“It makes a difference for a man to know that he can negotiate a fragile boat around a headland against fierce winds and churning water.” —from Rowing Against the Current by Barry Strauss
March 2011- Roger Reeves seeks balance while sculling in a homemade boat.
“The last time I was on the water, I broke ice all the way,” he reports with relish. “It requires total concentration to put out every erg of energy and move in concert with other guys of every imaginable shape. When you’re rowing, you can’t think about other stuff.”
“Other stuff,” for Reeves, is Down syndrome, a genetic disorder that has consumed his energy, time, intellect—indeed, his entire career—since arriving at Hopkins decades ago as a postdoc.
“I got one idea and never had another,” he quips, “so I stuck with it for 25 years.”
That one idea is currently fueling eight research projects in his lab, including a couple of multisite studies involving people, and half a dozen investigations that make use of transgenic mice and fluorescent zebra fish.
One study, which has the interest of a major pharmaceutical firm, is on the verge of a clinical trial. It’s a pharmacologic agent that, according to Reeves, shows great promise for improving cognitive ability in people with DS.
“I never thought I would get this far in my whole career,” says Reeves, who, as a brash youth with an interest in genetics, set out to tackle the toughest genetic problem he could find that might have hope of solution. “If we can really make a go of this—if it has an impact on these kids—I’ll never do anything else that even comes close.”
Known as trisomy 21 because it involves three copies of chromosome 21 instead of the usual pair (one from dad and one from mom), Down syndrome is caused by non-dysjunction of the chromosome during cell division, most often during egg development. It is the most complex genetic perturbation that’s compatible with human survival past term. There are more common trisomies at conception, but the others are nearly always lethal before birth. Trisomy 21 is a serious genetic challenge, too: Only about 50 percent of conceptuses with trisomy 21 make it to term.
This most complex disorder involves an entire chromosome and upwards of 300 genes. Although it results in universally recognizable phenotypes, or traits, Down syndrome can be maddeningly subtle at the molecular level, Reeves says, because changes in the expression of many of the affected genes are likely at levels too low to measure with any precision using current technologies.
“Reports of a 50-percent increase in the expression of such-and-such gene that is expressed at a really low level to begin with are often not repeatable,” he explains. “We have to look collectively at what these genes do. Trisomy 21 changes not only the expression of hundreds of genes on that one particular chromosome, but also the expression of genes throughout the genome.
“A particular cell that’s affected by trisomy may develop at the wrong time, or express too much of something that turns off another gene or signals neighboring cells to differentiate. And these signals are perturbed by the trisomic cell. The way this plays out is extraordinarily complex. I think I’m safe for not being able to figure this out before I’m ready to retire.”
Ever since he landed a faculty position here in 1986, Reeves has been “clawing through the NIH system” to secure funding in an underrepresented area where many believed progress was impossible. Identified as a syndrome in 1866, and affecting about 1 in 700 people, DS is a familiar and recognizable disorder that’s of medical interest mainly to clinicians trained in pediatrics. Since its genetic basis became known in 1959, DS has become the prototype of a chromosomal condition that defies intervention because it begins at the moment of conception, in most cases. Many important developmental events occur before birth in the brain, gut and heart, so the tendency has been to focus more on management—early education and supportive medical care—than biomedical treatment.
Even at this point in his career, Reeves finds himself constantly having to justify what he hopes to achieve with more basic research. He often finds it necessary to point out that all of us benefit from the genetic legacy of those who have Trisomy 21. Discoveries made while studying heart disease or cancer in the DS population indeed benefit others as well as those with DS.
Down syndrome never has been and likely never will be a marquis issue in terms of priority research. One reason is that most affected families aren’t exactly clamoring for a cure, observes George Capone, director of the Down Syndrome Program at Kennedy Krieger Institute.
While it makes good sense for science to attempt to uncover the mysteries of development and brain function as they pertain to DS, and while many parents of kids with DS might line up for a biomedical treatment if one was safe and effective, most come to terms with DS after a time and wouldn't change a thing about those children who are learning and progressing, Capone says, adding: “We, in the world of research, need to be careful not to superimpose our agenda on families.
“Parents of kids who aren’t doing well might love to have a magic bullet. But there probably never will be such a thing. Any kind of success we may have, be it pharmacology or signaling molecules or cell based therapies, is probably going to have an incremental benefit on how kids function. And it may well end up being some rational combination of those, along with interventions and therapies already used.”
Based on the work that he and Reeves are collaborating on, as well as research by others, Capone thinks there are biological mechanisms that likely can be leveraged to preserve functioning longer into the life spans of those with DS and maybe even—and this, Capone says, would be the holy grail—to redirect brain development earlier to achieve a higher level of integrity.
“That would mean intervening prenatally or very early post-natally,” he says. “We’re clearly not there.”
There’ve been other pharmacologic trials in the context of DS, but not always as well based on the science as the one he and Reeves are now involved in, Capone says. That’s because even when the science is good—meaning that it bears out in the animal model—pharmacology is a fairly narrow therapeutic approach. It depends on external cell receptors to be present and respond, he explains. And the thinking is that in DS, there’s perturbation at every level of the system: the cell signaling pathways, for instance, as well as the regulation of gene expression.
Clinicians like Capone and scientists like Reeves are working to discover the fundamental mechanisms of DS, the ones that matter more than others: Is it to produce more of the normal number of cells from early on? Is it to correct the signaling pathways that don’t seem as tightly regulated?
“Roger did a nice experiment with the sonic hedgehog (SHH) pathway to show that when you provide an agonist of SHH, which creates a normal level of signal, you can then get your cell number in the cerebellum up to a more normal number,” Capone says. “That’s exciting! That’s really novel! That’s beyond just pharmacology.”
If there is a constant with regard to DS, it’s variability, according to Reeves. When you look at any phenotype, any feature of DS, you see lots of variability: for instance, whether heart disease occurs and, if it does, what kind.
Atrioventricular canal (AVC) defect is a complex congenital anomaly that results in a large hole in the center of the heart. It’s the most severe structural defect a person can have, because basically nothing connects correctly in the heart. Its incidence in the general population is one in 10,000 and in the DS population, one in five, meaning babies with DS have a 2000-fold increased risk for AVC.
Intellectual ability also is hugely variable. And even more than heart disease, cognition is of utmost concern to families, says Reeves. His opinion is informed not only by having worked in the clinic alongside Capone but also by frequent interaction with the DS community.
“If I don’t go out and see kids with DS, and talk directly to parents and families about what’s really critical for them, then I don’t know how I should be using my time and talents,” he says. “I’d like to be relevant, just like everyone else.”
As a rule, the people he talks to are interested in seeing their children or their family members with DS have every opportunity to be able to live as independently as possible, he says, which means having jobs and drivers’ licenses, for instance. That’s why he’s so hopeful about ongoing research involving a drug that, he thinks, might optimize adaptive behavior by restoring balance to the brains of people with trisomy 21 as well as it did to those of trisomic mice.
In the hippocampus—that part of the brain that’s used to navigate landmarks and fix memories—things don’t work as well in people (or mice) with DS. Big electrical circuits flow through this region, and their activity is influenced by different inhibitory and excitatory inputs by neurons. In the trisomic mouse—and likely, in people too—there is an overabundance of inhibitory input relative to excitatory.
In functional tests of the hippocampus, such as one that measures the skills necessary to perceive spatial relationships among objects, pharmacological treatments completely restored the ability of the DS model mice to use their hippocampus by restoring that balance.
“The trisomic mice perform just like their normal littermates after treatment,” Reeves says. “It’s extremely exciting.”
Reeves’ own visuospatial skills allow him to find his way around a lab as well as a body of water, enabling him to practice science and to row. His hope is to be able to help enhance that same kind of cognitive functioning in DS patients so that they, too, can navigate more confidently through their own lives.
“There are those parents who insist, ‘I don’t want you making my child someone else,’” Reeves says. “And I tell them we aren’t messing with anyone’s mind. We are taking something that’s out of balance and putting it back into balance.”
-- Maryalice Yakutchik