Mouse genetics: The check-up

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Patients checking in to the German Mouse Clinic will undergo the most sophisticated medical testing in the world. But, finds Alison Abbott, the waiting list is becoming a problem.

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Each and every Thursday it is the same. At 10 a.m., the conference room at the Helmholtz Centre Munich starts to fill with top consultants and clinical researchers from the university hospitals in Munich, Bonn and Heidelberg. On the table is a stack — thicker than the city's telephone directory — of clinical data on a couple of hundred patients. The data are comprehensive — from blood analyses, to lung function, to metabolism. Some weeks there are brain and body scans in there too. After two or three hours of presentations and cross-speciality discussions, the group comes up with diagnoses they consider most likely.

It's a scene that could be imagined in any world-class hospital. But the patients involved are not human. This is the German Mouse Clinic, and the patients are genetically modified mice. The batteries of tests have been designed to identify every possible consequence of the animals' altered genes. And the results, the clinical scientists hope, will help them to work out what part each gene plays in cellular processes and in human disease.

Perhaps the most famous of the clinic's patients is the Foxp2 mouse, engineered to bear a 'humanized' version of the Foxp2 gene, implicated in the evolutionary development of human speech and language. The gene, modified in the mice so that it contains two amino-acid substitutions that are normally present only in humans, changed the animals' ultrasonic calls and reduced their propensity to explore, but had no effect on organs outside the brain (W. Enard et al. Cell 137, 961–971; 2009). "The negative results are as exciting as positive results," says Wolfgang Enard, a computational biologist at the Max-Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and creator of the Foxp2 mouse. He was asked by the clinic to send a second batch of mice because staff couldn't believe the brain-specificity that they were seeing. The discovery that the humanized gene affects specifically the animal's brain and vocalization supports the idea that the amino-acid changes were important in human speech evolution.

Everyone in the world is welcome to send their mutant mouse to the clinic, which opened in 2001. And many are starting to do so. "We are getting more and more requests, and a waiting list is starting to build up," says geneticist Martin Hrabé de Angelis, who conceived and heads the clinic.

Geneticists estimate that around half of the 20,000 or so mouse genes have been altered by various means to make mutant strains. Some of these have been created expressly as animal models of disease or to get at a particular biological mechanism; others as part of systematic gene knock-out programmes such as the Knockout Mouse Project centred at the US National Institutes of Health (NIH) in Bethesda, Maryland. Many of these animals go through check-ups in the labs of the researchers that made them. But some have no obvious defects — and, for almost all of them, the rigorous 'phenotypic' analysis that the mouse clinic provides could reveal more useful data about their condition.

Unknown associations

From the point of view of its patients, the mouse clinic offers two months of comfortable living interrupted by 320 individual tests in 14 clinical areas ranging from neurology, to vision, to immunology. They have roomy accommodation, good food and a warm, pathogen-free environment.

Owners of the mutant mice complete a collaboration agreement with the clinic, and funding from the German research ministry allows the service to be offered free. The collaborators then provide the clinic with 80 mice, and testing begins. Some of the tests involve just being watched. The mice are placed in an 'open field' — a flat board with a camera suspended above it — while staff observe their breathing, how much they explore a new territory and with what enthusiasm.

Other tests can be more challenging for the mice. To have their blood pressure measured, they are placed in a restraining box with their tails hanging out. An air cuff, similar to the arm air cuff in a doctor's surgery, is wrapped around the tail. The procedure is done several times a day to follow the circadian changes in blood pressure. The mouse clinic has an array of sophisticated apparatus — for scanning the body in different ways, for example, or for assessing the structure and function of the heart using ultrasound — all scaled down to mouse size.

At some point in their stay, the mice make an excursion to the neurology clinic. There they get to playfully hang on a rod while a scientist, by lightly pulling on their tails, gauges how strongly their paws can grip. The mice also balance on the 'Rotarod', which turns at increasing speed until they fall off, to gauge coordination. In the sealed perspex cube of the metabolic chamber researchers measure the amount of oxygen the mice breathe, the carbon dioxide they exhale and the heat they generate, to calculate basal metabolism. Everything the animals eat is weighed and every bit of faeces combed through, to determine how much energy they have absorbed from food.

Then, for those unlucky mice that are selected, comes pathology, histology and, as the web page euphemistically declares, 'chemical carcass analysis'.

All these tests and more are the fodder for the clinicians' Thursday discussions, to which the owners of the mice are invited. On the basis of the diagnoses, the clinical team may advise the owners to dig more deeply into particular phenotypes in secondary and tertiary screens that the clinic can perform. Something abnormal in antibody measurements, for example, might point to more complex allergy tests. Hesitancy in the open field, or a wobble on the Rotarod, might prompt advice to run brain tests, such as electroencephalograms, as well as sophisticated tests for memory, depression or anxiety, or sensory or motor function. Such screens are inevitably more time-consuming, more expensive and more complex than the primary screen.

Famous patients

Few other mouse facilities in the world perform such a breadth of phenotyping tests; hence few other mice on the planet are as closely scrutinized as the ones that enter this clinic. The level of data analysis and the generation of testable hypotheses also differentiates the German Mouse Clinic from screening offered elsewhere. Karen Svenson, who runs a mouse clinic at the Jackson Laboratories in Bar Harbor, Maine, says she hopes that "in the near future there will be an international effort to support worldwide clinic approaches", like that used by the Munich clinic.

More than 200 mutant mouse lines have been put through their paces at the German clinic since it opened. The Helmholtz Centre Munich supplies many of them from its programmes for creating mutant mice. One of these, the Aga2 mouse, is among those patients of the clinic with the most potential to influence medical practice. As a model for brittle bone disease, or osteogenesis imperfecta, it carries a mutation in the Col1a1 gene that is crucial in collagen production and mutated in the majority of people with this condition. It had been assumed that early death was usually a consequence of a stiffened ribcage. Unable to breathe deeply, patients succumb to multiple pneumonias.

“If we had had mouse hospitals earlier we could have advanced circadian biology by a decade. John Hogenesch ”

Hrabé de Angelis was surprised when the clinical parameters thrown up in the primary mouse screen pointed in a different direction. "The blood pressure measurements weren't normal and there was something not quite right about the breathing," he says. The next round of screening revealed that the mutated Aga2 gene actually causes direct, and fatal, damage to the lungs and heart. Joan Marini, an expert in osteogenesis imperfecta at the NIH, says that the insights offered have been "tremendous". "It will make clinicians more attentive to early preventative measures such as pulmonary exercise or bronchodilators, which could help keep the lungs elastic for longer," she says.

The clinic's waiting list is only likely to grow. Most biomedical researchers would like their mice to have more than one mutation per gene, to explore their different biological effects. On top of this, they are starting to recreate in mice the more complex types of genetic alterations that have been associated, however loosely, with human disease. Dusan Bartsch, a molecular biologist at the Central Institute of Mental Health in Mannheim, Germany, for example, engineers in mice specific genetic architectures that are frequently found in people with mental disorders such as schizophrenia. These include absent regions called 'microdeletions' and copy number variations, genetic regions that are repeated different numbers of times. "We are sending these mice to the clinic because there is just no way of predicting what other parameters could be affected by these complex gene changes," Bartsch says.

Hrabé de Angelis still wants to improve the range of testing. The phenotype expressed by any organism is dependent on the environment in which the organism finds itself. So the mouse clinic is piloting a new phase in which mice are tested in five different types of environment — what Hrabé de Angelis refers to as envirotypes. These include exposing the mice to stress, exercise or infection, giving them high-calorie 'cafeteria' diets and placing them in 'city' air polluted with diesel fumes.

But testing each mouse in the five envirotypes takes time, which will only make the waiting list even longer. To help keep pace with the number of mutant lines being created, Hrabé de Angelis is pinning hopes on winning long-term funding for the 'Infrafrontier' consortium, a European Union project to develop mouse functional genomics and, in particular, to upgrade other, smaller, mouse clinics around Europe so that they can perform at least the first round of screens. These are the Mouse Clinical Institute in Strasbourg, France, the UK Medical Research Council's Harwell unit and the Wellcome Trust Sanger Institute in Hinxton, UK, but others are now planned in Spain, Italy and the Czech Republic. There are already mouse clinics either open or planned in China and Japan.

Circadian biologist John Hogenesch from the University of Pennsylvania, Philadelphia, muses on how much faster his own field might have developed with the systematic phenotyping these clinics offer. The first mouse mutant with a disturbed circadian clock was made in 1997 (D. P. King et al. Cell 89, 641–653; 1997) and since then others have been found in individual laboratories. "If we had had mouse hospitals earlier," says Hogenesch, "we could have advanced circadian biology by a decade."

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Abbott, A. Mouse genetics: The check-up. Nature 460, 947–948 (2009) doi:10.1038/460947a

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