Professor Wendy Bickmore, MRC Human Genetics unit, Edinburgh
This year is the 60th anniversary of the discovery of the structure of DNA by James Watson, Francis Crick and Maurice Wilkins, aided by Rosalind Franklin. Weíre all familiar with images of the DNA double helix from school textbooks, newspapers and even company logos. But the reality is a lot more complicated, as more than two metres of this elegant twisted ladder has to be squished into the nucleus of each one of our cells, and then it has to be organised, copied and used.
To find out more about how our cells achieve this incredible feat of packing, I spoke to Professor Wendy Bickmore from the MRC Human Genetics Unit in Edinburgh.
Wendy - We used to know what a gene was. We could identify it from the sequence of bases in the DNA because they obviously coded for proteins. So, we could the start of a gene which we call a gene promoter and then the bit of the gene that codes for the protein. And so, we can say, the gene starts here and it ends here. But now, what we realise all of a sudden is actually, that isnít all the gene comprises. A gene needs that core bit of sequence that codes for the protein and the promoter thatís going to drive the transcription of that bit of DNA into RNA, but it also needs an increasingly complex surrounding region of the genome to help control when and where, and how strongly that gene is expressed in development.
Kat - Because obviously, we have somewhere between 20,000 and 30,000 genes. They're not just on all the time in all our cells.
Wendy - No. I think one of the Ė maybe disappointing things in the sequencing of the human genome was that actually, we didnít have very many more gene than a worm has and I guess we felt affronted by that. We thought we were a bit more complicated. So, the realisation since that time has actually been, itís not how many genes youíve got, but what you do with them, how you control them.
Kat - Not what you got, itís what you do with it that counts.
Wendy - Absolutely, yes.
Kat - So, if you think about these 30,000 genes scattered through the millions and millions of base pairs of DNA that we have that it adds up in every cell of our body to about 2 metres of DNA. How is it organised? How do you compress all that into the nucleus of a single cell and then start to switch genes on and off in the right time and the right place?
Wendy - We actually think the two problems are actually intimately connected. So, if you think about the 2 metres, your DNA thatís going to fit inside the cell nucleus which is probably about on average 10 millionth of one metre in diameter, thatís a kind of a big packaging problem and itís about more than a thousand fold of condensation of the DNA sequence youíve got to do. And people used to think, ďWell, thatís just an issue of space and youíve got to get in the space, and you just squish it down.Ē
Now, we realise actually, itís how you do that squishing and folding that helps to control whether a gene is able to be activated and read in a particular cell type and not in another one. So, I think if you think of the Ė you know, people make the analogy of the human genome as a book Ė encyclopaedia or instructions of how to make an organisms Ė you can't read the page of instructions when the book is closed. The book has got to be open to the right chapter and the right page to actually read the recipe for that particular gene and particular cell type. So actually, opening and closing down regions of the genome in terms of the way the string is folded up is actually intricately tied into whether the gene gets switched on or switched off.
Kat - To use that string analogy that you just mentioned, if you have a gene and then you have the enhancers that kind of tell the gene, ďBe on. Be offĒ how far away from the actual gene themselves can they be?
Wendy - In terms of the actual DNA sequence themselves, we know that the controlling elements, what we call the enhancers can be 1 to 2 million base pairs away from the gene. Itís an extraordinarily long length in terms of just a DNA sequence. But in terms of real spaces inside the cells, what does that mean? So thatís the question that really interests me. And we think that an enhancer can act upon a gene as long as itís within about half a micron distance, so a half a millionth of a meter.
Kat - So, itís got to be kind of close enough to get a sniff of the gene and turn it on.
Wendy - Well, thatís one model of how enhancers work. Does the enhancer of the piece of DNA that is the enhancer Ė I donít know Ė so it actually have to come over and touch the gene and switch some magic way, communicate with it directly? Or is it some other mechanism that doesnít really require the two bits of DNA to directly talk to each other. I prefer perhaps the model where they talk to each other indirectly by sharing proteins.
Kat - So, it's kind of just a lump of stuff and they're all part of this complex and thatís how the information gets transferred.
Wendy - Yes. They both hang out in the same part of the cell nucleus where there's high concentrations of goodies to turn genes on.
Kat - Another aspect of your work that always interested me is that in all our cells, we have 23 pairs of chromosomes. Thatís 46 lengths of DNA string. How are they organised? Are they just all mixed up like 46 bits of string in a bundle, or do different chromosomes hang out in different places?
Wendy - Yes, our genome is not a plate of spaghetti. If we take the pasta analogy a bit further, itís probably a bit more like gnocchi. So each individual chromosome occupies its own space in the nucleus which we call a chromosome territory and we can see that because one of the great things about the human genome is, because itís so complicated and large, we can actually see it with and light microscope. And we can use fluorescent tools to actually see individual genes and individual chromosomes so we can paint chromosomes in different colours, so we can see that the chromosome territory for chromosome 18 which you might paint in red is in a very different and distinct place from the chromosome territory for chromosome 19 which you might paint in green. So, we can kind of do colour by numbers of the human genome.
Kat - And these pictures are very beautiful, but they're also Ė at least some of them are very static. What do we know now about how our DNA is moving around in the nucleus of our cells during normal life?
Wendy - So, if we step back and look at the chromosome territories that we just talked about, they're quite static. So, a chromosome is not able to move say, from one side of the nucleus to the other side of the cell nucleus within the lifetime of that cell. But an individual gene within that chromosome territory might be able to pop in and outside of the chromosome territory. So, we can actually see that happening in living cells. So, individual genes are pretty mobile, but again, constrained. We think of it as kind of dog on a leash. So, it can run around at will, but only so far. You're tied to the lamppost so you can't get to the other side of the road.
Kat - And is this tied into how they might be interacting with these enhancers, these switches as well?
Wendy - Absolutely, so if we watch a gene moving in a living cell, itís able to freely move. The dog on a leash can move over the space of about half a micron which is exactly the distance in the nucleus that an enhancer can work on a gene. So, for an enhancer to be able to contact a gene, itís got to be on a leash thatís long enough to kind of wander over that nuclear space and find it.
Kat - Where do you think this kind of research is going to go next? What are the real questions that you want to try and get handle on?
Wendy - I'm interested in both the basic mechanism of how something a million base pairs away can communicate to a particular gene at the right time and place of development. So, what are protein factors involved? Does it really involve the chromosome folding over and touching? But also, interested in how this plays out in human genetic variations, so a lot of the differences between us are in the bits of DNA that donít code for protein sequence and the non-coding bit which we now know as full of this regulatory enhancer DNA. So, how do these very subtle changes in our DNA sequence between individuals affect the way we look, risk factors for various diseases, how high we are for example, or the colour of our eyes?
Kat - Or even things like how we behave?
Wendy - And of course, behaviour as well. I mean, the brain is a biological organ. It's controlled by gene expression so no reason to think that some behavioural traits aren't going to be due to single changes in these enhancer elements.
Kat - And what are you really excited about that seems to be just coming to focus now?
Wendy - I'm really excited by technology developments actually. Theyíve really opened our horizons. We used to be constrained, looking at one gene at a time and doing very small scale experiments. Now, we can scan across whole genomes between multiple individuals and different types of cells, and really bring a much more comprehensive view of the genome.
Kat - That was Professor Wendy Bickmore, from the MRC Human Genetics Unit in Edinburgh.