Wednesday, October 27, 2010

exciting news!

The PI of my lab was recently awarded an NIH New Innovator Grant to the tune of 1.5 million AFTER overhead (so, 2.6 million total.  Insane...the extra 1.1 million pays for MIT space, janitors, supplies like paper towels, etc...).  This is a very exciting thing for our lab and for our team.

that's my PI!

read more here

And since the abstract has been published, I thought I'd do a bit of translating, given how, um, dense it is.  (abstract will be in blue, explanation will be in black)

Transcript localization shapes many fundamental processes including cell polarity, migration and neuronal activity, and impacts diverse biological processes such as development, memory and learning.

Transcript refers to an RNA message.  When you think of how your DNA influences your cells, imagine DNA as a book.  A really, really, long book.  Now, to get information out of this book and doing something in the body, you have to open the book to a specific page and copy a passage to something called RNA.  Since DNA is a paired script in the book, it only copies half of it to the RNA---the molecules look like this:  DNA is on the left and a helix, RNA is on the right and is kind of half of a helix. 

All of those shape things are the letters by which the book of your genes and DNA are read:  A, T, G, C and U--it always astonishes me that with 26 letters and different combinations, we can end up with Shakespeare, but our bodies make us with just 5.

Cell polarity refers to the orientation of cells.  Since you have a head and feet, you are polar.  So are plants with flowers and roots.  On the other hand, a soccer ball has no polarity; it's the same on all sides.

Migration - just like Canada geese in the fall, both cells and things inside of cells move from place to place.

Neuronal activity is a fancypants way of saying "things in your brain working."

Development in biology refers to the period of time before you have gained some particular level of maturity.  This could mean development as a fetus, or it could mean development as you transition from a child to an adult. 

Although attention has been focused on localization of a few selected transcripts, recent global analyses indicate that the phenomenon is extremely common. 

A "few selected transcripts" are those that are studied first and found to be really important.  In this case, the abstract is saying a few important things have been studied, but it looks like we should study rarer transcripts in order to find more things out. 

In many cases, different transcripts are observed to have distinct sub-cellular spatial localization patterns. 

Sub-cellular means within the cell.  This is a cell:

There are lots of these cells in your body, and they all have a different purpose (help with muscle contraction, transmit nerve impulses, absorb digested food).  The cell above is just a generalized cell.

The word sub-cellular recognizes the space anywhere inside that cell. Spatial localization patterns is a fancy way of saying that these transcripts (RNA) sometimes end up congregating in different parts of the cell, just like hipsters with their PBR at a seedy neighborhood bar, students hanging out in the library, or people like me trawling the thrift store.  It's the same thing---these are different transcripts in different places.  It doesn't meant that I don't got to library, but it means there is a pattern where I go to the thrift store more often than the library.

Several prominent examples of specific transcript localization shaping processes such as body axis polarity in Drosophila and synaptic plasticity in neurons suggest the potential for there being direct functional significance of transcript localization, now recognized to be a commonly observed phenomenon. 

The concept of transcript localization shaping processes isn't as complicated as it sounds.  If we continue with the thoughts of Boston as a cell, and all the different buildings around it were locations that people could be, these people in different places affect how Boston functions.  For example, construction workers in South Boston help to build a new high rise; this changes how Boston is.

In the same way, when you have RNA transcripts spread over an entire cell, you cause different things to happen in different places.  So---if you have a certain transcript in a certain place, you can change what direction the cell moves.  The example above is "body axis polarity" in Drosophila (fruit fly) - in this case, talking about changing the intended head/thorax/abdomen orientation of a fly 90 degrees during development.  That's kind of insane.  But you can do it!  Simply by putting RNA transcripts in one place and moving them to another, you can completely change how the cell looks.  Similarly, you take all the construction workers from South Boston and put them in Somerville along with all the other construction workers in Somerville, you end up with---a lot of construction in Somerville.  It's the same in a cell, believe it or not!

And it's funny--plastic to me means very hard and rigid, which is why it's so ironic that in a scientific sense, plastic means able to adapt. These fly cells are able to adapt depending on where the RNA goes, which is a little bit crazy. But true.  You do reach a certain point at which things are "decided" - but early enough in development, you can definitely change the outcome. 

Plasticity in neurons refers to the idea that although it's a bit trickier to come up with new neurons than it is new skin cells, neurons make new connections all the time, and these influence memory and how your brain works.  If you didn't have plastic neurons, you wouldn't be able to learn!
Unfortunately, we have very limited understanding of the protein factors required for achieving specific transcript localization patterns. 

If DNA is the book of life, and RNA is a copied page from that book, a protein is what happens when that page is read aloud; imagine that you were in the world of the Pagemaster... (come on, I know you've seen the movie.  Me at age 8 had a completely helpless crush on Macauly Culkin/the boy in the actual book.  I was big into realism, knowing that I'd probably end up dating an incredibly dorky boy someday and love it).   Anyway, whatever is said aloud comes true, which while very cool is a bit daunting in the story.  But in this case, the proteins become everything that makes up the cell, or help create things that make the cell (example: plant cell walls are all made of starch; but this starch is processed by proteins).   

Anywho, this particular sentence brings up that the RNA must have some way to get to the places it goes, and these probably involve proteins; in Boston, you could walk, you could take the T, you could bike...similarly, science expects RNA to have a whole slew of ways to get to these different places, but doesn't have a really good idea of what they actually are (I vote hovercar).

Moreover, we lack strategies for selectively perturbing transcript spatial distribution in a manner compatible with understanding the associated functional consequences.

Gosh.  We don't have a good idea of what they are, and we don't know how to figure out what they are.  Oh science.  Thanks for your clarity.  But, basically we're stuck.  And that's what this proposal is trying to address.

This proposal addresses these needs by introducing a method permitting regulated targeting of a given transcript to a sub-cellular location, the latter being driven by known or putative localization factors under evaluation. 

So...what we need is something that will allow us to tag along with a transcript of our choice and try and see what's along for the ride.  Or, in plainer terms, a GPS with a video camera attached to a person to show where they go, how they get there, and who they go with.  We're basically super-spies.  Putative is a fancy word for suspected, and in this case we have some clues, but we don't know for sure.  So we need to do a bit of stalking and investigation.

In this approach, transcript localization is entirely experimentally controlled, and is conditional upon either small molecule or peptide signals applied to target cells using high-resolution chemical gradients and post-translational protein localizing modifications, respectively. 

And as super-spies, we control the RNA movement by adding a small molecule or a peptide. 

In science, a small molecule is something little that can get into a cell.  Some recognizable ones are sugars like glucose, or an antibiotic like tetracycline.  We would add these to cells very precisely, and see what happens.  A "high resolution chemical gradient" means that adding this molecule would be very accurate (high res, just like an LCD tv). 

On the other hand, the peptide would be a programmable "PS" put in the DNA book and therefore also in the copied RNA message.  So, if the RNA words on the copied page from the DNA book read something originally like "Help move sugar," we could add a specific PS that says "Actually, help move only fructose."  (something we can do by cloning).  This PS message is called a "post-translational protein localizing modification."

This broadly applicable method has the potential to advance our basic knowledge of the cellular mechanisms underlying transcript localization, and to probe the associated functional implications at both the cellular and organism levels. 

This will help us figure stuff out!

Public Health Relevance: Sub-cellular RNA localization into discrete, transcript-dependent patterns is now recognized to be a widespread phenomenon in many cell types and organisms, including humans.

This is something every researcher has to add to a grant for the National Institutes of Health.  Specifically, what does this project do to positively impact human health?  The argument here is that, even though there is no mention of any disease at all in this proposal, knowing more about the basics can be really helpful.  You know the people who won the 2009 Nobel Prize in Medicine?  Their work was very basic research on things called telomeres...which, as it turns out, are really important in cancer.  They didn't set out to revolutionize how we think about cancer.  But they did. 

Also, the abstract and this last bit is to inform a generalized public what the research is all about, which kind of cracks me up.  I'm a graduate student in this field, and it was impossible to wade through this without copying it into Word, bumping it up to a size 16 font, and reading it aloud in my head, pausing after each sentence.  Meaning?  The whole way we go about "informing the public" is oftentimes a complete joke.  And that's the basics of what I want to do when I grow up; make this sort of thing interesting to learn instead of impossible.

In several well-studied cases, transcript localization is required for establishing proper cellular function, and defects in this process contribute to developmental, cognitive and other neurological problems in humans. 

Aha---here's the public health; there are definite diseases, especially in the brain, that happen simply because there is RNA in places it's not supposed to be.  Or, there are escaped convicts from jail robbing a bank; not quite a good thing for Boston, and it's the same for the cell.

The proposed research will introduce new methods for understanding and manipulating the mechanisms underlying RNA sub-cellular localization, and has the potential to improve both our understanding and treatment of disease processes associated with RNA localization defects.

This research will look into new methods for learning why RNA goes where it goes, who it goes with, and how it gets there. 

We're the superspy tagging different suspects and following their every move to see what happens. And as soon as we know these particular things ---the whos, the wheres, the whats---we can begin to address catching these suspects...or figuring out how to correct a disease in the brain caused by this sort of problem.  But first--you've gotta do your homework and reconnaissance.

Phew.  That was a lot of science.  Time for a porcupine that thinks it's a dog:

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