On 19 November 2014 the journal Nature published the conclusions of a study carried out by the Encode international consortium, comparing the systems controlling gene activity in mice and in humans. The four articles on this topic found new similarities but also differences. However, this was only the visible tip of a massive undertaking that gave rise to a dozen publications in all, in five different journals.

Laboratory mice are much in the news, in the scientific world at least. A month earlier the journal Science explained how genetic engineering and new transplant techniques have kindled hope of understanding and treating cancer. Researchers set forth their dream of genetically modifying a mouse or implanting a human tumour in order to reproduce a patient’s condition and find the right molecules for their treatment.

However at the end of October the New England Journal of Medicine published an account of three clinical trials of prospective tuberculosis treatments that was much less flattering for the rodents. Researchers had tested three new drug regimens that had worked well for mice; on humans they proved a complete failure. “These trials cost at least $200m,” says Dr Clifton Barry. “In a way, it’s to be expected. Research is expensive. But this setback was foreseeable, like all the others we’ve seen in the past 40 years involving tuberculosis and mice. Yet no one seems particularly bothered.”

Barry, 52, is a key figure in his field. Heading the tuberculosis research programme at the National Institute of Health, based at Bethesda, Maryland, he has published many articles on the subject, in particular relating to mice. But in the past three years he has lost patience with the little animals. “They’re fine for ordinary work like toxicology trials. Perfect for checking that no unwanted side-effects crop up when we try a new molecule. But it’s a complete mistake to think they represent a good model of human disease,” he adds.

They’re fine for ordinary work ... But it’s a complete mistake to think they represent a good model of human disease

Tuberculosis in mice is simply not the same as in humans, as he explains. Mice do not cough, nor are they contagious. More importantly when humans breath in the Koch bacillus, it triggers an immune response. White blood cells surround the bacteria and aggregate forming granulomas. The resulting fibrous mass contains the bacilli, but does not kill them. Some 2 billion people on Earth are healthy carriers of the disease. In some cases they ultimately develop the disease, but most them never even find out what they are harbouring. For mice the picture is quite different: there are no healthy carriers and no granulomas. The bacterium attacks the organism, progresses and finally prevails.

Barry spent years investigating this crucial difference, convinced that a grasp of the mechanisms at work in mice would contribute to understanding the disease in humans. But three years ago a South Korean scientist asked him to test an antibiotic, Linezolid, previously used to treat respiratory conditions. “He assured me that he had obtained spectacular results on his patients,” Barry recalls. “I was doubtful. I tried it on mice and got no result. But he insisted so much I finally organised a human trial. I was amazed. The previous treatments had been discovered without animal experimentation. Forty years on, it was the same […] This disease claims almost 2 million lives every year. I couldn’t go on looking after mice any longer. It’s a dead end.”

So are mice a trap? Has medical research all over the world taken the wrong course? Our question prompts a smile from Xavier Montagutelli, head of the animal facilities at Institut Pasteur, in Paris. He explain how these small mammals came to play such an important part in laboratory research. Gregor Mendel started breeding mice in the mid-19th century, but his bishop thought such work unseemly in an Augustinian friar. So Mendel switched his attention to sweet peas. In 1902 the French scientist Lucien Cuénot picked up this work and applied it to mice. Meanwhile Clarence Little in the US created a “pure-strain” mouse. “He noticed that mice were not adversely affected by consanguinity, unlike rabbits or hamsters,” Montagutelli says. “So you can obtain identical individuals and test any hypothesis.” For each step forward in medical science, researchers took advantage of the rodents’ characteristics, charting their reaction to infectious disease or radiation, environmental upsets or genetic modification.

Mice have many advantages for research, as Montagutelli explains. “They are small and inexpensive, they reproduce quickly – every three months you obtain a new generation – and they age quickly too, making them ideal for studying age-related complaints. We know how to freeze their embryos, sperm and ova. We now know how to manipulate their genes, adding one, knocking out another, and replace a base pair to see what happens. They are remarkable tools.”

A quick look at the list of Nobel prizes for medicine confirms their contribution: discovery of sulphonamides in 1939; penicillin, 1945; yellow fever vaccine, 1951; polio vaccine, 1954; cellular origin of retroviral oncogenes, 1989; HIV-Aids virus, 2008; not to mention prions in 1997. Each time mice played a key part. In the 1980s nearly one-in-three Nobel prizes for medicine were awarded to work on mice. “In genetics, cancer, immune response, embryonic and nervous systems and infectious diseases … in short in most fields, mice are valuable,” Montagutelli adds.

Facebook Twitter Pinterest Could the era of scientific testing on rodents be approaching its end? Photograph: Tetra Images/Alamy

While at Institut Pasteur, we also met Jean-Marc Cavaillon, head of the cytokines and inflammation unit, and a specialist in toxic shock. “There is a problem”, he says very simply. He has just returned from a conference in Seoul and shows us his presentation. Here is a monoclonal antibody that treats a lymphoma in mice, but would send a human being to intensive care. Here again is an anti-inflammatory drug that is good for a rodent but deadly for us. “These are just a couple of examples. Mice are great for basic research, for understanding overall patterns and grasping mechanisms. But once you start modelling a human disease to find the right treatment, you run up against major differences between us and mice,” he asserts.

Shaw Warren, a US paediatrician and professor at Harvard Medical School, was responsible for striking the most deadly blow against humble lab mice. In 2003 he had just completed a sabbatical at Institut Pasteur, where he had studied the behaviour of mouse and human cells in a given milieu, alongsideCavaillon. On returning to Boston he joined up with several other researchers to launch a programme observing gene behaviour in the event of septicaemia, the sort of infection that all hospitals dread. He spent five years on painstaking work that he believed was original and relevant. But when he came to publish his findings the leading journals objected that they had not been compared with the baseline rodent model.

Undaunted Warren brought new members into the team, now 39 strong, and systematically compared the genes affected by septicaemia, as well as two other inflammatory conditions, burns and physical injuries. He hoped to obtain a comprehensive map. But the contrary was all too apparent: “the responses in corresponding mouse models correlate poorly with the human conditions”, the team reported. Which might explain the failure of 150 molecules for combating septicaemia, tested at great expense over the past 10 years and marketed on the grounds that sick mice seemed to respond favourably.

Published by the Proceedings of the National Academy of Sciences in February 2013 the article unleashed a storm of criticism. This was of course partly due to its conclusions, which seemed likely to contaminate all the branches of medicine dealing with inflammation, from cancer to Alzheimer’s. But also because the New York Times revealed that Nature and Science had rejected the article.

Mice are great for basic research ... But once you start modelling a human disease, you run up against major differences

Opponents of lab mice produced more and more evidence. Paracetamol and aspirin are both deadly to mice. Thalidomide, prescribed for pregnant women in the late 1950s to alleviate morning sickness, resulted in many thousands of congenital malformations, despite having been successfully tested on mice. They pointed out that the obese, sedentary rodents found in laboratories can only be used to model humans in a similar condition, certainly not the healthy individuals on which research supposedly focuses. They emphasised that 95% of the drugs thought to be promising after experiments on mice, fail when subjected to clinical trials. Furthermore, the number of new drugs being developed has never been so low, yet their cost has soared (over $4bn per molecule reaching the market is a common estimate). Not to mention those who condemn such practices on the grounds of cruelty to animals, stressing that 15m mice perish annually in US labs and a further 7m in Europe. “It may seem a lot,” Montagutelli agrees, “but it’s only equivalent to 1.6 mice for every European who dies.”

The furore ultimately died down and two years later life goes on. “There’s the weight of history, all the accumulated skills, and the production facilities which cannot be stopped just like that,” says science historian Jean-Paul Gaudillière and a specialist on mice. Researchers need to publish too. “With their short life cycle mice are a boon for producing articles. ‘Publish or perish’: the old saying is truer than ever today,” he adds.

However, everyone agrees that practices must change for the sake of good science. Yann Hérault, head of the Mouse Clinical Institute near Strasbourg, is counting on the arrival of new lineages to diversify the genetic heritage of the animals being studied. “For decades we’ve been selecting them to make analysis as accurate as possible, but we’ve lost in breadth,” he says. Barry has switched to another model, now using marmosets. Fellow researcher JoAnne L Flynn prefers crab-eating macaques. “It’s a difficult choice,” she says. “Monkeys are terribly expensive [about $5,500 compared with $20 for a mouse], they take up much more room, require specialist staff, don’t lend themselves to the same genetic engineering and only have one baby a year. Added to which they cough and are consequently contagious. We have to take a lot of precautions to protect our health.” We ask how she can sacrifice them under these conditions. Flynn is lost for words, so Barry chips in: “It’s a wrench. They’re close to us and highly evolved. I’d much rather not, but in the meantime humans are dying.”

Other researchers dream of biotechnology taking the rodents’ place. “What with animal models being pushed to their limits and the financial crunch, governments and the pharmaceutical industry have had to change their policy,” says François Busquet, who heads the Centre for Alternatives to Animal Testing in Brussels.

Cavaillon and Warren have yet another suggestion. “Instead of focusing on the supposed similarities between mice and humans, perhaps we should be looking at their differences. Mice are 100,000 times more resistant to bacteria than we are. That’s an established fact, which could serve as inspiration,” says Warren. “Rather than making mice like humans, we could do the opposite,” the Frenchman adds. Perhaps things are finally looking up for lab mice.

This article appeared in Guardian Weekly, which incorporates material from Le Monde