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The Applicability of Mouse Models to the Study of Human Disease

Affiliations.

1 Lung Biology Group, Lund, Sweden.
2 Department of Experimental Medical Science, Lund University, Lund, Sweden.
3 School of Life and Health Sciences, Aston University, Birmingham, UK. [email protected].
PMID: 30788814
PMCID: PMC7121329
DOI: 10.1007/978-1-4939-9086-3_1

The laboratory mouse Mus musculus has long been used as a model organism to test hypotheses and treatments related to understanding the mechanisms of disease in humans; however, for these experiments to be relevant, it is important to know the complex ways in which mice are similar to humans and, crucially, the ways in which they differ. In this chapter, an in-depth analysis of these similarities and differences is provided to allow researchers to use mouse models of human disease and primary cells derived from these animal models under the most appropriate and meaningful conditions.Although there are considerable differences between mice and humans, particularly regarding genetics, physiology, and immunology, a more thorough understanding of these differences and their effects on the function of the whole organism will provide deeper insights into relevant disease mechanisms and potential drug targets for further clinical investigation. Using specific examples of mouse models of human lung disease, i.e., asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis, this chapter explores the most salient features of mouse models of human disease and provides a full assessment of the advantages and limitations of these models, focusing on the relevance of disease induction and their ability to replicate critical features of human disease pathophysiology and response to treatment. The chapter concludes with a discussion on the future of using mice in medical research with regard to ethical and technological considerations.

Keywords: Disease; Ethics; Genetics; Immunology; Model; Mouse; Physiology.

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Review Article
Published: February 2007

Humanized mice in translational biomedical research

Leonard D. Shultz 1 ,
Fumihiko Ishikawa 2 &
Dale L. Greiner 3

Nature Reviews Immunology volume 7 , pages 118–130 ( 2007 ) Cite this article

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There is a growing need for animal models to carry out in vivo studies of human biological systems without putting individuals at risk. Severely immunodeficient mice engrafted with human cells and tissues, known as 'humanized' mice, facilitate progress in studies of human haematopoiesis, immunity, gene therapy, infectious diseases, cancer and regenerative medicine.

Advances in the generation of humanized mice have depended on a systematic progression of genetic modifications in immunodeficient mouse hosts and on improvements in engraftment techniques.

Mice homozygous for the severe combined immunodeficiency ( scid ) gene mutation or for targeted mutations at the recombination-activating gene 1 ( Rag1 ) or Rag2 loci, accompanied by a targeted mutation at the interleukin-2 receptor γ-chain ( Il2rg ) locus, support greatly increased engraftment and function of human haematopoietic stem cells (HSCs) and peripheral-blood mononuclear cells (PBMCs) compared with previous immunodeficient mouse models.

The development of immunodeficient mice that are humanized by engraftment of human lymphoid tissues, HSCs and PBMCs provides an opportunity to carry out translational research on human immunity and autoimmune diseases. These models are also being used to study the biology of human pathogens responsible for AIDS and several other infectious diseases.

Humanized mice are being increasingly used as hosts for human malignant cells in studies of carcinogenesis, tumour metastasis and cancer therapy. The phenotypic and functional characterization of human tumour stem cells is also being advanced through the study of humanized mice.

The potential for new advances in our understanding of human immunology and other areas of human biology that is supported by studies in humanized mice remains promising. Additional genetic and technological modifications will accelerate progress towards the development of a functional human immune system in mice.

The culmination of decades of research on humanized mice is leading to advances in our understanding of human haematopoiesis, innate and adaptive immunity, autoimmunity, infectious diseases, cancer biology and regenerative medicine. In this Review, we discuss the development of these new generations of humanized mice, how they will facilitate translational research in several biomedical disciplines and approaches to overcome the remaining limitations of these models.

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Humanized mouse models for immuno-oncology research

Generation of the NeoThy mouse model for human immune system studies

Naturalizing mouse models for immunology

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Acknowledgements

We thank E. Leiter, D. Serreze, M. Berry and A. Rossini for valuable discussions. We are supported by the β-Cell Biology Consortium and Autoimmunity Prevention Centers of the National Institutes of Health (NIH; USA), the Juvenile Diabetes Research Foundation (International), the American Diabetes Association, and the Diabetes Endocrinology Research Center, the National Cancer Institute Center, the National Institute of Allergy and Infectious Diseases and the National Heart, Lung and Blood Institute of the NIH. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Shultz, L., Ishikawa, F. & Greiner, D. Humanized mice in translational biomedical research. Nat Rev Immunol 7 , 118–130 (2007). https://doi.org/10.1038/nri2017

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Mice are the most commonly used animals in medical research. This trend looks likely to continue now that both mouse and human genomes have been mapped ( 80% of human genes are exactly the same as those found in mice, and at least a further 10% are very similar) allowing human genetic disorders and diseases to be studied with greater accuracy.

Often, the only way of determining the function of a human gene is to insert it into, or remove it from, the mouse genome. Many thousands of mouse strains now exist, some frozen as embryos. Eventually, such techniques could lead to new methods of preventing, treating or even curing genetic diseases and other diseases with a genetic component.

Around 87% of all genetically modified animals used in research in the UK are mice [ UK 2020 figures ].

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Mice ( Mus musculus ) belong to the family rodentia (rodents) and are one of the most common mammals on Earth. They are small animals that grow to the size of 12cm long. Mice are omnivores, their diet consists of a mixture of both plant and animal matter, essentially mice can eat anything they like! Mice have been used in research for more than a century with the first use of mice in genetics dating back to 1902. They are the most commonly used animal in Great Britain.

Why are mice used in research?

Mice have many characteristics that make them ideal laboratory animals. Firstly, some diseases are modelled well in mice as human and mice share some anatomical, physiological, and genetic features. Conveniently, due to the successful sequencing of the mice genome, scientists can produce genetically modified mice and introduce or remove particular genetic features to make the mice better disease models. Mice have a relatively short gestation period and have multiple births, allowing researchers access to a lot of mice in a short amount of time. Their relatively fast ageing process also makes them great models for studying the effects and process of ageing. Finally, b ecause of their size, they are convenient for researchers and animal technicians to house and care for.

What types of research are mice used in?

Mice are versatile, they are used in a range of research from genetics to virology, oncology and many more. Notably, mice and other animals have been very important in the development of Herceptin, a monoclonal antibody used in certain types of breast cancer. Herceptin was the first monoclonal antibody successfully used to treat cancer. The HER2 protein, which makes breast cancer cells grow and duplicate was discovered in rat tumours, however, years later the monoclonal antibodies were used in mice to target the HER2, which successfully reduced tumour growth. The protein was discovered in rat tumours and years later, the antibodies were used to target the HER2 in mice. Herceptin is a humanised mice antibody, being 95% human and 5% mice.

More recently, mice have been instrumental in the search for a coronavirus vaccine. Researcher’s ability to genetically modify mice has been especially useful in breeding mice that are susceptible to the SAR-COV-2 virus. The mice ACE2 receptor is different from the human ACE2 receptor, exempting mice from being infected by the virus. Scientists altered the mice ACE2 receptor to become more human and allow the mice to get the virus and display symptoms of the covid-19 disease. When research began for the vaccine for the virus, mice with humanised ACE2 receptors were the best animal model at researchers’ disposal.

How are the mice looked after?

The use of animals in research is highly reg ulated, an important part of that regulation is ensuring the animals are housed and cared for correctly. Laboratory mice are housed similarly to pet mice, in cages lined with soft, absorbent bedding. In the laboratory the cages are made of see-through plastic so that they can be seen without disturbing them. Mice are given fresh food and water each day and are usually fed a specially constructed diet that meets all their nutritional needs. It is also important that animals have enrichment (things to entertain them), so they will usually have areas where they can hide away and objects to climb and gnaw on.

Because mice are highly social animals, it is very important that they are housed in groups, or at a minimum pairs. There are only a few exceptional circumstances where mice would be kept alone, usually for their own safety.

Find out more about mice in research with our '10 facts' infographic .

See also our pages on GM mice and breeding , mice and stem cell research , our video of mice, and animal research.info on mice and GM mice .

Mice in research: https://www.yourgenome.org/facts/why-use-the- mouse -in-research

Herceptin: https://www.understandinganimalresearch.org.uk/news/herceptin-first-monoclonal-antibody-treatment-for-cancer

Coronavirus and mice: https://www.sciencemag.org/news/2020/04/mice-hamsters-ferrets-monkeys-which-lab-animals-can-help-defeat-new-coronavirus

Mice: https://www.britannica.com/animal/ mouse -rodent/Geographic-distribution-and-habitat

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Ethical care for research animals

WHY ANIMAL RESEARCH?

The use of animals in some forms of biomedical research remains essential to the discovery of the causes, diagnoses, and treatment of disease and suffering in humans and in animals., stanford shares the public's concern for laboratory research animals..

Many people have questions about animal testing ethics and the animal testing debate. We take our responsibility for the ethical treatment of animals in medical research very seriously. At Stanford, we emphasize that the humane care of laboratory animals is essential, both ethically and scientifically. Poor animal care is not good science. If animals are not well-treated, the science and knowledge they produce is not trustworthy and cannot be replicated, an important hallmark of the scientific method .

There are several reasons why the use of animals is critical for biomedical research:

• Animals are biologically very similar to humans. In fact, mice share more than 98% DNA with us!

• Animals are susceptible to many of the same health problems as humans – cancer, diabetes, heart disease, etc.

• With a shorter life cycle than humans, animal models can be studied throughout their whole life span and across several generations, a critical element in understanding how a disease processes and how it interacts with a whole, living biological system.

The ethics of animal experimentation

Nothing so far has been discovered that can be a substitute for the complex functions of a living, breathing, whole-organ system with pulmonary and circulatory structures like those in humans. Until such a discovery, animals must continue to play a critical role in helping researchers test potential new drugs and medical treatments for effectiveness and safety, and in identifying any undesired or dangerous side effects, such as infertility, birth defects, liver damage, toxicity, or cancer-causing potential.

U.S. federal laws require that non-human animal research occur to show the safety and efficacy of new treatments before any human research will be allowed to be conducted. Not only do we humans benefit from this research and testing, but hundreds of drugs and treatments developed for human use are now routinely used in veterinary clinics as well, helping animals live longer, healthier lives.

It is important to stress that 95% of all animals necessary for biomedical research in the United States are rodents – rats and mice especially bred for laboratory use – and that animals are only one part of the larger process of biomedical research.

Our researchers are strong supporters of animal welfare and view their work with animals in biomedical research as a privilege.

Stanford researchers are obligated to ensure the well-being of all animals in their care..

Stanford researchers are obligated to ensure the well-being of animals in their care, in strict adherence to the highest standards, and in accordance with federal and state laws, regulatory guidelines, and humane principles. They are also obligated to continuously update their animal-care practices based on the newest information and findings in the fields of laboratory animal care and husbandry.

Researchers requesting use of animal models at Stanford must have their research proposals reviewed by a federally mandated committee that includes two independent community members. It is only with this committee’s approval that research can begin. We at Stanford are dedicated to refining, reducing, and replacing animals in research whenever possible, and to using alternative methods (cell and tissue cultures, computer simulations, etc.) instead of or before animal studies are ever conducted.

Organizations and Resources

There are many outreach and advocacy organizations in the field of biomedical research.

Learn more about outreach and advocacy organizations

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Stanford Discoveries

What are the benefits of using animals in research? Stanford researchers have made many important human and animal life-saving discoveries through their work.

Learn more about research discoveries at Stanford

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Why we need female mice in neuroscience research

Catherine Caruso

HMS Communications

Findings reveal that despite hormonal fluctuations, female mice exhibit more stable exploratory behavior than their male peers

Mice have long been a central part of neuroscience research, providing a flexible model that scientists can control and study to learn more about the intricate inner workings of the brain. Historically, researchers have favored male mice over female mice in experiments, in part due to concern that the hormone cycle in females causes behavioral variation that could throw off results.

But new research from Harvard Medical School challenges this notion and suggests that for many experiments, the concern may not be justified.

The study results, published March 7 in Current Biology , reveal that female mice, despite ongoing hormonal fluctuations, exhibit exploratory behavior that is more stable than that of their male peers.

Using a strain of mice commonly studied in lab settings, the researchers analyzed how the animals behaved as they freely explored an open space. They found that the hormone cycle had a negligible effect on behavior and that differences in behavior between individual female mice were much greater. Moreover, differences in behavior were even greater for males than for females, both within and between mice.

The results underscore the importance of incorporating both sexes into mouse studies, the research team said.

“I think this is really powerful evidence that if you’re studying naturalistic, spontaneous exploratory behavior, you should include both sexes in your experiments — and it leads to the argument that in this setting, if you can only pick one sex to work on, you should actually be working on females,” said Sandeep Robert Datta , professor of neurobiology in the Blavatnik Institute at HMS, who co-led the study with Rebecca Shansky of Northeastern University.

From rodents to humans: A history of bias

As neuroscientists strive to better understand the human brain, they routinely turn to the mouse, which Datta considers “the flagship vertebrate model for understanding how the brain works.”

This is because mouse and human brains share a considerable amount of structural organization and genetic information, so scientists can easily manipulate the mouse genome to address specific experimental questions and to build models of human diseases.

“Much of what we understand about the relationship between genes and neural circuits, and between neural activity and behavior, comes from basic research in the mouse, and mouse models are likely going to be really central tools in our fight against a broad array of neurological and psychological diseases,” Datta said.

“I think this is really powerful evidence that if you’re studying naturalistic, spontaneous exploratory behavior, you should include both sexes in your experiments — and it leads to the argument that in this setting, if you can only pick one sex to work on, you should actually be working on females.” Sandeep Robert Datta, professor of neurobiology in the Blavatnik Institute

For more than 50 years, researchers have preferentially used male mice in experiments, and nowhere has this practice been more prominent than in neuroscience. In fact, a 2011 analysis found that there were over five times as many single-sex neuroscience studies of male mice than of female mice. Over time, this practice has resulted in a poorer understanding of the female brain, likely contributing to the misdiagnosis of mental and neurological conditions in women, as well as the development of drugs that have more side effects for women — issues outlined by Shansky in a 2021 perspective in Nature Neuroscience .

The disparity in sex representation common in animal research has also been historically mirrored in research involving human subjects.

“This bias starts in basic science, but the repercussions are rolled into drug development, and lead to bias in drugs being produced, and how drugs are suited for the different sexes,” said lead author Dana Levy , a research fellow in neurobiology at HMS. For example, Levy noted that conditions such as anxiety, depression, and pain are known to manifest differently in female mice and women than in the male mice that are more often used in early-stage drug testing.

To address the problem of sex bias in scientific research, the National Institutes of Health published a policy in 2016 requiring researchers to include male and female subjects and samples in experiments. However, follow-up studies that look across scientific disciplines and examine neuroscience specifically indicate that progress has been slow.

The reasons for such a long-standing bias in neuroscience are complicated, Datta said: “Part of it is just plain old sexism, and part of it is conservatism in the sense that people have studied male mice for so long that they don’t want to make a change.”

Yet perhaps the biggest reason for excluding female mice, Datta said, stems from a widespread assumption that their behavior is broadly affected by cyclic variations in hormones such as estrogen and progesterone — the rodent version of a menstrual cycle, known as the estrous cycle. According to Datta and Levy, estrous status is known to have a strong effect on certain social and sexual behaviors in mice. However, data on the influence of estrous status in other behavioral contexts have been mixed, resulting in what Datta calls “a genuine disagreement in the literature.”

“We wanted to measure how much the estrous cycle seemed to influence basic patterns of exploration,” Datta said. “Our question was whether these ongoing changes in the hormonal state of the mouse affect other neural circuits in a way that’s confusing for researchers.”

“We assumed, like everybody else, that adding females was just going to complicate our experiments,” Levy added, “And so we said, ‘why not test this.’”

Testing assumptions

The researchers studied genetically identical males and females from a common strain of lab mouse in a circular open field — a standard lab setup for behavioral neuroscience experiments. In practice, the test involved placing a mouse in a 5-gallon Home Depot bucket for 20 minutes and using a camera to record the mouse’s movements and behaviors in 3D as it freely explored the space. The researchers swabbed each female mouse to determine its estrous status and repeated the bucket test with the same individual multiple times.

“This is a very interesting example of how assumptions that affect the way that we conduct and design our science are sometimes just assumptions — and it is important to directly test them, because sometimes they’re not true.” Dana Levy, a research fellow at Harvard Medical School

The team analyzed the videos with MoSeq, an artificial intelligence technology previously developed by the lab. The technology uses machine learning algorithms to break down a mouse’s movements into around 50 different “syllables,” or components of body language: short, single motions such as rearing up, pausing, stepping, or turning. With MoSeq, the researchers gathered in-depth, high-resolution data about the structure and pattern of mouse behavior during each session.

The researchers found that estrous status had very little effect on exploratory behavior in female mice. Instead, patterns of behavior tended to vary much more across female mice than they did throughout the estrous cycle.

“If you give me any random video from our pile, I can tell you which mouse it is. That’s how individualized the pattern of behavior is,” Datta said, which suggests that in behavioral studies, “a dominant aspect of variation in the data is the fact that individuals have subtly different life histories.”

When the researchers compared female and male mice, they found something that surprised them: Males also exhibited individuality of behavior, but they had more behavioral variation within a single mouse and between mice than females.

“People have been making this assumption that we can use male mice to reliably make comparisons within and across experiments, but our data suggest that female mice are more stable in terms of behavior despite the fact that they have the estrous cycle,” Datta said.

A case for change

Scientists generally agree that including female mice is important from a fairness perspective, Datta noted, yet some have remained concerned that it could complicate their research. For him, the new findings make a strong scientific case for using female mice in experiments.

“The fact that female behavior is more reliable suggests that including females might actually decrease the overall variability in your data under many circumstances,” Datta said.

Based on their findings, researchers in the Datta lab have already switched from male mice to mixed groups or female mice in their other experiments that involve circular, open-field testing.

Datta cautioned that the study looks at only one mouse strain in one lab setup, and so the results cannot be generalized to other strains and setups without further testing. However, he noted that the strain and setup are commonly used in neuroscience research, including in early-stage drug development to test how a potential drug affects mouse locomotion.

Datta said that the findings “should encourage folks who are interested in drug development in this context to include both sexes in their analysis.”

Now, Datta and Levy are interested in exploring how internal states beyond hormonal status, such as hunger, thirst, pain, and illness, affect exploratory behavior in mice.

“The question is, who wins in this tug-of-war between your current internal state and your individual identity,” Levy explained.

They also want to delve deeper into the neural basis of the individuality of mouse behavior that they saw in the study.

“I was shocked by how much stable variation between individuals we were observing — it’s like these mice really are individuals,” Datta said. “We’re used to thinking of lab mice as interchangeable widgets, but they’re not at all. So, what is controlling these individualized patterns of behavior?”

“We want to understand the mechanisms of individuality: how variability between individuals comes about, how it affects behavior, what can alter it, and what brain regions support it,” Levy added.

To this end, the Datta lab is examining mouse behavior from birth until death to understand how individualized patterns of behavior emerge and crystallize during development, and how they change throughout life.

The researchers also hope that their work will open the door for more rigorous, quantitative research on whether and how the estrous cycle affects mouse behavior in other contexts, such as completing complex tasks.

“This is a very interesting example of how assumptions that affect the way that we conduct and design our science are sometimes just assumptions — and it is important to directly test them, because sometimes they’re not true,” Levy said.

Additional authors include Nigel Hunter, Sherry Lin, Emma Robinson, Winthrop Gillis, Eli Conlin, and Rockwell Anyoha of HMS.

Datta is on the scientific advisory boards of Neumora, Inc., and Gilgamesh Pharmaceuticals, which have licensed the MoSeq technology.

The research was supported by the NIH (U19NS113201; RF1AG073625; R01NS114020), the Brain Research Foundation, the Simons Collaboration on the Global Brain, the Simons Collaboration for Plasticity in the Aging Brain, the Human Frontier Science Program, and the Zuckerman STEM Leadership Program.

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Why Do Medical Researchers Use Mice?

From formulating new cancer drugs to testing dietary supplements, mice and rats play a critical role in developing new medical wonders. In fact, 95 percent of all lab animals are mice and rats, according to the Foundation for Biomedical Research (FBR).

Scientists and researchers rely on mice and rats for several reasons. One is convenience: rodents are small, easily housed and maintained, and adapt well to new surroundings. They also reproduce quickly and have a short lifespan of two to three years, so several generations of mice can be observed in a relatively short period of time.

Mice and rats are also relatively inexpensive and can be bought in large quantities from commercial producers that breed rodents specifically for research. The rodents are also generally mild-tempered and docile, making them easy for researchers to handle, although some types of mice and rats can be more difficult to restrain than others . [ Why Do Mice Poop So Much? ]

Most of the mice and rats used in medical trials are inbred so that, other than sex differences, they are almost identical genetically. This helps make the results of medical trials more uniform, according to the National Human Genome Research Institute. As a minimum requirement, mice used in experiments must be of the same purebred species.

Another reason rodents are used as models in medical testing is that their genetic, biological and behavior characteristics closely resemble those of humans, and many symptoms of human conditions can be replicated in mice and rats. "Rats and mice are mammals that share many processes with humans and are appropriate for use to answer many research questions," said Jenny Haliski, a representative for the National Institutes of Health (NIH) Office of Laboratory Animal Welfare.

Over the last two decades, those similarities have become even stronger. Scientists can now breed genetically-altered mice called "transgenic mice" that carry genes that are similar to those that cause human diseases. Likewise, select genes can be turned off or made inactive, creating "knockout mice," which can be used to evaluate the effects of cancer-causing chemicals (carcinogens) and assess drug safety, according to the FBR.

Rodents also make efficient research animals because their anatomy, physiology and genetics are well-understood by researchers, making it easier to tell what changes in the mice's behaviors or characteristics are caused by.

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Some rodents, called SCID (severe combined immune deficiency) mice, are naturally born without immune systems and can therefore serve as models for normal and malignant human tissue research , according to the FBR.

Some examples of human disorders and diseases for which mice and rats are used as models include:

Hypertension
Respiratory problems
Parkinson's disease
Alzheimer's disease
Cystic fibrosis
HIV and AIDs
Heart disease
Muscular dystrophy
Spinal cord injuries

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Mice are also used in behavioral, sensory, aging, nutrition and genetic studies, as well as testing anti-craving medication that could potentially end drug addiction .

"Using animals in research is critical to scientific understanding of biomedical systems leading to useful drugs, therapies and cures," Haliski told Life's Little Mysteries.

Originally published on Live Science .

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Cellular therapy targeting senescent cells may improve health in mice

Aging Biology Biomarkers Chronic Conditions Geroscience

A new cell therapy targeting senescent cells may improve metabolic and physical function in mice, according to an NIA-funded study. Senescent cells , which are cells that have stopped dividing but do not die off when they should, have been linked to many aspects of aging and disease. In the study, published in Nature Aging , senescent cells were safely and effectively removed from the tissues of mice, leading to better health.

Looking down on cubes, each with a bullseye on its top side; all but one are dark gray, one is yellow, and it has a short arrow sticking from its bullseye.

Every day, damaged cells die and are replaced by new, healthy cells. As we age, the body may not remove damaged cells as efficiently as it used to, and although these cells stop dividing, they do not die. These damaged cells that linger — senescent cells — contribute to inflammation and age-related decline, such as metabolic dysfunction and decreased physical fitness. Drugs called senolytics eliminate senescent cells but require continuous treatment.

A new method of eliminating senescent cells involves modifying T cells, a type of immune cell, to express chimeric antigen receptors (CARs) on their surface. These CAR T cells are engineered to recognize and eliminate cells that express a specific protein found on many senescent cells. A team led by researchers from Cold Spring Harbor Laboratory, Memorial Sloan Kettering Cancer Center, and other institutions developed CAR T cells that recognize a protein found on many senescent cells.

The researchers tested the senolytic CAR T cell therapy in mice and found that it could eliminate senescent cells. The treatment improved metabolic function — for example, glucose tolerance — and exercise capacity in older mice. Next, they treated young mice given a high-fat diet to induce premature aging. These mice experienced similar improvements to their metabolic function. Additionally, the scientists gave young, healthy mice a single treatment of CAR T cells. The treatment prevented metabolic decline for more than a year; a substantial period, as their average lifespan is two years.

These findings suggest therapeutic potential for targeting senescent cells with CAR T cell therapy in humans. Future studies may explore the broader application of this targeted cellular therapy in addressing additional age-related diseases and potentially extending longevity, building on the outcomes observed in mouse studies.

This research was supported in part by NIA grants R01AG082800, R01AG065396, and U01AG077925.

Reference: Amor C, et al. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction . Nature Aging . 2024;4(3):336-349. doi: 10.1038/s43587-023-00560-5.

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Drugs That Work In Mice Often Fail When Tried In People

Richard Harris

Most new drugs don't work when tested in people. One of the big reasons is the use of animals in research.

Most potential new drugs fail when they're tested in people. These failures are not only a major disappointment, they sharply drive up the cost of developing new drugs.

A major reason for these failures is that most new drugs are first tested out in mice, rats or other animals. Often those animal studies show great promise.

But mice aren't simply furry little people, so these studies often lead science astray. Some scientists are now rethinking animal studies to make them more effective for human health.

When scientists first started using animals in research over a century ago, the animals were not regarded as human stand-ins. Scientists studying rats were initially trying to understand rats, says Todd Preuss , an anthropologist at the Yerkes National Primate Research Center at Emory University.

"As this process went on, people stopped seeing them as specialized animals and started seeing them more and more as prototypical mammals," Preuss says.

But is a rat really a generic mammal? Preuss says emphatically no. But that's how rodents were pitched when they became products sold to scientists.

"It wasn't strictly a financial interest," he says. The sellers "really believed that you could do almost anything" with these animals. "You could learn about almost any feature of human organization, you could cure almost any disease by studying these animals."

That was a dangerous assumption. Rats and humans have been on their own evolutionary paths for tens of millions of years. We've developed our own unique features, and so have the rodents.

So it should come as no surprise that a drug that works in a mouse often doesn't work in a person. Even so, Preuss says there's tremendous momentum to keep using animals as human substitutes. Entire scientific communities are built up around rats, mice and other lab animals.

"Once these communities exist, then you have an infrastructure of knowledge: how to raise the animals, how to keep them healthy," Preuss says. "You have companies that spring up to provide you with specialized equipment to study these animals."

The rat holding facility at Hazelton Laboratories in Washington, D.C., in 1967. Fox Photos/Getty Images hide caption

The rat holding facility at Hazelton Laboratories in Washington, D.C., in 1967.

Chances are, people studying the same disease study the same tailor-made strain of animal. Journals and funding agencies actually expect it.

"So there's a whole institution that develops," Preuss says.

And it's hard to interrupt that culture. (Preuss spoke about this subject in a 2016 talk at the National Institutes of Health.)

You can get a glimpse of the scale of this enterprise by passing through one of hundreds of facilities nationwide devoted to the care and feeding of mice. On the Stanford University campus, attendants roll supply carts through fluorescent-lit hallways and past row after row of doors at an expansive mouse facility.

I'm guided through the labyrinth by Joseph Garner , a behavioral scientist at the Stanford University Medical Center. We go into a windowless room stacked floor to ceiling with seemingly identical plastic cages full of mice.

The philosophy behind mouse research has been to make everything as uniform as possible, so results from one facility would be the same as the identical experiment elsewhere.

But despite extensive efforts to be consistent, this setup hides a huge amount of variation. Bedding may differ from one facility to the next. So might the diet. Mice respond strongly to individual human handlers. Mice also react differently depending on whether their cage is up near the fluorescent lights or hidden down in the shadows.

Garner and colleagues tried to run identical experiments in six different mouse facilities, scattered throughout research centers in Europe. Even using genetically identical mice of the same age, the results varied all over the map.

Garner says scientists shouldn't even be trying to do experiments this way.

"Imagine you were doing a human drug trial and you said to the FDA, 'OK, I'm going to do this trial in 43-year-old white males in one small town in California,'" Garner says — a town where everyone lives in identical ranch homes, with the same monotonous diets and the same thermostat set to the same temperature.

"Which is too cold, and they can't change it," he goes on. "And oh, they all have the same grandfather!"

The FDA would laugh that off as an insane setup, Garner says.

"But that's exactly what we do in animals. We try to control everything we can possibly think of, and as a result we learn absolutely nothing."

Garner argues that research based on mice would be more reliable if it were set up more like experiments in humans — recognizing that variation is inevitable, and designing to embrace it rather than ignore it. He and his colleagues have recently published a manifesto , urging colleagues in the field to look at animals in this new light.

"Maybe we need to stop thinking of animals as these little furry test tubes that can be or even should be controlled," he says. "And maybe instead we should think of them as patients."

That could solve some of the problems with animal research, but by no means all.

Scientists make far too many assumptions about the underlying biology of disease when creating animal models of those illnesses, says Gregory Petsko , who studies Alzheimer's disease and other neurological disorders at the Weill Cornell Medical School.

"It's probably only when you get to try your treatments in people that you're really going to have any idea how right those assumptions were," Petsko says.

In his field, the assumptions are often poor, or downright misleading. And Petsko says this mindset has been counterproductive. Scientists in his field have "been led astray for many years by relying so heavily on animal models," he says.

For many years that was simply the best that science could do, Petsko says. So he doesn't fault his colleagues for trying.

"What I am saying is at some point you have to cut your losses. You have to say, 'OK, this took us as far as it could take us, quite some time ago.'"

For neurological diseases, Petsko says, scientists might learn more from studying human cells than whole animals. Animals are still useful for studying the safety of potential new treatments, but beyond that, he says, don't count on them.

Preuss at Emory agrees that using animals as models of disease is a big reason that many results in biomedical research aren't readily reproducible. "I think that we have means to resolve that, though."

How? "You have to think outside of the model box," he says. Mice and rats aren't simplified humans. Scientists should stop thinking they are.

But Preuss says scientists can still learn a lot about biology and disease by studying animals — for example, by comparing how humans and other animals differ, or where they share common traits. Those can reveal a lot about biology without assuming that what's true in a rat is likely true in a human.

"Scientists need to break out of a culture that is hampering progress," Preuss says. That's tough to do right now, in a world where science funding is on the chopping block. Many scientists are reluctant to take a risk that could backfire. But the upside could benefit us all, in the form of a better understanding of disease, and effective new drugs.

Richard Harris did some of the reporting for this story while researching his book Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Billions. You can contact him at [email protected] .

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Keto diet enhances experimental cancer therapy in mice

At a glance.

Researchers showed how a ketogenic diet can enhance the effects of an experimental anti-cancer drug and starve pancreatic tumors in mice.
The findings suggest that diet might be paired with drugs to block the growth of certain types of cancerous tumors.

Cancer cells need fuel to survive and thrive. The energy they need usually comes from glucose in the blood. Some studies have shown that intermittent fasting or a ketogenic diet—high in fat and low in carbohydrates—can help to protect against cancer. These cause the body to break down fat to form molecules called ketones, which can serve as the body’s main energy source while glucose is scarce. Fasting and ketogenic diets likely work by limiting the amount of glucose available to feed cancer cells. But some cancers, such as pancreatic cancer, can also use ketones as an energy source.

A research team led by Dr. Davide Ruggero of the University of California, San Francisco, set out to better understand the underlying gene activities and metabolic pathways affected by diet and fasting. They hope to use this knowledge to enhance cancer therapies. The team focused on a protein called eIF4E (eukaryotic translation initiation factor), which is often hijacked by cancer cells. Results appeared in Nature on August 14, 2024.

The researchers found that chemical tags called phosphates are added to eIF4E as mice transition from fed to fasting. Further analyses showed that this phosphorylated eIF4E (P-eIF4E) plays an important role in coordinating the activity of genes involved in processing fats for energy during fasting. When mice were placed on a ketogenic diet instead of fasting, the P-eIF4E protein similarly triggered a shift to using fat for energy.

The scientists next asked how fasting activated eIF4E. They found that free fatty acids, the small molecules released by fat shortly after fasting begins, activated a chain of events leading to eIF4E phosphorylation. This suggests that free fatty acids have a dual role, serving both as an energy source and as signaling molecules that boost fat-based energy production during fasting.

To assess the relevance of these findings to cancers that can thrive on fat, the researchers combined a ketogenic diet with an experimental anti-cancer drug that blocks P-eIF4E. The drug is called eFT508 (or tomivosertib). They found that giving eFT508 alone did not slow the growth of pancreatic tumors in mice, likely because the tumors could survive with energy from carbohydrates. But when mice were given the drug while on a ketogenic diet, the cancer cells no longer had ready access to glucose or fat for energy. The cells then starved, and growth declined.

"Our findings open a point of vulnerability that we can treat with a clinical inhibitor that we already know is safe in humans,” Ruggero says. “We now have firm evidence of one way in which diet might be used alongside pre-existing cancer therapies to precisely eliminate a cancer.”

—by Vicki Contie

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Study reveals the benefits and downside of fasting

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Low-calorie diets and intermittent fasting have been shown to have numerous health benefits: They can delay the onset of some age-related diseases and lengthen lifespan, not only in humans but many other organisms.

Many complex mechanisms underlie this phenomenon. Previous work from MIT has shown that one way fasting exerts its beneficial effects is by boosting the regenerative abilities of intestinal stem cells, which helps the intestine recover from injuries or inflammation.

In a study of mice, MIT researchers have now identified the pathway that enables this enhanced regeneration, which is activated once the mice begin “refeeding” after the fast. They also found a downside to this regeneration: When cancerous mutations occurred during the regenerative period, the mice were more likely to develop early-stage intestinal tumors.

“Having more stem cell activity is good for regeneration, but too much of a good thing over time can have less favorable consequences,” says Omer Yilmaz, an MIT associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the new study.

Yilmaz adds that further studies are needed before forming any conclusion as to whether fasting has a similar effect in humans.

“We still have a lot to learn, but it is interesting that being in either the state of fasting or refeeding when exposure to mutagen occurs can have a profound impact on the likelihood of developing a cancer in these well-defined mouse models,” he says.

MIT postdocs Shinya Imada and Saleh Khawaled are the lead authors of the paper, which appears today in Nature .

Driving regeneration

For several years, Yilmaz’s lab has been investigating how fasting and low-calorie diets affect intestinal health. In a 2018 study , his team reported that during a fast, intestinal stem cells begin to use lipids as an energy source, instead of carbohydrates. They also showed that fasting led to a significant boost in stem cells’ regenerative ability.

However, unanswered questions remained: How does fasting trigger this boost in regenerative ability, and when does the regeneration begin?

“Since that paper, we’ve really been focused on understanding what is it about fasting that drives regeneration,” Yilmaz says. “Is it fasting itself that’s driving regeneration, or eating after the fast?”

In their new study, the researchers found that stem cell regeneration is suppressed during fasting but then surges during the refeeding period. The researchers followed three groups of mice — one that fasted for 24 hours, another one that fasted for 24 hours and then was allowed to eat whatever they wanted during a 24-hour refeeding period, and a control group that ate whatever they wanted throughout the experiment.

The researchers analyzed intestinal stem cells’ ability to proliferate at different time points and found that the stem cells showed the highest levels of proliferation at the end of the 24-hour refeeding period. These cells were also more proliferative than intestinal stem cells from mice that had not fasted at all.

“We think that fasting and refeeding represent two distinct states,” Imada says. “In the fasted state, the ability of cells to use lipids and fatty acids as an energy source enables them to survive when nutrients are low. And then it’s the postfast refeeding state that really drives the regeneration. When nutrients become available, these stem cells and progenitor cells activate programs that enable them to build cellular mass and repopulate the intestinal lining.”

Further studies revealed that these cells activate a cellular signaling pathway known as mTOR, which is involved in cell growth and metabolism. One of mTOR’s roles is to regulate the translation of messenger RNA into protein, so when it’s activated, cells produce more protein. This protein synthesis is essential for stem cells to proliferate.

The researchers showed that mTOR activation in these stem cells also led to production of large quantities of polyamines — small molecules that help cells to grow and divide.

“In the refed state, you’ve got more proliferation, and you need to build cellular mass. That requires more protein, to build new cells, and those stem cells go on to build more differentiated cells or specialized intestinal cell types that line the intestine,” Khawaled says.

Too much of a good thing

The researchers also found that when stem cells are in this highly regenerative state, they are more prone to become cancerous. Intestinal stem cells are among the most actively dividing cells in the body, as they help the lining of the intestine completely turn over every five to 10 days. Because they divide so frequently, these stem cells are the most common source of precancerous cells in the intestine.

In this study, the researchers discovered that if they turned on a cancer-causing gene in the mice during the refeeding stage, they were much more likely to develop precancerous polyps than if the gene was turned on during the fasting state. Cancer-linked mutations that occurred during the refeeding state were also much more likely to produce polyps than mutations that occurred in mice that did not undergo the cycle of fasting and refeeding.

“I want to emphasize that this was all done in mice, using very well-defined cancer mutations. In humans it’s going to be a much more complex state,” Yilmaz says. “But it does lead us to the following notion: Fasting is very healthy, but if you’re unlucky and you’re refeeding after a fasting, and you get exposed to a mutagen, like a charred steak or something, you might actually be increasing your chances of developing a lesion that can go on to give rise to cancer.”

Yilmaz also noted that the regenerative benefits of fasting could be significant for people who undergo radiation treatment, which can damage the intestinal lining, or other types of intestinal injury. His lab is now studying whether polyamine supplements could help to stimulate this kind of regeneration, without the need to fast.

“This fascinating study provides insights into the complex interplay between food consumption, stem cell biology, and cancer risk,” says Ophir Klein, a professor of medicine at the University of California at San Francisco and Cedars-Sinai Medical Center, who was not involved in the study. “Their work lays a foundation for testing polyamines as compounds that may augment intestinal repair after injuries, and it suggests that careful consideration is needed when planning diet-based strategies for regeneration to avoid increasing cancer risk.”

The research was funded, in part, by a Pew-Stewart Trust Scholar award, the Marble Center for Cancer Nanomedicine, the Koch Institute-Dana Farber/Harvard Cancer Center Bridge Project, and the MIT Stem Cell Initiative.

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A new study led by researchers at MIT suggests that fasting and then refeeding stimulates cell regeneration in the intestines, reports Katharine Lang for Medical News Today . However, notes Lang, researchers also found that fasting “carries the risk of stimulating the formation of intestinal tumors.”

Prof. Ömer Yilmaz and his colleagues have discovered the potential health benefits and consequences of fasting, reports Max Kozlov for Nature . “There is so much emphasis on fasting and how long to be fasting that we’ve kind of overlooked this whole other side of the equation: what is going on in the refed state,” says Yilmaz.

MIT researchers have discovered how fasting impacts the regenerative abilities of intestinal stem cells, reports Ed Cara for Gizmodo . “The major finding of our current study is that refeeding after fasting is a distinct state from fasting itself,” explain Prof. Ömer Yilmaz and postdocs Shinya Imada and Saleh Khawaled. “Post-fasting refeeding augments the ability of intestinal stem cells to, for example, repair the intestine after injury.”

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How early-stage cancer cells hide from the immune system

MIT biologists found that intestinal stem cells express high levels of a ketogenic enzyme called HMGCS2, shown in brown.

Study links certain metabolites to stem cell function in the intestine

Intestinal stem cells from mice that fasted for 24 hours, at right, produced much more substantial intestinal organoids than stem cells from mice that did not fast, at left.

Fasting boosts stem cells’ regenerative capacity

“Not only does the high-fat diet change the biology of stem cells, it also changes the biology of non-stem-cell populations, which collectively leads to an increase in tumor formation,” Omer Yilmaz says.

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Noncoding RNA Terc-53 and hyaluronan receptor Hmmr regulate aging in mice

by Higher Education Press

In a study appearing in Protein & Cell researchers investigated the physiological functions of Terc-53 by creating transgenic mice that overexpress this noncoding RNA. They observe that Terc-53 overexpression affects normal aging in mammals, contributing to cognitive decline and shortened lifespan.

The work is titled " Noncoding RNA Terc-53 and hyaluronan receptor Hmmr regulate aging in mice"

Mechanistically, they find that Terc-53 binds to and promotes the degradation of Hmmr, leading to enhanced inflammation in tissues and accelerated aging. They also note that Hmmr levels decrease with age in certain brain regions , similar to Terc-53's pattern, and that restoring Hmmr levels can improve cognitive abilities and reduce neuroinflammation markers.

Key findings from the study include:

Terc-53's Role in Aging: Terc-53 overexpression in mice leads to age-related cognitive decline and a shorter lifespan, indicating its involvement in normal mammalian aging processes.
Hmmr as Effector of Terc-53: Hmmr is identified as a target of Terc-53, with Terc-53 mediating its degradation. This degradation increases inflammation, contributing to accelerated aging.
Restoration of Hmmr Improves Cognition: Supplementing Hmmr in the hippocampus of aging Terc-53 transgenic mice reverses cognitive decline, suggesting a potential therapeutic strategy for age-related cognitive issues.
Tissue-Specific Aging Patterns of Hmmr: Hmmr's involvement in aging appears to be tissue-specific, with varying expression patterns across different organs.

The study highlights the complexity of aging in mammals and the significance of noncoding RNAs and proteins that emerged late in evolution. It demonstrates that Terc-53 regulates organismal aging through the stability of Hmmr and the modulation of neuroinflammation.

The findings open new avenues for understanding and potentially treating age-related physical disabilities and improving health span. By identifying Hmmr as a critical mediator of Terc-53's effects on aging, the research suggests that strategies aimed at stabilizing Hmmr could mitigate age-related cognitive decline and inflammation.

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An Overview of Typical Infections of Research Mice: Health Monitoring and Prevention of Infection

James r. fahey.

1 The Jackson Laboratory, Bar Harbor Maine

Haiyan Olekszak

There are many reasons to keep research mice healthy and free from infections. The two most important of these are to protect the health and welfare of research mice and to prevent infections from negatively impacting research. Just as the genetic integrity of a mouse strain will influence the reproducibility and validity of research data, so too will the microbiologic integrity of the animals. This has been repeatedly demonstrated in the literature of laboratory animal sciences wherein the direct impact of infections on physiologic parameters under study have been described. Therefore, it is of great importance that scientists pay close attention to the health status of their research animal colonies and maintain good communications with the animal facility personnel at their institution about mouse health issues. This overview provides information about animal health monitoring (HM) in research mouse colonies including commonly monitored agents, diagnostic methods, HM program, risk assessment, and animal facility biosecurity. Lastly, matters of communication with laboratory animal professionals at research institutions are also addressed. © 2015 by John Wiley & Sons, Inc.

Introduction

The quality of animals used in research has a direct impact on the value of that research. In the context of research mice, this means using animals that are genetically appropriate for the specific investigation and free of the variability induced by infections. From a genetic perspective research scientists address animal quality issues by testing their mice for consistency of genetic background, and in the case of genetically engineered mutant mice (GEM), for direct evidence that specific genes of interest are present (or absent in the case of knockouts). It is prudent to do this testing prior to embarking on an expensive research project (Fahey et al., 2013 ). Similarly, it is prudent to verify the health status of research mouse colonies to exclude mice compromised by infections. Even in the absence of clinical signs of disease, infections in mice are well known as a source of variability that can have adverse effects on research or may present a health hazard to laboratory staff (i.e., zoonotic infections of mice) and thus should be avoided when doing research.

Prevalence surveys of murine infectious agents taken at research institutions in North America (Carty, 2008 ), Europe (Mähler and Köhl, 2009 ), Japan (Hayashimoto et al., 2013 ), Australasia (McInnes et al., 2011 ), and Taiwan (Liang et al., 2009 ) over the past decade have demonstrated that infectious agents are still quite prevalent in research mouse colonies. The species and prevalence of the agents (viruses, bacteria, parasites and fungi) established in these surveys were dependent on the geographic areas and institutions under study. Nonetheless, these data point out that despite efforts taken at many research institutions worldwide to eliminate infectious agents and elevate the health status of their animal facilities, infectious agents of mice still persist. Moreover, novel infectious agents of mice are being discovered more frequently now as genome sequencing methods become faster and less expensive. Murine astrovirus (MuAstV) is such an example. The virus was first identified in 1985 by electron microscopy following an outbreak of diarrhea in a colony of nude mice and not further characterized until 2013 by use of viral metagenomics (Kjeldsberg and Hem, 1985 ; Ng et al., 2013 ). The availability of sophisticated molecular diagnostic techniques, the increased use of immunodeficient, transgenic, and humanized mice, and the increasing exchange of research animals and animal products among laboratories nationally and internationally guarantee that this trend of emerging/re‐emerging infectious agents will continue.

To circumvent problems generated by infections in research mice, mouse colonies should be regularly tested for infectious agents and measures taken to prevent, control and eliminate infections. A survey of animal health professionals at research institutions across the U.S. (Carty, 2008 ) reported that routine HM programs afford the optimal means of detecting disease outbreaks in animal facilities. The Federation of European Laboratory Science Associations (FELASA) regularly emphasizes this fact by meticulously outlining rodent HM guidelines for research animal facilities (Mähler et al., 2014 ). HM programs are generally based on long‐established standardized lists of target organisms (Tables (Tables1 1 and and2) 2 ) as well as recently discovered microorganisms. Yet, it is common for institutional laboratory animal veterinarians to tailor HM programs to meet their facilities’ specific needs in a cost‐effective manner, since the prevalence of murine pathogens varies by institution. Understanding HM programs is essential to the well‐being of one's animals as well as the preservation of data integrity. For this reason, it is important, especially for graduate students, postdoctoral fellows, new investigators and others with limited experience in dealing with infections in mouse colonies that they become familiar with the HM programs at their own institutional animal facilities. In addition to discussions with animal health professionals at your research institution, further resources on this subject are available at a number of laboratory animal associations (see Internet Resources below) and at professional mouse vendors to assist scientists in understanding the vagaries of health surveillance.

Viral Infectious Agents of Mice

Viral agents	Virion	Risk level /prevalence	Recommended tissues for PCR testing


Minute virus of mice	Non‐enveloped	B/low	Mesenteric lymph node, spleen, intestine
Mouse parvovirus	Non‐enveloped	B/high	Mesenteric lymph node, spleen, intestine

Ectromelia virus	Enveloped	A/low	Spleen, skin lesion, feces

Murine adenovirus‐1	Non‐enveloped	A/low	Lung
Murine adenovirus‐2	Non‐enveloped	B/low	Feces, intestine

Murine cytomegalovirus	Enveloped	B/low	Salivary gland, spleen
Mouse thymic virus	Enveloped	B/low	Salivary gland

Mouse polyomavirus	Non‐enveloped	C/low	Mammary gland, skin


Mouse hepatitis virus (polytropic)	Enveloped	A/high	Mesenteric lymph node, feces, lung
Mouse hepatitis virus (enterotropic)	Enveloped	B/high	Mesenteric lymph node, feces
Murine norovirus	Non‐enveloped	D/high	Feces, intestine
Murine astrovirus	Non‐enveloped	D/high	Feces, intestine
Theiler's murine encephalomyelitis virus	Non‐enveloped	B/low	Feces, intestine
Lactate dehydrogenase‐elevating virus	Enveloped	B/low	Spleen

Lymphocytic choriomeningitis virus	Enveloped	A/low	Kidney, urine, blood
Sendai virus	Enveloped	A/low	Trachea, lung
Hantavirus (ambisense ss RNA ±)	Enveloped	A/low	Trachea, lung
Pneumonia virus of mice	Enveloped	C/low	Trachea, lung

Mouse rotavirus (EDIM)	Non‐enveloped	B/high	Feces, intestine
Reovirus	Non‐enveloped	C/low	Feces, liver, lung

Common Bacterial, Mycoplasmal, Fungal, and Parasitic Infectious Agents of Mice

Agent	Sample	Methods of diagnosis

.	Respiratory swab, wash fluid	Microbiologic culture
Cilia‐associated respiratory bacillus (CAR bacillus)	Serum/respiratory swab/respiratory wash fluid	MFI , ELISA , IFA , PCR
	Colon or cecum/feces	Microbiologic culture
	Serum	MFI , ELISA , IFA
	Skin scrape/swab, oropharyngeal swab	Microbiologic culture; PCR
	Oropharyngeal swab	Microbiologic culture; PCR
.	Colon or cecum/feces	PCR
	Oropharyngeal swab/colon or cecum/feces	Microbiologic culture; PCR
	Serum/oropharyngeal or nasal swab/lung wash	MFI ; PCR ; microbiologic culture
	Oropharyngeal swab/colon or cecum/feces	Microbiologic culture; PCR
	Oropharyngeal swab, colon or cecum/feces	Microbiologic culture; PCR
.	Colon or cecum/feces	Microbiologic culture; PCR
.	Colon or cecum/feces	Microbiologic culture
	Oropharyngeal swab	Microbiologic culture; PCR
	Oropharyngeal swab	Microbiologic culture
.	Oropharyngeal swab	Microbiologic culture; PCR

	Serum/urine/kidney/brain	MFI ; PCR
	Lung	PCR


	Cecum/colon	Microscopy; PCR
./flagellates	Cecum/colon	Microscopy; PCR
	Cecum/colon	Microscopy; PCR
	Cecum/colon/anal tape sample	Microscopy; PCR
	Intestine	Microscopy; PCR

	Fur	Direct microscopy
	Fur	Direct microscopy
	Fur	Direct microscopy

General Review of Mouse HM Programs

When performed regularly, animal HM provides animal facility veterinarians a continuous flow of test data enabling them to assess and adjust preventative medicine programs designed to reduce and eliminate pathogenic organisms. For example, in the 1960's and 1970's, early in the development of HM programs in animal facilities, murine pathogens were very prevalent and the goal of HM was primarily to identify the disease agents causing illness and deaths in mouse facilities. Today, many of these disease agents have been completely eliminated or severely reduced in mouse colonies and monitoring of mice is aimed at exclusion of unwanted infectious agents.

A HM program should contain the selection of infectious agents, diagnostic methods, preventive measures and response plans for dealing with biosecurity breaches and disease outbreaks. There are basic guidelines for establishment of standard HM programs (Mähler et al., 2014 ). However, designing such programs requires a risk assessment of the potential exposure of mice to infectious agents relevant to each particular institution and therefore must be adaptable and somewhat flexible. A variety of factors must be taken into consideration: the types of studies being conducted, caging systems, numbers and types of mouse strains being housed, local prevalence of specific infectious agents, animal care practices, health history, facility infrastructure, presence of non‐murine animal models, and available funding. Typically, as part of the HM planning process, the facility laboratory animal veterinarians engage in dialog with research investigators to acquire detailed information regarding researchers’ individual needs. As such, productive collaborations between research scientists and veterinarians are essential for developing and implementing a cost‐effective HM program.

With the rise of worldwide exchange of genetically engineered mutant mice (GEM) and biological materials, international harmonization of HM standards has been proposed along with promoting the 3Rs (i.e., replacement, reduction, and refinement) in animal use (Nicklas, 2008 ; National Centre for the Replacement, Refinement & Reduction of Animals in Research, 2014 ). Pharmaceutical companies and commercial vendors have made efforts toward such standards based on recommendations by FELASA and other international institutions. However, HM programs in research institutions and universities are more complex than commercial vendors, given the many different factors to be considered as mentioned above. Universal standards will thus not be applicable or feasible.

Infectious Agents of Research Mice

Viral infections of mice.

Table Table1 1 summarizes viruses that are commonly tested for in‐mouse HM programs. Viral infections of mice are the greatest concern to laboratory animal veterinarians and animal facility personnel because of their potential for spread across a facility, the diseases they can cause and their impact on research. There are seventeen viral species in Table Table1 1 many of which have substrains or additional serotypes that infect mice. However, the prevalence of these viruses varies greatly, with some no longer found in research animal facilities. Some viral infections, such as murine cytomegalovirus (MCMV), mouse thymic virus (MTV), murine polyomavirus (MPyV), ectromelia virus (ECTA), reovirus (REO) have declined significantly since the 1990's and have become rare or nonexistent in mouse colonies. Based on serological or polymerase chain reaction (PCR) data from the past fifteen years (Weisbroth, 1999 ; Prichett‐Corning et al., 2009 ; Mähler et al., 2014 ), the most prevalent viral agents in contemporary mouse facilities are mouse norovirus (MNV), mouse hepatitis virus (MHV), mouse parvovirus (MPV), and mouse rotavirus (MRV, known as epizootic diarrhea of infant mice, EDIM). Agents such as MNV and MPV are shed in mouse feces for as long as 2 months, even by immunocompetent mice. Additionally, small non‐enveloped viruses (i.e., MPV, MNV, MRV) are very resistant to chemical or environmental inactivation. In contrast, although MHV does not remain active for long periods in the environment, it is highly contagious and thus continues to be a major infectious agent in mouse facilities, especially in conventionally housed mice. It is likely that some agents may be prevalent simply because they are newly recognized (i.e, MNV, MuAstV; Kjeldsberg and Hem, 1985 ; Karst et al., 2003 ; Ng et al., 2013 ). A recently discovered murine virus, murine astrovirus (MuAstV; Ng et al., 2013 ) has not yet been the subject of widespread surveillance so the prevalence of this virus in research animal facilities is unknown at this time.

The significance of these viral infections to scientists is their potential impact on research, which varies depending on route of infection (i.e., natural versus experimental infection), host factors (i.e., mouse strain, age, immune competency), and virus factors (i.e., virulent versus avirulent strain; Fox et al., 2006 ; Percy and Barthold, 2007 ; Besselsen et al., 2008 ; Mähler et al., 2014 ). Laboratory animal veterinarians often classify murine viruses into risk groups according to the significance of interference with research, infectivity and potential for spread and difficulties with detection and elimination. In Table Table1, 1 , a simple classification scheme of A to D is based on these criteria. Viruses in groups A and B are more likely to adversely affect research and for group A, present the risk of human infection. Viruses in group C have minimal impact on research and are not common whereas those in group D are recently discovered viruses whose impact on research is not well known. For example, lymphocytic choriomeningitis virus (LCMV) and hantavirus are at risk level A because of their zoonotic potential, that is, their ability to infect humans as well as mice. A few other viral agents, including murine adenovirus‐1 (MAdV‐1), ECTA, MHV polytropic strains, and Sendai virus (SV), are also classified as risk level A because they are capable of causing clinical illness in both immunocompetent and immunodeficient adult mice. Viruses at risk level B may interfere with specific experiments involving the host immune system (parvovirus, MCMV, MTV, lactate dehydrogenase‐elevating virus [LDEV], MHV enterotropic strains), central nervous system (Theiler's murine encephalomyelitis virus, TMEV), or gastrointestinal systems (MAdV‐2, MRV).

Natural transmission of murine viruses occurs most commonly through the fecal‐oral route or fomites (e.g., MAdV, ECTA, MNV, MuAstV, EDIM, TMEV, MHV, REO). Other transmission routes include direct contact (e.g., parvovirus, MTV, MCMV, LCMV), respiratory (e.g., MPyV, pneumonia virus of mice [PVM], SV, MHV), and vertical transmission (e.g., LCMV, LDEV; Fox et al., 2006 ; Percy and Barthold, 2007 ).

Contaminated biological materials are a common source for inadvertent viral infection during experimentation. For example murine tumors, hybridomas, ascites fluid, embryonic stem cells, in vitro fertilized embryos, gametes, cell lines, and even viral stocks introduced into mice can cause infections unless the materials are screened for infectious agents first (Nicklas et al., 2010 ). This is particularly important for banked biologicals that may have been frozen before an infection was detected in the mouse from which the materials were derived, or before sufficiently sensitive tests were available for detection of the specific infectious agent.

Bacterial, Fungal and Parasitic Infections of Mice

Table Table2 2 demonstrates species of bacteria, fungi and parasites for which research mice are commonly tested. Regarding bacterial infections, the actual species of bacteria isolated from infected mice vary to a great extent depending on the genetics and phenotype, age, and immune status of the mice, as well as environmental factors such as heating, ventilation, and air conditioning (HVAC), human traffic flow, husbandry practices (e.g., bedding type, caging system), preparation of animal supplies (sterile versus non‐sterile), and human contact with mice. For example, virtually all mouse strains are susceptible to infection with opportunistic bacteria such as Staphylococcus aureus, Klebsiella oxytoca , Pasteurella pneumotropica , Proteus mirabilis and Helicobacter spp . and these species are commonly found in many mouse facilities (Prichett‐Corning et al., 2009 ; Treuting et al., 2012 ). Yet, taking certain precautions in mouse‐housing facilities can substantially reduce the prevalence of opportunistic bacterial infections. This topic will be discussed below under disease prevention. The preponderance of bacterial infections of mice is non‐lethal, subclinical infections. Asymptomatic mice may only be identified at the time of health monitoring when microbial cultures or PCR yield positive results. In a number of animals, however, infections with bacterial opportunists can present as clinical cases, such as bite‐wound and retrobulbar abscesses, conjunctivitis, otitis, rectal prolapse and other overt signs of infection (Treuting et al., 2012 ).

Fungal infections of mice are less common than bacterial infections. The two principle fungal infections of mice are caused by Encephalitozoon cuniculi and Pneumocystis murina . These are two unusual organisms previously considered to be protozoan parasites, but recently reclassified as fungi based on genomic sequencing data (Katinka et al., 2001 ; Chabe et al., 2011 ). Generally, Encephalitozoon infections are more of a concern in rabbits; however, mice can be susceptible to infection. Pneumocystis infections are of greatest concern in immunodeficient mouse strains as described below in the section Monitoring Immunodeficient and GEM Strains.

Both endo‐ and ecto‐parasite infections of mice are still prevalent in research mouse facilities, but their rate of prevalence is far below the more common bacterial and viral infectious agents discussed above (Pritchett‐Corning, et al., 2009 ). The existence of parasitic infections in research mouse facilities may be the result of unidentified or untreated enzootic infections of existing mouse colonies; most mice infested with endo‐ and ecto‐parasites are asymptomatic and may harbor a low parasite burden that is difficult to detect via standard HM methods. Other factors that may contribute to the continued presence of parasites in some research colonies may include unregulated movement of mice between institutional animal facilities and a lack of proper quarantine procedures that allow for ample time for testing or treatment of imported mice. Additionally, pinworm infections may be particularly problematic due to treatment failure, persistence of eggs in the environment and diagnostic inefficiencies. Although parasitic infections do not typically cause clinical signs in either immunocompetent or immunodeficient mice, there is evidence that these infections do cause physiologic changes that may significantly impact research studies (Beattie et al., 1980 ; Bugarski et al., 2006 ; Michels et al., 2006 ).

Principal Diagnostic Methods for Infectious Agents of Mice

The standard practice at most research institutions that house mice is to submit HM samples, or mice, to commercial diagnostic laboratories (see Internet Resources for commercial diagnostic laboratories). Some research institutions have in‐house laboratory animal diagnostic laboratories, however, these are generally small laboratories that lack the scientific capabilities of the commercial labs. Nonetheless, in‐house laboratories can provide quick answers to pressing questions about infections in mice by providing microbiologic culture, or other diagnostic procedures that do not require an intensive investment in scientific instrumentation as is done at commercial laboratories. The information below provides insight into the choice of diagnostic methods used in commercial diagnostic laboratories and the rationale for their use in determining whether or not an infection is present in a mouse colony.

Serology is the primary laboratory method used for monitoring viral infections in mouse colonies. Several non‐viral infectious agents of mice can also be detected by serology because these infectious agents also reliably provoke an antibody response in immunocompetent mice (e.g., Mycoplasma pulmonis , Cilia‐associated respiratory [CAR] bacillus, Clostridium piliforme and E. cuniculi ; Table Table2). 2 ). The benefits of serologic testing are that it is relatively inexpensive, yet provides information about current and previous infections that have occurred in a mouse colony because serum antibodies generally persist in mice for months after resolution of an infection. Additionally, current serologic test platforms such as the enzyme‐linked immunosorbent assay (ELISA) and multiplexed fluorometric immunoassay (MFI, Luminex) enable the detection of multiple infectious agents from a single serum sample. Both assay platforms can also be used as high throughput systems and are the most cost‐effective diagnostic systems for large‐scale surveillance. Another serology test, the indirect immuno‐fluorescence antibody (IFA) assay is often used to confirm equivocal results of ELISA or MFI because of its sensitivity and specificity. However, performing IFAs is labor intensive and highly dependent on the technical expertise of the observer, so it is not used as frequently as ELISA or MFI. Commercial diagnostic laboratories will provide the user information on how to prepare blood samples for serology testing as well as providing shipping forms and packaging. Furthermore, commercial diagnostic laboratories will provide information on choosing the best serologic test for a given circumstance.

Molecular diagnostics

PCR is the most common molecular assay for detection of DNA agents (DNA viruses, bacteria, parasites) and reverse transcription (RT)‐PCR for RNA viruses used in laboratory animal diagnostic laboratories. These assays detect a specific region of genomic nucleic acid (DNA or RNA) of infectious agents and can be used at any time during active infection. Confirmatory tests for positive PCR results include direct sequencing of PCR‐amplified DNA fragments, an alternative PCR assay with the same DNA/RNA, or the same PCR assay with different specimens. PCR has been increasingly used as a part of laboratory animal HM programs because of its significant advantages over serology or microbiologic culture (Compton and Riley, 2001 ). PCR is also valuable as a noninvasive antemortem test that has proved both practical and useful for detection of certain infectious agents shed in fecal samples (Tables (Tables1 1 and and2 2 ).

The major limitation of PCR as a diagnostic tool is that for most agents, PCR can only detect active infections. Therefore, PCR is best used as part of routine HM to detect the presence of unknown infections in samples regularly submitted to a diagnostic laboratory. PCR is, however, especially effective in detecting infections in immunodeficient, GEM, and aged mice since infections often persist in these mice and the probability of detecting a pathogen is increased. Since PCR is used to detect the infectious agent itself, tissue selection for PCR testing requires that the individual making this selection has an understanding of the pathogenesis of the specific infectious agent so that tissue tropism and duration of infection are taken into account when deciding on the most appropriate sample to collect (Tables (Tables1 1 and and2). 2 ). Another limitation of PCR is its dependence on proper sample handling during collection and processing to avoid cross‐contamination or sample degradation, which may result in false‐positive or false‐negative results.

Microbiologic culture

Microbiologic culture is utilized for detection of bacteria and fungi in samples from mice. Samples are cultured in nutrient broth and then subcultured on nutrient agar plates or selective media in agar when there is increased growth (seen as turbidity) in broth cultures. The presence of bacteria or fungi is assessed by the development of colonies on agar plates. Bacteria of interest can be further identified to species level using instruments such as the VITEK identification card system (BioMérieux), biochemical tests, or simply by colony characteristics (e.g., morphology, color, smell). Sample source and properties of bacteria being monitored determine types of medium (selective or differential) and incubation conditions (aerobic or anaerobic; Fox et al., 2006 ; Percy and Barthold, 2007 ). Microbiologic culture and identification of bacteria and fungi is labor, equipment and expertise intensive.

Parasitology

Direct microscopic examination of fresh samples is frequently used as the primary detection method for identification of endo‐ and ecto‐parasites. Endoparasites such as Trichomonas can be identified in cecum and colon tissues minced in saline. The same is true for other protozoan parasites. Identification of pinworms and pinworm eggs can also be done microscopically. To enhance this process the eggs can be concentrated by pre‐treatment of gut content samples with zinc or sodium sulfate whose specific gravities enable the eggs to “float” on top of the medium after centrifugation. The eggs are then adhered to a glass cover slide, attached to a microscope slide and observed under a microscope. Ectoparasites such as fur mites are also identified by direct microscopic evaluation of mice or of plucked fur samples from their head and neck. In all cases, expertise in microscopic identification of parasites is required to reliably confirm the presence of parasites. Currently, the trend in parasite diagnostics is leaning towards the use of PCR as the preferred method of detection.

Monitoring Immunodeficient and GEM Strains

Immunodeficient and GEM strains have greater susceptibility to infectious agents than their immunocompetent counterparts and this must be taken into consideration when testing them for infectious agents. For example, P. murina is a ubiquitous opportunistic pathogen that in immunocompetent mice produces a clinically silent infection controlled by a T‐cell mediated immune response. However in many immunodeficient mouse strains, Pneumocystis produces lethal pulmonary infections (Weisbroth, 2006 ). Since many GEM strains are “immunovague” (Treuting et al., 2012 ), that is, have an unknown or variable capacity to mount an effective acquired immune response, these strains should be considered potentially susceptible to lethal Pneumocystis infections. Currently, the best method of identifying Pneumocystis in mice is via PCR on a sample of lung tissue from potentially affected animals. This requires that the mice be humanely euthanized and a piece of lung submitted to a diagnostic laboratory. Ideally, for routine health surveillance of immunodeficient mouse colonies, mice taken directly from immunodeficient stocks or immunodeficient sentinel mice should be tested regularly for the presence of Pneumocystis in a mouse room.

Immunodeficient mice are also generally more susceptible to infections with opportunistic bacteria than are their immunocompetent counterparts. Abscesses, bite‐wound infections, otitis media, and unthrifty appearance due to internal infections can result from exposure of immunodeficient mouse strains to opportunistic bacteria that might otherwise be non‐pathogenic in immunocompetent mice. Helicobacter spp., K. oxytoca, Klebsiella pneumoniae, S. aureus , some species of coagulase negative Staphylococcus, Pasteurella pneumotropica and Corynebacterium bovis are among the more commonly identified opportunistic bacteria in infected immunodeficient mice. Sources of these bacteria (see Table Table2) 2 ) include the local environment, human caretakers and research personnel, unsterile materials (e.g., feed, caging, bedding) that have not been sterilized.

Infectious viral agents usually cause acute infection in immunocompetent mice, followed by complete recovery without clinical signs. In contrast, infections in immunodeficient mice may be asymptomatic and persistent. The mice become chronic carriers of virus and serve as a source of infection for other colonies, especially if the virus is shed in feces.

Prevention of Infections

Measures designed to prevent infections of research mice ensure the health and welfare of these animals that are valuable investments both experimentally and financially. Biosecurity measures, that is, the sum of risk management practices, employ barrier systems to minimize the risk of introduction (bio‐exclusion) and spread (bio‐containment) of infectious agents within or between laboratory animal units and can be implemented at all levels of a research animal facility from building design to personnel activity in a mouse room. Examples of biosecurity applied at the building level are high‐efficiency particulate air (HEPA) filtration of room air, room access controls for personnel so that only approved individuals can enter a mouse room, detailed procedures for movement of personnel and mice from room to room, use of construction materials that can withstand repeated chemical disinfection, and physical separation of areas where clean, sterilized caging materials are prepared and handled away from mouse waste and dirty cages. Generally speaking, research investigators, postdoctoral fellows and graduate students are not involved in the oversight or use of biosecurity measures at this level. These are overseen by the facility management staff. Nonetheless, especially for the novice mouse user, you can discuss the building level biosecurity measures at your institution with the facility management staff to gain an understanding of the current measures in place.

Mouse room level biosecurity is very critical and presents an opportunity for mouse users to participate in the protection of their animals from exposure to infectious agents. Mice are generally housed in either conventional cages with or without a filter top and placed on racks in an open room, or in individually ventilated cages (IVC), or rack and cage systems in which the cage (with or without filter) is securely attached to a specially designed rack that provides HEPA‐filtered input and exhaust air with no exposure to room air. IVC caging systems are considered very secure with regard to exposure of mice to adventitious infectious agents. Though IVC caging offers greater protection of mice to inadvertent exposure to infectious agents, for both cage types, IVC and conventional, the real risks are associated with handling of mice during cage changes, experimental use, and other handling that present opportunities for exposure of mice to infectious agents. Thus, applying strict biosecurity steps at these critical junctures pays off by reducing the risk of an outbreak.

What steps can help? Direct human contact with mice is inadvisable as it increases the risk of transmission of human opportunistic bacteria to the mice by exposure to human skin, breath, nasal or oral secretions. Forceps that have been treated with a disinfectant, or disinfected gloved hands should be used to pick up and handle mice. The specific combination of personal protective equipment (PPE) varies with the institution and is in most cases chosen by the animal facility and veterinary staff; however, in general, personnel that routinely work with mice should always wear gloves and a clean lab coat or scrubs. Mask, bonnet, and shoe covers or dedicated mouse room shoes should be worn in higher health status rooms. Immunodeficient and GEM mice housed in high level barrier rooms generally require more stringent PPE, such as sterilized PPE that may also include face shields or powered air‐purifying respirators (PAPRs) to further prevent inadvertent exposure of the mice to infectious agents. Additionally, sterilization of all of the materials to which mice in high barrier rooms are exposed (cages, bedding, feed and water) is performed to eliminate infectious agents that may be present in these materials. The specific PPE you use in preparation for handling mice should be discussed with your animal facility staff.

Following institutional biosecurity practices is prudent, as each of the PPE items mentioned serves to reduce exposure of mice to human microflora and mouse pathogens, as humans may also serve as unintentional fomites for agents that were acquired in the environment outside of the mouse facility.

Further biosecurity steps should be taken during experimental manipulation of mice and movement of animals back and forth to a laboratory, or during movement between mouse rooms. Research procedures ideally should be done in a mouse‐room‐associated procedure area to avoid transporting the mice out of the housing room. The procedure room and equipment should be routinely disinfected by the users to prevent the transmission of infectious agents between mice from different projects or, in the case of shared procedure rooms, between mice from different mouse rooms. In those cases in which mice are taken from a mouse room to a research laboratory for experimental manipulation, the same precautions for handling the mice in a mouse room apply to handling the mice in a laboratory. Additionally, if possible, the mice should be returned to a mouse room dedicated for the purpose of housing mice that have been in a laboratory or otherwise out of the mouse room of origin. Check with the animal facility staff at your institution to determine if such facilities are available.

It is also important to be aware of institutional procedures pertaining to the movement of mice between different housing rooms. While it would be ideal for all research mouse colonies to be free of all infectious agents and to maintain them using stringent biosecurity measures, this is often not feasible in many institutions due to the high cost of maintaining such operations on a daily basis. Therefore, physical separation of mice based on health status and regulation of mouse movement and human traffic is another biosecurity measure that is employed at many institutions. For this reason, movement of mice between mouse rooms is inadvisable unless it is a controlled move sanctioned by the veterinary staff. Additionally, each mouse room may have its own environmental microflora as well as that present in the mice. For this reason, moving mice around to different rooms has the potential of altering that microflora, which is a change that could impact research results.

It is not in the purview of this article to provide an exhaustive list or discussion of biosecurity procedures. However, it is important to note that testing all biologicals used in mice (e.g., cells, antibodies, proteins, other biological molecules) for the presence of pathogens is critical for the prevention of inadvertent transmission of infectious agents. Furthermore, quarantine of newly imported mice and testing them for infections prior to release into the general population will prevent the transmission of infections potentially carried by these mice. We strongly advise scientific personnel to contact their animal care staff for information on the biosecurity procedures at their institution.

Communication between Researchers and Animal Care Staff

Although modern detection methods and HM programs have facilitated the eradication of many infectious agents that were common in research colonies decades ago, contemporary research colonies require collaborative efforts in order to prevent unexpected outbreaks.

Generally speaking, animal care personnel consists of veterinarians, facility managers, and animal caretakers, who all share the common goal of ensuring research integrity through the proper care of research mice. To achieve this goal, the animal care staff must be familiar with each investigators’ research animal models and objectives. Communication between research personnel and members of the animal care staff plays a critical role in maintaining appropriate HM programs, biosecurity practices, and quarantine procedures that serve to prevent infectious outbreaks. Effective communication between research and animal care personnel ensures that the HM program and biosecurity measures employed are suitable for the types of research mice within a given mouse room and that health testing is properly performed, test results are correctly interpreted, and unforeseen events within the animal facility are promptly dealt with. When unexpected events occur, such as discovery of ill or dead animals or issues with the mouse housing room (e.g., variations in temperature, light, humidity), it is recommended that research personnel discuss the issues with the facility staff immediately to get advice and assistance in dealing with the situation.

The animal care staff can also assist new members of the scientific community in becoming familiar with the use of mice in their research. For example, research institutions have required training programs for new animal users. These programs present an opportunity for scientists to find out pertinent information about the overall facility, the animal health programs and the legal and institutional requirements for using mice. We urge you to communicate regularly with the animal care staff at your institution to maintain an open dialog about your research needs and to get updated information about the health status of the facility.

Fahey, J.R. and Olekszak, H. 2015. An overview of typical infections of research mice: Health monitoring and prevention of infection . Curr. Protoc. Mouse Biol. 5 :235‐245. doi: 10.1002/9780470942390.mo150023 [ PMC free article ] [ PubMed ] [ Google Scholar ]

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Internet Resources

Guidelines for HM Programs/Laboratory Animal Health.

Commercial Laboratory Animal Diagnostic Laboratories.

Mouse Vendor Health Reports.

http://www.felasa.eu/recommendations/recommendation/recommendations-for-health-monitoring-of-rodent-and-rabbit-colonies/
http://dels.nas.edu/ilar
http://www.aclam.org/
https//www.aalas.org/
http://www.criver.com/products-services/basic-research/health-monitoring-diagnostic-services
http://www.idexxbioresearch.com/radil/Health_Monitoring/Health_Monitoring_Overview/
http://jaxmice.jax.org/genetichealth/index.html
http://www.taconic.com/breed-your-model/health-testing
http://www.criver.com/products-services/basic-research/health-reports
http://www.harlan.com/about_harlan_laboratories/quality_programs

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Research Scientist, Comparative Medicine- Research Collaborations

About the role.

Your Key Responsibilities:

Perform state-of-the-art animal experimentation with the highest ethical and technical standards, setting up and animal models independently or through the team.
Able to perform advanced, intermediate, and basic technical skills (compound administration by PO, IV, SC, IP, etc. routes, blood sample collection via different routes (ex: tail snip/vein, saphenous, abdominal aorta, vena cava, etc.). Tissue collection, clinical observation, necropsy etc.) on applicable in-house species (Mouse, Rat, Rabbit)
Participate in scientific discussions, performing critical review of experimental protocols and identifying the best approach for in-vivo studies according to project needs.
Continuously evaluate, and train on newest techniques and build scientific knowledge to ensure state-of-the-art in-vivo work.
Closely interact with scientific customer base, providing optimal support, ability to build up a robust professional network and generate high quality data.
Interest in data interpretation, statistics, and presentation, to propose next steps to customer.
Be an excellent team player and show potential to operate within the Team to ensure appropriate performance, training, and professional development within the Team.
Rota, weekend duties, early morning, or late evening dosing
Routinely responsible for ensuring own compliance with all institutional and regulatory protocols, policies, and guidelines.
Responsible for pursuing continuous learning/professional development opportunities, enhancing/expanding skill set, and reviewing CM techniques.

Role requirements:

BS or Master’s in Life Sciences or equivalent experience
Experience in a technical skills tract laboratory animal program or 3+ years preferred.
Strong commitment to animal welfare, research support, and high quality in-vivo focused science
Theoretical and practical expertise in animal experimentation with focus on small animals.
Hands on expertise with multiple animal disease and mechanistic models
High ethical approach, committed to high standards of animal welfare.
Strong customer-orientation, used to communicate with a broad range of stakeholders, strong aptitudes as a team player.
Fluency in English.
Must be able to lift 50 lbs., be able to work from a standing position for prolonged periods of time and perform repetitive motion tasks.

Schedule: full time, shifted schedule

Includes either Saturday or Sunday

Some weekend on call, BR holiday coverage required.

Commitment to Diversity & Inclusion: The Novartis Group of Companies are Equal Opportunity Employers and take pride in maintaining a diverse environment. We do not discriminate in recruitment, hiring, training, promotion or other employment practices for reasons of race, color, religion, gender, national origin, age, sexual orientation, gender identity or expression, marital or veteran status, disability, or any other legally protected status. We are committed to building diverse teams, representative of the patients and communities we serve, and we strive to create an inclusive workplace that cultivates bold innovation through collaboration and empowers our people to unleash their full potential.

Novartis Compensation and Benefit Summary: The pay range for this position at commencement of employment is expected to be between $39.13- $58.72/year ; however, w hile salary ranges are effective from 1/1/24 through 12/31/24, fluctuations in the job market may necessitate adjustments to pay ranges during this period. Further, final pay determinations will depend on various factors, including, but not limited to geographical location, experience level, knowledge, skills, and abilities. The total compensation package for this position may also include other elements, including a sign-on bonus, restricted stock units, and discretionary awards in addition to a full range of medical, financial, and/or other benefits (including 401(k) eligibility and various paid time off benefits, such as vacation, sick time, and parental leave), dependent on the position offered. Details of participation in these benefit plans will be provided if an employee receives an offer of employment. If hired, employee will be in an “at-will position” and the Company reserves the right to modify base salary (as well as any other discretionary payment or compensation program) at any time, including for reasons related to individual performance, Company or individual department/team performance, and market factors.

Why Novartis: Helping people with disease and their families takes more than innovative science. It takes a community of smart, passionate people like you. Collaborating, supporting and inspiring each other. Combining to achieve breakthroughs that change patients’ lives. Ready to create a brighter future together? https://www.novartis.com/about/strategy/people-and-culture

Join our Novartis Network: Not the right Novartis role for you? Sign up to our talent community to stay connected and learn about suitable career opportunities as soon as they come up: https://talentnetwork.novartis.com/network

Benefits and Rewards: Read our handbook to learn about all the ways we’ll help you thrive personally and professionally: https://www.novartis.com/careers/benefits-rewards

EEO Statement:

The Novartis Group of Companies are Equal Opportunity Employers who are focused on building and advancing a culture of inclusion that values and celebrates individual differences, uniqueness, backgrounds and perspectives. We do not discriminate in recruitment, hiring, training, promotion or other employment practices for reasons of race, color, religion, sex, national origin, age, sexual orientation, gender identity or expression, marital or veteran status, disability, or any other legally protected status. We are committed to fostering a diverse and inclusive workplace that reflects the world around us and connects us to the patients, customers and communities we serve.

Accessibility & Reasonable Accommodations

The Novartis Group of Companies are committed to working with and providing reasonable accommodation to individuals with disabilities. If, because of a medical condition or disability, you need a reasonable accommodation for any part of the application process, or to perform the essential functions of a position, please send an e-mail to [email protected] or call +1(877)395-2339 and let us know the nature of your request and your contact information. Please include the job requisition number in your message.

A female Novartis scientist wearing a white lab coat and glasses, smiles in front of laboratory equipment.

IMAGES

Why Mice are Ideal For Testing and Research
Mice in medical research
Medical Research Scientists Examines Laboratory Mice kept in a G
Animal Testing is Vital to Medical Advances
Scientists Successfully Slow Aging in Mice Using Stem Cells
A history of mice in scientific research :: Understanding Animal Research

COMMENTS

The Mighty Mouse: The Impact of Rodents on Advances in Biomedical Research
Abstract. Mice and rats have long served as the preferred species for biomedical research animal models due to their anatomical, physiological, and genetic similarity to humans. Advantages of rodents include their small size, ease of maintenance, short life cycle, and abundant genetic resources. The Rat Resource and Research Center (RRRC) and ...
The Applicability of Mouse Models to the Study of Human Disease
The Mouse: From Pest, to Pet, to Predominant Tool in Medical Research. Although the genetic lineages of mice and humans diverged around 75 million years ago, these two species have evolved to live together, particularly since the development of agriculture.
Why Mice for Biomedical Research?
The impact of mouse-based research on biological discovery and medical progress over the past century has been profound. Read the background of most Nobel Prizes awarded in Physiology or Medicine and you'll find mice used for the research — in fact, 26 Nobel Prizes can be directly tied to JAX® Mice.
Mice as experimental models for human physiology: when a few degrees in
For practical and scientific reasons, mice have become the model organism of choice for a huge swath of biomedical research. Mice thrive and breed well in a laboratory environment, can be housed economically, and powerful experimental approaches are now widely available to alter gene expression and to specifically evaluate molecular, cellular ...
Why are mice excellent models for humans?
Mice are small and relatively economical to maintain, making them the ideal laboratory animal model. Thousands of laboratory mouse strains are now available, so scientists can therefore choose the ideal mouse model to study different diseases and disease processes. And the mouse genome is easily manipulated in order to create even more precise ...
The Applicability of Mouse Models to the Study of Human Disease
Abstract. The laboratory mouse Mus musculus has long been used as a model organism to test hypotheses and treatments related to understanding the mechanisms of disease in humans; however, for these experiments to be relevant, it is important to know the complex ways in which mice are similar to humans and, crucially, the ways in which they differ.
Our mice, our hope
Mice are essential in medical research because most diseases cannot be modeled in a test tube and require experimentation in a whole organism. The Jackson Laboratory pioneered the use of mice in disease research, and our mice and research programs have contributed to important medical breakthroughs ever since. Organ transplants, glaucoma ...
Humanized mice in translational biomedical research
Humanized mice, or mouse-human chimaeras, have been developed to overcome these constraints and are now an important research tool for the in vivo study of human cells and tissues. Humanized ...
Mice in medical research
Mice are the most commonly used animals in medical research. This trend looks likely to continue now that both mouse and human genomes have been mapped (80% of human genes are exactly the same as those found in mice, and at least a further 10% are very similar) allowing human genetic disorders and diseases to be studied with greater accuracy.Often, the only way of determining the function of a ...
WHY ANIMAL RESEARCH?
There are several reasons why the use of animals is critical for biomedical research: • Animals are biologically very similar to humans. In fact, mice share more than 98% DNA with us! • Animals are susceptible to many of the same health problems as humans - cancer, diabetes, heart disease, etc. • With a shorter life cycle than humans ...
Why we need female mice in neuroscience research
Historically, researchers have favored male mice over female mice in experiments, in part due to concern that the hormone cycle in females causes behavioral variation that could throw off results. But new research from Harvard Medical School challenges this notion and suggests that for many experiments, the concern may not be justified. The ...
Why Do Medical Researchers Use Mice?
In fact, 95 percent of all lab animals are mice and rats, according to the Foundation for Biomedical Research (FBR). Scientists and researchers rely on mice and rats for several reasons. One is ...
Health Evaluation of Experimental Laboratory Mice
INTRODUCTION. Both investigative and veterinary staffs monitor the health and well-being of mice that are used in research. Indeed, this level of responsibility and care is mandated by the Public Health Service based on the Guide for the Care and Use of Laboratory Animals (National Research Council. 2011).The Guide is "intended to assist investigators in fulfilling their obligation to plan ...
Rewinding the Clock
Mice whose endothelial cells lacked SIRT1 had poor exercise tolerance, managing to run only half the distance covered by their SIRT1-intact peers. ... The work was supported by the Glenn Foundation for Medical Research (grants RO1 AG028730 and RO1 DK100263), and by the National Institutes of Health/National Heart, Lung and Blood Institute ...
Cellular therapy targeting senescent cells may improve health in mice
A new cell therapy targeting senescent cells may improve metabolic and physical function in mice, according to an NIA-funded study. Senescent cells, which are cells that have stopped dividing but do not die off when they should, have been linked to many aspects of aging and disease.In the study, published in Nature Aging, senescent cells were safely and effectively removed from the tissues of ...
Why do we need mice for medical research?
It's important to note that the past seven decades of successful organ transplantations depended on research using mice. Jackson Laboratory scientist George Snell won the 1980 Nobel prize for his work in the 1940s establishing how the body's immune system recognizes the difference between its own tissues and foreign invaders.
Medical Research Using Animals Often Fails To Produce Drugs That Work
Garner and colleagues tried to run identical experiments in six different mouse facilities, scattered throughout research centers in Europe. Even using genetically identical mice of the same age ...
Old mice grow young again in study. Can people do the same?
In Boston labs, old, blind mice have regained their eyesight, developed smarter, younger brains and built healthier muscle and kidney tissue. On the flip side, young mice have prematurely aged ...
Keto diet enhances experimental cancer therapy in mice
The drug is called eFT508 (or tomivosertib). They found that giving eFT508 alone did not slow the growth of pancreatic tumors in mice, likely because the tumors could survive with energy from carbohydrates. But when mice were given the drug while on a ketogenic diet, the cancer cells no longer had ready access to glucose or fat for energy.
Advances in Transgenic Mouse Models to Study Infections by Human
Transgenic mice provide a basis for research of disease pathogenesis after infection with human-specific viruses. Today, humanized mice can be found at the very heart of this forefront of medical research allowing for recapitulation of disease pathogenesis and drug mechanisms in humans. This review discusses progress in the development and use ...
Study reveals the benefits and downside of fasting
In a study of mice, MIT researchers have now identified the pathway that enables this enhanced regeneration, which is activated once the mice begin "refeeding" after the fast. They also found a downside to this regeneration: When cancerous mutations occurred during the regenerative period, the mice were more likely to develop early-stage ...
Noncoding RNA Terc-53 and hyaluronan receptor Hmmr regulate aging in mice
By identifying Hmmr as a critical mediator of Terc-53's effects on aging, the research suggests that strategies aimed at stabilizing Hmmr could mitigate age-related cognitive decline and inflammation.
An Overview of Typical Infections of Research Mice: Health Monitoring
Similarly, it is prudent to verify the health status of research mouse colonies to exclude mice compromised by infections. Even in the absence of clinical signs of disease, infections in mice are well known as a source of variability that can have adverse effects on research or may present a health hazard to laboratory staff (i.e., zoonotic ...
Research Scientist, Comparative Medicine- Research ...
Research Collaborations (RC) is a centralized core unit within In vivo Science & Technology (IST), Comparative Medicine (CM). RC is responsible for performing best-in-class in-vivo studies together with developing key animal models and cutting-edge technologies needed for Biomedical Research (BR) drug discovery and development process.
Column-US Treasury Plays Cat and Mouse With Debt Sales :Mike Dolan
US News is a recognized leader in college, grad school, hospital, mutual fund, and car rankings. Track elected officials, research health conditions, and find news you can use in politics ...

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