The Future Cure for Down Syndrome?

I’ve recently been working with long-noncoding RNAs (lncRNAs), which are functional nucleic acid polymers (generally longer than 200 nucleotides) that are not translated into proteins. LncRNAs often play roles in gene regulation (promotion or repression of gene transcription), which is exciting because there are new mechanisms of action being discovered all the time, but this does add a new level of complexity to gene regulatory networks that’s going to take quite some time for the scientific establishment to sort through.

One of the best understood lncRNAs is called XIST (Borsani et al., 1991; Brockdorff et al., 1991, 1992; Brown et al., 1991, 1992; Clemson et al., 1996). It runs the show called X chromosome inactivation (XCI), which is the silencing of one of the two X chromosomes in mammalian females. Many XIST transcripts coat the X chromosome targeted for silencing by binding all over it, thereby preventing the genes from being transcribed. XIST also recruits silencing machinery such as Polycomb Repressive Complex 2 to label the chromosome as inactive, so transcription machinery won’t try to transcribe its genes. This process is very important, because if the extra X chromosome is not silenced in females, the amount of X-linked genes that are expressed doubles. This has proven to be a fatal gene dose at an early stage of embryonic development in mice lacking the Xist gene (Marahrens et al. 1997). Interestingly, some human breast and ovarian tumors have been found to have two active X chromosomes (Liao et al., 2003), so XCI is also being studied by cancer biologists, but this is another topic for another day. (Learn more about XIST and XCI here). 

You may have made the connection by now between X inactivation and Down syndrome (a.k.a. trisomy 21), a disease characterized by the inheritance of an extra copy of chromosome 21 in humans that results in cognitive disability, heart defects and many other complications. I had the same epiphany about a week ago: if the biological machinery already exists to silence an extra chromosome copy, then why can’t we use this to silence the extra chromosome 21 carried by people with Down’s? When I looked it up, I was happy to see that a group of scientists at University of Massachusetts Medical School (UMMS) had already beat me to it. Their study, published in Nature last July, describes the details of how Jeanne B. Lawrence, PhD, and her team inserted XIST at one chromosome 21 in cells donated by a Down’s patient. …And it worked! At the molecular level, the extra gene expression caused by trisomy 21 results in defects in cell proliferation and in neural cell differentiation, but both of these defects were reversed by Lawrence and her team when they silenced one extra chromosome 21 copy with XIST. (Read more about this study in the article published by UMMS, July 2013). 

For me, the craziest part is that this system of chromosome inactivation already exists in the bodies of patients with Down syndrome, and all there is to be done is to use it on a different chromosome set. Now, we’re nowhere near creating the actual therapeutic cure for babies or children with Down syndrome (live humans are in some ways very different than stem cells), but this inches us further toward a future IVF treatment. And I, for one, am REALLY excited.

Discussion Topic: While it’s an amazing thing to be able to come up with a truly original idea in science, I think it’s also a great feeling when I think of solution to a problem on my own, then have it validated by learning that someone else has done it and it has worked. What are some original ideas that you’ve had, but then found out had already been thought of/invented by someone else?



One thought on “The Future Cure for Down Syndrome?

  1. Pingback: Gene Editing, Part II: It’s Freaking Insane | SciCrazy

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