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ENCODE reveals junk DNA not junk after all -

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HideRobyn Williams: You're about to meet an Australian, one of the top researchers in the world, who says our brains work, we're conscious because of viral remains which are jumping around inside our heads. It's incredible stuff. He is Professor John Mattick, and he took over as director of the famous Garvan Institute in Sydney earlier this year. He's been known for years as disputing the furphy that most of our DNA is rubbish, filler, junk, holding together the real stuff that makes genes. Just like only 4% of the universe is matter, it doesn't mean that the rest is a waste of space. John Mattick:

John Mattick: When we discovered the human genome only devoted a tiny fraction of its DNA sequence to making proteins, it was immediately and universally assumed that the rest of it had to be some sort of evolutionary debris. That's one possibility of course.

Robyn Williams: Did it make you cross when they said that?

John Mattick: No, it didn't make me cross. Look, at the time this was happening, which was in the '70s, I was a PhD student and then a post-doc, so I was just emerging as a scientist myself. My overriding feeling in those days was how do these guys know so much?! Because I was still trying to absorb all this.

But I was really intrigued by it, and I became even more intrigued when it became obvious that everybody was sweeping this under the intellectual carpet. This was the biggest surprise in the history of molecular biology. Bob Williamson, whom you know and who was for many years director of the Murdoch Institute in Melbourne, wrote a wonderful editorial in Nature, the first sentence of which I'll never forget, he said, 'Once again we are surprised.'

And somebody once said the best science is done at the point of greatest surprise, then if that's true then that was not true for molecular biology because within 6 to 12 months the world all the way to Francis Crick had condemned these intervening sequences, vast tracts of stuff that became to be called junk, as non-functional, simply because it didn't fit this paradigm.

And I remember...I don't know if it was that night in the pub or sometime later, I thought to myself, hang on, there is another possibility and that is that this stuff, which is actually transcribed into RNA but not going on to make protein, may in fact be transmitting some other form of information.

Robyn Williams: And now there's ENCODE. The Economist magazine last month in a two-page spread called it 'The new world of DNA'. The journal Nature devoted an entire issue almost to ENCODE, yet another massive achievement in 2012 this year of mega science stories.

But back to junk, or non-junk, and John Mattick.

John Mattick: The weird thing which knocked everybody for six was that the messenger RNA was huge, and the protein coating sequences are just in tiny little blocks. Anyway, it was one of two possible hypotheses, that this stuff in the middle of genes which was made into RNA and then cut or spliced out was just discarded and recycled, and that ended up in all the textbooks without a shred of proof, but it was actually only one of two possible hypotheses.

The other was that, no, the RNA which was being spliced out was actually itself sending some information into the system. And when that occurred to me (this is in the late '70s) I thought, wow, I don't know if that's right, but if it is, that is very interesting because it means the system is much more complex, much more sophisticated and much different to the way we conceived it.

And then I fast forwarded in my head and just said, well, if this is important...I stressed if at this point...then it must be important to multicellular organisms because it blows out in multicellular organisms. The more complex we are, the more of this stuff we have. And I thought, maybe it's a parallel communication system that is organising the development of the system.

Robyn Williams: It's a software, it's a timing system perhaps.

John Mattick: Yes, I think that you've got to be careful about these analogies because some people take them too literally, but as a guide to the way of thinking about it I think that's correct. It's almost like the architectural instructions, the software for the assembly and operation of the system, whereas the proteins, the conventional genes, are the components of the system.

Robyn Williams: Sure. Let me give an analogy which is going to be unbelievably simplistic. I've got in my cells, and listeners have got in their cells, sufficient genes to be a teenager or a baby or an old person, someone who is in adolescence, and yet what we normally do is go through a sequence of events, so we're not suddenly a teenager tomorrow again (I wish I could be!) but we have a system whereby we age in a predictable way.

Similarly I've got in my cheek cells and my knee cells and my elbow cells the instructions to be livers, to be brains, to be all sorts of different tissues, organs, and yet the cheeks have got cheek cells behaving like cheek cells, the knees have got knee cells behaving like knee cells, they know what they have to do. So in terms of timing and identity, there is something coordinating them. Are we talking about that sort of coordination in the so-called junk?

John Mattick: Yes, that's a very good way of putting it. It's actually even better (or worse, depending on your point of view) than that, because these same set of genes that are differentially expressed in cheek cells versus bone cells in the knee or whatever are actually the same set of genes that worms in the soil have. So the other amazing thing that particularly came out of the gene projects a decade ago when they first sequenced human and mouse DNA and other species is we've got the same set of genes. It is not identical, but by and large humans have about 20,000 to 23,000 protein coating genes, so do all other mammals and vertebrates, C. elegans, and even sponge. And most of those genes code for proteins that have the same sorts of functions.

So it's really obvious when you stand back from it that not only do you need a differential timing and regulation thing to produce the 100 trillion specialised cells and also, more importantly perhaps, the architecture of a human. For example, Robyn, you and I have hundreds of muscles. Each one has the same sorts of cells, they can be slightly different in different muscle contexts, but much the same sorts of cells. But each one of these muscles and has a different architecture, different anchor points. You know, the muscles in your chest versus your face or your fingers. So the amount of information required to specify the architecture...and yet the muscle proteins, the genes, the coding for the muscle functional components, like myosin, are the same.

So it's about architecture, it's about development. So we use much the same set of proteins as most other animals. We have a few innovative ones that have come along, invertebrate or mammalian or primate evolution, but most of the evolution, most of the diversity between species and most of the differences between us as individuals is not in a part set, it's actually in this extraordinarily sophisticated set of instructions that orchestrates our development. And by the way, the thing you realise only when you look back from it is that the same set of systems has been rendered plastic in the brain, and that's the secret to the evolution of cognition as well.

Robyn Williams: Okay, so here we have 2012. It's been a huge year for science. We've got the SKA, the square kilometre array, with got the Higgs boson, we've got Curiosity landing on Mars, and now, just a matter of days ago, we've got ENCODE. What is ENCODE in terms of what we've just been talking about?

John Mattick: ENCODE is an acronym which really says we wanted to identify all of the functional elements in the human genome to see what the whole dynamics of the structure and outputs of the genome are, to get a better baseline for understanding human biology. It is really the second...the first ENCODE paper I think was published in 2007 which was an extensive analysis of 1% of the human genome as kind of a warm-up. That worked so well and produced such interesting information that the powers that be in the United States and the Wellcome Trust and other places around the world then funded this giant project where laboratories all over the world were analysing the human genome from one perspective or another. So it's a catalogue of functional elements.

Robyn Williams: An encyclopaedia, as you said.

John Mattick: Yes.

Robyn Williams: And it's showing what the biochemistry is of these different parts of the DNA.

John Mattick: That's right.

Robyn Williams: In summary, what does it now enable us to do?

John Mattick: It's given us an extraordinary catalogue of the different RNAs and proteins that are produced...actually one of the weaknesses, and I don't mean this as a criticism, I think everybody realises that it's a weakness, is that they primarily studied cell lines, not human tissues, largely because it was easier and different laboratories could be working on the same material. So it's a good catalogue. But for me, and I think for nearly everybody, it's a question of, well, what was the surprising things you found? It's nice to know you've got these proteins expressed in hair cells and these are neurons, but what's the headline here, what is the unexpected thing?

Well, it wasn't unexpected to me because it was obvious a long time ago, but in a sense the field has been dragged...I wouldn't say kicking and screaming so much, but certainly reluctantly to a conclusion they haven't quite fully grasped yet.

What they found was that at least 20% of the genome, based on only cell lines, so you can imagine what more were going to find when we get into the brain, which is much more complicated, based on limited analysis of 147 cell lines, at least 20% of the human genome shows evidence of being biologically functional. And at leased 80% of the genome has indices of biochemical function. That is, they produce protein or an RNA or they have some structure in the chromatin that's specific.

Only 1% of the human genome codes proteins. The rest of it, by and large, was considered junk, and now we've got a paper coming out saying it least 20% is biologically relevant, at the least 80% is biochemically relevant. And they are minimum estimates. So what's going on? The bottom line is that the old conception which came out of studying bacteria, that doesn't explain all of these functional elements. So the bottom line, which they hint at here but really don't say explicitly, is that we misunderstood the system for the last 50 years because of this apparently reasonable but ultimately incorrect assumption that most genetic information in humans is transacted by proteins.

You asked me before how I got into this, that was 30-odd years ago. Since then it has become increasingly obvious that the whole genome is copied deferentially, dynamically into RNA. And the short answer to that, because it has to be answered, you can't just say it's expressed and it's got to be functional, that's just one of two possibilities, the short answer, Robyn, is that the evidence is now pretty compelling that these RNAs are controlling the site specificity of the proteins that organise the genome, and organise it in different ways in cheek cells and knee cells. That's the bottom line.

Robyn Williams: One thing that I find rather peculiar, and I've talked to you about this before, when we have invaders, like particularly viruses, they colonise us, they make us do what they want done to make more of them. And so we've got traces in our genome of viruses. But one would expect that if they stopped being functional to make those more viruses, there'd be kind of scars in the DNA that would in fact be junk because they wouldn't be doing anything much because they are not making viruses. Have those traces been turned into something useful because they are there, those remnants of viruses?

John Mattick: I think the short answer is yes, but I think there's a better way of putting it. It was actually a very famous evolutionary biologist called James Shapiro in Chicago who gave me a heads-up on this. And those interested in this should go and read his stuff, he's brilliant. He pointed out to me that viruses have been part of the evolutionary conversation since time immemorial, maybe even before cells evolved. The viruses are packets of genetic information that jump around. And so they are extraordinarily not only versatile but also influential in the whole evolutionary process.

About half of our genome at least that we can recognise is derived from the signatures of retroviruses or what's called retrotransposons, but it's really a fine line between what is a virus and what's a retrotransposon. These are basically jumping bits of DNA. So yes, I think the general conclusion when people were shocked, another one of the many shocks that wasn't responded to well, that they find that much of the human genome was comprised of this stuff, it was assumed that this was selfish DNA. Books were written about it, that there was a graveyard of these viruses and retrotransposons, these nasty things.

But in fact there is another possibility which is again more interesting, that is that these retroviruses are not just agents of change in evolutionary time but they may have been domesticated and be agents of change in real time. And in fact a paper in Nature that I was privileged to be a minor co-author on early in the year showed that this is actually happening in the brain. These virus sequences are actually waking up in our brain and moving around, probably, this is just early days, but probably to create the extraordinary diversity that we need to have a functioning brain.

Robyn Williams: Viruses are helping us have functioning brains? That's extraordinary.

John Mattick: Viruses are not just things that invade us and give us the flu or something, viruses are things that move around, and they actually move around inside us as well. I mean, a much more mature and sophisticated way of thinking about viruses is as sequences that are mobile but where our system has made use of them and where they've contributed to our dynamics but we've domesticated them. So this whole simpleminded idea that genes make proteins and viruses make us sick and we just see the whole world through those lenses is wrong.

In fact I was privileged to be guest speaker at the Stanford Genetics Department retreat in Monterey in California couple of weeks ago, and the title of my lecture there…I said, well, I'm chief provocateur here today…was Most Assumptions in Molecular Biology and Genetics Are Wrong, and most of them are wrong because they are based on what were reasonable but ultimately false premises.

So I think everybody has to stand back now and say, okay, what do we know and what don't we know. There's a general assumption that the human genome is far more sophisticated than we were and still are, that evolution got there eons before we did and we have to sit back and just absorb this information and try to make sense of it, and assume, wrongly at the margins but I think largely correctly, that we don't yet understand fully enough that most of what we see in there is not noise, most of what we see in there is not junk. There will be some remnants of it, scars as you say, but that most of it is likely to be meaningful and functional and we've just got to have the wit and the patience to work out what it is.

Robyn Williams: And my final question; now you are back in Sydney at the Garvan Institute, are you still doing work at the bench?

John Mattick: I am now moved on, in a sense, to being interested in how this system has been rendered plastic in the brain. Sydney has fabulous neuroscience, and one of the attractions of coming here was to engage with that community. In the Garvan there's such fantastic opportunity here, so it's been a busy year. But I'm rebuilding the grid around the role of this junk DNA and the plasticity of these sequences, both the movement of the transposons, the viral sequences, and also rewriting the RNA sequence by context dependent enzymes as likely the molecular basis of cognitive processes. So yes, I get to the end of the day and I struggle to find a few hours to push along but once things settle down I'll be back there.

Robyn Williams: Terrific, thank you. Welcome back.

John Mattick: It's a great pleasure to be back, thank you Robyn.

Robyn Williams: The new director of the Garvan Institute in Sydney, fresh from many years at the University of Queensland. And I still find that idea of jumping viruses driving our brains astounding.

Guests
John Mattick
Executive Director
Garvan Institute
Sydney Australia
http://www.garvan.org.au/about-us/our-people/professor-john-mattick
Credits
Presenter Robyn Williams Producer David Fisher