“It’s about making mouse models that better reflect human metabolic and neurological diseases – that are more relevant to model human physiology and disease. There are different ways of doing this, one is co-housing laboratory mice with farm or pet store mice so that the former acquire more mature immune systems that more closely resemble an adult human immune system. We are looking at the evidence that points in the direction of making mice models less ‘clean’ and more useful,” said Carlos Ibáñez of the Department of Neuroscience, Karolinska Institute, Peking University and the Chinese Institute for Brain Research.
“Mouse models have enabled breakthroughs in our understanding of metabolic regulation and brain function, but it has become increasingly clear that they present many shortcomings when translating observations to humans,” he explained. “Humans are infected with a variety of acute and chronic pathogens over the course of their lives, and pathogen-driven selection has shaped the immune system of humans. The same is true for mice. However, laboratory mice traditionally used for biomedical studies are bred in ultra-hygienic environments, and kept free of specific pathogens.”
“While this has benefitted research by avoiding confounding factors and making mouse cohorts more homogenous, recent studies have indicated that pathogen infections are important for the basal level of activation and the function of the immune system,” he continued. “Although laboratory mice have immune systems akin to that of a human newborn, altering the living conditions of laboratory mice profoundly affects the cellular composition of the innate and adaptive immune systems, resulting in cellular and molecular patterns that more closely reflect the immune signatures of adult humans. These environmental exposures can potentially improve mouse models of human disease.”
STIAS Permanent Fellow Ibáñez was giving an update on his work on Alzheimer’s Disease and obesity.
“We work in a basic biology laboratory with a focus on two diseases – Alzheimer’s and obesity,” he said. The work involves molecular and cellular studies and includes understanding cell-signalling mechanisms and the role of soluble signals and their receptors in these conditions – “we call the biochemical reactions that lead to information transfer between cells in all tissues and organs of the body signalling”.
In this work laboratory mice are an important tool. “They have a short gestation period, and reach maturity and fertility very quickly,” said Ibáñez. “We can change their DNA and genetics, alter the sequence of specific genes, and measure the impact on functioning and behaviour.”
Mice share nearly 90% of genes with humans and can be used to model 65% of human diseases. With so-called ‘knock-out’ mice you make custom changes in the genome by inactivating a gene and with ‘knock-in’ mice you alter the gene but it’s still there – “like taking away a piece of a car then seeing how it runs”.
“You can use mice models to model conditions ranging from cancer, obesity, heart disease, Alzheimer’s, arthritis and diabetes to addiction, anxiety and aging.”
Mice models have led to substantial breakthroughs in our understanding of Alzheimer’s Disease and obesity.
“Nothing in biology makes sense unless it’s in light of evolution,” said Ibáñez. He pointed to obesity as being a result of a modern lifestyle which is largely sedentary but with high calorie and, specifically, high fat intake. “We are modern humans with a Stone Age body and physiology which is adapted to preserving energy and saving calories. This makes it difficult to lose weight and keep it off. Our lifestyle has evolved faster than our genes.”
Obesity is related to a range of diseases including stroke, liver disease, type-II diabetes, heart disease, osteoarthritis and colon cancer.
Ibáñez explained that understanding obesity is about investigating the role of adipose tissue in controlling metabolism. They are specifically looking at the activin receptor ALK7 in adipose tissue, and at whether blocking it could facilitate weight loss.
“We have found that if you knock out the ALK7 receptor gene the mice are protected from obesity induced by a high-fat diet. For mice on a normal diet 5% of calories come from fat, in high-fat diets 60% of calories are from fat. Without the ALK7 receptor gene they don’t gain as much weight, the metabolic rate is higher, and the adipose tissue works faster.”
Alzheimer’s Disease is a neurobiological condition and the main cause of dementia in humans.
“It’s about the shrinkage of the brain,” said Ibáñez, “both in terms of dying neurons and in breaking their connections or synapses”. Alzheimer’s is characterised by the generation of peptides of amyloid-β which clump together into plaques as well as intracellular neurofibrillary tangles of the P-Tau protein. These trigger inflammation, malfunction and degeneration eventually leading to death.
Work in Ibáñez’s laboratory includes genetic, electrophysiological and behaviour tests in mice. Using these models they hope to determine the role of specific cell receptors linked to neuronal damage – changing or removing parts of these receptors to see if this results in less production of the amyloid plaques. Thus far they have found in mice that a knock-in mutation to the P75 receptor and a change in the amino acid C259A reduces the formation of plaques and improves memory.
“One change to P75 reduced plaque formation by about half,” said Ibáñez.
Immunity, inflammation and microbes
But it’s not just about receptors, the immune system (both innate and adaptive) also plays an important role.
“In obesity, adipose tissues become infiltrated by a host of immune cells producing inflammatory molecules that drive insulin resistance. In Alzheimer’s Disease, brain microglial cells became activated, thereby amplifying plaque and tangle damage, and contributing to the demise of synapses and neurons,” explained Ibáñez.
Some inflammation is good in cleaning and supporting cells “but inflammation can get out of hand causing more damage”.
He also pointed to the problem of the gut microbiome. “There are more microbial cells in the gut than anywhere else in the body – the highest microbial density on earth,” he said. “The gut microbiome has a profound effect on multiple tissues and organs including the brain.”
“If the immune system, inflammation and the gut microbiome are all important in Alzheimer’s Disease and obesity – we should be able to model those conditions better in mice,” he added.
‘Clean’ in a dirty world
And this is where the ultra-clean laboratory mice model falls short.
“Laboratory mice are born and bred in an ultra-clean environment to keep natural infections out. This means they have stunted immune systems devoid of all the defences human immunity develops in a world teaming with microbes,” he said. “This has serious implications for taking research from the laboratory to clinical trials.” (Currently overall the success rate for moving therapies from animals to humans is only about 10 – 15%.)
He pointed to research showing that laboratory mice specifically lack fully mature cytotoxic and memory T cells but that altering their living conditions affects cells of the innate and adaptive immune system making it more like a human immune system.
There are a number of ways to do this including co-housing laboratory mice with wild mice, directly infecting laboratory mice with pathogens; transferring wild-mice faeces to germ-free pregnant laboratory mice; and, transferring laboratory mice embryos to wild females.
But there are many unknowns and a lot of research still to be done including answering questions about the stability of the wild-mice microbiome and immune system once in the laboratory; fully unpacking the underlying mechanisms; understanding at which points the immune system becomes involved; and, whether a wild-mouse gut has a protective or detrimental impact in a disease like Alzheimer’s.
In discussion, Ibáñez addressed the issue of animal experimentation.
“Alzheimer’s is a complicated disease. We still have much to learn,” he said. “To bring new knowledge you need to do experiments in animals before moving those advances to humans. No public-health agency in the world would approve any new therapy that has not been thoroughly tested in animals prior to it being used in humans. That’s how all therapies and treatments are developed, including the vaccines that we are all taking, surgical procedures and drugs. There are both ethical as well as scientific reasons to care for the well-being of research animals, and of course the costs have to justify the benefits.”
For more background information see our previous news stories and also the in-depth interview with Ibáñez in our newsletter https://stias.ac.za/news-and-events/newsletters/2020-4/
Michelle Galloway: Part-time media officer at STIAS
Photograph: Noloyiso Mtembu