Can we re-programme cells with the wrong numbers of chromosomes?

22 August 2017

Interview with

Dr James Turner, Crick Institute London

Scientists have discovered a way to put right cells that contain the wrong numbers of chromosomes - these are the chunks of DNA that contain our genes. Normally, human cells contain 23 pairs of chromosomes, with one of each pair coming from each of two our parents. But, occasionally, something goes wrong and one or more extra copies can crop up in some - or all - of our cells. This happens quite often in the sex chromosomes - these are the X and Y chromosomes you have if you're a man and the two X chromosomes you carry if you're a woman. About one in 500 men has an extra X chromosome in their cells, and this can affect their fertility by preventing healthy sperm production. Chris Smith spoke to James Turner, at the Crick Institute in London, who has potentially found a way to fix this, and possibly other problems like it…

James - You’re trying to set up in a dish a system for studying the precursors of these sperm cells in a mouse model. These are mice that have these equivalent conditions to what humans do so three sets of chromosomes instead of two sets of chromosomes. To do that the first thing that you had to do was to make stem cells from these animals because if you have a stem cell, a stem cell is essentially that can give rise to any cell of the body and can also renew itself, then you can prompt those cells to differentiate into sperm.

So we started by taking small pieces of skin from the ears of the mice that had these conditions and we performed a process called reprogramming; they essentially convert from being a skin cell back into a stem cell. When we did that we found, to our surprise, that a number of the stem cells that we recovered from this process of reprogramming had actually converted their sex chromosome number from three to two. For example, if we start with a mouse that was XXY and we recovered from that mouse stem cells that had an X chromosome and a Y chromosome, so the usual two sex chromosomes. This really surprised us because it suggested that the process of reprogramming is somehow correcting this chromosome abnormality.

Chris - If you do this experiment in a mouse that doesn’t have this chromosomal abnormality to start with so it doesn’t have XXY for example, it has just XY, does the same thing happen or is this purely happening in the context of when you start with an abnormal number of chromosomes?

James - That’s where things get really interesting. We do see loss of one of the two sex chromosomes if we start with an XY, but the frequency at which that happens is very, very low compared to if you start with a cell that has three sex chromosomes. The term we actually use is three sex chromosome biased chromosome loss or trisomy biased chromosome loss.

Chris - It’s almost as though the stem cell, when it’s being made, can count chromosomes, knows there’s something wrong with the number of chromosomes related to the sex chromosomes, and does something to correct the process?

James - Sure. That would be the immediate conclusion - a very exciting conclusion. Actually, what we think is happening is, potentially, something rather more pedestrian. We think that during the process of reprogramming what’s happening is that this is actually quite a stressful event for the cell to go through and so although we need to do more experiments to work out exactly what’s going on, what we think is happening is that if, at some level, within that pool of cells within a dish you have one or two cells that are spontaneously losing that extra chromosome, and that  when you subject those cells to reprogramming there is some selective advantage or better ability for those cells that are corrected to accelerate through the reprogramming process and divide perhaps more rapidly than the cells that retain the three sex chromosomes.

Chris - Does this process apply just to the sex chromosomes, or if I took an individual, say with Down’s Syndrome who has too many copies of chromosome 21, does that also correct itself?

James - Yes. We performed two experiments. We used the mouse model of Down Syndrome, so this is a mouse that carries a copy of human chromosome 21. We performed exactly the same experiment and what we found was that some of the stem cells that we recovered had indeed lost this copy of human chromosome 21. We think that this is probably just the tip of the iceberg. There could be many, many different sorts of additional chromosome-type abnormalities that could be corrected using this process.

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