Mice hold key to genetic secrets
(China Daily)
Updated: 2005-10-17 05:56

It may be small, furry and too fond by far of the contents of our cupboards, but the humble mouse has great things going for it. It now transpires that Mus musculus is remarkably similar to Homo sapiens. Indeed, each of us shares 99 per cent of our genes with it.

Not only are mouse genes like ours, so are the development of their embryos, their patterns of disease and even their behavioural problems. Mice get stressed, too.

These similarities are about to be exploited by the scientific community. Mice are to become researchers' main vehicles for unravelling humanity's genetic secrets.

In Venice over the weekend, scientists launched a US$180 million EU programme to breed millions of genetically engineered mice. The aim is to recreate all the main human ailments diabetes, heart disease, cancer and mental illness in the mouse. In doing so, the genetic and environmental roots of these conditions will be exposed and new paths to the creation of drugs and treatments revealed.

"The European Union has recognized the power of mouse genetics," said the project's co-ordinator, Professor Wolfgang Wurst, at the launch.

The EuroMouse project has been set up as a successor to the human genome project, which was completed three years ago. That vastly expensive programme of DNA sequencing unravelled the make-up of each of the 20,000 genes that constitute the human constitution. But scientists still do not know what half of those genes do or what proteins they make.

"It was like creating the scientific equivalent of War and Peace, but in a foreign language," said Dr Ewan Birney, of the European Bioinformatics Institute in Cambridge. "All human nature was there on the pages, but we couldn't read them. Now we are finding ways to translate those pages and the mouse is going to be crucial."

The fact that mice and men are so similar is startling, scientists admit. "They are small and furry. We are large and unfurry," said Dr Steve Brown, of the Medical Research Council's mammalian genetics unit in Harwell. "There would certainly appear to be few points of comparison. Yet they often get ill like us and display symptoms of diseases like ours." In addition, each of the 20,000 genes that make up the mouse genome has been sequenced, in detail, as part of a programme that has paralleled the Human Genome Project. "Only mouse and human genes have been studied with this precision," added Birney.

The EuroMouse programme will involve using a strain of mouse known as the BL/6 or Black Six. These are already used extensively in laboratory experiments and are completely inbred. Each male is an exact clone of all other Black Six males, and similarly for females, no matter if used in an Australian or an Austrian laboratory.

From their populations of Black Sixes, EuroMouse scientists will take embryos, delete or modify one of the genes in them, and then put the genetically engineered embryos back into mice wombs to create a new population, one that has a single mutant gene inside each member.

This process will then be repeated for each of the mouse's 20,000 genes. "Eventually, this will give us 20,000 strains of mice, each with a different mutated gene," added Birney.

Each mouse strain will then be observed to see how this mutation manifests itself in the animal's appearance and behaviour. Thus, scientists will find out what each mouse gene does and, from that, what each corresponding human gene does.

But scientists also want to find out what different gene combinations do to different people. The main diseases that afflict humans are influenced not by single genes, but by groups, and environmental factors are also involved.

"To do that, we will let different strains breed with each other, producing offspring that have several mutant genes," added Brown. "And we also add genes that produce different amounts of proteins inside our bodies. The effect will be to create very complex genetic strains that we can study and from which we can tease out the effects of many genes on an individual."

An example of the kind of work that will follow from EuroMouse has already been carried out in the US. Cardiovascular specialists in Boston have found that a version of a gene, called NKX2.5 or the Tin Man gene (named after the Tin Man in The Wizard of Oz, who had no heart), can cause problems in the development of heart walls in both mice and humans.

"But not everyone who has the mutant gene gets heart problems," said Dr Nadia Rosenthal, of the European Molecular Biology Laboratory in Monterotondo, Italy. "Some other factor must be involved, possibly involving another mutant gene, and mouse genetics should help pinpoint it."

The crucial factor, added Rosenthal, is that genes clearly interact inside the body. "No gene is an island. That is why we have to use whole organisms like mice. Cell cultures will not do." Given that many millions of genetically engineered mice are going to be made as part of the EuroMouse project, scientists stress this last point.

Other research on mice at Rosenthal's institute has shown that a gene for a serotonin receptor in the brain, if not switched on during a period equivalent to human adolescence, can lead to the development of chronic anxiety in adults.

Similarly, work by Karen Avraham, of Tel Aviv University, has shown a mutant version of the gene Connexin 26 produces deafness - in mice and humans by failing to ensure the proper development of cells that support the main part of the inner ear.

"We are only just starting to learn about ourselves from studies of the mouse. It is going to be pivotal to medicine in future," said Brown.

Mice, and rats, have been crucial in the development medicines used today. Scientists based at the University of Boston have even grown a human ear on the back of a mouse - with no adverse effects to the rodent. The aim is to develop techniques that could allow doctors to regrow noses and ears for humans.

(China Daily 10/17/2005 page7)