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  • >> Ladies and gentlemen welcome to the 2013 Royal Society GlaxoSmithKline Prize

  • Lecture. I'm Jean Thomas, I'm the Biological

  • Secretary and I have the housekeeping duties of asking you to turn off your

  • mobile phones, please, because the lecture is being recorded and webcast.

  • And also, to tell you in the that actually, I hope, unlikely event that

  • there's a fire, you don't go out through the usual doors but you, because of the

  • snow and whatever, you go out through these doors instead.

  • So, 2013 is the Royal Society Year of Science and Industry.

  • This is the year when the society will showcase excellence in UK industrial

  • science and strengthen links between the society industry and academia.

  • The Royal Society recognizes that world class research and development in the UK

  • industry is essential for transforming innovative ideas into commercially

  • successful products into its economic growth and securing the science space.

  • And it will be proactive in anticipating, understanding, and responding to the needs

  • of industry's scientists. Symposia and meetings with high industry

  • interests have been added already to the society's calender which already includes

  • longstanding initiatives in scientific excellence, such as the Royal Society

  • Industry Fellowship and the Brian Mercer Awards for Innovation and Feasibility.

  • So, the year of science, science and industry will bring a renewed focus on

  • engaging with the industrial sector to develop cogent arguments that high level

  • investment in the UK science space is essential for international

  • competitiveness. Something we would all, I'm sure, sign up

  • to. Now, to the prize and the lecturer, the

  • Royal Society GlaxoSmithKline Prize and Lecture is awarded biannually for original

  • contributions to medical and veterinary sciences published within 10 years of the

  • date of the award. The prize consists of a very nice gold

  • medal, an even nicer check for 2,500 pounds, and the recipient is called upon

  • to deliver an evening lecture at the Royal Society which is why we're all here this

  • evening. And this is really a, a capacity audience,

  • and the reason we're a few minutes late starting is that there is an overflow

  • room, and I don't remember that in the last, certainly, in the last four years of

  • chairing these evening lectures. So, Adrian has really put in a big crowd

  • tonight. So, no pressure there, Adrian, at all.

  • It was, the award was initially established following a donation from the

  • Wellcome Foundation. First award was made in 1980 the centenary

  • of the work and foundation and since 2002, it is being supported by GlaxoSmithKline

  • Limited. So, this year's recipient of the prize is

  • Adrian Bird an old friend and colleague, I'm delighted that he's received this

  • award. Adrian has held the Buchanan Chair of

  • Genetics at the University of Edinburgh since 1990.

  • And he's a member of the Wellcome Trust Center for Cell Biology in Edinburgh.

  • His research focuses on the basic biology and biomedical significance of DNA

  • methylation and other epigenetic processes.

  • His laboratory identified CpG islands as gene markers in the vertebrate genome.

  • And he discovered proteins that read the DNA methylation signal to influence

  • chromatin structure. Mutations in one of these proteins, MECP2,

  • and I'm sure we'll hear a lot more about this, this evening, causes the severe

  • neurological disorder Rett Syndrome, which is the commonest genetic cause of mental

  • retardation in females. Adrian was made a Fellow of the Royal

  • Society back in 1989. He's received several awards, numerous

  • awards for his work, including notably the Louis-Jeantet Prize for Medicine, the

  • Charles-Leopold Mayer Prize of the French Academy, and the Gatineau Prize.

  • This evening, it's the turn of GSK and the Royal Society to give him this special GS

  • Royal Society, GSK prize. And has to give his lecture in order to

  • earn that. His lecture is entitled, as you can see,

  • Genetics, Epigenetics, and Disease. So, Adrian, over to you.

  • >> Thank you very much, Jean. Thank you very much for this award.

  • It's a great honor to, to be asked to give this lecture.

  • And thank you very much for braving the elements to come and listen.

  • I think, probably the title of Genetics, Epigenetics, and Disease is broad enough

  • that it sounds like it's going to change all our lives in this next 45 minutes.

  • But in fact, I'm going to focus on a relatively small part of it ultimately.

  • But I'm going to start off reasonably broad.

  • There's one deliberate mistake on the, the first slide.

  • I hope it's the last one. It's the year.

  • So let's go back in time to the draft sequence of the human genome because this

  • was a, heralded as a, a time when biology really became a, a hard science.

  • If you like, it was seen as the, the beginning of the end.

  • We now knew the entire code for all, we knew the sequence of all the genes

  • required to make a human being. But it's pretty clear that it was actually

  • the end of the beginning. And the somewhat apocalyptic predictions

  • that now one simply had to automate, the discovery of all the medical innovations

  • that would result from the genome sequence was premature.

  • In fact, it's likely in my opinion that there's still another century of biology

  • to be done and this will be an exciting century of discovery converting the

  • promise of the genome into the reality of biomedical applications.

  • And that, one of the issues I think that, that, that we would really love to be able

  • to solve, a big, a big question if you like, is where DNA, despite being the

  • thread of life, you can put it in a tube and gaze, gaze at it for as long as you

  • want and it remains utterly dead. So the question is really what does it

  • take to make it alive? When Craig Venter synthesized a bacterial

  • genome an important synthetic biology milestone, it had to be put into a living

  • cell before it became alive. How can one bypass that?

  • As the chemists say, you only really understand something if you can make it.

  • We can't actually make life but it would be good to know some of the rules required

  • to do that. So, some key unanswered questions about

  • the genome that, that remain and this is only a selection.

  • First of all a basic fact, genes make proteins, here is the chromosome, here is

  • the sequence of the genes, there is the RNA.

  • It encodes the sequence of the amino acids that lead to the protein that folds up to

  • then do all the lifelike things that are required.

  • But how are only the right genes expressed in a cell type?

  • This has been a question, a long standing question.

  • Do we know the answer to it? Why globin is expressed in blood cells and

  • keratin is expressed in skin cells, etcetera.

  • We, we approximate knowledge about it, but actually, there's an enormous amount to

  • find out. Most of the genome is actually

  • inaccessible. This is this gray, it's rather difficult

  • to look at this picture I think because the DNA is gray and looks although it

  • should be in the background but this is a nucleusome, the repeating unit of the, of

  • the chromosome, if you like. The fundamental repeating unit.

  • And the DNA clings to the outside of it. And proteins that want to make genes

  • active, can't actually get at the DNA properly.

  • So, how does the gene activation machinery gain and how does it keep access?

  • Again, we have some beginning answers to this, but we don't, by any means, have a

  • full picture. Protein-coding DNA sequences are only 1%

  • of our genome. So, if you look at a piece of the human

  • genome, you see these vertical stripes correspond to the bits of this gene that

  • are separated from each other. In fact genes are fragmented and they are

  • a tiny minority of all the DNA. What is the rest of it for?

  • There is an enormous, there's a vast majority that is, that we can't explain.

  • This isn't the case with all organisms. This, for example, is yeast, and you can

  • see now the genes are packed together. It's difficult, it used to be said

  • casually that the rest of this DNA was just junk.

  • But now, it's sort of almost politically incorrect to call it junk.

  • It's particularly after the encode project which found lots of potential regulatory

  • sequences throughout here. So, this other DNA is doing stuff.

  • And perhaps, it's doing stuff that makes for example, humans and other mammals far

  • more complex than yeast. So finally, there are questions almost

  • sociological questions. Does the environment have any impact on

  • gene expression? And this is a, a question I'll allude to

  • in a moment. But it's not one that is the main subject

  • to this, this talk. So, I put in the title Epigenetics because

  • I'm quite mine, our work is quite often described as epigenetics.

  • It literally means above or in addition to genetics.

  • But the definition has been controversial and I'm just going to skim somewhat

  • lightheartedly over some of this because it's, it's at meetings to do with

  • Epigenetics. One can see various opinions expressed

  • with varying degree, this one I believe was in Barcelona with great vehemence.

  • So, let me just try to sort of consolidate this.

  • The original epigenetics definition comes from Conrad Waddington, who was actually

  • my predecessor as Buchanan Chair, Chair, Chair of Genetics in Edinburgh.

  • And what he meant was in contrast to pre-formationism, but the development

  • proceeded by the gradual unfolding of the information in the genes, to produce the

  • whole organism. So, for him, how information of the genes

  • is read during embryo, during embryonic development to give the whole organism was

  • the essence of what epigenetics was about. We would now call this developmental

  • biology. How the genotype gives rise to the

  • phenotype. But it's acquired, or a sort of, a special

  • status in epigenetics, really, because of this iconic picture, the epigenetic

  • landscape. I'm not going to dwell on this either.

  • Because quite honestly, having had it explained to me several times, I'm never

  • totally sure, exactly how this helps. It's a picture of a bull rolling down a

  • hill. The number of options for the bull get

  • progressively less. But I don't feel that this encapsulates

  • anything very useful. This, however, is a fundamentally

  • important question that remains on our agenda.

  • Second definition of epigenetics which is rather different has actually different

  • origins epistemological origins. How characteristics are inherited across

  • cells or organism generations without changes in the DNA, its sequence, itself.

  • An example of this is this cat, the so-called tortoise shell cat, or calico

  • cat, in, in, in the US, which has these patches of fur.

  • It has two x chromosomes. One of them has a gene that gives black

  • fur, the other one has a gene that gives orange fur, and cells early in

  • development, inactivate one or the other of those chromosomes for, for reasons we

  • don't, which I will, I will come back to actually, a little bit later.

  • And you get a patch of skin because the cell that originally inactivated the

  • orange fur gene gave rise when it divided to cells that did exactly the same thing.

  • So, that was inherited. All the gene or the, the DNA is still

  • there in these cells, in, in the orange ones, and the black ones, but there is

  • difference that is inherited and that's epigenetic according to this definition.

  • So, heritable traits of this kind might be influenced by the environment.

  • And this is sort of revitalized that an ancient argument about nature versus

  • nurture, where nature is genetics, the idea that we're, our genes are, are in

  • control and nurture is the opposite, the idea that our environment determines who

  • we are. Of course, it's a mixture of both but

  • epigenetics has given a, a, a new lease of life to the nurture argument.

  • And so, one can see articles such as this and there are many examples I could have

  • chosen why your DNA isn't your destiny, the new science of epigenetics reveals how

  • choices you make can change your genes and those of your kids.

  • Now, I'm not an expert on some of the epidemiology behind this, but the, the

  • molecular biology, in my opinion, is far less convincing than it is for other

  • aspects of epigenetics. It is, however, an extremely interesting

  • idea, that the environment can give rise to changes that get passed on, but it is

  • systematically overstated in a lot of places one finds it described.

  • So, one has to be circumspect about the, this kind of argument in my opinion.

  • There are couple of excellent examples in plants, in worms where immune, immunity is

  • involved, but some of the more sociological aspects, in my opinion,

  • require further evidence. So, I'm sticking with this as my example

  • of heritable epigenetics. It's closer to the molecular biology we

  • actually understand. So, Epigenetics 3, biological significance

  • of the epigenome. Another definition, it's risen

  • pragmatically. What is the epigenome?

  • Well, here is a genome of a, of a cell. It's, it's the chromosomes that were

  • obviously designed for an experiment because there are fluorescent pinpoints

  • here. Ignore those, that's a human chromosome

  • compliment. If you explode those chromosomes, you see

  • beads on a string and this is that repeating unit I referred to earlier, the

  • nucleosome with the DNA going round the outside.

  • It looks like beads on a string. So, the epigeno, epigenome refers to

  • markings of those beads, of that string of beads in such a way that the region, it is

  • regionally, regionally adapted to its function.

  • So, for example, there can be a region where gene is stably ON, and there is a

  • whole plethora of marks that appear that reinforce that decision.

  • And similarly stably here, a gene OFF, such as the black-coat gene in our orange

  • patch of fur. And again, you get adaptation, and this is

  • the epigenome, and the study of what the epigenome means, is another definition of

  • epigenetics. So, you have DNA methylation here where

  • these methyl groups are added to the DNA. You can't do much to DNA without changing

  • its propterties, its important properties. Almost, the only thing it seems you can do

  • is put these methyl groups on and even that is bad in a way.

  • I don't have time to go into, it causes an increase in the frequency of mutations.

  • But the, by far, the most elaborate way of marking the chromosomes, is via these

  • beads which, invisibly on any of the structures I've shown you before

  • previously, have tails. And these tails are basically ticketing

  • entities that you can add chemical information to.

  • That the cells can write information in the form of chemical alterations.

  • And so, you add this and, that says, stably ON or stably OFF.

  • Again, we have the broad outlines. We can correlate quite a lot of these with

  • activity and silence. But if you were to ask exactly what each

  • of these modifications does, we have, still have a lot to learn.

  • So, if you like, it's the, epigenetics is the structural adaptation of chromosomal

  • regions so as to register signal, or perpetual, perpetuate altered activity

  • states. And importantly, proteins that read these

  • marks, write the marks, or erase the marks, remove the marks are implicated in

  • human disease and quite a lot of excitement in pharma including GSK is

  • devoted to finding out what these drugs might be good for in terms of human

  • disease. So, epigenetics then embraces key unsolved

  • problems in Biology, how, how the genotype give rise to phenotype, that's the

  • Waddington one, how traits are inherited across cell or organism generations

  • without changes in the DNA sequence and how structural adaptation of the genome

  • facilitates gene activity programs. As far as I'm concerned, this is not a

  • word one needs to dwell on with sort of almost a theological interest about what

  • it means. Everything it possibly means is

  • interesting. So, let's get on with studying it.

  • And I, I like to think of it as how the genome is organized and managed to make

  • DNA if you like, come alive. So CG is one such signal it's one of those

  • marks and you'll notice CG is not actually a, a mark, it's actually a sequence, it's

  • a 2 based pair sequence. Dna sequences that recognize proteins are

  • usually longer than that because they're rarer.

  • If you have a sequence of one base, every few bases you come across it, and it

  • doesn't have much information. Two bases is not much better, but

  • nevertheless, as you will see, CG is used as a genetic signal and also as an