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.

travelling salesmen

A conversation with a friend about PKR has prompted me to write a bit about one way by which your body processes information and solves problems to keep you healthy. Please bear in mind that I'm not a human biologist - or rather I'm a biologist who does not study humans - so this might be a bit rough on any specialists out there. Please call me on my mistakes.

Your immune system is a miracle of rare device and here's a bridge over any chasms in your memory. When a foreign agent (such as a virus, bacteria or fungus) enters your body, if you are lucky, it will encounter a dentritic cell (DC for short). DC are highly mobile cells which guard your skin, the lining of your nose, lungs and intestines and will engulf any invader. You can see two DCs in action on wiki, the one on the left somewhat pathetically drags a fungal conidia around while the one on the right enthusiastically gorges itself on four whole ones. Ha! The unfortunate condia will then be broken down - digested - and parts of some of its proteins will be used to inform the rest of your body about the attack. The DC will migrate to a lymph node and present these little snippets of protein (an antigen) to T-cells.

cute dog from here

OK, so the faithful DC has made it to the lymph node and hopefully presents its chewed-up bit of fungal conidia protein as an antigen on its surface. Your body has population of around 25 million different T-cells which can recognise various different antigens. The DC will sit relatively still in the lymph node (having changed shape en route) and the smaller T-cells will rush by. If the antigen 'matches' a receptor on the surface of a T-cell then the two will bind quite tightly and the T-cell will pause. These T-cells will become killers; once activated by having matched an antigen to their receptor, they will go off and kill other cells - your other cells - that are presenting the same antigen on their surfaces. You see, other cells in your body will very nobly advertise that they are infected by a fungus (or whatever) and the activated T-cell will assist their suicide and prevent you from being overrun (with fungus or whatever).

But there's a problem here; very low numbers of a specific antigen are presented to very very many T-cell receptors. How can your body be sure to test all possible T-cell/antigen combinations efficiently? Remember that time is essential - once a bug gets inside you it can reproduce every 20 minutes or so and you want to nip that exponential growth early. Joost Beltman et al didn't buy the standard explanation - that T-cells would 'run and tumble' to a set program, say run for 2 microns and then tumble twice to find a new direction and hence sample lots of antigens. Even though it looks very much like that in real fluorescent-labelled cells and here in Beltman's simulation.

ah the inimitable xkcd

Running and tumbling is quite a complex thing for a cell to do. Is there an internal clock? How does a cell know how many runs to a tumble will be best? Are there any mutants out there; people with T-cells which only run or tumble insistently? And such behaviour is not appropriate at all times - once out on the prowl looking for sick cells to kill, should a T-cell be quite so giddy? No is the short answer; Beltman convincingly shows that the physical structure of the lymph node makes for efficient sorting by forcing T-cells into little turbulent streams. I think that this is a really neat solution to the problem. Take a moment to enjoy the slightly nauseous viewpoint of a T-cell being turbulently sorted. So there's no need for a complex run/tumble program. It's also noteworthy that Beltman and co. used a nice combination of real-life observations, maths and computer simulation and then went back to do some more RL observations.

To some extent (and with hindsight) the problem was a bit of an artifact created by the methods everyone used to view T-cell dynamics in the lymph node. Because fluorescence detection can easily become saturated only a small portion of T-cells could be labelled for viewing, so only a few individuals in a crowd could be tracked. But running and tumbling is not such a bad idea...plenty of cells are famous for just that sort of thing and even have some fascinating receptor dynamics and I'll talk about them in a future post.

I just love the way that nature solves these problems, getting that turbulent flow just right is a feat of engineering and fluid dynamics. Then using physical structure to tackle an NP-complete problem, well you've gotta admire it.