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Thought I’d pass along a little good news and some fascinating and very cool science.
Dr. Jeanne Lawrence’s team at the University of Massachusetts Medical School in Worcester published in yesterday’s issue of Nature (warning, paywall) what I consider an amazing accomplishment. They have managed to shut down, in cultured stem cells from a patient, the extra copy of chromosome 21 that causes Down’s Syndrome. It has created quite a scientific and media frenzy, and has been covered in multiple TM and other news sources. See a brief interview with Lawrence here. I haven’t seen it diaried yet, so I thought I’d put it out here. The reason for the fuss is that this is certainly the biggest step forward in DS since the creation of a mouse model, which in itself was exciting and fuel for a tremendous amount of creative research, but which hasn’t led to enough in the way of specific knowledge or paths to treatments.

DS, as many here know, is caused by trisomy 21, which means that the cells of DS people have 3 copies of chromosome 21. Each cell in humans has 23 pairs of chromosomes, but in trisomies like DS, there is a 3rd copy of a chromosome, in DS, #21. The extra copy somehow causes the errors in growth and metabolism that lead to the intellectual and developmental problems associated with DS.  Down’s is the most common cause of learning disabilities, affecting almost 1 in 700 live births in the US. That’s a big number. And a lot of heartbreak. One point many are not aware of is that the severity of DS varies tremendously from individual to individual. Not all DS kids make it to the mainstream of school and a job and interactions with the public. Many spend almost their whole lives institutionalized and cared for, severely intellectually disabled, unable to perform even the most basic self-help tasks. And there are many medical complications which also vary widely from person to person, which I mention briefly below. For more on that aspect of DS, see the short list and links from the Mayo Clinic.  

Lawrence’s group took advantage of a fascinating natural event that is extraordinarily commonplace but wonderfully mysterious. The sex of mammals is determined by the X and Y chromosomes, males being XY and females being XX. To keep gene expression levels normal (“dosage compensated”), every cell in a female’s body has one copy of the X chromosome switched off. This is accomplished via the expression of a single silencing gene from one of the X’s, a gene called XIST (pronounced “exist”). The XIST DNA is transcribed into RNA and spliced and processed like any gene encoding a protein, but XIST RNA never gets out of the nucleus to be “translated” into an amino acid sequence to make a protein. Instead, it remains an RNA and accumulates in the nucleus. There, it “paints” the X chromosome from which it is being expressed and causes it to shut down and condense into what is called a Barr body, a dense bit of DNA visible in the microscope from which only the XIST gene is expressed. Amazingly, this happens in each cell independently, meaning that the choice of which X is silenced is random, shutting off the X from the woman’s mother in half the cells and from the father in the other half. The biological reason for this is that too much of a good thing is bad. Some genes, when expressed at twice the normal level, are lethal to the cell, so survival requires turning one X chromosome off.

Dr. Lawrence’s team did a lot of the basic science heavy lifting on the workings of XIST (see here and here, for example), then inspiration struck. She realized that if XIST could shut down a whole X chromosome, might it be possible to put it into ANY chromosome and shut that one down? If so, would it be an avenue to shutting down trisomy chromosomes as in Down’s?  There were many reasons this might not work at all.

Despite the many possibilities for failure, the answer was an amazing “yes”. The team made what are called induced pluripotent stem (IPS) cells derived from a DS donor’s cells. IPS cells have the ability to differentiate into various cell types needed to develop all the tissues and organs of the body. Lawrence’s group then inserted and copy of XIST into a specific spot of chromosome 21 in the IPS cells in such a way that the XIST gene can be switched on simply by adding an antibiotic drug to the cell cultures. They found that it could turn off genes up and down the extra 21 but not on the other copies of chromosome 21 nor on other chromosomes. In the XIST-on state, the cells’ characteristics were normalized in culture. Gene expression was normalized, cells grew more normally, they formed neuronal cells normally, and other defects were corrected.  

 The prospects for this are exciting. One mystery of DS is how the various manifestations of it are caused by the extra gene copies. There are many symptoms of DS which can vary greatly from person to person. They include intellectual disability from relatively mild to extremely severe, heart problems, early onset dementia, gastrointestinal problems, increased likelihood of leukemia, and others. The problem is that, despite the availability of mouse models of DS, there has been no way to investigate in a clean system how the trisomy messes up the balance of gene expression and therefore cell function. With a new set of tools using this XIST silencing strategy, it will now be possible to dissect out which genes are responsible to for the problems in various tissues and organs.

 As a simple starting point, this alone could be huge. It may be that there are already drugs that can prevent some of the damage caused to certain organ systems now that we will have a means to discover the specific causes. Other, new drugs can also be investigated for those properties. Further down the road, it may also be possible to perform “chromosome therapy” to shut off the extra chromosome in the bone marrow, for example, to reduce the risk of leukemia or immunodeficiency. Way down the road, even earlier, broader correction of gene expression might be possible, but that probably would require such early intervention during embryogenesis that it would be impractical.

 As in almost all “breakthroughs,” this is the result of years of hard slogging in the lab, of creative minds working together to make conceptual leaps and solve a myriad of technical problems. Brilliant. The work was funded in part by your tax dollars via NIH grant money. There was also  public/private collaboration with Merck, which had some of the molecular tools needed to carry out the gene targeting work.

Beyond the potential for progress in understanding and maybe treating DS, the work by Lawrence’s group also brings hope to studying some long-troubling questions in basic cell biology, namely what the heck is all that repetitive DNA and non-coding RNA doing in the nucleus, and what are the previously unexpected roles they may play in genome regulation. Stay tuned.

 It is important to make two final points. There is a strong sense of community for people with DS and other related problems, and there can be resentment toward efforts to “correct” it because it implies that DS people are somehow less than “normal.”   Of those people I would ask that this research be seen in light of working toward preventing specific health and learning disabilities that often make DS people’s lives an endless series of medical and social emergencies. Second, any thought of this being a “cure” should be seen in the far-off future. I see a good 5 years of work before treatments for tissue-specific problems can be identified and perhaps treated in some cases. Any thoughts of “chromosome therapy” should be at least 5 more years away. In the meantime, there is now, at last, a tool to investigate the nitty gritty details of how this all-too-common chromosome glitch disrupts normal growth and development.


11:28 AM PT: UPDATE. many thanks, all, for your rec's. This is the obligatory thank you for putting on the wreck list for the first time. I'm very pleased to see such enthusiasm for science here. Nothing like a sea of rational, caring, inquisitive, reality-based people. Guess that's a left wing tendency.

Originally posted to p gorden lippy on Fri Jul 19, 2013 at 08:34 AM PDT.

Also republished by Parenting on the Autism Spectrum and SciTech.

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