Video transcript: Neverending DNA and immortal worms

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February 2012

Dr Aziz Aboobaker from the University of Nottingham

Video shows clips of him collecting samples of water from public parks

Well I am Aziz it is nice to see some of you again it has been a while and we have been continuing our work with the so called immortal worms and since those first set of videos came out a lot of people have been in touch asking about how do we know whether these worms are really immortal.

Video shows a microscopic view of planarian worms

So these are planarian worms that are free living worms that live in fresh water lakes and ponds. You can probably go to your local park and if you have a pond or river you go the river's edge or the bank hopefully you can find some of these worms. The reason we use them in research is because they have amazing powers of regeneration.

Video shows various cross-scetions of planarian worms

They have a population of adult stem cells and this population of stem cells allows them to regenerate and some people refer to them as immortal. I think the best demonstration of that is to show you the regenerative capacity of one individual worm so in there I have a population of worms boxes and boxes that I can show you that all come from one worm that has been cut again and again into smaller pieces.

Video shows a scapel being used to cut a planarian worm in half

What literally cut?

Dr Aziz Aboobaker
Yes we have taken a worm and cut it into several pieces and each piece goes and generates a whole new worm and we can just keep doing that.

So that is really the best demonstration that they might be immortal and this led to, in 1814, a guy call Dalyell was referring to them a immortal under the edge of a knife almost immortal under the edge of a knife.

Video shows a refridgerated room full of boxes

So in here we have our stock of planarians, flat worms and we keep our stock here so if people want to do experiments they can come and take worms and take them to the lab and do various things with them and chop them up, inject them, knock out genes, look for different genes express and what they do. The stock that we have we work with mainly come from one individual worm so I am just going to show you at the moment how many worms we have from that one individual. We have to promise not to play the Benny Hill music back when you speed up. They will start moving soon.

Video shows Dr Aziz Aboobaker placing about five big tupperware containers onto a table and opening them up to reveal hundreads of worms floating (alive) in fluid

All from one worm?

Dr Aziz Aboobaker
Yes all from one worm. Well they are going to be clones of each other so during a normal life cycle the animals actually when they get to a certain size fish are naturally all we have done is speed it up for convenience so every worm in here because it came from one individual should be a clone of the original worm bearing in mind mutations may have occurred during cell division and DNA replication and some individuals might have acquired differences from each other but essentially yes they are going to be clones of each other it is such a shame you can't see any of it but often you see them on the side stretched out ready to fission you sort of see them on the edge of the box their heads pulling away from the tail.

The first worm the pre generator you know the mother of all these worms how do you choose that one? It is a special time or was it arbitrary?

Dr Aziz Aboobaker
It was arbitrary yes we just picked one worm we had from a stock sent to use from another group that has been working with these worms for a lot longer than we have and we just started cutting it. That first worm was probably cut into three and those three were cut several times and so forth. So this is one demonstration of how the worms are immortal we can get all these worms from a single individual. It would also be possible to keep one animal happy it shouldn't die it should respond to food, grow a bit, shrink a bit when it doesn't get any food and as long as it doesn't get infected with anything it should live forever but of course we would like to test that so as a scientist we have slightly high standards of proof.

Video shows hundred of worms wriggling around in a deep petry dish

So one way to prove they are immortal would just be to stay here forever and just watch an individual worm and show it just kept living and keep looking after it unfortunately that's not very practical at least not for an individual scientist so there are other ways we can try and test whether these worms are immortal. So for animals to be immortal there are certain things it must be able to do ok, so for example with human beings we get older so our ability to heal our ability to replace our skin cells gets worse as we get older we get crinkly and start to get creases under our eyes etc and part of that is because as we get older our ability to replace our aged cells decreases and the way we replace our cells is just like the worms is from pools of stem cells so we have stem cells just like the worms but there is a big difference between our stem cells in our bodies than the worms. Stem cells in the worms appear to be able to just keep dividing on and on without any limit as you can see from the number of worms. All those worms have come from individual worms growing from cuts making new worms they eat and get bigger and then you can cut them again and make more worms so those stem cells keep dividing. We don't do that we get fatter and thinner during our lifetime but generally we get older and older and eventually old age is basically a lack of our bodies ability to keep repairing the normal damage of wear and tear that happens during our daily life.

But humans go on forever don't they we do kind of reproduce and more of us exist like the worms?

Dr Aziz Aboobaker
So what that is sexual reproduction so the way we reproduce is we have egg and sperm come together and a new embryo develops and a new individual forms gives rise to new life. Part of that process is rejuvenation of the stem cells in a sense so in a sense if you like our germs lines our stem and our eggs are in a sense immortal because they keep being used to reproduce new animals so on and so forth. These worms are asexual the worms I have shown you today are asexual in a sense that they don't go through that bottle neck of having an individual egg cell and individual sperm cell come together.

At various intervals the video shows live planarian worms swimming around in fluid (water)

They just have a pool of stem cells that consistently rejuvenate the animal. So what we did was we sat down a few years ago we made a list of things we would expect in an immortal animal to be able to do in terms of molecules so we go down and look at the DNA of these animals and how the DNA is maintained. There is a list of criteria that must be true for the stem cells of these animals to keep going to allow them to be immortal and we kind of put them in temporal order of when they would become a problem and the first one in terms of temporal order is the ability to actually maintain the length the ends of the DNA inside the cell so in all animals whenever a cell divides the DNA needs to be replicated.

Video shows Dr Aziz Aboobaker holding a string apart, then knotting it, then adding another piece of string to illustrate his point

So if you imagine I take this piece of string as an example as a model of DNA and DNA has a string shape obviously tied into a double helix and during cell division we need to make an exact copy of all the DNA in a cell and this DNA process essentially involves, if I get another piece of string, getting an enzyme called a preliminaries and just copying the DNA along, ok, but there is a problem with that process and the mechanics of the process which are quite complicated but essentially what is means is that you need a piece of DNA at the to act as a primer or a beginning point for this preliminaries to bind and synthesise new DNA and as a result of the process what actually happens is the very end of each string of piece of DNA each chromosome doesn't get replicated properly by this mechanism so you lose it. As we get older and our stems cells in our body keep diving the DNA at the ends of the chromosomes get shorter and shorter.

Video shows Dr Aziz Aboobaker chopping the string with a pair of scissors

The reason it isn't bad news because all animal chromosomes have protected structures at end which consist of sequence in a sense doesn't matter so much because it doesn't code for genes and these structures are called telomeres and they are maintained by an enzyme called telomerase so there is a balance between telomerase activity which re-extends these chromosome ends and cell division so as cell division occurs these telomeres these special structures get shorter and telomerase comes along and makes them longer again. But there is a limit to the extent to which telomerase does this and that is very important actually for human aging and human health in general. I will explain why in a minute. But essentially what happens in stem cells is that you get the chromosomes end gets to a critical length and the cell decides well that's it I'm not going to divide anymore because I've reached this critical length if this end gets any shorter I am going to start damaging genetic material that is important and decides that well the only way to cope with this actually is to stop dividing and that's because in those cells telomerase is longer active to keep re-lengthening the chromosome end.

One theory of human aging is that aging is a result of the lose of chromosome ends resulting in the ability of stem cell they actually loose the ability to divide.

So in cancers for example where cells keep dividing its almost all cancers 90% of cancers have actually re-activated the telomerase enzyme when they shouldn't and these cells keep dividing so if you like ageing can be seen as a balance in some respects between ageing, ok you want to live for as long as you can and you also want to avoid cells that divide out of control and they way to control that is to put that length limit on.

Video shows a microscopic view of a planarian worm

So we sat and thought about the worms and if they are immortal they must have a method for overcoming this problem so they must have a way of keeping the ends of the chromosomes intact and if they don't have this they probably can't be immortal because the chromosomes ends will get shorter and shorter and the genetic material will eventually be damaged and they would not be able to keep going. So we have apotheosised this is what you sit down and think and how can we test this we apotheosised that these animals would have a method of indefinitely as in forever potentially maintaining chromosome ends and we went and tested that idea. So the way we do that is we actually looked at these animals and looked at two things one is the activity of the enzyme telomerase and whether it is there at all and whether it is able to maintain the chromosome ends and then we also measured the length of the chromosomes and what we found was really exciting we found that if you had a worm and you kept it in culture but you didn't cut it and you didn't allow it to fission naturally the chromosome ends just get shorter and shorter and for us we take that to mean aging which is obviously bad but we don't take those worms and allow them to fission we allow them to regenerate or we cut them so we artificially cut them and make them regenerate the chromosome ends actually recover and get longer.

So these animals have the ability to rejuvenate their chromosome ends we is what we predicate if they were immortal so one of the criteria they would need to full fill for being immortal worms has been the fulfilled so we are really happy with that result because it fits in with our ideas that these animals might potentially be immortal.

So the skill which my graduate student Thomas Tan developed was to be able to measure two things one was the actual length of the telomere structure and to do that he had to essentially take worms which he knew the age of or he knew how long it was since they last regenerated and grind them up, run their DNA the DNA which corresponded to the telomere on a gel and take a radioactive probe and throw it on the DNA and that allowed him to measure the length of that end structure.

Video shows Dr Aziz Aboobaker pointing to the published research which shows a diagram comparing DNA lengths

I can actually show you if you like what that looks like between my fingers you can see here one of our animals that hasn't regenerated for about 3 months and we've taken that animal and we have cut it, let it regenerate, then measure the telomere length ago. Yeah so when Thomas first came to me and showed me some of these gels and experiments I just thought he had got them the wrong way round because obviously they don't fit with what we necessarily expect of an animal which has a lot of cell division, an animal which is getting older we would expect the telomere to get shorter.

But this is expected as well.

Dr Aziz Aboobaker
Well yeah it was very surprising to get such a clear result though my first reaction to him was you've just loaded them the wrong way round so instead of getting young and old you've got old and young essentially and of course you had to go back and do all the experiments again and convince me that this was what he was seeing so that was a eureka moment yeah for me.

Video shows the tupperware conatiners Dr Aziz Aboobaker opened up earlier, then earlier footage of his 2008 research days and responses on YouTube

So those first videos are made in 2008 so that was 4 years ago now and the questions some of the people ask are they really immortal? Are you sure? Part of the impetus for doing this work so obviously when I went to give formal talks to other scientists but also talks to the public and also the feedback from the YouTube videos was that are they really immortal? How do you know? It was kind of a circular question and we thought it must be a way if we sit down and think about it we can actually get some way towards either proving or disproving that this is really the first step we made the radical step we've made towards proving that the imperial that the data we collected so in the way the view has kind of helped cos we would have shyed away from this question because it is quite a difficult one it was pretty hard work to do this work so we would have shyed away from it but actually a lot of the feedback we got from public engagement was that can you prove it? And so we have gone some way towards that.

The public drives trends and fashion and pop music and films so why not science? Science can be a part of that well I mean obviously there is also the major goal which is to find out things which are useful or find out things which will advance our knowledge in a way that underpins human health, underpins medical research or the work that we do but I think that the public can also be involved in the science in a very active way and become interested in the science in the same way that they are interested in all these other things. Why not? I don't see a problem with that. Because obviously it makes you think if 20 people write a comment are they really immortal and have a little discussion about how you could prove it how you couldn't prove it I mean however naive some of them are that really as a scientist you have to take note of that and go a lot of people seem interested in this so maybe this something we should do.



Videos by Brady Haran.

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