Tag Archives: mice

Of Mice and Mammaries, Part 3: Modelling Human Breast Cancer

In light of Breast Cancer Awareness Month, Justin Varholick traces how mice have helped breast cancer research over the past century. In the third post of this 4-part series, we look at advances made from the 1970s to present time and how mice are being used as a model for humans.

Over the past two weeks, in Parts 1 and 2 of this series, we discussed how scientists discovered mammary tumors in mice, and how some mice have the mouse mammary tumor virus (MMTV) – which spreads cancer to offspring through the mother’s milk. After scientists found it difficult to grow MMTV in a petri dish, they realized that they had to continue studying mammary tumors in the mouse itself. This week we will focus on how scientists validated – and are continuing to validate – mammary tumors in mice as a model for understanding human breast cancer.

Validating mice as a model for humans is not an easy task. Scientists must be able to show that the cause, development, or progression of the tumors are similar between mice and humans. However, human breast cancer is often caused by many different factors and does not always develop or metastasize consistently. Thus, scientists can only model certain aspects of breast cancer. For example, they might be able to model a cause of cancer but not the development or progression.

1975 to Present — Stem cells and pre-cancer stages

Stem cells of mammary tumors have become a valuable tool throughout the years because they allow scientists to study cells that may one day become cancerous, and determine ways to prevent them from becoming cancerous.

Original image by Science Magazine

Stem cells of mammary tumors were first identified in 1975 by Dr. Barry Pierce. Since this discovery, scientists have isolated these stem cells and tested different factors to prevent the stem cells from becoming cancerous. Unfortunately, no major findings to definitely prevent stem cells from becoming cancerous have been found.

Although no major findings have been found, stem cell research is very promising. Mice with mammary tumors that are caused by pre-cancerous stem cells often have tumors that are similar in shape to those found in humans. Thus, although we do not yet understand which factors may directly cause stem cells to become cancerous, the development and progression of the tumors in mice and humans are similar – making them a good model for research.

1980s to Present — Genetically Engineered Mice

While research on stem cells was underway, some scientists began exploring the idea of genetically engineering mice to have mammary tumors. This research would help scientists understand which genes are associated with mammary tumors, and also provide scientists with mice that reliably have mammary tumors from different genetic causes.

Genetically Engineered Mice

Because much research was already done on MMTV, the first genetically engineered (GE) mice were those that were genetically engineered to have MMTV. Unfortunately, GE mice with MMTV genes could not be used to understand human breast cancer. One reason was because human breast cancer is not caused by a virus. The second reason is because the types of tumors that develop from MMTV differ in cellular shape and structure compared to human tumors. Because mammary tumors in GE mice with MMTV are caused by different factors, and develop and progress differently, this makes them a poor model for research.

Although these first GE mice cannot be used as models, their creation helped scientists make different GE mice with tumors almost indistinguishable from human tumors. To make these GE mice, scientists inserted genes into mice that were associated with breast cancer in humans. These genes were erbB2 and myc. Because these genes caused mammary tumors in both humans and mice, this made them a good model for future research.

Unfortunately, breast cancer in humans is not always caused by genes. Some breast cancer is caused by abnormal hormone levels, carcinogens, and other factors that we do not yet understand. Also, because breast cancer has different causes this also means it has different pathways of development.

These differing factors make studying breast cancer difficult. But by studying more and more about mammary tumors in mice we may be able to build better models that will one day lead to better treatment options.

Justin Varholick

To be continued…

Tune in next week to learn which treatments scientists have discovered for humans by using mice as models. I will also cover the potential future of breast cancer research – patient derived xenografts.

References:

  1. Cardiff R, Kenney N. (2011). A compendium of the mouse mammary tumor biologist: From the initial observations in the house mouse to the development of genetically engineered mice. Cold Spring Harb Perspect Biol. 36(6).
  2. Medina D. (2010). Of Mice and Women: A Short History of Mouse Mammary Cancer Research with an Emphasis on the Paradigms Inspired by the Transplantation Method. Cold Spring Harb Perspect Biol. 2(10).
  3. Cardiff R, Couto S, Bolon B. (2011). Three interrelated themes in current breast cancer research: gene addiction, phenotypic plasticity, and cancer stem cells. Breast Cancer Research. 13(5).

Mice and the Mycobiome: How Animal Models Will Help Us Understand the Microbial World In Our Gut

Rebecca Drummond, PhD, is a post-doctoral scientist working at the National Institutes of Health, USA. Dr Drummond’s research aims to understand why some people get fungal infections and others do not. To do this she must understand how the immune system prevents fungal infections and the risk factors that make an infection more likely. In this blog, Rebecca explains how mice can help us to understand how bacteria and fungi can affect the immune system and development of gut-related disorders, like irritable bowel disease (IBD).

Our intestines are home to billions of microbes, which help digest food and maintain a healthy immune system. These microbes, known as the ‘microbiome’, are a mixture of bacteria, fungi and viruses, and individual species can have a huge impact on the health of our gut. The bacteria in our microbiome has been studied for decades, using samples from human volunteers and mice. While human research has allowed us to make connections between microbiome patterns and disease, it’s the work with mice that actually help us understand the fine details of how bacteria in our gut may cause or prevent disease. In contrast to research on gut bacteria, research into the fungal population (the ‘mycobiome’) within our intestines has lagged behind. This is because this branch of life is often underappreciated and misunderstood, but this is now beginning to change and recent studies indicate that the mycobiome can profoundly impact the health of our gut.

Since fungi are common inhabitants of our intestines, one of the major interests in the field is how these intestinal fungi affect the health of our gut and what harm they might do if they ‘escape’. Fungal infections are one of the hardest to diagnose and treat, killing more than 2 million people every year and are also responsible for exacerbating other diseases like asthma and inflammatory bowel disease (IBD). Yet, fungi receive a surprisingly small amount of attention in the news and research community.

Microscopy image of fungi in a mouse intestine. Yeast cells interact with the cells of the intestine (epithelium) and mucus. Image courtesy of Dr Simon Vautier, NIH.

It’s therefore important to understand how our immune system handles fungi and prevents an infection. It’s well accepted that some species of bacteria in our gut can promote healthy intestines (probiotics or ‘good bacteria’ – you’ve probably seen these sold in yoghurt at the supermarket), while other bacteria can cause stomach ulcers. It’s therefore reasonable to assume that different fungal species might have similar benefits or health risks, and some recent research has shown that this is the case. For example, inflammatory bowel disease (IBD) is a condition where the immune system attacks the intestine for reasons that we don’t yet fully understand, and it’s long been known that proteins in our blood (antibodies) that stick to a fungus called Saccharomyces cerevisiae (anti-S. cerevisiae antibodies: ASCA) correlate with the incidence of IBD. So, if you have IBD, it’s likely that you have more ASCA in your blood. Moreover, mutations in genes that are needed to activate immune responses against fungi have been repeatedly linked to IBD and an overgrowth of fungi in the gut. Studies using samples from IBD patients have shown that a disturbance (‘dysbiosis’) of the mycobiome is a common occurrence in IBD; patients with IBD have increased amounts of a fungus called Candida albicans, and the ratio between different fungal species is not normal in IBD patients compared to people who have never experienced IBD.

It’s therefore important to understand how our immune system handles fungi and prevents an infection. It’s well accepted that some species of bacteria in our gut can promote healthy intestines (probiotics or ‘good bacteria’ – you’ve probably seen these sold in yoghurt at the supermarket), while other bacteria can cause stomach ulcers. It’s therefore reasonable to assume that different fungal species might have similar benefits or health risks, and some recent research has shown that this is the case. For example, inflammatory bowel disease (IBD) is a condition where the immune system attacks the intestine for reasons that we don’t yet fully understand, and it’s long been known that proteins in our blood (antibodies) that stick to a fungus called Saccharomyces cerevisiae (anti-S. cerevisiae antibodies: ASCA) correlate with the incidence of IBD. So, if you have IBD, it’s likely that you have more ASCA in your blood. Moreover, mutations in genes that are needed to activate immune responses against fungi have been repeatedly linked to IBD and an overgrowth of fungi in the gut. Studies using samples from IBD patients have shown that a disturbance (‘dysbiosis’) of the mycobiome is a common occurrence in IBD; patients with IBD have increased amounts of a fungus called Candida albicans, and the ratio between different fungal species is not normal in IBD patients compared to people who have never experienced IBD.

Candida albicans is found as a yeast in our gut. Image from Wikipedia

In human studies like this, we can only ever make assumptions from this type of data, but it is difficult, if not impossible, to determine causality. It’s not clear whether the mycobiome dysbiosis in IBD patients is a cause of the IBD, or a consequence. To help understand these sorts of correlations and make sense of them, we can use mice as a model system. Mice are commonly used for immunology research because the immune system is similar between different species of mammals; mice have the same types of immune cells that carry out similar functions as their human counterparts. We know this because mutations in genes that are important for preventing IBD or fungal disease cause similar diseases in mice as they do in humans. Mice also provide us with a way of obtaining samples of intestine tissue, since it would be difficult to find human volunteers for such research which would also suffer from the lack of laboratory controls. The complexity of the gut also means that we can’t use petri-dishes, because we simply can’t model the thousands of interactions happening in the gut in a petri-dish.

We can also breed mice so that they have no bacteria or fungi in their intestines. These are known as ‘germ-free’ mice and are particularly useful for studies that want to analyze how an individual species of bacteria or fungi affects the intestinal immune system and our metabolism; something that isn’t possible to do in humans. To give an example, if you take germ-free mice and feed them the yeast S. cerevisiae (the one that ASCA binds to and indicates IBD), you can make the symptoms of IBD worse. Researchers showed that this was because S. cerevisiae caused a build-up of uric acid as it grew in the intestine. Uric acid activates our immune cells so they become over-excited and start to attack the intestine, basically causing symptoms of IBD. These types of experiments can help us understand the possible mechanisms resulting in IBD and the roles our microbiota might play in the development of this disease.

Germ-Free Animal Facility. Animals are bred and kept within isolator units to keep them sterile from outside bacteria, fungi and other microbes found in the environment. Photograph courtesy of Yasmine Belkaid, NIAID, NIH.

In addition to looking at individual species, we can also use mice to understand relationships between bacteria and fungi living together side-by-side in the gut. Changing the amount of fungi in the gut, by introducing a new species in the diet or depleting lots of fungi at once with antifungal drugs, subsequently changes the amounts of different bacteria in the gut. The same is true when you do the opposite experiment – antibiotic treatment (which kills off the bacteria, not the fungi) causes fungi in the intestine to grow like crazy, a phenomenon known as a fungal bloom. These blooms are thought to be one of the ways a patient could contract a dangerous blood-poisoning fungal infection called systemic candidiasis, which if treated, still only has a 50/50 chance for survival.

So, if fungi can exacerbate IBD and be a potential source for blood-poisoning, should we be treating patients with antifungal drugs to prevent this? For IBD at least, mouse models suggest that this strategy won’t work. Mice treated with antifungal drugs weren’t helped at all – they actually developed worse IBD after treatment than mice that were left untreated. This was because the antifungal drug treatment doesn’t completely get rid of all the different species of fungi in the gut. Instead, you get rid of some species, and the remaining fungi (which are resistant to the drugs) start to grow and takeover. This is what we call a dysbiosis of the mycobiome, and we’ve seen it before – in patients with IBD.

The number of papers discussing the mycobiome has seen a 10-fold increase since 2013, indicating that awareness of fungi and fungal infections is on the rise. More research is needed to understand our relationship with fungi and this critically depends on using animal models, without which we wouldn’t have learned how the fungi and bacteria in our guts exacerbate diseases like IBD. By better understanding this, we can begin to decide what to do about it and develop treatments for the future.

Rebecca Drummond

Research Roundup: Chimpanzees with Alzheimer’s, mice with autism, the shrinking bat genome and more

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • Signs of Alzheimer’s found in chimpanzees for the first time.  Melissa Edler, of Northeast Ohio Medical University, and her colleagues, studied twenty brains of older chimpanzees and found more than 50% had beta-amyloid plaques and early forms of tau tangles similar to that seen  in humans with Alzheimers.  Another researcher, Mary Ann Raghanti of Kent State University, Ohio, whose lab in which the work was conducted, points out that the samples were not accompanied with cognitive data and there are no current examples of chimps with Alzheimers-like dementia.  This may show that although chimps demonstrate physiological aspects of the disease, they do not exhibit the cognitive decline as seen in humans. Raghanti says, “If we can identify those differences between the human and chimp brain then we might be able to pinpoint what is mediating the degeneration. That could be a target for drug treatment.”
CC-BY-NC-SA

Chimpanzees at NCCC (not related to above study). Photo credit: Kathy West.

  • Human embryos edited to stop diseases using CRISPR. In a massive collaborative effort, researchers in the USA and Korea, have for the first time “freed embryos of a piece of faulty DNA that causes deadly heart disease to run in families.” Hypertrophic cardiomyopathy, is a common heart disorder, affecting approximately one in every 500 people, and can lead to cardiac arrest. In this study, “sperm from a man with hypertrophic cardiomyopathy was injected into healthy donated eggs alongside Crispr technology to correct the defect” — and in 72% of the embryos the disease-causing mutation was removed. Safety and efficacy evaluation of the CRISPR technique is still under scrutiny, and this evaluation owes much to animal research as we have previously highlighted in our research roundups. This research was published in the journal Nature.

  • ‘Autistic’ mice affect the behaviour of their littermates. Researchers at Cardiff University, led by Dr Stéphane Baudouin, genetically altered mice to exhibit symptoms of autistic spectrum disorder and found that other unaltered mice became less social. The mice altered mice had the neurolignin-3 gene turned off, changing their behaviour. Wild-type mice in the same cage ceased to be interested in the smells of the urine of other mice – a standard test for social behaviour in mice. When the Neurolignin-3 gene was turned back on, both the altered mice and the wild-type in the cage returned to their ordinary behaviours. Dr Badouin also found that the ‘autistic’ tendencies of the mice were worse when the mice where housed with wild-type mice compared with housed with other altered mice. This study was published in eNeuro.
  • Genome elasticity and shrinking found in bats. The size of genomes are known to vary across the animal kingdom: hummingbird — 1.11 billion base pairs (bp); human — 3.42 bill. bp; leaf insect — 7.82 bill. bp. These sizes are typically maintained across millions of years, but when they do change it is usually an increase in size from the addition of transposons. Transposons are classically referred to as “jumping genes” and partly drive genetic evolution. Researchers at the University of Utah recently studied size change of genomes and transposons in the common little brown bat (Myotis lucifugus) and found something interesting. Around 40 – 50 million years ago, the genome had gained 400 million transposons and shrunk in size — over a small amount of time (in evolutionary terms) the genome dramatically changed. Because genomes serve as the raw materials to living life, this is a huge finding. Furthermore, mammalian genomes are widely recognized as monotonous — rarely changing in size over time and rarely gaining many transposons, however it now appears the little brown bat is an anomaly. Further research on these bats and other mammals will help us better understand the relationship between genes and evolution.
  • A less invasive form of swabbing is being investigated as a means of refinement aiming to improve the welfare of zebrafish. Zebrafish use continues to increase, because of their utility as a model organism for investigating both basic and applied biological mechanisms related to health and disease. Previously, the collection of DNA from zebrafish was done via fin clipping — a fairly invasive procedure performed without anesthesia. With funding from the NC3Rs, researchers at the University of Leicester’s Department of Neuroscience, Psychology and Behaviour are systematically exploring a new technique. Here, “researchers gently stroke a swab along the flank of a netted fish and takes just a few seconds to complete. Previous research by this team has already shown that this technique collects ample material for DNA analysis.” This two year project will investigate the potential benefit to the animals’ wellbeing by comparing the standard method to the newly proposed one.

Research Roundup: Brain circuits for dominance, new HepC rodent model, eye repair in zebrafish and more

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • Brain circuits for social dominance discovered. For humans and most other animals, a previous history of winning dictates continued social dominance. In a study recently published in Science, Zhou et al. may have found a neurological explanation for this “winner effect”. They show, using mice, that the dorsomedial prefrontal cortex (dmPFC) mediates behavior in a social conflict. Using optogenetic methods, researchers stimulated the dmPFC using light and found that this was sufficient to induce “winning” in mice tested on a task used to measure social dominance. Interestingly, this also worked in mice that were previously shown to be a “loser” when paired with another mouse in the task. If an analogous mechanism present in humans, this study could be of major importance in understanding various relevant psychiatric conditions associated with social behavior. This research was published in the journal Science.

  • New animal models for hepatitis C could pave the way for a vaccine. This discovery is a stepping stone towards the development of a vaccine for Hepatitis C which affects nearly 71 million people worldwide. Although there is now a cure for Hepatitis C, most people go undiagnosed leading to damage of the liver. Until now, an animal model was not available for vaccine development because hepatitis C is highly specific affecting only humans and chimpanzees. This breakthrough comes as a result of a collaborative effort with Ian Lipkin, a researcher at Columbia University, who was studying pathogens of common rats in New York City. He found a rat version of the hepatitis virus and after sharing his work with Dr. Charlie Rice, a researcher in virology at The Rockefeller University, they found a way to infect mice with the rat version of the virus. There are differences between the primate and rodent version of the virus but there is hope that “this research will help unravel mechanisms of liver infection, virus clearance, and disease mechanisms, which should prove valuable as we work to develop and test hepatitis C vaccines that can help to finally eradicate the disease around the world.” This study was published in Science.
  • A study in zebrafish found that the immune system controlled its ability to regenerate eye tissue. Researchers at John Hopkins are studying the ability of zebrafish to repair damaged eye retinal tissue using the regenerative response of Müller glia Having found that microglia, a type of cell involved in immune response, were the only cells able to penetrate the blood-retinal barrier, they prevented these cells from functioning, resulting in almost no regeneration from the Müller glia cells. A better understanding of this process could help scientists unlock human eye regeneration. Dr Jeffrey Mumm noted, “humans still have the genetic machinery needed to regenerate retinal tissue, if we can activate and control it.” This study was published in PNAS.
  • Early disruption of gut microbiota shapes later health. The gut microbiome plays an important role for health in humans and all living animals. In a recent study published in Nature Communications, researchers discovered that disruption of gut bacteria in frogs during the tadpole stage of maturation had negative effects on how adult frogs dealt with parasites. This effect may also be present in humans. Wherein, early-life disruption of human microbiota may stimulate the development of an under-reactive immune response to infections in adulthood.

  • Potential treatment for infants exposed to alcohol in utero identified. In the United States 1-5 percent of children are diagnosed with fetal alcohol spectrum disorder, which impairs learning, is linked to later-life behavioral problems, cardiovascular problems, and delayed development. In efforts to reverse these negative effects, scientists at Northwestern University treated rat pups, exposed to alcohol in utero, thyroxin or metaformin. Thyroxin is a hormone that is reduced in pregnant women that consume alcohol, and also in infants with fetal alcohol spectrum disorder. Metaformin is an insulin sensitizing drug that is found at higher concentrations in alcoholics. Both drugs reversed memory deficits, independently, as a consequence of in utero alcohol exposure. “We’ve shown you can interfere after the damage from alcohol is done. That’s huge,” said lead investigator and senior author Eva Redei. “We have identified a potential treatment for alcohol spectrum disorder. Currently, there is none.”The researchers are now looking for funding for clinical trials. This study was published in Molecular Psychiatry.

Research Roundup: 50,000 lives saved by organ transplants, transgenic sheep aid in Huntington’s disease, smell relates to weight gain in mice, and more!

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • The UK’s National Health Service (NHS) Blood and Transplant say that 50,000 people in the UK are alive thanks to organ transplantation. This includes 36,000 kidney patients and almost 10,000 liver patients. Animal and human studies have continually improved the way we conduct transplants; in the early 1990s a transplanted kidney had a 66% chance of being functioning five years later, that figure is now 87%. The first successful liver transplant was done in dogs in 1958 by Dr Thomas Starzl, with the first human transplant following five years later. Before this was possible, many studies in dogs by Dr Roy Calne were required to improve immunosuppression drugs and prevent organ rejection. The history of organ transplant development owes much to animal studies.
  • Transgenic sheep are to be used to understand early warning signs of Huntington’s disease. Huntington’s disease (HD) is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain. The child of every parent with Huntington’s disease has a 50% chance of inheriting the disease and it is estimated that 300,000 Americans and 6,700 people from the United Kingdom suffer from Huntington’s disease. Professor Jenny Morton, from the University of Cambridge, is tackling this debilitating disease by trying to understand its early warning signs, in genetically modified sheep which carry the genetic mutation that causes Huntington’s disease. She states “Until now, much of our effort has been based on research on mice or rats, but sheep should make better research subjects. Not only do they live much longer than rodents, their brains are larger and closer in size and structure to humans.”

    Prof. Jenny Morton with transgenic sheep. Photo: A. Olmos, the Observer.

  • Weight gain from eating fatty foods may be reduced – but only if you can’t smell your food. In a new study, researchers gave regular doses of diphtheria toxin to genetically modified mice which caused their sense of smell to be suppressed. These mice were then fed either a normal diet or fatty foods that induce obesity. After three months, they found that the odor deprived mice weighed slightly less than mice with their sense of smell intact. However, in the group that was fed fatty foods – they found that mice that could not smell weighed 16% less than mice that could. Interestingly, there was no difference in the amount of food that was consumed by either group or in the amount of activity in the home cage. Rather, this difference seemed to be caused by the way that they created and metabolized brown fat. In a separate experiment, looking at mice with a “sharper sense of smell”, these mice also became obese – but similar to the anosmic mice – not because of differences in the amount of food consumed. These results highlight the intimate role of smell in the process of metabolism — but it should be noted that this process may be different in humans — if simply for the amount of brown fat that we store relative to our furry counterparts. This research was published in the journal Cell Metabolism.

Obese (L) and lean (R) laboratory mice. Source: t-nation.com

  • The bacteria in our gut may influence our emotions. The number of reported links between our brain and our gut are increasing in frequency — and this should be of no surprise because the enteric nervous system is the second largest nervous system in our body. Previous research in mice has highlighted that the bacteria in the gut may affect your mood or emotion, including those related to anxiety and depression. Now, a similar link has been found in humans (women). Analyzing the faecal matter of 40 women, researchers identified two groups of bacteria which appeared to have an impact on the brain. In seven women whose gut primarily contained the bacterial group Prevotella, “a greater connectivity between the emotional, attentional, and sensory brain regions, while having smaller and less active hippocampi, the region of the brain that is related to emotional regulation, consciousness and the consolidation of short-term memories into long-term ones.” In contrast, in the guts of the remaining thirty three women the bacterial group, Bacteroides These women were found to have a different type of brain — “The frontal cortex and the insula – regions of the brain linked to problem-solving and complex information processing – had more gray matter than the other group of women. Their hippocampi were also more voluminous and active.”   This research was published in the journal Psychosomatic Medicine.

  • Prairie dogs protected from plague by vaccine developed in field trials. In an April’s research roundup, we wrote about a vaccination campaign that was planned for prairie dogs in an effort to save the black footed ferret. Because of the Sylvatic plague, prairie dogs living in the habitats of the black footed ferret are now in danger of being decimated and spreading this disease to the ferrets that eat them. A recent study published by the Researchers at the University of Wisconsin – Madison and U.S. Geological Survey’s National Wildlife Health Center, describes that the vaccination campaign was successful. Colonies of prairie dogs that received the vaccination were twice as likely to survive than those that did not — and the odds were even higher for juvenile animals. The study aims to develop a method to control disease in endangered or threatened wildlife through the provision of vaccine-laden bait – and could later include drones and all-terrain vehicles to aid in the dispersal of the vaccination. This research was published in the journal EcoHealth.

 

 

 

Research Roundup: Artificial bile ducts, saving bat populations, safety of CRISPR and more

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • CRISPR gene editing technique argued to be probably safe. In a previous research roundup, we highlighted the ongoing debate with respect to the safety of the CRISPR-Cas 9 gene editing technique. In that study, it was argued that despite using this technology to restore sight to mice, when looking at the whole genome of the animals, hundreds of areas other than that targeted DNA sections were affected in three of those mice. In a new preprint of an article (non-peer reviewed), researchers argue that the differences that were found were simply a consequence of genetic relatedness rather than unexpected mutations. While it is still far from certain which side is correct, such dialogue and debate highlight the stringency that most treatments that eventually make it humans go through before introduction to the general population — much in part because of animal research.

  • Artificial bile ducts successfully grown in the lab and transplanted into mice could help treat liver disease in children. Scientists in Cambridge, UK, have developed a new method for growing artificial bile ducts in the lab and successfully transplanting them into lab mice — a development that could one day be used to treat liver disease in children. The discovery could also reduce the need for liver transplants in these patients. The researchers extracted healthy cells (called cholangiocytes) from bile ducts and grew them into functioning 3D structures known as biliary organoids. Researchers then grew the organoids on a “biodegradable collagen scaffold” in order to shape the organoid into a tube, which they then transplanted into mice to replace damaged bile ducts. The transplants were successful, and the animals survived without any further complications. The scientists emphasized the “power of tissue engineering and regenerative medicine that these results demonstrate. “These artificial bile ducts will not only be useful for transplanting, but could also be used to model other diseases of the bile duct and potentially develop new drug treatments,” said Dr. Fotrio Sampaziotis, lead author on the study.
    The research was published in Nature Medicine.
  • Antibodies of mother halt placental transmission of cytomegalovirus in monkeys. In our research roundup two weeks ago, we highlighted the debilitating effects of CMV on infants. Approximately 50% of all humans over the age of 40 harbour the CMV, and over 1 million infants a year are infected worldwide. Here, for the first time, researchers studied whether the offspring of mothers exposed to CMV specific antibodies, would confer protection to their offspring from the virus in utero. In the first experiment they found that dosing with CMV antibodies prevented abortion of the fetus and in a second experiment found that a higher dose completely blocked transmission of the virus.While the virus in rhesus macaques is not identical to that in humans (RhCMV) much can be learned from studying this derivative of the disease in non-human animals – similar to the study of SIDS in our understanding of AIDS. In terms of the applicability of this work, lead author, Cody Nelson, a PhD student at DUke university says “Ending congenital CMV infection is likely going to require an effective vaccine given before pregnancy, similar to how the rubella vaccine has eradicated congenital rubella syndrome in the Americas.” This research was published in the journal JCI Insights.
  • Thermal imagery of bat hibernation suggests group behavior for combating white-nose syndrome. Insect-eating bats play a large role in pest control services, likely saving the U.S. agriculture industry upwards of $3 billion a year. However, white-nose syndrome is a fungal disease that has been spreading rapidly across North America for the past decade and is causing steep declines in bat populations. A recent study by researchers at Massey University in New Zealand, used temperature-sensing cameras on hibernating bats with white-nose syndrome to better understand how some bats survive white-nose syndrome during hibernation, while others do not. Interestingly, they found that a species of bat (Indiana bats, Myotis sodalis) — that is less affected by the disease than others (little brown bats, M. lucifugus)– slowly warmed up as a synchronous group, which may have enabled body temperatures to be less conducive to fungal growth and increase the bat’s ability to survive the disease. Not only does this basic research help us  towards finding solutions to mitigate the declining bat population, but it also may help scientists in the future to combat disease in astronauts who will hibernate during long-term space travel.

A northern long-eared bat was affected by white-nose syndrome in Illinois. Credit: J.R. Hoyt.

  • Cilene Lino de Oliveira has won the Basel Declaration Society 2017 Award for Education in Animal Research. Oliveira, from the Department of Physiological Sciences at the University of Santa Catarina, teaches the University’s “Laboratory Animal Care and Welfare” course. The award will give her the opportunity to do an EU course in animal welfare at the Institute for Laboratory Animal Science at the University of Zurich.

Research Roundup: Heart regeneration, understanding of organ rejection, the saliva of ticks and more

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • An understanding of the genetics that allow sea anemone to regenerate their heart could one day help human patients. Sea anemones are quite unique when compared to typical vertebrates (e.g. humans) — for example, they have genes that can produce heart cells even though they themselves do not have a heart. The also have the capacity to to regenerate where, for example, if an anemone is cut into pieces, each piece will regenerate into a new anemone. When analyzing the relationship between this regeneration capability and the functioning  of the “heart genes” in sea anemones, scientists at the University of Florida discovered that the genes interact with one another differently than human “heart genes”. Heart genes in humans have what are called lockdown loops, which tell the heart genes to turn on and stay on for the entire lifetime of the animal. Sea anemones do not have these lockdown loops, which allows them to turn cells with heart genes into any other kind of cell for regeneration. By further investigating the evolution of lockdown loops for sea anemone to vertebrates, scientists may be able to better understand possibilities for regeneration in vertebrates, who do not currently regenerate tissue — many lizards can regenerate tails, which is another line of research in this field.  This study is a perfect example on how basic research in organisms completely different from humans may one day have large reaching effects on human health. This study was published in the journal Proceedings of the National Academy of Sciences.

Image courtesy of Whitney Lab for Marine Bioscience

  • Earliest molecular events leading to organ rejection identified in mice. Organ rejection remains a problem for transplant recipients — approximately 50% of all transplanted organs are rejected within 10 to 12 years. While methods are available to reduce the risk of organ rejection — such as immunosuppressant drugs — understanding the early molecular steps via which the body identifies cells as “non-self” provides important insight to reduce such risk. Fadi Lakkis, M.D., a senior co-author and scientific director of University of Pittsburgh’s  Thomas E. Starzl Transplantation Institute (STI) says, “For the first time, we have an insight into the earliest steps that start the rejection response.” The team hopes that  manipulating these earliest steps will disrupt the rejection process eliminating or minimizing transplantation failures. The study was a collaborative effort between researchers at the University of Pittsburgh, the Hospital of Sick Kids, the University of Toronto and Kobe University.  Using mice, they identified that a molecule called SIRP-alpha leads to the innate immune system activation and response, and that this molecule differs between non related individuals. In particular, when foreign tissue is transplanted, the SIRP-alpha of this new tissue binds to a receptor called CD47 in the host. This binding is what triggers the activation of the immune system leading to the rejection process. Both humans and mice express SIRP-alpha. Researchers say that sequencing this gene to identify potential donors and recipients may lead to lower organ rejection rates.  They also found that blocking the binding of SIRP-alpha and CD47 prevented the activation which may be used to find new ways to prevent organ rejection for patients that are not an exact match. This research was published in the journal Science Immunology.
knockout mice, animal research, animal rights

Laboratory mice (image courtesy of NIH)

  • Insight into how humans developed their daytime vision comes from research on chick embryos.  Humans — along with other primates, various fish, reptiles, and birds — have a small spot in the center of their retina that allows them to have sharp vision in the daylight. Although, researchers have long acknowledged the existence of this spot, little has been known about the development of this sharp vision spot, known as the fovea, in humans. Researchers at Harvard Medical School recently investigated the development of this sharp vision spot in chickens, and found that growth factors involved in such development are regulated by enzymes that degrade retinoic acid, a derivative of Vitamin A, that plays important roles in embryonic development. Such pioneering work on the development of structures involved in having sharp vision (e.g. fovea) may help scientists to one day combat medical conditions involved with losing sharp vision (e.g. macular degeneration).
  • A protein found in the saliva of ticks could help treat Myocarditis, according to researchers at the University of Oxford. Ticks are often able to feed on their hosts for over a week thanks to proteins in the saliva, called evasins, which prevent inflammation by binding to and neutralizing chemicals called chemokines. These chemokines also cause inflammation in myocarditis, heart attack and stroke. The scientists were able to grow tick saliva in yeast, using synthetic genes, thereby avoiding needing to individually milk ticks for their saliva. This study was published in Scientific Reports and was funded by the British Heart Foundation.

  • Transcranial stimulation and/or physical therapy improves walking speed in Parkinson’s disease. Parkinson’s disease is a debilitating movement related disorder that affects approximately 10 million people worldwide. In America alone, this translates into a combined cost of approximately 25 billion dollars a year. Like many diseases with such a high prevalence, research is focused on two key aspects — understanding the etiology and the development of effective treatments of the disorder. Animal models, in mice, primates and other mammals, are integral in making progress in both aspects. For example, transcranial stimulation as a proof of  principle owes much to animal models – both in terms of its development and in relation to its evaluation of efficacy. Here, we see a good example of how basic research in animal models leads to improved quality of life due to a debilitating disease. In humans, these researchers found that noninvasive brain stimulation and physical therapy — alone or in combination — improve some measures of walking ability in patients with Parkinson’s disease. This study was published in the American Journal of Physical Medicine & Rehabilitation.