Sam Janes, UCL
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Where do the cells lining the airway arise, and how does smoking affect them? A study recently carried out indicates that the airways of smokers age twice as quickly as non-smokers, having serious consequences for their health.
Sam - So, my name is Sam Janes, and Iím working as a Wellcome Senior fellow at University College London. For some time, many have felt that the organs of our body rely on stem cells to repopulate all the cells in our organs when we need them. So, these stem cells should be capable of producing daughter cells of lots of different types. Now, most of this has come from data from mice, where itís possible to track individual cells over time, but this has never been possible in humans. So, we were looking to see whether stem cells really existed in the airways, and in the lungs, there are cells that secrete mucus, there are cells that have little cilia on them, and there are basal cells which are chunky little cells which sit right at the bottom on what we call the basement membrane, which is like the pavement of the lining of the airways.
Chris - And those chunky cells, are they the stem cells?
Sam - From mice, it has been felt that basal cells are stem cells of the airways. So, I suppose that was what we were expecting to see with our work.
Chris - And now, tell us how you actually did this?
Sam - Itís quite a challenge in humans, because what we actually need to do this, is to be able to see a stem cell and then see how it divides and look at what we would call itís daughter cells to see what type of cells they are. And to do that in a human, is pretty well impossible on any internal organ in particular. But what we found was that there was a scientist, Sir Nicholas Wright at Barts and the London, and he had worked on a way of staining and seeing individual cells for an enzyme that was produced by the mitochondria within our cells. And what he found actually was if this mitochondria had some sort of genetic mutation, which just actually occurs by chance. If those mutations collected, eventually an individual cell would stop expressing that enzyme. Now that means that with this stain, you can see that cell and you can also see daughter cells which have come from that individual mutation.
Chris - Because they also carry the same mutation and therefore, will have the same funny staining pattern.
Sam - Exactly.
Chris - So, you can use this unique labelling of cells in order to track individual lineages of cells.
Sam - Thatís right. So, when we look down the microscope at these cells, so these are in patients that have undergone some sort of lung surgery and had an area of lung taken out. We put the stain on so we can see these cells that are lacking the enzyme, and when we actually pluck out these cells individually and test their DNA, we can prove that they are indeed all related.
Chris - And returning to the question you started with, which is what do these stem cells turn into? What do you find when you examine all of those clones of cells that have come from one source stem cell?
Sam - Well, what we found was actually pretty interesting. So, the individual clones of cells were all identical and within them, they had lots of different cell types. But there were two really important things. One, was that every cluster had a basal cell, whereas other cells were sometimes missing from these clusters. So, that means that the basal cells are indeed the progenitor cells, but what was really intriguing was that when we showed the results to a mathematician in Cambridge called Ben Simons, he looked at these and said, actually these arenít related and in fact, what these clones are doing is entirely by chance. So, in fact these arenít preprogrammed stem cells that are doing a particular job but in fact, basal cells that are just dividing by chance and so they may divide to reproduce themselves, they may divide to become a different type of cell type, or they may just die.
Chris - So, what are the implications of this?
Sam - There are a number of implications. The first is, as many of us know, thereís a great deal of research looking at regeneration of organs and thereís been a feeling that you must get the stem cells and understand what the stem cells of an organ are, to be able to regenerate it. Our data from the airways of humans suggests that that isnít the case - you simply need to collect a broad population of these basal cells. The second thing that was quite interesting was that we looked at non-smokers and compared them to smokers, and what we found in smokers was that the whole process is basically speeded up by two. Now this is quite important because, one, it suggests that the airways of smokers are aging twice as quickly as they should, but the second thing is, these clones are expanding twice as quickly. So, if you ended up with a clone with genetic mutation which may contribute to forming a cancer, then that clone is already spreading twice as quickly.
Chris - But going back to your method, is it possible that what youíre seeing is an artefact of the fact that the cells have a mutation?
Sam - Yes. So, thatís a really important point because youíre quite right. If the mutation led to some sort of advantage for these cells, then they may be expanding more quickly than we would expect. But, quite a lot of work has been done with these mitochondrial mutations, and these mutations arenít thought to effect the way the cells proliferate or survive at all.