It’s all about ribosomes

What is all about ribosomes?  Undoubtedly, readers will quickly make the connection between the title of this short essay and the recent awarding of the 2009 Nobel Prize in Chemistry to three whose work has centered on the ribosome.  The Nobel prize announcement emphasized the links between ribosomes and antibiotics, rightly focusing attention on the fact that many antibiotics target the bacterial ribosome, different as it is from its eukaryotic (cytosolic) counterpart in important ways.  What I want to do is to ramble on about some other aspects of ribosomes that I find fascinating.  Hopefully, by turning some features of biology on their heads, readers will think differently about genomes, gene expression, and other facets of molecular biology.

First, lets move beyond the clinical applications, step back for a few moments, and look at the ribosome in the cell.  With all due respect to plant scientists who hold up rubisco as the most abundant protein in nature, the ribosome is arguably the most abundant complex in nature.  There may be as many as 10^7 ribosomes in the cytoplasm of a mammalian cell, each consisting of four RNAs and more than 80 proteins.  The energy budget of a cell is similarly skewed towards the ribosome – I have read estimates placing the proportion of the cellular energy budget that goes to translation as being between 30%-75%.  For comparison, transcription is usually estimated as consuming 5% of the energy of a cell, and DNA replication a much smaller fraction than even this.  These are interesting numbers and should make one pause whenever statements to the effect that genome size may be selected for or against based on the appeals to energy efficiency.  When it comes to the gene expression machinery, it is translation that most significantly impacts the energy budget of the cell.

In eukaryotes, three of the ribosomal RNAs (or rRNAs) are encoded in a single transcription unit.  This unit is present in many copies, such that 200 or more copies of the rRNA transcription unit may exist in a typical genome.  The fourth rRNA (so-called 5S rRNA) is also encoded by a highly-repeated gene family (again, many more than 200 members).  Ribosome biogenesis is organized within its own cellular compartment (the nucleolus) and occupies the talents of more than 200 proteins (over and above the actual subunits of the ribosome itself).  In terms of protein, this amounts to between 2 and 10% of the total genetic resources of a cell.  In terms of gene expression, this range is higher.  In terms of RNA, transcription of rRNA consumes a disproportionate amount of the efforts of the cell, such that two RNA-dependent RNA polymerases are dedicated to the production of ribosomal RNAs (I know, polIII also makes tRNAs, etc., but I’m invoking poetic license here).

The story in prokaryotes is equally impressive.  Bacterial cells may possess as many as 100,000 ribosomes, with as much as 50% of the dry mass of a bacterial cell consisting of the prokaryotic ribosome (three RNAs and more than 50 proteins). Ribosomal protein synthesis may consume 30% of the cell’s translation energy budget, and rRNA transcription may acocunt for as much as 70% of all transcription that occurs in a bacterial cell.  E. coli possesses seven rRNA transcription units (or operons); the ca. 30,000 bp of coding information amounts to about 1% (in round numbers) of the total bacterial genome.  The 50+ ribosomal protein genes are almost 2% of the total number of bacterial genes.  I haven’t an off-the-top of my head number for the numbers of proteins that are involved in bacterial ribosome assembly, but it should be clear that ribosomes are the single most prominent feature of the bacterial cell.

The point of these preceding paragraphs is to impress upon the reader that ribosomes are important.  But it is also to lay a foundation for a somewhat unconventional way to look at a cell.  Usually, and especially when thinking about genetics, gene expression, and the like, the emphasis is on DNA.  Cellular reproduction is about DNA replication, heredity is about DNA transmission, gene expression is about the handling of DNA. But what if we place the ribosome at the center of the cell (as the preceding considerations would seem to demand)?  For example, we might consider cellular reproduction as a matter of the reproduction and propagation of ribosomes.  This changes the way we might view the process of heredity – DNA would amount to a storage form for ribosomal RNA, akin (in some senses) to the way that DNA is a storage form of a sort for retroviruses (1). Replication would amount to the process of rRNA transcription.  In this context, organismal and population biology reduces to a matter of the ways by which ribosomal RNAs can propagate and compete in the biosphere, and natural selection (when it is in operation) becomes at its core a matter of the effects of variability on the functioning of the ribosome.  Etc., etc., etc….

This may sound like an interesting but pretty arcane exercise, to turn so much of biology on its head like this.  But this perspective has much applicability to the origin and early evolution of life.  I think that, for the most part, it is accepted that the so-called RNA World was a precursor to the world of life as we know it.  However, most of the interest in the RNA World seems (to me, at least) to revolve around the origins and nature of the first replicating RNA genome.  One theme of sorts is that, whatever the first RNA genome, it was eventually supplanted by DNA and is probably lost irretrievably to the darkness of the very distant past.  The above considerations permit a somewhat different (NOT exclusive of other views, just something I don’t see often mentioned) perspective to be developed.  Conveniently, this perspective allows me to mention one controversy that accompanies the 2009 Nobel Prize in Chemistry.

One possible “slight” in this years award is the fact that Harry Noller was not among the prize recipients.  I don’t intend to speculate about the internal machinations, rumors, politics, are like subjects, but raise Noller’s name because he was the pioneer who championed the idea and established the fact that the ribosome is a ribozyme; peptide bond formation is catalyzed by rRNA and not protein.  In light of the above, it follows that the most important and central feature of living things is a catalytic RNA.  I would argue that the origins of this catalytic RNA lie at the heart of the origins of life.  Whatever and however RNA was produced at the dawn of (prebiotic) life, the first threshold to be crossed involved the origination of the peptidyl transferase core of the rRNA.  As Peter Moore suggested (in so many words) in his chapter of The RNA World, the origin of life is a matter of the origin of the ribosome.  And, as I hint at above and in the footnote, the evolution of life as we know it may in some ways be viewed as the evolution of, not a DNA World, but a Retro World.  What follows from this is the realization is that, far from being lost in the deep past, the first RNA genome is actually very much alive today; it is ribosomal RNA.

(1).  The parallels with viruses are much more numerous, but for now I will not explore this theme, EXCEPT to explicitly state that we can correctly consider life as we know it to be “retro” – an RNA genome (ribosomal RNA) that replicates through an elaborate DNA intermediate. Perhaps some readers might get interested in this, either here or in their real lives.

About these ads

11 Responses to It’s all about ribosomes

  1. Clem Weidenbenner says:

    Arthur:
    Ok, I’ll bite. First off I do have to tip my hat – I love to see someone get so passionate about their favorite subject. That said; let me play the contrarian for a minute to draw you out on a couple things and perhaps develop the whole concept even more.

    I make a living breeding soybean. So maybe I’m a plant scientist. As such I do consider rubisco a fairly significant protein. And so long as we’re turning some conventional ideas upside down, consider that if rubisco were a cleverer and more ambitious enzyme we might not need so much of it. So if expediency (effectiveness, efficiency – pick your favorite) is to count for something, the RNAs and rubiscos of the cellular world come out at the short end rather than at the top. Sure, you can’t get along without RNA as you can manage without rubisco, but still – why so awful much? It would seem that in the name of conserving energy the cellular machinery would be well served to find either alternate ways to do what RNAs do – or at least make the RNA machinery more efficient. Has anyone looked at the cellular RNA budgets across evolutionary time to see whether RNAs take up fewer resources now than in more primitive cell types?

    Have to run, but want to return to this line of thinking… a retro notion if you will.

  2. Arthur Hunt says:

    Hi Clem,

    Thanks for the comment (and apologies for the slow response). Your questions are intriguing. I wish I could come up with a clever retort to your statement about rubisco. I guess maybe if rubisco were really so clever, it would have seen what its original activity would have led to (high atmospheric oxygen) and figured out ahead of time a mechanism that would not be so poisoned by oxygen.

    As for the question “why so much RNA?” – I guess one place I think I am going is the idea that rRNA is the end-all of life. If we think of success in nature in terms of reproductive success, then rRNA is the ultimate success story. It’s not so much that life needs so much rRNA, but rather that rRNA has taken over (and did, many eons ago) life processes to its own ends.

    Do eukaryotes devote fewer resources to the ribosome than prokaryotes? I don’t know. Perhaps so, but I suspect that the difference, if it exists, is not much more than a factor of 2 or 3 (at least in terms of overall demand son the cell).

  3. Clem Weidenbenner says:

    “Figured out ahead of time” – now that’s certainly one way to turn a notion on its head! We humans have our hands full anticipating the consequences of our actions, imagine the simple cells in the primordial ooze sitting around the coffee table debating whether future atmospheric oxygen concentrations will be beneficial or not. Sounds like a ‘Far Side’ cartoon. Lucky for them we oxygen scavengers came along.

    As an “ultimate success story” I do think you make a credible case for rRNA. At least I’ll be giving RNA more attention downstream.

    So far as ribosomal commitment differences between prokaryotes and eukaryotes, there are the obvious competing interests of managing additional infrastructure (nuclear machinery) that could tip the scales. But this is a very macro scale issue. My own selfish interest goes to changes that occur within smaller groups of more closely related organisms – say within a family like the grasses or legumes. There are plenty of adaptations that higher plants are into (and doing quite well with), and it seems these adaptations play off of RNA regulatory mechanisms in concert with DNA. Epistasis fascinates me, and while one can model some epistatic effects without consideration of RNA, I wonder whether that view is not just too simplistic. The road from genotype to phenotype goes through the forest of RNA. We should not miss the forest for the trees.

  4. Joe G says:

    The ribosome- a genetic compiler!

    More evidence for Intelligent Design:

    The ribosome is a genetic compiler!

    The enzyme machine that translates a cell’s DNA code into the proteins of life is nothing if not an editorial perfectionist.

    Think about it-

    What happens to a newly written or modified computer code that has an error? All new and modified codes have to go through a compiler.

    A compiler is nothing if not an editorial perfectionist!

    I bet if we were to watch we would see the compiler doing its thing right up to the point the error occurs and then spits it out much faster than if the code was OK, ie error free.

    Biologists need to be introduced to and experience computer science.

    Then this sort of discovery wouldn’t be so “shocking”.

    Compiler- source code in, object code out. Ribosome- mRNA in (string of nucleotides), polypeptide out (string of amino acids).

  5. Clem Weidenbenner says:

    @Joe G:
    You may be onto something – exposing biologists to computer science. I’ll bet no one has ever thought of that. I know the computer science I took in grad school way back in the stone age couldn’t possibly have any resemblance to modern software. We started coding in machine language then we moved on to compiled code of some old software called ‘C’. Now folks are working with a statistics program called ‘R’. Shows how old I am :)

    But seriously Joe, the compiler metaphor is simply that – a metaphor. There are piles of papers demonstrating efficient translation of mutant code (to make a mutant protein). Mutations are errors – at least in the sense that they don’t accurately reflect a pre-existing piece of code (wild type sequence). So how is such a ribosome an editorial perfectionist? Compilers, BTW, can still compile badly written code – that is code that is semantically acceptable but has logical problems (doesn’t perform the intended function). In this sense the compiler is a bit like a spell checker that won’t flag a word that is spelled correctly in one sense but is not the correct spelling for the application (e.g., their vs they’re). Why would an intelligent designer allow such?

    In the end though it is exactly this allowing minor errors to get translated that provides some of the grist giving rise to variable types from which natural selection can choose. Thus leading to a system that really is pretty cool – whether ‘designed’ or not.

  6. Joe G says:

    Clem,

    The ribosome could just be far more advanced than the compiliers we now use.

    And perhaps not all mutations are accidents/ errors- that is why they get translated.

  7. Clem Weidenbenner says:

    @Joe G:
    The notion that a ribosome is more advanced than a computer compiler gets no argument from me. But I still miss the implication that because a biomolecular complex can do its job extremely well that is evidence for the handiwork of an intelligent designer. Is it not also possible the ribosomes we see today were crafted in a crucible of trial and error – rewarding successes and punishing failures? If evolution offers us anything its a paradigm for building hypotheses that we can test experimentally. So, if these super ribosomes in today’s flora and fauna result from a long march of selection we should be able to find more primitive types.

    Granted one can suggest that some intelligence designed all the various types and its only from our human perspective that these types form a trail. But then where is the predictive power in that? If once we figure out how these molecules work and how older types progressed to modern types we can then manipulate the system to make new types that are measureably superior in some way. Would doing this make us intelligent designers?

    I think of mutations as sequence variances. I did use the word ‘error’ earlier. Maybe an oversimplification on my part. Sorry… The compiler metaphor was trashing code errors and I just followed along. But however a sequence comes to be modified (inversion, deletion, UV radiation damage…) the fact that it is modified is where selection gets a chance to weigh the value of the modification once the translation machinery allows it to go through. And weighing the relative value of different types is nature’s job.

  8. Joe G says:

    Clem,

    There isn’t any data that shows ribosomes can be formed via an accumulation of genetic accidents.

    What is the predictive power in saying all ribosomes “evolved” via an accumulation of genetic accidents?

    The debate is not about evolution but whether or not blind and unguided processes can produce such a thing.

    The point being is that ribosomes could have been designed to evolve.

    The point of the compiler comparison is that I say that ribosomes are run by software- IOW they are not just a sum of their parts.

    And it is that software, not only the hardware config, that provides solid data for the design inference.

    Now all I have to do is separate the software from the hardware so that we can study it.

  9. Dave Wisker says:

    Speaking of compilers, in my mainframe programming days, a COBOL compiler once gave me the following message:

    “Use of parentheses accepted but with doubts as to meaning”

  10. Clem Weidenbenner says:

    Dave:
    Great!! Evidence to be sure of an intelligent designer (or at least one with a sense of humor).

    I once had to piece together some code to change a little program we were using in the lab. Late into the night, in a comment I just put “Trust me”. With deadlines everywhere a full explanation of what I was trying to accomplish seemed a waste of precious time. The program ran for several weeks without a hitch. The lab boss wasn’t into coding, but he did have to justify the work we were into. So one day he asks me for a copy of our “homemade” code. It goes over to some IT guys on campus and apparently one of them was going through it and upon arriving at my terse avoidance of expanation wasn’t amused. Lab boss comes back with a print out of my code – “Trust me” circle in big red marker. I just shrugged and smiled. Evidence for the lack of an intelligent designer.

  11. Dave Wisker says:

    Clem,

    Everybody knows “real” programmers don’t comment their code. ;) I also managed programmers for many years in a maintenance environment where there was often little time for the reflection required for good comments. What I noticed was, the best programmer/analysts wrote code that was fairly easy to follow anyway.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Follow

Get every new post delivered to your Inbox.

Join 30 other followers

%d bloggers like this: