Elizabeth Fisher and Victor Tybulewicz have made a new mouse

John Langdon Down was a progressive liberal Victorian doctor who first described the constellation of features that we now know as ‘Down syndrome’ in 1862. In 1959, almost 100 years after Down published this description, Jerome Lejeune discovered that people with Down syndrome have an extra copy of chromosome number 21. Instead of the usual 46 chromosomes, they have 47. 

This was a seminal moment in the history of Down syndrome research, as it told us that the syndrome does not arise from abnormal genes, or gene mutations, but from simply having one extra dose of normal genes – three copies of the genes on chromosome 21, rather than the normal two.  So Down syndrome is a gene dosage problem.

However, we know that human chromosome 21 carries at least 250 genes, so working out which genes are particularly important for DS is a complex problem.

Important to study genes
We are interested in understanding the genetic causes of Down syndrome (DS) for two reasons.  People with DS have a greater frequency of many disorders (such as autoimmune diseases, heart defects, diabetes) than the rest of the population, so if we can work out which genes on chromosome 21 are associated with specific aspects of the syndrome, we can try to target therapies to help alleviate these disorders in both the DS and chromosomally normal population. 

Secondly, we don’t know very much about how abnormal gene dosage causes disease. It’s turning out that many other disorders arise from abnormal gene dosage, often caused by tiny deletions or duplications in individual chromosomes.

Mouse models
We can start to work out which genes on human chromosome 21 give rise to the learning difficulties, which underlie the heart defects, and so on, by studying the chromosomes from some people with DS. But we cannot refine this work to tell us exactly which genes are important, and we cannot then experimentally test our findings.  For this reason, and because DS involves a complex interaction of the whole body, most groups working on the molecular genetics of DS work with mouse models. 

As we share the same ancestor as mice, we naturally share the same genome and the same genes – and generally the same disorders.  However, no naturally-occurring mouse has the same arrangement of chromosomes as humans do, and therefore none has the exact equivalent of human DS. Therefore, over a decade ago, we set out to make a new kind of mouse model to help us understand DS in humans.

A new mouse
Using a mix of old technologies used for culturing cells, and newer technologies such as manipulating mouse embryonic stem cells, we have put human chromosome 21 into a mouse so that the new strain of animal really does model human DS.  This mouse has three copies of the genes on chromosome 21 instead of the normal two, just as humans with DS do. In this animal we find learning and memory defects, heart defects and other characteristic alterations. 

In effect, we have made a ‘super transgenic’ mouse. Rather than carrying one or two human transgenes (like the mice we’ve been making for the last 25 years or so), our new mouse carries 250 human genes (which is still less than one per cent of the genome).

Understanding and therapies
The importance of the new mouse is two-fold.  Firstly, it is a technical step forward in transgenic techniques that will help us understand other human disorders that arise from abnormal chromosome number (and these are reckoned to account for at least five per cent of pregnancies and are mostly lethal). 
Secondly, we will now be able to breed this mouse to other mice that, for example, carry only one copy of a gene of interest, and thus we can say whether that ‘candidate’ gene has specific effects, for example on heart development. In this way we can work out which genes and which regions of the chromosome are important for DS, in a way that we could not do with existing models. 

The generation of the new mouse model took us more than a decade, and we envisage that working out which of the 250 genes on chromosome 21 cause which aspects of DS, will also take a long time. Nonetheless we are optimistic that this will eventually lead to a better understanding of the syndrome and hence point us to possible therapies.

Professor Elizabeth Fisher is at the Institute of Neurology, London

Victor Tybulewicz is at the National Institute for Medical Research, London