We don’t know all the players which is why finding good drugs is so hard

My cousin married a high school dropout 2 years ago.  Not to worry —  he dropped out of high school to go to college, and has a PhD in EE from Berkeley and has worked at Bell labs.  He was very interested in combining his math and modeling skills with my knowledge of  neurology to make some models of CNS function.  I demurred, as I thought we knew too little about the brain to come up with models (which I generally distrust anyway).  The basic problem was that I felt we didn’t know all the players in the brain and how they fit together.  Forget consciousness and higher brain function, just ask your friendly neighborhood neuroscientist why we need sleep, or how or where memories (of anything) are stored.  We simply don’t know.

Readers of “In the Pipeline” are well aware of the sufferings of organic chemists, as big Pharma either fires or outsources them. Why should this be happening?  The short answer is that not many new blockbuster drugs are forthcoming.  People trying to come up with new drugs don’t have the luxury of waiting until our knowledge is more complete, so that we know just what to target.  They are basically shooting in the near dark, hoping they hit something.  It would be nice if we at least knew all the players in the cell, but we don’t.  So drug chemists fire their guns at proteins which we at least know something about.

A paper in the 10 February ’11 Nature (vol. 470 pp. 284 – 288) shows this in spades.  To follow the rest of this post you’ll need to have the following two old posts under your belt (unless you’re a molecular biology maven).

https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/

https://luysii.wordpress.com/2010/07/11/molecular-biology-survival-guide-for-chemists-ii-what-dna-is-transcribed-into/

Messenger RNA (mRNA) doesn’t hang around forever in the cell — if it did, the cell would explode as ribosomes would endlessly translate its message into protein.  It’s quite tricky to measure protein half lives, and the latest trick is something called ‘bleach chase’ (Science vol. 331 pp. 683 – 684 ’11).  It’s also tricky to measure mRNA half lives in the cell.  So mRNA must be degraded.

There are a variety of mechanisms for mRNA degradation.  The one of great recent interest involves microRNAs, which base pair with the 3′ untranslated region (3′ UTR) of mRNA leading to its degradation. That’s not the subject of the paper.  The mechanism under discussion in the Nature paper involves a protein called Staufen.  It binds to the 3′ UTR of a variety of mRNAs leading to their degradation.  RNA can loop back on itself forming a double RNA helix, which is the structure Staufen binds to in the mRNA coding for one protein called ARF1 (honest to God).  However other mRNAs that Staufen helps degrade don’t have such a structure.

.

It turns out that Staufen  binds to a double stranded RNA helix all right, but one formed from one molecule of the mRNA and one molecule of something called lncRNA.  The name lncRNA comes from the old proteincentric era, when DNA not coding for protein was thought not to code for anything.  lncRNA stands for long noncoding RNA (noncoding for protein that is).  Since lncRNA is RNA this means it was transcribed from the genome.  Definitions vary but most lncRNAs contain over 5000 nucleotides.  Moreover lncRNAs  are transcribed by the same enzyme which transcribes mRNA (RNA polymerase II).

It gets worse.  If anything fits the definition of ‘junk DNA’, it is the Alu element.  They are around 300 nucleotides long, and the human genome contains a mere 1,400,000 of them.  So Alu elements represent at least 10% of our genome.  No one thought they did anything, being ‘selfish DNA’ whose only function was to proliferate in our genome.  However, the double helix that Staufen is binding to is formed by an Alu repeat in the 3′ UTR of the mRNA and another Alu repeat in a lncRNA.   A given lncRNA can lead to degradation of a variety of Staufen targets.

Is this of any importance?  You bet.  How long a given mRNA hangs around is one determinant of how much of a given– protein a cell contains.  Too much or too little can kill you — depending on the protein.

What do we know about lncRNAs and other RNAs not coding for protein?  Not much.  Some of these RNAs  are shorter, so they are called ncRNAs.  The following is a quote from the paper.  “There are estimated to be tens of thousands of human ncRNAs that have little or no ability to direct protein synthesis and that are distinct from ribosomal RNAs, transfer RNAs, small nuclear RNAs, small nucleolar RNAs, siRNAs and microRNAs.”

What are all of them doing?  We don’t know.  Would the cell bother to waste the energy making them if they weren’t doing anything?  I doubt it.  Could they be drug targets?  Of course.   But not until we know what they do.

Saying that we need curiosity driven basic research is an old bromide, and somewhat self-serving, but we really do.  There really is no other solution to the current impasse in drug development.

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