vroeger een kop met zwart haar, en dat is nu allemaal grijs geworden en je krijgt gelaatstrekken. Maar verders, lichamelijk… Ik ben wat zwaarder geworden uiteraard. Kilootje of vier, vijf zwaarder dan toen ik wedstrijden bokste. Dat is eigenlijk het enigste.

WIM EN PIET VAN KLAVEREN (69):
P: Ik heb lucht genoeg, ik loop gewoon, ik eet gewoon. We zijn wat zwaarder als vroeger natuurlijk, dat natuurlijk als element.
W; Grijs worden, en de kaalheid neemt wat toe.
P: Maar van zichzelf, lichamelijk merk ik het niet hoor. Beslist niet.
BOKSERS IN TRAINING

KAREL HOOGENDOORN (62):
Ik heb langer rust nodig na m’n training en dat merk ik wel. Vroeger ging ik vanuit m’n werk trainen en nu als ik thuis kom, dan krijg ik wel m’n bakkie koffie, maar dan ga ik lekker gestrekt op de bank, want dan ga ik lekker m’n rust nemen.

DICK VRIENS (63):
Ik bedoel als je nu ‘s avonds thuis kom, dan ben je afgeserveerd.

02:26

DR. RON DEPINHO,
SHOWING THE MICRO-INJECTION LAB:
So this is where we do our mouse engineering. We manipulate our stem cells here, using standard techniques for gene targeting and homologous recombination and then we take these manipulated stem cells and we inject them in embryos and that’s done with equipment that makes use of micro-injection stations such as this in which these micro-manipulators are used to pick up cells and inject them into embryo’s. To generate mice that will harbour the mutation that we have engineered.

03:20

BEELD: MITOSE; ANIMATIE TELOMEREN; CELKWEEK

COMMENTAAR
Veroudering, zo heeft men ontdekt, heeft te maken met inkorting van chromosomen. Bij iedere celdeling worden de chromosomen gekopieerd, maar gaat er een stukje van het uiteinde van het chromosoom verloren. Deze uiteinden heten telomeren.
Telomeren worden wel vergeleken met de plastic uiteinden van veters. Bij iedere deling rafelt het uiteinde een stukje uit en uiteindelijk kan de cel niet meer delen en sterft.
Menselijke cellen bereiken dit stadium na zo’n vijftig, zestig delingen. In een celkweek komt de groei dan tot stilstand en ook in het lichaan raakt de rek eruit.

04:00

BEJAARDE BOKSERS:

WIM EN PIET VAN KLAVEREN:
W: Je hebt gauwer een beetje pijn in de knieën, maar vroeger was
je niet zo gauw stram als tegenwoordig.
P: Ja, je bent wat stijver geworden natuurlijk he.

KAREL HOOGENDOORN:
Ze hebben dus kraakbeen uit me knie weggehaald en toen heb de dokter tegen me gezegd: je moet geen touwtje meer springen, want dat constant springen dat is nadelig.

GERRY SPAAY:
Zal maar zeggen vroeger kon ik met me handen zo met gestrekte benen zo de grond raken en nu kom ik net over me knieën. En dat wordt ieder jaar wordt dat iets minder. En dat heb ik met die chrirug opgenomen en hij zegt dat is gewoon een kwestie van die tussenwervelschijven, die zijn versleten.

04:40

DR. RON DEPINHO
The issue of how telomeres relate to age related manifestations in the organism relates in part to the fact that telomeres are important for cell division.
The ability to maintain organs, such as the skin or hair as a function of age require constant renewal, having short telomeres and diminished proliferative capacity would adversely affect those processes, so would lead to things like balding for example.

05:26

BEELD:
MICRO-INJECTION STATION; CELDELING; ANIMATIE TELOMEREN.

COMMENTAAR
Verkorting van telomeren, wat hetzelfde is als veroudering, blijkt vreemd genoeg een omkeerbaar proces te zijn. Zo begint ieder embryo met telomeren van volledige lengte. Blijkbaar zijn deze telomeren in de geslachtscellen van de ouders tot de oorspronkelijke lengte teruggebracht.
Geslachtscellen zijn hiertoe in staat dankzij een speciaal enzym: telomerase.
Door genetische manipulatie heeft DePinho het telomerase uit weten te schakelen waardoor de muizen binnen enkele generaties te kampen kregen met korte telomeren.

DR. RON DEPINHO:
These are genetically engineered mice and we have here a mouse that is of similar age, that does not show these signs of aging. It does not have any hair greying and it has full coat of hair and as you can see it’s larger and healthier than mice that are genetically engineered.
It tells us that the genetical manipulation that we have caused in these mice have predisposed these mice to some signs and symptoms of aging. Not all of them, but a subset of them.

07:03

STADSBEELD NEW YORK

COMMENTAAR
Aan de Rockefeller University in New York werkt de van oorsprong Nederlandse celbiologe Titia de Lange. Zij ziet duidelijke paralellen tussen Ron DePinho’s experiment met muizen en de ouderdomsverschijnselen bij mensen.

PROF. TITIA DE LANGE
CELBIOLOGE ROCKEFELLER UNIVERSITY, N.Y.
Ron’s experiment is absolutely striking, it’s a spectacular experiment. And the result is visually striking because this mouse goes bold, it has a bold patch and it looks rather like some of my friends. There’s a region of the mouse where there’s no longer any hair. And it’s really a striking example of how you can create mouse model systems that really faithfully recapitulate certain aspects of human biology.
So what does it really tell us?
The mouse has shortening telomeres and it goes bold. Well, it tells you that in a whole organism, this view of that the shortening of telomeres can limit the lifespan of cells actually turns out to be true. Because the boldness most likely is due to some depletion, some loss of cells that normally create hair and the mouse is no longer able to do that.
Now let’s turn it around and ask: my friends who are slightly bold, are they bold because their telomeres have run out on their head. And a lot of people jump to that conclusion. One of my colleges here at the university immediately came over and wanted me to inject his head with telomerase. That’s a hard conclusion to draw, because the systems are different and male balding is a different phenomenon than hair loss in a mouse and so it’s not immediately clear that human hair loss is due to telomere shortening but it’s a really good possibility.

09:13

BEELDEN LABORATORIUM

COMMENTAAR:
Er is een samenhang geconstateerd tussen korte telomeren en ouderdom. Maar zijn korte telomeren ook de oorzaak van ouderdom? Of slechts een gevolg? Deze vraag heeft lange tijd het wetenschappelijk debat over telomeren bepaald. Tot in 1997 een experiment aan de South Western University in Texas degenen die het proces van telomeerverkorting als oorzaak van veroudering zagen, gelijk leek te geven.

PROF. TITIA DE LANGE:
What really changed the field and really and ended this whole debate whether telomeres shortening could be causal in aging was an experiment in which people reversed this process and that experiment was made possible through the isolation of an enzyme that can add telomeres back to chromosome ends. Once that enzyme was isolated, the gene that encodes the enzyme was cloned, was made in large amounts and could be used to then put the gene back into these cells and the cells then would express that enzyme and actually now no longer have shortening telomeres, but keep their telomeres in tact. And those cells when grown for two months didn’t stop dividing.. And in fact, this experiment was done two years ago and the cells are still growing. They’re in California and they’re still turning and turning. And they behave as immortal cells.

10:42

BEELD: LAB. TEXAS
NERVEUS MUZIEKJE

COMMENTAAR
Het spraakmakende experiment dat gewone cellen het eeuwige leven wist te geven werd uitgevoerd door de celbiologen Woody Wright en Jerry Shay.

PROF. JERRY SHAY
SOUTH WESTERN UNIVERSITY, TEXAS I can remember very clearly when we saw the first research experiment that indicated that simply introducing telomerase in the normal cells turned on the enzyme telomerase. It was interesting, because I was looking at it with two of the postdoctoral research fellows in the laboratory. And when I saw that jar, I said: you guys remember this because this is the first evidence that a single protein, a single gene could actually turn on this whole enzyme complex. And at that point we didn’t really know that it would extend the lifespan. It was several months later that we actually found that out. But it was very very exciting time for me.

11:32

PROF. TITIA DE LANGE:
What Jerry Shay and Woody Wright did was reintroduce telomerase in cells in the lab and these cells are really truly immortal. And this has now been done with a large variety of different cell types and in some cases it seems that some other genetic changes are required to immortalise the cells, but for quite a considerable number of cells, telomerase activation seems indeed to be sufficient to immortalise the cells. So extrapolating from that to the human body -and there is no reason we could not extrapolate from that, because the cells these people work with were cells taken directly from the human body- it should be possible to create the same situation in people. Introduce telomerase and make a patch of cells somewhere in your face that keep growing for ever, won’t senescence.

12:28

BEJAARDE BOKSERS IN TRAINING

COMMENTAAR:
Telomerase als verjongingsmiddel. Zou daar nou belangstelling voor bestaan?

PIET VAN KLAVEREN (69):
Het zou dom zijn als ik neen zou zeggen natuurlijk.Als er een bepaald midel uitgevonden wordt als verjongingskuur, daar stap ik absoluut in natuurlijk.

DICK VRIENS (61):
Daar zou ik totaal niet in geloven. Ik zou ook daar geen preparaten voor innemen.

WIM VAN KLAVEREN (69):
Dat zou prachtig zijn als die chromosoomverderlingen als je die wat jonger zou krijgen dan schreidt de ouderdom ook achteruit.

GERARD VAN MEEL (66):
Ja dat ligt er een beetje aan, daar zullen dus ook wel andere kanten aanzitten aan zo’n verjongingskuur, neem ik aan. Dan denk ik dat goed zou moeten weten allemaal voordat ik daartoe zou overgaan.

13:30

PROF. TITIA DE LANGE:
Well, I must tell you that it’s striking to me the number of people that are really interested in having this done. I actually get emails from people who volunteer to come to my lab and function as some sort of experimental guinea pig and I would then do telomerase therapy to them. And there is a fairly strong commercial endeavour on going to elaborate on these plans and to try to really create a situation where some population of cells were taken out of the body, their telomeres elongated, telomerase restored in the cells and to put back in.

14:12

BOKSER MET BOKSBAL

PROF. TITIA DE LANGE:
So the worry with this kind of approach would be that you make cells that inappropriately grow and the reason why this is a real worry is that we’ve known now for about ten years that there is a specific cell type that has done that. It has done exactly that experiment. It has been able to activate telomerase, and has been able to achieve inappropriate extended growth or immortalisation in human bodies and that type of cell is the cancer cell. So we now know that almost human tumours have found a way around this telomere problem.

15:01

MICROSCOOP: GROEI KANKERCELLEN

PROF. TITIA DE LANGE:
And so when you think about this, nature is actually telling us something, tumours -almost all human tumours- activate telomerase, and so what we would be doing if you take cells from the human body and activate telomerase in those cells, you really would be doing something that cancer cells do and so it’s possible that you would actually promote tumour genesis and increase the frequency of cancer occurrence in people by introducing telomerase.

STADSBEELDEN BOSTON

15:39

COMMENTAAR:
In Boston werkt Ron DePinho aan het Dana Farber Cancer Institute. Ook hij is zich bewust van de relatie tussen telomerase en kanker. Maar volgens hem biedt die link juist een veelbelovend perspectief voor de kankerbestrijding.

DR. RON DEPINHO:
The idea is that if you can turn off telomerase in a cancer cell, that that would then lead to shortening of telomeres, genetic chaos and catastrophe and ultimately that cell would not survive because it’s genetic information would not be stable and the cancer cell would die. This is why there is a significant amount of interest and excitement in trying to design therapeutic agents that would inhibit telomerase in cancer.
And those activities, although not yet fully mature, are almost certainly going to lead to excellent compounds that will inhibit telomerase. And such agents would be expected to have a very potent impact on cancer cell growth.

16:51

COMMENTAAR:
Telomerase als doelwit van kankerbestrijding zou dus kunnen leiden tot een nieuwe klasse van chemotherapie. Hoe reëel is die verwachting?

PROF. TITIA DE LANGE
It sounds like a fairly good target and I think, as always is the case, one really doesn’t know how an inhibitor is going to work in he clinic until one actually puts it in people. I think we’ll see that happening within the next few years. And I’m optimistic and I hope that a good drug will come out of the telomerase research that will help people treat many cancer, maybe not all but many cancers in an improved manner.

17:40

COMMENTAAR:
Titia de Lange zelf heeft fundamenteel onderzoek gedaan naar telomeren. Ze wilde begrijpen waarom en hoe telomeren zo’n belangrijke rol spelen bij veroudering en kanker.
Onder de microscoop worden telomeren zichtbaar als oplichtende puntjes. Wanneer telomeren te klein worden, sterft de cel. Dit leek een algemeen geaccepteerd gegeven, maar Titia wilde begrijpen waarom.
Afgelopen voorjaar werd haar zoeken beloond.

PROF. TITIA DE LANGE
It’s now become clear what is going on. In our body, every single cell that we have, has a very vigilant mechanism to look for broken DNA. This is very important. As we sit here, we’re getting radiated from outer space and our DNA is broken all the time and it doesn’t really harm us too much, unless we fry ourselves in the sun, because there are enzymes that see these breaks, that find the broken DNA and then fix it. And if they can’t fix it, the cell is wired such that it dies.
And if you think about that, that’s really a problem: because, as you know, our genetic material is not just one long piece of DNA, but it’s organised on seperate chromosome. And each chromosome has a piece of DNA in it, our body, our cells are carefully looking for broken DNA all the time and so, why are they not panicked constantly by the fact the that are so many DNA ends in our cells that are just the natural ends of our chromosomes?
Why do the cells not pay attention to that DNA, why do they ignore that. So I thought well maybe what’s the case is that this DNA is not just sitting there as DNA, but there are proteins that recognise that boring sequence that go and sit over it and form a big complex and sort of cap the chromosome end. And now the cell can’t see that there is an end of the DNA because there is sort of a little cap right over it.
Now that was my working hypothesis, and I worked with that hypothesis in mind for the last ten years. And I was completely wrong. It’s one of the greatest things in science that it’s wonderfull when you’re wrong. So, what we did is we isolated these proteins and lo and behold they were there and they were very interesting proteins. And in fact if we took them off the telomeres, cells were: oooh! chromosome ends and died immediately. So it looked like we were right. And we were fairly pleased with ourselves, ’cause we had this working hypothesis and got the proteins and it all turned out to be right. But we were so wrong. The whole solution to the problem is very different. What these proteins do is they take the telomeric DNA, the special sequence DNA, take the end of the chromosome and tuck it back in. Very similar to just sticking your hand in your pocket, that’s what the proteins do.
The cells have very simple solutions to this telomere problem. This is a chromosome and it’s very long. This chromosome stretches out way across the water there way to the your airport where you’re leaving from etcetera, etcetera. But at the very end of the chromosome, the DNA rather than just sticking out, you can see forms a large loop. This is what we call a T-loop, for a telomere loop. And the deal is that the proteins that we’ve been working with for so long, don’t really cap over the end, but they execute this looping job. They take the telomeric DNA, move it back and tuck the end back into the chromosome. And now it’s very obvious, of course the cells don’t see that their chromosome ends, because there really are no chromosome ends. Our chromosome don’t end in anything. They loop back and hide their ends very effectively inside of the rest of the chromosome.
So what does that really tell us about this whole aging and cancer story. Now, you can now understand why cancer cells are so carefull to activate telomerase. Because they need to maintain they nice little loops at their chromosome ends. If they don’t have those loops, the cells will see the chromosome ends as broken DNA and they will die. So the cancer cells MUST maintain these loops. And similarly you can understand, or imagine at least, how in our aging cells the cells may notice that the telomeres are gone. Because as the telomeres shortens, the loop will get smaller and smaller, but in the end this piece of DNA will be so tiny that, even though my proteins are very good at making these loops, can no longer do this and then the thing floops out and the cells will realise that they will have ends to their chromosomes, and they will react to the ends as if it is broken DNA. And we know that the way cells react to broken DNA is just like an aging cell: it either dies or it stops dividing just sits and it’s just like what happens in the aging cells in our body.

23:18

WIM EN PIET VAN KLAVEREN:
W: Dan maar gezond ouder worden.
P: Ja, hoe realiseer je dat?
W: Ja, gezond ouder worden. Niet vergeetachtig worden zoals jij.
P: Er zijn mensen die leven zoals de wereld het niet toestaat, die worden 93. Er zijn mensen die lopen in het gareel die worden 63.
W: Als je zo mooi lichaam gehad heb van Onze Lieve Heer, om dat op een bepaald manier zo te verzieken. Met ander woorden: je longen kapotroken, je eigene helemaal lam eten enzovoorts enzovoorts. Dat is zonde. En dat is jammer

AFTITELING

SAMENSTELLING & REGIE Jos Wassink

RESEARCH Ger Wieberdink

CAMERA Willem Heshusius

GELUID Charles Kerstens

MONTAGE Jack van Doornik
MIXAGE Jack Bol
KLEURCORRECTIE Hans Buitink
LEADER Bob Takes
COMMENTAAR Tessel Blok
REDACTIE Hansje van Etten
Hilbert Kamphuisen
Simon Rozendaal
Karin Schagen
Annemiek Smit
Marjan Tjaden
Jacqueline de Vree
Jos Wassink
Monique van de Water
Ger Wieberdink

ARCHIEFMATERIAAL NPS
BBC
Oxford Scientific Film

MMV Sportvereniging ‘Ick Waek’,
Rotterdam
Ferry Barendrecht
Nancy Robinson, Geron Corporation
Jim Horner
Lynn Emerson
Tod Ringler
Prof Jan Hoeijmakers,
celbiologie Erasmus Universiteit

ONDERZOEKERS Steven Artandi
Maria Blasco
Lynda Chin
Roger Greenberg
Carol Greider
Jack Griffith
Jan Karlseder
Peter Lansdorp
Han-Woong Lee
Lennard Rudolph
Agatha Smogorzewska

PRODUCTIE Madeleine Somer
Karin Spiegel
EINDREDACTIE Rob van Hattum
Copyright � VPRO, 1999
24:30

english version