As breakthroughs in science go, few in recent decades have been larger than the creation of genetically-modified animals.
In the 1970s, scientists described how they had created mice with foreign DNA inserted into their genetic material, although it took until 1982 for researchers to demonstrate the successful breeding of genetically engineered mice.
Since then, such mice have become a favourite tool of scientists across the globe. Thousands of types have been produced, differing in terms of which gene has been manipulated and they have offered huge amounts of information about the function of an array of mouse genes – and human genes, too.
Recently, in what is believed to be a first in the Arab world, scientists at the Arabian Gulf University in Manama, Bahrain, announced that they had produced a new form of transgenic mouse.
“Already, the technology is 30 years old worldwide, but it’s the first time it’s been done locally,” said Professor M Dahmani Fathallah, the molecular biologist who spearheaded the research.
Mighty Mouse – three ways GM mice have helped
Analysing mice genetically engineered to produce the hepatitis B surface antigen (found in the blood of people infected with hepatitis B) has led to a better understanding of how the disease operates and causes illness.
Mice have been genetically engineered to help produce human monoclonal antibodies used to combat types of cancer, such as advanced bowel cancer. Compared to some other ways of producing the antibodies, costs can be modest, with high yields.
Transgenic mice have been models to give a better understanding of the pathogenesis of, for example, breast cancer. Studying different knockout mice has helped identify the steps that lead to the disease, and to analyse how chemotherapy treatments work.
Transgenic mice are created by inserting embryonic stem cells transformed with foreign DNA into a mouse blastocyst, a simple structure formed before the embryo that contains a mass of cells. An alternative method involves injecting foreign DNA into the male genetic material of a fertilised egg. In both cases, the transformed material is then implanted in a mouse that acts as a surrogate mother.
Although many researchers have produced genetically modified mice, typically each type has a different gene – the mouse genome contains more than 23,000 protein-encoding genes – that has been knocked out or deactivated.
This allows scientists to study the function of that particular gene, a tool that is all the more powerful given that it can uncover details of how many human genes behave. As the United States’ National Human Genome Research Institute puts it in a briefing document: “Overall, mice and humans share virtually the same set of genes.”
The Bahrain group, from the Department of Life Sciences and the Al Jawhara Centre for Molecular Medicine and Inherited Disorders, spent about two-and-a-half years producing mice that have an altered version of a gene, ISRAA, that is thought to connect the immune system and the nervous system.
Scientists call ISRAA a “nested” gene because it is located within another gene, in this case one involved in the production of spermatozoa.
Like some other nested genes, ISRAA is embedded within a section of the host gene called an intron, a region of DNA that does not code for protein.
The idea that the immune and nervous systems interact is, said Prof Fathallah, a very old one, dating back “thousands of years”, even to the time of the Ancient Greeks.
“When we feel good, we’re not sick; when we feel depressed and our central nervous system is affected, we get sick. This is exactly what our research is all about,” he said.
Further details of the work will be revealed in a scientific paper due to be published in the journal Plos One. It is thought that the gene may play a role in “how the immune system handles tumours”.
“We’ve definitely generated good insight of the function of this gene and we will validate this in this animal. It’s a basic strategy – it’s been used for years, but with conventional genes. We don’t know of a specific knock-out on this nested gene [having been done before],” said Prof Fathallah.
The researchers believe they are the first to knock out an intron-embedded gene on a living animal.
Instead of using a mouse, a cell line could be employed to analyse the gene but it would lack the “physiological insight” that comes from working with a whole animal, according to Prof Fathallah, who is from Tunisia.
Although various creatures, including chickens, sheep and other farm animals, have been genetically engineered, mice are particularly useful for research.
“They breed relatively quickly, they’re born after about 20 days and they’re sexually mature six weeks later. You can get lots and lots of generations,” said Prof John Wood, of University College London, who has used genetically modified mice to mimic the situation of people who are unable to feel pain.
This work has allowed the UK researchers to highlight the importance in pain perception of a type of sodium channel in cell membranes.
Drug treatment allowed a middle-aged patient who had been unable to feel pain to do so for the first time.
Overall, efforts to characterise mice genes have been “tremendously informative about a lot of potential conditions”, according to Prof Wood, and information is shared through a comprehensive international database.
Progress is likely to accelerate thanks to the development, in recent years, of a new way to edit genes, known as CRISPR – clustered regularly interspersed short palindromic repeat.
The technique is based on a method used by bacteria to protect themselves: they add the DNA of invading viruses to a database, which enables them, on later occasions, to identify and destroy attackers.
When the bacteria, using their own database, recognise an attacking virus, they deploy an enzyme, Cas9, that cuts the viral genome. This CRISPR/Cas9 defence system, with its ability to target particular DNA sequences, is now being used by scientists to alter the genetic material of plants and animals, including mice.
“It makes constructing mice with interesting mutations quite easy,” said Prof Wood.
Other scientists have also praised the technique, with one group of American researchers saying that it “enables one to manipulate the genome with unprecedented simplicity and speed”.
So with their arsenal of techniques strengthened, more researchers from this region may, in future, be able to follow the lead of the researchers in Bahrain and create transgenic mice of their own.