CMT Science #3 and the tinkler

I seems the instrument makers have rallied into action. I welcome hjmooij as instrument maker #4 – an outstanding noisey artist.


INSTRUMENTS (#4)
post by hjmooij

the tinkler

the tinkler is the instrument name.
hypothesis: it'll make tinkling noises

will start construction soon. updates as progress is revealed.





CHARCOT MARIE TOOTH
post by Tim Phillips

CMT Science #3: a summary of the research (why we're raising money)!

The discovery of the cause of CMT 1a, explained in the last post (CMT Science #2), led to an important research program, STAR (Strategy To Accelerate Research), initiated and funded by the CMTA. (Hence this project's fundraising). In case you forgot, the discovery was that in someone with CMT 1a, something called a Schwann cell is producing too much protein, which causes the insulation around the peripheral nerves to break down.

The STAR program was established to bring together leading Schwann cell researchers from around the world in order to work out how to stop the harmful over production of this protein, PMP22, in people with CMT 1a.

There are many creative scientists that are key to different stages of this research. The first big step was to create a stable cell line of CMT affected Schwann cells, this was engineered by Ueli Suter and his colleagues at ETH Zurich, Switzerland in 2009. (It was also Dr. Suter who initially demonstrated that the over-expression of PMP22 causes CMT 1a).

Once achieved, the next step was to test hundreds of thousands of compounds on the cell line to see if any of them reduced the production of the protein, PMP22. This is achieved quite ingeniously (at least to the non-scientist like me) with the help of high-throughput screening.


The picture above shows a Kalypsys robot at the NCGC (NIH Chemical Genomics Center in Rockville, Maryland) holds a 1536-well plate similar to those that will be used during the high-throughput screening (HTS) of the CMT 1A cell line. That means it can test 1536 samples at once.


Very basically, the stable CMT cell line is created in a Petri dish by combining affected Schwann cells with tumor cells, these regenerate so keep the cell line ‘alive’ or stable. The cell line has also been kitted out with carefully manipulated phosphorescence from fireflies! More specifically this is a florescent marker
called Luciferase. It naturally lights up as the protein PMP22 is produced, so the amount of light given off is indicative of the amount of PMP22 produced.

Image showing variance in emitted light from cells with Luciferase.

Now a machine, like the one pictured above, can take the cell line, test a compound on it and monitor if the light produced diminishes. If the light does diminish, then less protein PMP22 is being produced and the compound is a candidate for treating CMT 1a. The powerful machines at the NCGC (under the guidance of Dr. Jim Inglese, Dr. Sung-Wook Jang and Dr. Doug Auld), enabled the research team to test 350,000 drugs and other compounds in the NIH chemical library as reagent, this is high-throughput screening.

BIG NEWS!
The big news is that the first round of screening just finished and looks very promising. There were 810 candidates identified, 10 of which are already approved for public use. The next stage is a second round of testing for these candidates. In the meantime there are two other crucial projects being run concurrently.
- One, currently being undertaken by Klaus Nave at the Max Planck Institute for Experimental Medicine in Gottingen, Germany, is focused on developing a laboratory model of the disease to understand if the effects observed in High-throughput testing will also be observable in animals.
- The other, being pursued by John Svaren in his lab at the University of Wisconsin at Madison, is designed to further the understanding of how PMP22 is expressed and regulated and discover whether the same constructs will be observed in humans.

It is the combination of all this research that should make the STAR program both successful and efficient. STAR is privately funded by CMTA members, supporters, friends and family. Together, we need to raise $9 million over the next 3 years to complete the initiative. This is achievable with your help – please consider donating.


If you know of any recent publications or papers that discuss this work further, I’d love to read them – please add a comment with a link.


Links:
http://www.charcot-marie-tooth.org/STAR.php
CMTA’s description of the STAR program

http://www.charcot-marie-tooth.org/STAR_update3.php
Latest update



That’s enough science for now! The next post will be far more personal…

CMT Science #2, "You Can Ring My Bells"

Introducing... Instrument maker extraordinaire #3, Maria Mortati.

Check out her website: http://mortati.com/

INSTRUMENTS

post by Maria Mortati

"You Can Ring My Bells" part 1:

The inspiration for this piece was both magical and opportunistic. It's based on a mechanical bells piece at the Museum of Jurassic Technology...


...and inspired by something in a Rube-Goldbergesque segment from a piece I did with some friends years ago at the Exploratorium. One of the team members took threaded rods and washers and spun them, which created a wonderful bell-like sound, similar to the MJT sculpture.


The opportunistic part comes from working with what I have around the house- and old desktop-sized prototype that I'm cannibalizing, and lots of parts from other prior projects:


I started with the sound, and testing various types of washers:


So far I have found that using smaller washers on a threaded rod makes a nicer sound than larger washers. Not what I was expecting.


The idea is that you'll crank a handle and you get a tinkling bells sound. Let's see how it comes together.



CHARCHOT MARIE TOOTH

post by Tim Phillips

CMT Science #2

I’m pleased to say that a lot of people have been asking me to describe in more detail what is happening with the current research that this project is helping to fund. Over my next 2 posts I hope to address the nerds among us, I'll explain the (very) basic genetics behind CMT1a and an overview of the STAR program (Strategy To Accelerate Research); a remarkable collaboration of prominent international scientists, initiated and funded by the Charcot Marie Tooth Association (CMTA), working towards treatments and cures for CMT.

What makes the current research around CMT so interesting (and promising), is that the scientific understanding has reached a finite stage. Scientists have identified the specific physical cause for certain types of CMT. They have identified the gene defect that results in the condition and can recreate it in a laboratory. Now they are testing different compounds to see which ones counteract the gene defect and stop or even reverse the physical condition, i.e. be therapeutic agents for CMT1A and other forms of CMT.

“CMT is unlike other neuromuscular disorders because its causes have been pinpointed, leading to the identification of at least 33 specific gene defects. More importantly, the fact that these genetic mutations can be replicated in laboratory models and grown as tissue cultures opens an extraordinary window of opportunity to develop treatments and cures for CMT in the immediate and foreseeable future.”
(Taken from The CMTA website: http://www.charcot-marie-tooth.org/STAR.php)

More on that in the next post, first we must do basic genetics...

There are lots of different types of CMT. The STAR program is concentrating on type CMT 1a to start with because it is both the most common and understood. As in my CMT Science #1 post, I’m going to do the same, it is also the type I have so that which I know most about. However, all the types (of which there are about 30, some more understood than others) are connected, so it is anticipated that the research will lead to treatments for them all.


CMT 1a:
Let’s start with some biology basics so this isn’t too abstract of an explanation.

YOU are made up from lots and lots of cells.
The cells have different important parts, the core being the nucleus. (Hopefully this is ringing some bells from school).

Within the nucleus of the cell are chromosomes, these are the things that define what the cell is a does. They carry all of the information used to help a cell grow, thrive, and reproduce. Chromosomes are organized structures of DNA. Segments of DNA in specific patterns are called genes. Your genes make you who you are. There we go, full circle, back to YOU.



So let's change this to ME, as I have CMT1a.
As with most people, I have 23 pairs of chromosomes. However, pair number 17 isn't how it's supposed to be... it is mutated so that it produces something it shouldn’t. It creates a duplication of a gene within something called a Schwann cell.


So this is all a leads up to understanding that someone with CMT 1a has Schwann cells that are abnormal, herein lies the key discovery towards treating CMT. The Schwann cells in the body are an integral part for the peripheral nerves. They are there to produce a protein (PMP22) and myelin – which if you remember (see post CMT Science #1) makes up the insulation for peripheral nerve cells. The duplicated gene in the Schwann cells causes them to produce more of the protein (PMP22) than they should. The result is that it causes the myelin sheaf around the axon of the peripheral nerve to deteriorate – Hence the cause of all the symptoms of CMT 1a.



I'll explain how this discovery has led to ground breaking research in the next post, CMT Science #3, but here is a taster talking about how innovative the research program is.

CLICK HERE TO SEE THE VIDEO
On June 15, 2010 the U.S. House of Representatives' Committee on Energy and Commerce, Subcommittee on Health, held a hearing titled "NIH in the 21st Century: The Director's Perspective." Testifying before the Congressional Subcommittee was NIH-Director Dr. Francis Collins. During Dr. Collins' testimony, the exchange on the video above occurred with Representative Eliot Engel.

CMT science #1 (and the benefits of belly flopping)

INSTRUMENTS (#1)

Against all natural instincts, it appears that sometimes it is better to belly flop than dive...

I've been working on the manual pump idea for the bubble organ by making some mockups of the drawing in my last post (so have a look there if you don't get how it works).

It's pretty simple. The valve is made by some weights sealing a piece of rubber over the air intake holes. When you lift the handle, you lift the weights, so the air intake holes open.

The 1/2 inch pipes on the side of the bucket are just for guidance, otherwise it just flops around. They can easily be improved I think.

Here it is in action:

I then tried to make a more compact version, which is where I realized it is better to belly flop than dive. The compact version technically works, but it is just so aerodynamic that it plunges into the water too fast to be useful.

The wide brimmed bucket has lots of surface area, so like the belly flopper, sinks slowly, producing a long and steady stream of bubbles.

I like the fact this instrument is getting bigger and bigger!

CHARCOT MARIE TOOTH

CMT science #1:

I’m obviously not going to explain everything at once, so in the spirit of all good scientific explanations, let’s begin with an assumption and then I’ll try to explain it later in another post. The assumption is that people with CMT have a defect in one of their genes, specifically one that makes proteins within the peripheral nerves.
[There are also many types of CMT, so for the moment I’ll just explain type CMT1a, as it is both the most common and the type that I have].

Peripheral nerves provide a feedback loop between the brain and the rest of your body. They transmit action signals to your muscles to make things move; they transmit sensory signals back to your brain so it know what's happening in the world. Without them you can think a lot, but nothing will happen and you wouldn't know where you were.

If we imagine that the peripheral nerves are wires carrying signals, it makes sense that they need to be insulated (covered in plastic) for them to work, otherwise the signals travel too slowly or get lost.

This is the root of the problem for people with CMT1a.


For a nerve, the insulation is called myelin. The defective gene I mentioned causes this insulation to breakdown (demyelination). Then the signal traveling along the nerve wire (axon) gets lost.

CMT affects the hands and feet most, because they have the longest peripheral nerves (i.e. the longest wires), so the most chance of the signal being lost. The reality of this for me is that most affected muscles either don’t move when I want them to, or move/cramp much later; most affected sensory nerves send no feeling to the brain, or I feel them much later (I get this quite often when someone has trodden on my foot, strange to feel when the culprit has long left the scene)...