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…
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…
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