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.

I cannot stand on a moving bus

With this blog I'm very excited to introduce Nicole Burggraaf who has kindly offered to write a post on CMT. I'm excited because the project is working, a network is forming - please read, comment and share to make it stronger. Nicole and I haven't met in person, but we have 'CMT creates: music' in common!

INSTRUMENTS (#1)

post by Tim Phillips

Modular Bubbles.

In thinking about how to develop the bubble organ, I decided it would be most fun if it was very flexible in its configuration. I.e. It could be set up in a whole number of ways. In the spirit of the project, I also decided it should be possible to make it a social instrument to play. For this reason I've decided to make each note (manual pump & sounding tube) an individual module. Then you can just set up some or all of the notes however you like. They could be a giant circle so many people have to move around to play it, or a select scale arranged so that one person can play, and everything else you can imagine...

This will probably make more sense if I show you the single note module I've made.

It is very similar to the last prototype, just a little neater. Having two of the same bucket means they slot perfectly together and there is no need for guides. Hanging the weights that close the valve inside means they can be anything so long as they're heavy and they don't get in the way. I'm pretty happy that the design is getting simpler (if bigger) as I develop it - surely a sign of progress.

Here's how it works: (blackboard style)

CHARCOT MARIE TOOTH
post by Nicole Burggraaf

I Cannot Stand on a Moving Bus.

I lost my virginity in university. No wait---let me clarify, (less my parents be reading this who – despite my marriage and 4 year old son – still believe to the core that I still have mine) I lost my CMT virginity in university.

Although I walk with a limp and my feet are surgically carved like a Thanksgiving turkey, my CMT goes largely unnoticed. The only years I found CMT a true struggle were my middle elementary school years when I found myself in a school where teachers coveted athletic prowess over intelligence and with kids whose taunts could make Kim Jong-il cry. But time passed, kids forgot the lyrics to “Walk Like a Nicole” (to the tune of The Bangles “Walk Like an Egyptian”) and I had the most wonderful grade 6 teacher who boosted my self-esteem by encouraging my love for writing.

Being symptomatic as a toddler, I’ve unknowingly crafted my little “Nicole ways” of coping with my CMT. I don’t purchase anything with small buttons, as my shaky hands can’t do them up. I instinctively know when to sit down and take a break when my legs are getting tired. I married a man who makes the bed, as my arms are not strong enough to lift the mattress. (He also gives me pedicures to keep my calluses at bay, uncurls my hammertoes to clip my toenails and massages out my leg cramps. He is, indeed, “One of the Good Guys”.)

So to summarize, up until university, I had never really viewed my CMT as a disability. It was more like an everyday annoyance….like soggy cereal or Celine Dion.

When I was 19, I moved 45 minutes down the road to “The City” to earn a degree. University was filled with fabulous firsts – my first time living away from home, my first time having a roommate, my first time eating Norma’s – the cafeteria lady – Turkey Schnitzel. It was also my first time relying on public transportation…namely, the bus.

The first time I took the bus, it was to go downtown for a Frosh pubcrawl. It was basically an attempt to make the first years on my residence floor a cohesive unit of togetherness via booze….lots and lots of booze. (Incidentally, this works. Drunkenness = public puking and/or making out with a stranger = drunk stories = friendship.)

So we all piled onto the already crowded #7 bus and a grabbed the overhead pole, designed for standers to have something to brace themselves with, and continued to chat with my fellow froshers. The bus lurched forward and I fell forward and onto the lap of a stranger. I quickly apologized, made some lame joke about getting my sea legs, stood back up and rejoined still standing friends. I clung for dear life – while trying to maintain a casual outward appearance – waiting desperately for a seat to become available. For the record, I made it downtown but how we got home still remains sealed in the “Lost life of Drunk Nicole” portion of my brain.

I quickly grew accustomed to university life. I learned to save my quarters for the washing machine, that attending group sessions was more important than attending lectures and that eating poutine every night at midnight will cause you to gain 15 pounds in 8 weeks. **tear**

Everything about university was great…except for the bus. I would find myself walking a few bus stops down in hopes of getting on before the masses to secure a seat. A full bus would approach me and I would have to quickly debate whether to stand or wait for the next one in hopes it would be less full.

Now – this is where the non-CMTer is probably wondering: “Why doesn’t she just ask someone for their seat?”

OK. So bus pulls up. You get on to discover the bus is full. The front seats are designated “Reserved Seating” and the decal features hieroglyphs of a pregnant woman, elderly person with cane, person in a wheelchair or person with Seeing Eye dog. No where is there a hieroglyph of a 19 year old girl with a less than visible disability. Then, if you do ask for a seat, I feel compelled to launch into an explanation of CMT and its effects on me personally. I have yet to find a way to encapsulate CMT into a 10 second spiel so I’ve never attempted it. Then there is the fear that if I take a “Reserved Seating” spot, and someone who is depicted on the hieroglyph above me gets on, I will feel compelled to give up my seat. Because – really – the only thing visibly wrong with me was that I still listening to cassettes on my walkman!

One day I came to the realization that I could get a special bus pass, designating me as someone who was in need of the “Reserved Seating” despite outward appearances. So I got the appropriate forms completed by my family doctor, presented it to the bus authorities and was quickly granted a special pass.

I glanced down at my new, freshly laminated pass. There was my smiling mug and the caption “I cannot stand on a moving bus”. It was the first time ever I publically acknowledged that I have a disability. It was bittersweet. I was relieved I could ride the bus without having to play the “How can I get a seat/stay upright” game. But it was also the first time I had asked for permanent special status.

And that – for me – has been the most challenging part of CMT….acknowledging that it is a real disability.

In the grand scheme of things, Charcot Marie Tooth – is not the most haunting ailment/disease/disability out there. I’m sure the guy with Duchenne’s Muscular Dystrophy would look at me and my CMT and - rightfully - think “lightweight”. But on the other hand, there are millions of completely able bodied people out there who don’t have to cope with screeching leg cramps that come with CMT muscles or the routine scalding of your hands because you can’t tell if something is too hot due to severe neuropathy.

CMT has actually given me many things. The ability to overcome obstacles, the ability to laugh to keep the tears at bay, the ability to savor what physical abilities I have because, as CMT is a progressive disease, it may be gone. And it also reminds me that sometimes… I just have to take a seat.