RNAi

Posted on October 15, 2009 by Michael

RNAi is an arrestingly interesting little mechanism for protecting the health of cells. The “i” stands for interference, and with good reason. RNAi is made up of a series of molecules which work to detect and destroy possible viruses and RNA which could be viruses.

It was first detected in 1986 when an attempt was made to make a really, really purple flower. The reason was purely for aesthetics, but it would prove to be far more important.

Knowing the gene which coded for purple pigmentation in petunias, geneticists made the logical conclusion and figured adding a bunch of those genes to the flowers would increase the depth of purple coloring in them. But as it turned out, they were wrong. In fact, they were remarkably wrong. Instead of deep purple flowers, they produced white flowers. Not a hint of purple anywhere.

No one had an answer to why would be. It took 12 years until researchers came up with the answer (and another 8 until they were awarded a Nobel Prize).

When viruses invade a cell, they ‘seek’ to make copies of themselves by utilizing the available DNA source. Post-transcription, this comes out with a funny shape due to the RNA making a mirror image of itself. The RNAi then recognizes this strange shape and destroys it with dicers. But it doesn’t stop there. Any sequence which comes out of the nucleus thereafter is also destroyed. This prevents any of the viruses (hopefully) from being translated and replicating (thus exploding out of the cell and infecting other cells).

Something similar happened when the geneticists tried making the super purple flowers. There wasn’t a mirror-image RNA sequence, but there was a funny sort of shape created by all the extra purple pigmentation genes. The RNAi recognized this as a potential virus and began destroying it. All of it. This meant there were no genes for purple getting translated into proteins.

Example petunia plants in which genes for pigmentation are silenced by RNAi. (http://en.wikipedia.org/wiki/Rnai)

Example petunia plants in which genes for pigmentation are silenced by RNAi. (http://en.wikipedia.org/wiki/Rnai)

So far this is pretty exciting stuff. It’s a post-transcriptional defense mechanism against viruses no one ever knew existed. But it has so much more potential than just as a passing curiosity.

Think about it. If RNAi can essentially turn off genes by destroying them through a sort of sequence-detection, then what stops it from curing diseases? This discovery has the serious potential to cure all the major ailments facing the world today: AIDS, cancer, Alzheimer’s. There has already been success in treating macular degeneration. This is a disease where too many blood vessels are growing in the eye. It damages the retina over time and makes vision majorly cloudy and blurry. There are simply too many genes for blood vessels being produced. But one way to stop this disease is to stop that blood vessel growth. To achieve this, a patient is given an injection which contains a copy of the gene with its mirror image (two mirror strands of DNA). The RNAi detects this misshape and destroys it. It then destroys all other likewise sequences. The same principle could be applied to any number of diseases.

There is an excellent NOVA video on RNAi which can be viewed here. It’s certainly worth watching (and only 15 minutes long).

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That link

Posted on May 21, 2009 by Michael

I posted a link earlier. Here it is again.

However, though researchers have been able to show how RNA’s component molecules, called ribonucleotides, could assemble into RNA, their many attempts to synthesize these ribonucleotides have failed. No matter how they combined the ingredients — a sugar, a phosphate, and one of four different nitrogenous molecules, or nucleobases — ribonucleotides just wouldn’t form.

Sutherland’s team took a different approach in what Harvard molecular biologist Jack Szostak called a “synthetic tour de force” in an accompanying commentary in Nature.

“By changing the way we mix the ingredients together, we managed to make ribonucleotides,” said Sutherland. “The chemistry works very effectively from simple precursors, and the conditions required are not distinct from what one might imagine took place on the early Earth.”

Like other would-be nucleotide synthesizers, Sutherland’s team included phosphate in their mix, but rather than adding it to sugars and nucleobases, they started with an array of even simpler molecules that were probably also in Earth’s primordial ooze.

They mixed the molecules in water, heated the solution, then allowed it to evaporate, leaving behind a residue of hybrid, half-sugar, half-nucleobase molecules. To this residue they again added water, heated it, allowed it evaporate, and then irradiated it.

At each stage of the cycle, the resulting molecules were more complex. At the final stage, Sutherland’s team added phosphate. “Remarkably, it transformed into the ribonucleotide!” said Sutherland.

According to Sutherland, these laboratory conditions resembled those of the life-originating “warm little pond” hypothesized by Charles Darwin if the pond “evaporated, got heated, and then it rained and the sun shone.”

I figured I’d have more to add to this, but I don’t. At best I suppose I should point out that this experiment shows that general principles can result in RNA: do such-and-such in a certain order and you’re on your way. That’s an oversimplification, but it makes comprehending the origins of life a bit easier.

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Origins

Posted on December 23, 2008 by Michael

It’s only a matter of time until something very much like life is created in the lab. Until then, scientists are still working on how it happened, nearly 4 billion years ago. The research is promising.

With the aid of a straightforward experiment, researchers have provided some clues to one of biology’s most complex questions: how ancient organic molecules came together to form the basis of life.

Specifically, this study demonstrated how ancient RNA joined together to reach a biologically relevant length.

RNA, the single-stranded precursor to DNA, normally expands one nucleic base at a time, growing sequentially like a linked chain. The problem is that in the primordial world RNA molecules didn’t have enzymes to catalyze this reaction, and while RNA growth can proceed naturally, the rate would be so slow the RNA could never get more than a few pieces long (for as nucleic bases attach to one end, they can also drop off the other).

Ernesto Di Mauro and colleagues examined if there was some mechanism to overcome this thermodynamic barrier, by incubating short RNA fragments in water of different temperatures and pH.

They found that under favorable conditions (acidic environment and temperature lower than 70 degrees Celsius), pieces ranging from 10-24 in length could naturally fuse into larger fragments, generally within 14 hours.

The RNA fragments came together as double-stranded structures then joined at the ends. The fragments did not have to be the same size, but the efficiency of the reactions was dependent on fragment size (larger is better, though efficiency drops again after reaching around 100) and the similarity of the fragment sequences.

The researchers note that this spontaneous fusing, or ligation, would [be] a simple way for RNA to overcome initial barriers to growth and reach a biologically important size; at around 100 bases long, RNA molecules can begin to fold into functional, 3D shapes.

Enzymes basically make things go faster. That means that reactions that are caused by a particular protein (say, lactase breaking down lactose into its constituents – if you can’t do this or do it poorly, you’re lactose intolerant) can happen anyway, but they will happen far more slowly. In some instances, they essentially will not happen except by tremendous stroke of luck (though, again, the potential is always there).

What’s particularly interesting to note here is that it is very difficult to say what the pH balance of different bodies of water would be on an early Earth. It is entirely plausible that acidic levels would be higher, leading to the ability of these RNA molecules to form 3D shapes. And, of course, because biology is very much dependent on shape, these formations could act as proteins, if not plainly be defined as such. By doing this, a rudimentary evolution could begin to take place. We may not define these replicators as being life, but they would hold many of its characteristics – taking in energy and out, being subject to at least a form of natural selection.

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