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