caudoviral

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Once upon a time in the RNA World…

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Okay, so here is the promised speculation:

If we try to build a logically consistent hypothesis as to the steps between “not life” and “life”, our thinking naturally centres around something very much like RNA. In general inorganic chemicals do not become organic chemicals without an organic catalyst (thus the need for metabolism). So, there has always been a gulf there between the inorganic world and the so called “genetic takeover”. However, it seems that under certain circumstances two of the key components of life, Uracil and Cytosine, can arise from inorganic constituents. So we can hypothesis a form of proto-RNA.

However, these molecules would be very unstable and need to be kept in a particular aqueous medium. Thus we hypothesise the proto-cell. And more than just hypothesise, we can build such things in the lab out of simple fatty-acids. This proto-cell would have to be mostly permeable (as opposed to our modern semi-permeable membranes), since the absence of proteins precludes a complex membrane transport system and otherwise the proto-cell would lack the nutrients to thrive.

All of these things are nicely laid out in the review “The Origin of Life on Earth” by Ricardo & Szostak, 2009. However, there is one thing they notably do not cover. Let us imagine this environment proto-cells floating around in a soup of proto-RNA and various proto-metabolites drifting in and out through their fatty acid membranes. But here is the thing. If genetic material can freely diffuse through these membranes (and it can, since there is no way to stop it without stopping everything else) then how does any kind of proto-genome selected for and developed? If the genetic material of any cell is constantly being polluted by foreign material, nothing is going to happen, we are never going to get past this proto-stage. Indeed this infection of foreign material seems a great deal like our modern problem with viruses. So what is a cell to do? Exactly what single celled organisms do against viruses today.

See, bacteria generate a basic self/other dichotomy and protective response based on enzymes known as restriction/modification enzymes. This can be seen as the simple most instance of our much more complex immune systems that work through much different mechanisms but stem from a similar system of self/other recognition at a molecular level. Restriction enzymes cut DNA at specific point. Modification enzymes tag DNA to indicate that it should not be cut. When the system is working properly, all the DNA in a given cell is tagged. So any foreign DNA that enters is untagged, therefore not self, therefore cleaved to pieces by the restriction enzymes. It is conceivable that this system has its first roots in an RNA world where a membrane line defence against foreign genetic material was impossible, leaving the proto-cell to rely on a catalytic defence.

However, we must remember that this is an RNA world we are talking about. No DNA. No proteins. So, does that mean no enzymes? Well…you might think so. One of the things that tends to get glossed over in modern bio is the wonder of the ribozyme. Ribozymes are catalytic RNA. RNA that serves the same function as an enzyme (a brilliant example of RNA with catalytic activity is the ribosome, which is ~70% RNA including all of its catalytic sites). And ribozymes that function like restriction enzymes are extant today.

Now, it may never be possible to know what actually occurred at the dawn of life, but trying to produce logically consistent hypotheses is entertaining, and I think these putative proto-ribozymes fill a gap in the current theory and explain how the proto-genome could have the protection it needed to grow towards something resembling our modern day biology.

Hah, made it before midnight!

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Written by Caudoviral

01/27/2011 at 23:58

Posted in Biology, Uncategorized

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The failed promise of genomics

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Ironically, in certain circumstances, praise can do more damage than insult. One of my favourite television shows, Dylan Moran’s Black Books, has an episode in which the protagonist, Bernard Black, has a date ruined by one of his friends. However, instead of telling his date what a miserable bastard Bernard actually is, she does so by playing him up as impossibly brilliant (saying that he paints, and speaks seven languages, etc). Later, after things have begun to fall apart, he wheels on his friend and shouts: “You! What did you say to Kate? She thinks I’m the Renaissance!” I bring this up because an analogous relationship exists between Science, the Media, and the Public.

Perhaps in no place is this relationship so clear (in recent years at least) as it is with the subject of genetics & genomics. I often talk about “the failed promise of genomics”, and let me explain what I mean by that. If you ask a scientist: genomics is a fascinating field with a great many applications. It has been a vital step in understanding life and its tools will remain valuable in facing the challenges biology presents. It is the blueprint on which we will build many further endeavours. If you ask a journalist or (ugh) soft sci-fi author, genes are magic. Okay, maybe it isn’t that bad. But it’s close. And it becomes a problem when we look at scientific literacy and have to ask: who is the public getting their information from? Because it sure as hell doesn’t seem to be the scientist.

The Human Genome Project started in 1990. Even if there was a little bit of awareness before that, the HGP turned it into an obsession. Such is the vanity of H. sapiens. Suddenly genetics and genomics were catapulted from the scientists toolbox to the public eye. By the time the drafts were released in 2000 and 2003, we had genomania.

Genetic engineering and gene therapy had entered popular entertainment with films like Jurassic Park and Gattaca and games such as Metal Gear Solid and Bioshock. Our fiction portrayed genetics as mystically resurrecting dead species, fuelling dystopias, and granting abilities on par with magical powers. And the journalism on the subject hasn’t been much better. Over the past two decades we have been presented with everything from ‘obesity genes’ to ‘gay genes’ to a gene for every disease under the sun. Genes were suddenly the cause of and solution to everything.

But why does this happen?

Here we come upon one of the general principles involved in the distortion of science. Science is hard. It is a complicated field of study with a staggering amount of depth (biology with its irregularities and great breadth doubly so). Journalists have neither the training nor the time to accurately report on research. Genetics however has a simple, even elegant explanation. To the novice, a system of cause and effect presents itself. You can almost convince yourself there is a perfect little Mendelian world running with as much surety and clockwork as Newtonian physics. But once you reach the level of genomics (and  especially if you look into the newer studies of epigenetics and proteomics) this elegance breaks down. Such a breakdown isn’t pleasant. There is a parsimony and sense of ‘rightness’ to the “if I have gene A then I have trait A” paradigm. I have been in classes with students who have had total meltdowns over finding out that that is simply not true.

A full discussion of why that isn’t true is beyond the scope of this blog, but let me just throw out some examples: gene A might have multiple different alleles leading to multiple different products, each of those alleles might go through different processing, transcripts of gene A might be degraded by the protein product of gene B, the protein product of gene A might be degraded by the cell unless you also posses just the right amount of the protein product of gene C (or hell, maybe gene A doesn’t even get transcribed without gene C’s product promoting it!), maybe the protein product of gene D dimerizes with the protein product of gene A rendering it inactive (or maybe that is the only way to render it active), etc. And reasons like these just scratch the tip of the iceberg. The number of possible snafus in the pathway from genome to phenotype are so numerous that there is no such thing as a classic Mendelian single phenotype genetic disorder (something I will discuss in greater length if I ever get around to doing a write up on one of my favourite journal articles: Loscalzo, et al. 2007)

So what we have here, is an incredibly complex system with an enticing misconception just waiting to be picked up and ran with. It is a misconception that makes sense, it is a misconception that makes people happy, and it is a misconception that promises power over and easy solutions to all of the ills that surround us. The problem is that it doesn’t exist. And the scary part comes when you realise that it is kind of like crying wolf. How long until the public says: “Oh, geneticists, bah, they promised to cure my cancer and let me grow wings and have a dog-opus and make me not fat. I didn’t get none of that. And now scientists are asking for more money? Screw em.”

The human genome gives us a blueprint. Nothing more and nothing less. And don’t get me wrong. That is huge. But it is not the finished product. You can’t sit down and fly a jet, just because you have the blueprints. Hell, you can’t even necessarily build a jet just because you have the blueprints. But it is a vital step, and a really solid start. The problem is that “the failed promise of genomics” is really a misnomer. Because genomics never made these promises (well…perhaps we should say that it never made these promises outside of over-enthusiastic grant proposals). The media made promises for it, and the public becomes disappointed and disillusioned with the field when scientists can’t deliver on promises they never made in the first place. And without the support and funding of the public, science is going to fall flat.

Written by Caudoviral

01/11/2011 at 18:05

Posted in Biology, Uncategorized

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