Pope Francis greets Alberto di Tullio, 17, after letting him sit in the popemobile chair during the general audience in St. Peter's Square at the Vatican June 19. Di Tullio, who has Down syndrome, was treated to a literal spin in the popemobile when the pope turned the youth around in the white papal chair. (CNS photo/Paul Haring)
On August 15, 2013, developmental
biologist Jeanne Lawrence reported what many had previously considered inconceivable.
 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 DSeffectively 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.
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 twohence, 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.”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 genebigger than any gene ever
inserted into the human genomeinto 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
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
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 mammalusing
the same genome editing technique to shut down the extra chromosome in a mouse
engineered with a version of DS.
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
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
Lawrence also forecasts the
development of drug therapies modeled on her research. 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.
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 researchthat 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 trialsthat is, meet the stringent NIH and
FDA drug regulations, particularly those testing for toxicity levelswill they
be used with DS patients.
Professor Lawrence, revealing the
personal moral values that guide her DS research ,
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.
Defusing the concern of one Catholic
ethicistthat 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 embryosLawrence
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 conceptionand
even if they did, there’s no way to test whether their embryonic baby would
have DSthe 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.
Some parents of children with DS
express apprehension about accessing chromosome therapy. 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 essenceitself a composite of soul and bodythat 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 genomethe 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 Churchstarting with the ministry of the Divine Physicianthat
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
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].” 
“Putting a Face on Down
” by Leslie Fain
. Lawrence, J.B., et al “Translating
dosage compensation to trisomy 21” Nature
500 [15 August 2013] 296-302.
. “Shutting Down,” p. 3.
. Contents of a phone interview
with Professor Lawrence on 12/17/13.
. These responses from parents
who have children with DS were either voiced during interviews or posted in
comments to the articles cited here.