Saturday 21 February 2009

The Venus of Willendorf

How do we get from the information stored in DNA to us? From that now-famous linear sequence of Gs, Ts, Cs, and As to the living, breathing, molecular symphony of life? Well, I can't explain it (at least not all). But I can tell you about an amazing little machine that sits right on the cusp of that transformation and it is, quite probably, largely responsible for the way life has turned out. I'm talking about ribosomes and if you're not a biologist, then it's possible that you've not met one before, so please allow me to introduce you and may I also present the ribosome's more famous children; DNA and proteins. Ribosomes are, in my opinion the Goddesses of molecular biology, ancient, life-creating and humbling in their sophistication - and not dissimilar in shape to the lovely Venus.


Image from Wiki commons


Made famous by the human genome project and a nifty structure, DNA is probably a good place to start the tale, and wiki has a fine page about deoxyribonucleic acid, with some great images. But the gist for this story is that DNA consists of two opposing strands of nucleotides - or letters - and that A always pairs with T and C pairs with G. This means that if one strand reads AATTGCGA the opposing strand will read TTAACGCT. The strands have direction and this is important for their coding (by convention one strand is called 'sense' and is read left to right or 5'to 3'. The opposing strand is charmingly called anti-sense and runs 3' to 5'. The 3' 5' by the way, refers somewhat obliquely to the actual chemical structure at the end of the strands. This means that when one is given a random piece of DNA one can - with practice - tell which direction to read it. However, as with much of life, the sense or anti-sense requires context.

Image from this nice tutorial

In eukaryotes like us, DNA is stored in the nucleus of a cell, (number 2 in a previous post) but the message is actually utilised out there in the cytoplasm. So the part of the code we want to use - usually a gene - is first unwound and one strand is copied into RNA. Chemically RNA is much like DNA except for the addition of a little oxygen and hydrogen group: ribonucleic acid. Also RNA uses U rather than T, but otherwise the code still holds; C copies to G, T to A etc. Thus a mobile message is made which can be processed and exported from the nucleus. Copying a message before use is a smart idea, as those of us who have corrupted unique files know, and copying also allows for amplification. Ribosomes themselves are so highly abundant in a cell that the copying (transcription) of their genes makes prominent 'Christmas tree' structures of frenetic activity, indeed an entire substructure of the nucleus, the nucleolus, is dedicated to their processing and production.

The copied RNA message is processed before being exported from the nucleus, most eukaryotic genes contain internal sections (introns) that are removed before the message is read. Perhaps it will be useful to consider a gene as a section of DNA that encodes a specific function - as does a short program, say a Perl script, and the function can be edited a bit according to need, i.e. dropping a sub-routine. The nucleotide letters are the text, the coding regions of a gene are the functional lines of the program and the introns represent comments. So a gene can mean 'make a protein called PKR according to this sequence' or the same gene, with a bit of editing, can mean 'make protein PKRv2, which does not have this part here'. Genes also encode for ribosomes, even though ribosomes are not (entirely) made from protein: the main part of a ribosome is RNA. Like bricks RNA can do two - and more - things: structural (building a house) or carrying a message (a brick thrown through a window).

Compared to the staid DNA, RNA is a wayward genius, blithely rejecting a stable partnership with another strand and instead adopting a dazzling variety of 3-dimensional structures. This variety means that RNA can play several functional roles. RNA can be an information store - just like DNA - and many very successful viruses (e.g. smallpox) use RNA as their genetic repository. RNA can also function as an enzyme - breaking and making bonds - and this discovery fundamentally changed our view of the origin of life. Sidney Altman and Thomas R. Cech were awarded the Nobel prize in Chemistry (1989) for their discovery that the RNA transcripts of ribosome genes can process (or edit) themselves, this is called self-splicing.

The discovery that RNA could not only store information but could also 'do' things like self-splice was so staggering because until then these roles had been neatly divided between DNA (information storage) and proteins (the tools of the cell making structures and performing enzymatic tasks like digesting your lunch). But with this world-view how could life get started? We were in a chicken and egg situation - which came first and how did the roles become so divided? Discovering that the humble RNA could do both suddenly placed this molecule at the very foundation of all life on earth. Wow.

Image from Wiki commons

Above is an image of a small subunit of a ribosome, (a fully functional one consists of two such parts, small and large). The twisty tan part is RNA and the purple parts are proteins. As such the ribosome is an amazingly complex machine. In eukaryotes up to 80 protein components integrate with 4 strands of the RNA core structure. So, after processing, messenger RNA heads out of the nucleus into the cytoplasm where it will be read by ribosomes and the encoded protein will be synthesised. Once again - amazingly - it is the RNA that hogs all the essential functions, reading the genetic code, catalysing the synthesis of protein, carrying components of the new protein from other parts of the cell to the ribosome is done by RNA structures. Even proof-reading of the genetic code against the newly made protein is performed by the ribosome.

In a paper published this week Bokov and Steinberg describe a model for the evolution of ribosomes. The core part of ribosomes are mind-bogglingly ancient - 4 billion years old - and that really is the very dawn of life on this planet. Their work shows how modern ribosomes added parts and functions to an ancient core and that traces of this original - world altering - structure can still be discerned today. Imagine holding the Venus of Willendorf in your hand. This stone-age carving is about 26 thousand years old. The person who made her was a modern human just like us in every regard - except that the mountain of technology we now enjoy had not yet been created. Imagine carving that figure - it's highly skilled work - and the evident humanity in it grabs my heart. Well ribosomes are such statuettes revealing the common origins of all life and so sophsticated that we are only just begining to understand how they function.

At first I thought that the evolution of ribosomes initiated the end of an RNA-dominated world. After all ribosomes are genesis machines for proteins which dominate our cellular structures (OK as a protein scientist I might be slightly biased) but as new functions for RNA are discovered (and more Nobel prizes awarded) I suspect that we are still living in an RNA-world and just don't fully realise it yet. I'm sure that these other function of RNA will inspire future blogs but for now I will leave you with structure of a ribosome in your hands. Enjoy.

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