RNA viruses: constant annoyance and lethal disease

 

At the UCSC RNA Center, we are concerned with how RNA works.  RNA is often called a “cousin” of DNA, the more popular genetic material, because chemically it is similar, although biologically it is very different.  RNA is also a “genetic material”, because to be a genetic material simply means that it carries the instructions for making a protein of a certain type that does a certain job.  Holding these instructions is what DNA (the gene) normally does.  In fact in order to do its job, a gene (DNA) must be copied to make an RNA, which then carries the genetic code to the place where the proteins are made.  But, many viruses have no DNA.  Their genes are made of RNA. These viruses must do many things inside the cell using only RNA as an invading genetic code.  Given our special knowledge about how RNA works, we are in a good position to learn things that could help us stop these viruses.  The list of only mildly annoying to frighteningly lethal diseases caused by RNA viruses is long: HIV, the common cold, hepatitis, influenza, polio, mumps, measles, SARS, Ebola, etc.  These viruses cause much suffering around the world, but a major problem is that RNA viruses mutate very rapidly.  This means that new ones will always emerge and even the old ones will evolve to escape our vaccines and therapies.

 

A team approach to learning about RNA viruses

 

Recently we embarked on a study of the SARS virus RNA with our RNA Center colleagues Professors David Haussler and Bill Scott.  Each of us has contributed our special knowledge to the problem and together we found something new that could develop into something useful with future work.  When the SARS genome was sequenced and published in 2003, the Haussler group, experts in genome analysis, began analyzing the SARS virus genome, comparing it to the genomes of other viruses.  They rapidly found a small part of the RNA that was identical to many other viruses of the SARS type.  When we find a part that never changes we get excited.  RNA viruses mutate so rapidly that a never-changing part must represent something that cannot change without killing the virus (or we would see changes in the live virus population).  A part that cannot change might represent an Achilles heel that we could attack effectively without having resistant strains appear.  Structural biologist Bill Scott is one of the world’s experts in deciphering how an RNA looks at the molecular level, and knowing the shape of this part of the RNA would be essential to understanding its function and perhaps how to stop it from working.  There are no microscopes that can see with accuracy how an RNA looks, but other methods, such as X-ray crystallography can give us details at the atomic level where the shape is made.  This involves growing crystals of the RNA piece in the laboratory and bombarding it with X-rays.  The scattering pattern of the X-rays as they go through the RNA crystal can be used (after many complex calculations) to create a picture of the shape of the molecules that make up the crystal.  Bill’s lab was able to discover this shape.

 

We know what it looks like, but what does it do?

 

The shape of the SARS RNA piece that never changes is interesting and curious, especially to those of us who like to spend time looking at the shapes that RNA molecules can make.  Now that we know the shape, we want to understand exactly what it does and how it works.  David and Bill’s groups have done their job, first zooming in on this one small region and then describing its structure in amazing detail.  Work in the Ares lab to discover the function of this RNA is just at its earliest stages.  One of the things we expect about this bit of RNA is that it is like a puzzle piece with a special shape, and this shape fits into something else—another puzzle piece with a shape that matches it.  Since this part of the virus never changes, we think the other puzzle piece is a protein in the host cell that the virus RNA must attach to (or the virus will die).  The host cell might make as many as 100,000 different proteins—how do we sort through all those puzzle pieces to find the one that fits the special shape that the SARS RNA makes?  We are trying to take advantage of the fit we think will occur when the RNA piece comes in contact with the unknown protein.  We take a large culture of human cells grown in the laboratory and grind them up to free the proteins.  We make a cylinder containing an inert material to which is attached many copies of the SARS RNA piece.  When we push the proteins through this cylinder, most of them will pass through, since they won’t stick to the SARS RNA.  But some will, and these few proteins that can stick to the SARS RNA become our best candidates for the one the virus must attach to during infection.  Right now we think we have narrowed this list down from 100,000 to less than about 5, but proving which one it really is, and how the attachment of the virus RNA to this host protein helps the virus will take more work.

 

This research is supported by general research funds in the Ares lab.

 

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