The scientist's best friend: the mouse
They make a guest appearance in at least half of the articles on Medical News Today. They are responsible for many of the biggest breakthroughs in medicine, advancing our understanding of breast cancer, brain injury, childhood leukemia, cystic fibrosis, malaria, multiple sclerosis, tuberculosis and many other conditions. Surely, the contribution of mousekind to science cannot be underestimated. But what does the future hold for this furry staple of the laboratory?
Some sources claim that scientific research on animals has been practiced since at least 500 BC. Queen Victoria - monarch of the British Empire during much of the 19th Century - is notable for being the first celebrity anti-vivisection campaigner, and paintings from this period demonstrate scientific research being conducted on dogs.
However, it was not until the early 20th Century that science turned its attention to the humble mouse.
'The fancy mouse' enters the laboratory
In 1902, a period of newfound popularity for the "fancy mouse" - specially bred mice as pets, rather than pantry scourge - the early geneticist William Ernest Castle introduced the fancy mouse to his laboratory at Harvard University in Cambridge, MA.
Geneticists working under Castle were the first scientists to realize how inbred, genetically homogenous lines of mice could have an enormous impact on the study of genetics. They began to breed mice for this purpose, and many of the modern mouse types used in laboratories today - given names such as B6, B10, C3H, CBA, and BALB/c - can be traced back to the lines bred by these scientists.
Mice and humans share about 97.5% of their working DNA.
Castle's team were interested primarily in using the mice to demonstrate a genetic basis for cancer, but an important benefit of the genetically homogenous mice was that they allowed independent groups of scientists to be able to perform experiments on the same genetic material for the first time.
Now, a team of scientists in one part of the world could directly compare their findings with another team, without their results being confounded by the natural variation of animals.
The California Biomedical Research Association claim that almost every medical breakthrough in the last 100 years has been as a direct result of research involving animals. However, for much of the 20th Century, it was not the mouse that was medical science's favored animal subject, but the fruit fly, and then later - by the 1970s - the roundworm.
The move away from these species into scientific experimentation on mice was driven by humans' desire to better understand ourselves. In the common genetic ancestry that links all animal life on our planet, fruit flies and roundworms diverged from the line leading to mammals around 570 million years ago.
The divergence in the mammalian line between mice and people, however, was comparatively recent at only 60-100 million years ago.
Why mice?Mice and humans share about 97.5% of their working DNA. The mouse was the first non-human mammal to have its genome sequenced, which revealed that there are only 21 genes in human DNA that do not have a direct counterpart in mouse DNA, and only 14 genes unique to mice that are not found in humans.
Research in the early 1990s even suggested that a rough replica of the human genome could be constructed by breaking the mouse genome into 130-170 pieces and reassembling them in a different order.
A 2013 article in The Conversation on the role of the mouse in 21st Century science defined three main purposes:
- To aid understanding of the functional parts of the genome
- To act as models for the study of human disease
- To aid development of genomic-based therapies for human disease.
The authors of that article say the main advantage of the mouse as a subject is that, while human health is determined by a combination of our genes and the surrounding environment - where even identical twins will develop different medical histories over their lifetimes - genetic alterations can be much more precisely defined in laboratory mice.
Laboratory mice also live for only 2 or 3 years, giving researchers the opportunity to study the effects of treatments or genetic manipulation across a whole lifespan or even over several generations, which is not feasible in human subjects.
How can mouse trials be improved to better save human lives?
Recently, mice have been in the headlines as their value in medical trials is freshly debated.
Medical News Today reported on a study that applied 21st Century laboratory methods to an infamous phase 2 clinical trial in 1993, where five human subjects died as a result of taking the drug fialuridine.
Fialuridine had previously passed preclinical toxicology tests in mice, rats, dogs and primates - where no toxic effects on the liver were reported - and had been approved for testing in humans. Unknown to scientists then, though, the mechanism of a nucleoside transporter works differently in humans than it does in other animals. Consequently, five people in the clinical trial died from liver failure, and a further two survived but required emergency liver transplants.
A large international project is currently attempting to disrupt each gene of the mouse genome in turn, to document the effects of each disruption.
The researchers behind the new study wanted to see if "chimeric mice" could have detected the hepatoxicity of fialuridine, if they had been used in the original toxicology tests for the drug. Chimeric mice are mice that have some human cells. In this case, the mice had 90% of their liver cells replaced with human liver cells.
The researchers found that the chimeric mice displayed the same symptoms as the human participants in the 1993 trial. If these mice had been used in the preclinical testing for fialuridine, then the human deaths of the clinical trial would have been averted.
Speaking to Medical News Today, study author Dr. Gary Peltz urged the Food and Drug Administration (FDA) to better incorporate these kind of advances into drug evaluation to improve safety.
"This paper represents an inflection point for the chimeric mouse field," he told us. "It provides the first clear demonstration that studies performed in chimeric mice could improve drug safety, which in this case would have averted a tragedy caused by a human-specific drug toxicity."
Human disease forms of genes can also be inserted into the mouse genome, to replicate specific aspects of Alzheimer's, obesity, diabetes, blood defects, immune problems, kidney disease, cancers, neurological disorders and many other conditions. Organizations such as the Australian Phenomics Network are presently amassing a collection of mice representing the full spectrum of genetic variations that cause diseases in humans.
In addition, a huge co-ordinated international project is currently attempting to disrupt each gene of the mouse genome in turn, to document the effects of each disruption and assess its consequences for humans.
Dr. Michael Dobbie, of the Australian Phenomics Network, explains the benefits of this project:
"This dawning era of personalized medicine, offering precise diagnoses and therapeutic interventions, can only become a reality if we have on-hand high resolution model systems, such as mice, which have been altered to precisely mimic the disease condition on an individual basis. The tantalising dream of a medically-relevant 'avatar' is now within reach and the powerful genetic tool box offered by the mouse is the straightest road to that goal."
Although large research projects such as this point to a long future for the mouse in medical research, other new studies have found fallibilities in the mouse model.
Perhaps most surprising is the recent revelation that the outcomes of mouse trials can be confounded by the sex of the researchers. A study by researchers at McGill University in Montreal, Canada, claimed to confirm what some anecdotal evidence had suggested - that lab mice and rats become stressed in the presence of male - but not female - researchers, which could distort findings.
Another argument recently ignited over gender and mouse trials, this time concerning science's preference for using predominantly male mice in laboratory experiments. Traditionally, the estrous cycle of female mice has been perceived to confound the results of research in a manner that is difficult to control for, so about five times as many male mice are used in experiments as female mice.
However, this assumption has now been successfully challenged by scientists and feminist groups, who point out that females - rather than simply being a variation on a theme from males - may metabolize drugs at different rates to male patients, potentially causing very different drug responses that cannot be predicted if preclinical testing is limited to male mice.
This month, the National Institutes of Health (NIH) announced that this gender bias in mouse trials must end and that new policies governing the gender selection of animals in research will be unveiled in October.
Is animal testing soon to become a thing of the past?
Reports of flaws in the mouse model add to criticisms from some scientists and animal rights groups that animal testing - in addition to presenting ethical problems over treatment of animals - is an unreliable science.
Last year, Popular Science ran a piece claiming that 90% of drugs that pass animal testing subsequently fail in human trials as a direct result of genetic differences between species. The article also cited an emerging trend in using human cells as part of toxicology tests, rather than animal subjects, as a sign that human-specific studies may soon replace animal models.
"There are many reasons why the simplistic claim that 90% of drugs that pass animal testing fail in human trials does not hold up to scrutiny," Prof. Ruth Arkell from The Australian National University, who has written extensively on mouse trials before, told us. "One newly emerging appreciation is that our limited knowledge of human disease has, in the past, caused patients to be grouped together for clinical trials in inappropriate ways."
Prof. Arkell explains that in cancer testing, for instance, cancers now known to be of different classes were lumped in together, which meant that engineered mice would respond positively to drug treatments targeting certain mechanisms the scientists were looking at, but these drugs would not be beneficial in human subjects. The problem being one of scientific misclassification rather than a problem with the mouse model, per se.
In 2012, the NIH announced that they would phase out experiments on chimpanzees. The US is one of only two countries in the world (the other being Gabon) who still experiment on chimpanzees - an animal that humans share just under 99% of our DNA with. This has led to hope from some of a more general move away from animal experiments as new technological innovations emerge professing to enable higher clinical accuracy, without any attached ethical dilemma.
Some reports suggest that 90% of drugs that pass animal testing subsequently fail in human trials as a result of genetic differences between species.
Proposed alternatives to animal testing have generated intense speculation recently. These include the potential for testing on human organs grown in a laboratory from stem cells, such as the artificial skin unveiled last month by a team from King's College London in the UK.
"Using animals for testing is very costly and in many cases is not giving relevant results that can be extrapolated safely on humans," Dr. Dusko Ilic, who co-led the artificial skin project, told Medical News Today.
"Our model can be generated from induced pluripotent stem cells in unlimited number and all units are genetically identical, which can make comparison easier and less prone to errors," Dr. Ilic explains, adding that the stem cells can be generated from individuals with skin disease, which allows new drugs to be tested on disease-specific cells in the resulting epidermis.
Another much-hyped development comes in the form of the "biochips" pioneered by Harvard's Wyss Institute for Biologically Inspired Engineering. These devices mimic the functions of human organs, such as the lungs, heart, kidney and intestine. Each "chip" is a combination of living human cells and microfluidic technology.
The pharmaceutical company AstraZeneca have partnered with Wyss to use the chips in drug trials, and the NIH, FDA and US Defense Advanced Research Projects Agency have invested $150 million to speed development of the chips.
Medical News Today spoke to Michael Renard from Organovo Inc., a company pioneering the use of "bioprinting." Organovo develop a range of human tissue disease models for drug testing and medical research.
Their strips of bioprinted liver tissue - designed to replicate the cellular architecture of natural tissue - are said to retain organ-like functions for up to 40 days, a breakthrough that some have described as a milestone in toxicology testing.
Although Renard stressed that the intention of Organovo's bioprinting is not to replace animal testing, he had this to say on the benefits to research of the human-specific tissue offered by the company:
"Functional human tissue models hold the promise to add specific human information on a drug candidate, generating data from a controlled all human microenvironment at a level of complexity that mimics in vivo human tissue composition and behavior.
The intent of any new model that is introduced to the drug discovery process is to improve the predictive value and translational science between what is observed in the lab and what is observed in human trials and human treatment."
Whether these new technologies will diminish science's need for animal models remains to be seen. The testing of drugs in mice and other animals allows scientists to observe how a drug interacts with a complete circulatory system, including the effect it may have on different organs as it is pumped around a living body - an advantage that these modular systems are currently unable to compete with.
Certainly, with new lines of laboratory mice being produced at an ever-increasing pace, it seems that - for better or worse - the mouse is likely to remain a fixture of laboratories for some time.
Written by David McNamee
Copyright: Medical News Today
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