Prospective Chromosome Therapy for Down Syndrome: Hopes, Fears, and Ethics

On August 15, 2013, developmental biologist Jeanne Lawrence reported what many had previously considered inconceivable. [1] Her research team successfully silenced the extra chromosome 21 in Down syndrome (DS) stem cells. That is, in laboratory-grown cells, UMass Medical School scientists corrected the genetic fault responsible for the developmental and cognitive debilities associated with DS.

These astounding results prompted parents of children with DS, and interested scientists around the globe, to collectively wonder: Is it possible to move Lawrence’s lab research to the clinic? In short, could researchers design drugs that engineer the same chromosomal shutdown in people with DS—effectively reversing or at least attenuating related disorders?

This essay explains the investigation and its hopeful findings; examines Lawrence’s predictions of how her research might shape future clinical applications; considers the ethics of such therapeutics; and evaluates some preliminary parental responses to these prospective therapies.

The research

Persons born with genetic anomalies such as metachromatic leukodystrophy and Wiskott-Aldrich syndrome have inherited a single faulty gene that’s responsible for their respective disorders. Using viruses to smuggle in a working version of the defective gene, scientists have developed amazing remedial therapy for folks living with such diseases.

Persons with DS are born with three copies of chromosome 21 instead of the usual two—hence, the technical term trisomy 21. This condition is caused not by a single defective gene, but by hundreds of active genes on the extra chromosome. Hence, any correction of DS would necessarily require the daunting task of shutting down the entire third copy of chromosome 21 (C 21).

Based on years of studying the XIST (pronounced “exist”) gene, Lawrence and her team thoroughly appreciated the fact that women are the “masters of chromosomal silencing.”[2]The principal work of the XIST gene in the XX female is to inactivate one copy of the X chromosome in each of the woman’s cells, thereby averting the problems that might follow from a double dose of X-linked genes. The XIST gene exists on the X chromosome, and that’s precisely what it silences.

In a “huh, I wonder” moment, Lawrence, et al asked: If we could inject the XIST gene—bigger than any gene ever inserted into the human genome—into the right place on the third copy of C 21 in DS cells, would it silence the extra chromosome and all its negative effects? And, then, would it do so (A) without killing the cell and (B) without shutting down all three copies of C 21? After consultation with her geneticist colleagues, Lawrence and her research team agreed the only way to find out was to do the research. They applied for and received a grant from the National Institutes of Health, and the rest is history.

Six years of trial and error finally paid off. Lawrence’s team was successful in using a novel type of genome editing “to cut DNA at very specific points, to smuggle the giant XIST gene into a pre-defined [gene-rich core of] the extra 21st chromosome.” They did this in donated DS skin cells that were “reprogrammed into a stem cell-like state.” And, voilÀ, “XIST did its thing, ‘painting’ one of the three copies of C 21, and condensing it into a tight bundle. The genes on that copy were almost totally inactivated.”[3]

The investigators were subsequently able to create specialized brain cells from the DS stem cells and to observe the difference between what happened in one set of cell cultures in which the XIST gene was turned on and in the other set where the gene wasn’t activated. DS brain cells, treated with XIST, produced larger colonies of cells and were better at dividing into neuron-making cells.

The next step for the Lawrence team is to move from a laboratory dish of DS stem cells to a small mammal—using the same genome editing technique to shut down the extra chromosome in a mouse engineered with a version of DS.

Hopes  

As Lawrence points out: “The silencing of trisomy 21 by manipulation of a single gene in laboratory cells surmounts the first major obstacle to development of potential ‘chromosome therapy.’” Her hope is that “for individuals living with Down syndrome, this proof-of-principle opens up multiple exciting new avenues for studying the disorder now and brings into the realm of consideration research on the concept of ‘chromosome therapy’ in the future.”[4]

While Lawrence agrees with other researchers who suggest that the XIST technique may not be the most practical therapy to treat individuals with DS, she does see exceptions to that opinion. For example, many children with DS develop myeloproliferative disease, an overproduction of blood cells, which carries with it a high risk for leukemia. If a doctor saw children with this condition, Lawrence speculates, “it might be possible to activate XIST in their blood stem cells, to prevent them from developing cancer.”[5]

Lawrence also forecasts the development of drug therapies modeled on her research.[6] Relying on her team’s greater understanding of what goes wrong with trisomic cells, drug researchers should be able to expedite the development of pharmaceuticals that duplicate corrective genome editing. A future drug, for example, could target the neurons of DS patients. With its corrective mechanism, the drug could help to raise IQ enough to allow these individuals sufficient mastery of the “3 Rs,” as well as reasoning and social skills, to enable them to, say, drive a car or to live and work independently.[7]

Lawrence emphasizes that, long before the roll-out of any human clinical applications, both the XIST technique and drug therapies, whether administered pre- or post-natally, would be run through the gamut of murine research—that is, be applied to mice that have been engineered to have a form of DS. Only when these preliminary experimental therapies prove safe and effective for human trials—that is, meet the stringent NIH and FDA drug regulations, particularly those testing for toxicity levels—will they be used with DS patients.

Professor Lawrence, revealing the personal moral values that guide her DS research [8], states that, of all the rewards she has reaped from the long years invested in DS research, the greatest is hope. Hope that the therapeutic possibilities of chromosome therapy might discourage abortions as it encourages pregnant women to bring their babies diagnosed with DS to term.

Ethics

Defusing the concern of one Catholic ethicist—that radical hormone therapy (eradicating DS at its root) would involve a chromosome therapy for human blastocyst embryos that would likely involve risky experiments and destructive genetic testing on those embryos—Lawrence counters that the deliberate production of in vitro embryos with DS and then experimenting on them is not even a consideration and, even it were, it would be completely unethical under all current human research standards. If radical chromosome therapy would be done, she explained, it would need to be done in utero at the blastocyst stage. But since women don’t know they’re pregnant seven to eight days after conception—and even if they did, there’s no way to test whether their embryonic baby would have DS—the idea of in utero use of chromosome therapy at the blastocyst stage is technically and practically infeasible.

The eventual clinical use of pre- or post-natal chromosome therapy would be ethical under the following conditions: they (1) were thoroughly tested in animals; (2) had met all human drug safety and efficacy regulations from the FDA and NIH; (3) were proven to offer patients proportionate remedial benefits; (4) were cost-effective; and (5) were only administered with informed consent from the DS patient or his parent/guardian. That is to say, the use of chromosome therapy would be ethical if it met the same medical and ethical standards as any other currently approved medical therapeutics for cancer, heart disease, and dementia.

The chromosome therapy described here acts on specific somatic cells of a DS patient in order to correct the genetic overload that causes disorders. Doctors would use such therapy not to elevate the patient’s physical and mental capacities above the norm, but to normalize a DS person’s health. As such, the prospective therapy described would make no eugenic or promethean assault on the natural dignity of a DS person.

Fears

Some parents of children with DS express apprehension about accessing chromosome therapy.[9]  Even when asked to presuppose its morality, safety, and efficacy, one mother feared such treatment would change the “essence” of her daughter. Perhaps understanding the difference between substantial and accidental change in humans might help to dispel this misgiving.

Consider Andrea, this couple’s 13-year-old daughter who is living with DS. She has a unique essence—itself a composite of soul and body—that has received from God, at the moment of her conception, the act of existence. Andrea’s essence and existence constitute her substance, which can only be altered by coming to be (her conception) and by passing away (her death). Any other changes she may undergo in life, no matter how significant they may seem to us, rather than changing Andrea substantially, are only changes that modify her person in “accidental” ways, that is, in ways that represent a change to her properties. Some of Andrea’s properties touch on her essence, and some are less significant.

One of the most “essential” properties of the human body is its genome—the sum total of all the genetic information stored as long molecules of DNA sectioned into chromosomes. Of all the body-building tasks of human DNA, the most critical is to construct the brain and central nervous system. Hence, if a mother were gestating a baby with DS, she should view neuron-targeting chromosome therapy administered in the prenatal period as an opportunity to help her baby’s brain more effectively function as an instrument of conceptual thought. Andrea’s mother ought to view post-natal chromosome therapy in the same way and for the same reason.

The first principle of medicine, “Do no harm,” dedicates the healing arts to restoring and protecting the natural human capacities that constitute health. Therapy that would correct harm done to Andrea’s body and brain from genetic overload realizes perfectly the goal of restorative medicine. Furthermore, such intervention could potentially allow Andrea’s genes to build a brain that works more efficiently so that she, with her increased ability to think and to choose, might become a moral agent, the true author of her own deeds.

The specter of increased moral agency implicates a second fear expressed by the father of a daughter living with DS: “If, with this therapy, my child acquires more intelligence and freedom, won’t she lose the innocence she now has with DS?” Well, it is certainly true that, if successfully treated, this child would be capable of more responsible action and, with that freedom, the possibility to choose poorly. Nevertheless, shouldn’t we want every person to exercise rational intelligence and freedom? Isn’t this capacity part of the image of God that Christ came to restore in each of us? Shouldn’t we want to help this child maximize her potential by becoming the rationally intelligent, virtuous person she is meant to be? This is precisely why Jesus healed people; so that, like Peter’s mother-in-law, they can get up from their sick bed and freely and lovingly serve God and, in the process, joyfully evangelize others. Healing this child with chromosome therapy, then, would be giving her the capacity to be even more loving.

In a closely allied reservation, another couple worried that, in an improved state, their DS son might lose what they see as his mission in life, that is, to evoke greater unselfishness and love from those around him and, in this way, to make family and friends more saintly. But were this chromosome therapy to correct or diminish the child’s physical and cognitive disabilities, he would have an even greater capacity to actively love and serve those in his intimate circle. What’s more, besides inspiring others to be holy, this child could purposefully pursue sainthood for himself!

No one argues with the idea that parents ought to foster excellence in their children. For this reason, parents of DS children should make every reasonable and prudent effort to offer them the opportunity first, to be more healthy, and, second, to consciously make a gift of themselves and to receive others as gift. Isn’t it because of the great healing tradition of the Church—starting with the ministry of the Divine Physician—that hospitals and the art of medicine have flourished as a way to restore the body and mind? There’s no obligation to be sick or to stay sick. Quite the contrary. We’re obliged to seek healing for ourselves and others. So that, rejuvenated in body and/or mind, we, like the grateful leper healed by Jesus, can get up from our sick bed and “praise God in a loud voice.”

The balanced reasoning of another mother properly closes this discussion. Having evaluated prospective chromosome therapy in the context of the complete trust her DS daughter places in her, she concludes: If I would make the decision “that some of [my child’s] limitations must remain, when I had the option to remove them, I would betray that trust…and the best of everything I can give [her].” [10]

Related Reading: “Putting a Face on Down Syndrome” by Leslie Fain