on and off toggle switch
An on/off switch for Down syndrome

(World Down Syndrome Day, March 21, 2014)

As some of you may know last summer, scientists at UMass Medical School made a big discovery. They learned that a naturally occurring X chromosome “off-switch” could neutralize the extra chromosome responsible for Trisomy 21, also known as Down syndrome.i

The approach used by Dr. Jeanne Lawrence was inspired by the natural process that silences one copy of the female mammals’ two sex-determining X chromosomes during embryonic development. To prevent females from overdosing on these X chromosome genes, evolution invented a genetic element whose job is to deactivate half of those X chromosomes. They remain in the genome, but are not functional – gene silencing helps maintain similar expression patterns of X chromosomes in females and males. The X-inactivation gene (XIST), a large non-coding RNA molecule which covers the surface of one of the X chromosomes of female mammals, permanently blocks the expression, or activity of the genes on the affected X chromosome.

Dr. Lawrence mimicked this natural process by inserting the XIST gene into the gene-rich core of the extra chromosome 21 in patient-derived adult stem cells. In these laboratory cells they found that the RNA from the inserted XIST gene induced modifications that silenced the genes of chromosome 21, returning gene expression to near normal levels, even when measured eight different ways.

Now while this has been hailed in the press as a “cure for Down syndrome”, we are still only at the testing stage and any application to human subjects is still years away.ii However this potential for “chromosomal therapy” has stirred up controversy in the Down syndrome community, not dissimilar to how the development of cochlear implants have impacted the deaf community.

At one end of the spectrum, we have folks saying, “why wouldn’t you want to fix your child?” In the current era of pre-natal testing, this may be a real treatment option one day, and might affect the abortion rates of pre-natally diagnosed pregnancies, which have been increasing with each new pre-natal test that comes onto the market. iii, iv

At the other end, most parents of children with Down syndrome don’t think their child needs “fixing” and wouldn’t change anything about them. In fact, some worry that attempting any kind of therapy, let alone chromosomal therapy, would affect their child’s personality, which they would not want to turn “off”.

Others say, only use gene-silencing therapy to combat the ill-effects of Down syndrome. But where do you draw the line? Sure, for the obvious health issues such as the heart, digestive, hearing and vision challenges (if these can be individually identified and isolated chromosomally – we “fix” these now post-natally), but what about cognitive impairment levels, which universally affect all individuals with Down syndrome? Who’s to say where cognitive impairment begins? An IQ of 65, 70, 75? Just this month, the Supreme Court decided to revisit a case involving the execution of criminals with “mental retardation”.v 12 years ago, they removed the death penalty for criminals with an intellectual disability but left the details of defining what constitutes intellectual disability to the states, resulting in a range of IQ being used to apply the law. And is IQ really the right measure anyway? I’d offer up EQ or Emotional Intelligence as an alternative – the last time I checked, my 9-year old son with Down syndrome had a higher EQ than most people I know.

This raises some ethical questions – with IVF allowing parents to chose what type of children they want (ranging from sex selection to avoiding certain undesirable genetic conditions such as Down syndrome), to pre-natal testing & selective abortion, can we as parents be trusted to exercise good judgement over our choice? Again, I ask – where do we draw the line? Technology is only going to get better and soon we’ll be able to test pre-natally for things like same-sex preference. I suspect the media coverage would be dramatically different if we discovered a pre-natal test for the “gay gene” or found a genetic “treatment” for homosexuality. The latter certainly wouldn’t be hailed as a “cure for homosexuality”.

Having three copies of our 21st chromosome is one of the most common spontaneous “alterations” in our attempts at reproduction and if this is a natural part of the human condition, shouldn’t we embrace this diversity, much as the way we celebrate our differences in gender, color, race, national origin, religion, and sexual orientation? Social resistance to genetic selection is emerging. Earlier this year, North Dakota became the first state in our nation to pass a law prohibiting abortion for sex selection or genetic abnormalities such as Down syndrome.vi In social media, concern over genetic racism is rising. While chromosomal therapy might very well be a treatment in our lifetime, many in the Down syndrome community would like to propose a movement to celebrate chromosomal diversity instead. How very fitting in celebration of World Down Syndrome Day!

i Jiang, J. et. al. (2013). “Translating dosage compensation to Trisomy 21”. Nature, 500, 296-302.
ii Aleccia, J. (2011). “Could it be a cure?” NBC News. https://www.nbcnews.com/health/could-it-be-cure-breakthrough-prompts-down-syndrome-soul-searching-6C10879213, accessed February 2, 2014.
iii  Egan, J.F., et. al. (2011). “Demographic differences in Down syndrome live births from 1989 to 2006”. Prenatal Diagnosis, 31, 389-394.
iv  Messina, J. (2013) “Reflections on Down syndrome”. Disability INDEX. https://www.disabilityinfo.org/blog/?p=3682 , accessed February 2, 2014.
v  Clark, M., “Supreme Court to Consider What Defines Intellectual Disability”. Disability Scoop. https://www.disabilityscoop.com/2013/12/10/supreme-court-intellectual/18959/ , accessed Feb 2, 2014.
vi  The Prenatal Non-Discrimination Act (PREDNA) was signed into law on March 26, 2013, details https://legiscan.com/ND/bill/1305/2013 , accessed February 2, 2014.

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