Have you heard? Scientists have discovered a drug that cures Down syndrome with a single injection! Only they haven't. They've cured Down syndrome in mice with a single injection. Except... well... they haven't really done that, either.

Science has done an awful lot for mice. Cancer, Huntington's disease, old age, HIV. You don't worry about these things if you're a mouse, because science is on it. The latest breakthrough: yesterday, researchers published the results of a new treatment that has since been reported far and wide as a "cure" for or "reversal" of Down syndrome (in mice). These are, as is often the case with such claims, gross misrepresentations of the actual findings.



But this study, and its overhyped coverage, pose a unique opportunity for us to examine what it actually means when we "cure" a disorder like Down syndrome in an animal model. It also gives us a chance to explore what these researchers actually accomplished, which is still incredibly significant.

Here's the pithiest upshot of this research I can muster: researchers at Johns Hopkins University and the National Institutes of Health have identified a potent treatment for mice that exhibit hallmark symptoms of Down syndrome. A single dose of a chemical called SAG, delivered shortly after birth, seems enough to ameliorate major physiological and cognitive deficits associated with the disorder. But it doesn't correct all of them.

The research team, led by geneticist Roger Reeves, has published the results of its investigation in the latest issue of Science Translational Medicine. Over at Popular Science, where the treatment is described inaccurately as a "cure" in the headline, Shaunacy Ferro actually gives a great summary of the team's findings in the context of Down syndrome's classical symptoms:

People with Down syndrome usually have smaller brain volumes than control groups, including significantly smaller cerebellums, a portion of the brain involved in motor control. The researchers, led by Roger Reeves of the John Hopkins University School of Medicine, treated newborn mice that had been genetically engineered to have Down syndrome-like characteristics with a small molecule called SAG.

After a single injection of SAG on the day the mice were born, their cerebellums developed normally into adulthood. It improved their behavior, too: Mice treated with SAG performed just as well as normal mice on a memory and learning test.


Got it? Good. Let's unpack this.

The Animal Model is a Powerful but Imperfect Tool

Here's what's important to remember: like all preliminary biomedical investigations, Reeves and his colleagues used an animal model to assess the effectiveness of their treatment. In this case, they used a mouse genetically engineered to exhibit symptoms similar to the ones we see in humans with Down syndrome. As is typically the case, the genetic details of the disorder are not identical between humans and the model species.


Humans with Down syndrome carry an extra copy of their 21st chromosome. The resulting genetic imbalance has a significant impact on physiological and cognitive development. It's an incredibly common molecular mixup – by far the most common genetic abnormality in humans. In the U.S., one in every 691 children born carries a third copy of chromosome 21.

Just about every human on Earth comes genetically equipped with 22 pairs of autosomal (i.e. sex-independent) chromosomes and one pair of sex chromosomes (X and X/Y). But the mice used in research (Mus musculus) carry just 19 pairs of autosomal chromosomes and one pair of sex chromosomes. In other words: your standard lab mouse doesn't even have a 21st chromosome. How can we model Down syndrome in a species that lacks the chromosome associated with the disorder?


The answer: stretches of genetic information associated with Down syndrome are found sprinkled throughout the mouse's genome, and in fact occur most prevalently on chromosome 16. Equipped with this knowledge, researchers have genetically engineered a number of Down syndrome mouse models, each with its own special, technical-sounding name (Ts65Dn, Ts1Cje and Ms1Cje/Ts65Dn, to name a few). The mice used in this latest research were Ts65Dn mice. Each one carries a small, additional chromosome derived primarily from chromosome 16.

It's not a perfect analog for human Down syndrome (Ts65Dn mice exhibit a dosage imbalance for roughly half the genes found in a person with an extra 21st chromosome), but the effect on development is unmistakably similar: like humans with Down syndrome, Ts65Dn mice exhibit several of the disorder's physiological and behavioral symptoms. Two big ones:

  1. A smaller cerebellum (a region of the brain closely tied to motor control) with fewer neurons.
  2. Impairments to learning and memory, associated with physiological changes to the hippocampus.


So what did the researchers actually do?

Reeves and his colleagues were interested in studying the physiological and behavioral effects of a chemical called SAG on Ts65Dn mice. SAG is known to activate the Sonic hedgehog pathway, a molecular communication network so-named because fruit flies (another ubiquitous model organism) that lack the protein by the same name develop spine-like projections reminiscent of one video-game protagonist's.


Both the Sonic-the-hedgehog protein and Sonic-the-hedgehog pathway have been shown to play pivotal roles in the organization and proliferation of neurons in the developing brain. Crucially, Reeves and his team were interested in seeing what long-term effect an SAG dose administered shortly after birth would have on a Ts65Dn mouse as it progressed into adulthood.

The researchers demonstrated that a single dose of SAG administered to Ts65Dn mice right after birth caused their cerebella to develop like those of normal mice, growing to a comparable size and containing a similar number of neurons. This is a fantastic result!

But there's a caveat, because the researchers also demonstrate that something called long-term depression remains an issue in the cerebellar circuits of Ts65Dn mice that are treated with SAG. In neurophysiology, "long-term depression" is used to describe not an emotional state of being, but a signaling problem observed in the brain circuitry of people with Down syndrome. The upshot: SAG may help preserve the growth and structure of the cerebellum, but its effects on the cerebellum's function remain ambiguous, at best.


A couple more promising observations: Ts65Dn mice treated with SAG were shown to perform better on tasks that rely on learning and memory than mice that went untreated. Both of these faculties are closely associated with the hippocampus, a region of the brain that has been known to develop abnormally in humans with Down syndrome. When Reeves and his team examined the hippocampi of SAG-treated Ts65Dn mice, they found them to be more fully developed than the hippocampi of the untreated mice. In these model organisms, at least, SAG appears to have a normalizing effect on hippocampal development, and a positive effect on learning and memory. The researchers note, however, that Ts65Dn mice saw no benefit from SAG on tasks that rely on the normal function of the prefrontal cortex – a region of the brain associated with cognitive functions like planning, moderating social behavior, and decision-making.

The condensed version of the researchers' findings is that, in mice, SAG appears to have a normalizing effect on some of Down syndrome's trademark symptoms, and no observable effect on others. The results are promising, but, as is common in studies like this, a mixed bag. It is clearly a far cry from a cure. Even if it was accurate to say that mice can suffer from Down syndrome as we recognize it in humans, to say that they were "cured" of the disorder, when the mice clearly exhibit behavioral and physiological deficits, would be completely and utterly incorrect.

We're taught to be skeptical of how well research translates from animals to humans. As this JAMA article puts it: "patients and physicians should remain cautious about extrapolating the findings of prominent animal research to the care of human disease... even high-quality animal studies will replicate poorly in human clinical research."


What we're reminded of less often is that even the "high-quality" animal studies rarely warrant the use of a word as charged with underlying meaning as "cure." As Reeves himself noted in a statement: "Down syndrome is very complex, and nobody thinks there's going to be a silver bullet that normalizes cognition... Multiple approaches will be needed."

In medicine, the true cures tend to come few and far between. Even if you're a mouse.

Read the full study by Reeves and his colleagues in the latest issue of Science.