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How medical studies induce cancer in lab animals?

How medical studies induce cancer in lab animals?


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To test the effectiveness of drugs, they are typically tested on animals. How cancer is induced in lab animals to test the effectiveness of cancer drugs?


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.


Reproducibility: One cornerstone of science

Reproducibility is key to science. If science is the best method that we have of figuring out how nature works, if our hypotheses and theories are to have any basis in reality, then the observations upon which those hypotheses and theories are based must be reproducible. To the average lay person without a background in science, this doesn’t sound like a particularly difficult issue. After an interesting scientific paper is published, why can’t other scientists just do what the scientists publishing the paper did? However, as any scientist knows, particularly biological scientists, it’s nowhere near that simple. First, there is little or no reward for just reproducing the work of other scientists. Certainly, a scientist is not going to get a grant to reproduce those results, and publications reporting reproduced results will not be published in high impact journals. As the Reproducibility Project: Cancer Biology puts it:

Despite being a defining feature of science, reproducibility is more an assumption than a practice in the present scientific ecosystem (Collins, 1985 Schmidt, 2009). Incentives for scientific achievement prioritize innovation over replication (Alberts et al., 2014 Nosek, et al., 2012). Peer review tends to favor manuscripts that contain new findings over those that improve our understanding of a previously published finding. Moreover, careers are made by producing exciting new results at the frontiers of knowledge, not by verifying prior discoveries.

Which is, of course, true. Scientists go into science in the first place to make new discoveries, and translational scientists go into cancer research to discover new understandings of what causes cancer and how to use those new understandings to find new and innovative treatments for cancer.

Usually, one of the only times it’s deemed worthwhile to reproduce another scientist’s results is as the first step to trying to expand on the observations of that scientist, and that in fact is probably how most scientific research is replicated when it is replicated. Basically, you have to know that you’re doing things the same way and getting the same results using the same materials and methods before you can build on those results. Even so, such replications are usually not direct or complete replications usually scientists only replicate as little as they need to assure themselves they’re on the right track. Complete sets of experiments are rarely replicated, the more expensive and time-consuming the experiment the less frequently replicated.

Another aspect of reproducibility is how well scientists record their methods in scientific papers i.e., the transparency of science. The standard should be to record the methods in sufficient detail that a scientist knowledgeable in the field could replicate the experiments using the published description alone, but that standard is rarely met. If you read a number of scientific papers, you will find that there is huge variability in the amount of detail provided in the Methods sections of scientific papers. For some journals, like Cell, the amount of detail is pretty high, although often still not high enough to easily reproduce an experiment. For other journals (like, ironically enough, very high impact journals like Science and Nature ), the level of detail can be frustratingly low. For most journals, it’s somewhere in between. I, like any other scientist, know from personal experience, particularly during graduate school and my PhD studies, just how difficult it can be to look at the Methods section of a paper and figure out how to replicate an experiment as the first step towards asking additional experiments . Not uncommonly, it was necessary to contact the lab that published the work I was trying to replicate. Sometimes we needed their reagents, such as plasmids or other recombinant DNA constructs. Sometimes we needed help troubleshooting when we didn’t get the same results.

Reproducing prior results is challenging because of insufficient, incomplete, or inaccurate reporting of methodologies (Hess, 2011 Prinz et al., 2011 Steward et al., 2012 Hackam and Redelmeier, 2006 Landis et al., 2011). Further, a lack of information about research resources makes it difficult or impossible to determine what was used in a published study (Vasilevsky et al., 2013). These challenges are compounded by the lack of funding support available from agencies and foundations to support replication research. When replications are performed, they are rarely published (Collins, 1985 Schmidt, 2009). A literature review in psychological science, for example, estimated that 0.15% of the published results were direct replications of prior published results (Makel et al., 2012). Finally, reproducing analyses with prior data is difficult because researchers are often reluctant to share data, even when required by funding bodies or scientific societies (Wicherts et al., 2006), and because data loss increases rapidly with time after publication (Vines et al., 2014).

Finally, although not really discussed that much, there are intangible reasons—or seemingly intangible reasons—why it can be difficult to reproduce research. Some experimental techniques, for example, require considerable skill to produce meaningful measurements. Immunofluorescence, for instance, is one, particularly when using multiple antibodies to label different proteins with different fluorescent colors. Techniques that depend on surgical skill on small animals (e.g., mice and other rodents) are another. I’ve known a few scientists over the years who suddenly had trouble reproducing their own work when a skilled technician or postdoc left the lab. The explanation was not fraud but rather because the remaining personnel didn’t know all the ins and outs of the experimental technique. It’s not uncommon for a lot of time to be wasted due to loss of skilled personnel as those left behind troubleshoot and figure out subtleties of an experimental technique that aren’t recorded in their lab protocol books, no matter how detailed. Basically, the “institutional” memory of a laboratory is difficult to maintain, given that, other than the principal investigator and (sometimes) a permanent technician and/or lab manager, most personnel in labs are only there for at most a few years to get their PhD or do a postdoctoral fellowship. Turnover is high by design. Often there are little “tricks” or nuances to various experimental techniques to get them to work well that are lost when someone leaves a lab. That’s why maintaining protocol notebooks is so important, but few labs do this as rigorously as they should, and even detailed protocol books aren’t always enough.


Capturing cellular trajectories

This interplay of environment and cellular identity means that cancer cells might look stem-like under some experimental conditions but not in others, or might express different sets of genes depending on their neighbours. They also lack universal surface markers, making it even trickier to tag and study them. But researchers have devised a range of alternative strategies to track the cells’ trajectories, many of which are borrowed from the developmental-biology toolset.

To study stem cells in embryonic mammary glands, Fre and her team used a strain of mice called Confetti, so named because the cells can express four different fluorescent reporters. When the researchers treated animals with a chemical to induce reporter-protein expression at different times during development, the proteins were activated in various locations. Using fluorescence microscopy, the team could then see where cells of different lineages ended up in adult tissues. Vermeulen and colleagues have used a similar fluorescence-based approach to understand how the environment controls colon-cancer stem cells in cell culture studies 5 .

Genetic barcodes are another option for tracking cells when they acquire mutations and diverge into different subgroups. The approach gives each population of cells a fixed genetic barcode as the populations divide, the barcodes evolve. By sequencing all the barcodes in the population and comparing them, researchers can then work out how the different cells relate to one another, and their relative contribution to the growth of the tumour.

Early variants of this approach relied on static barcodes carried inside lentiviruses, used as a way to insert the sequences into a pool of cells at random. Now, the gene-editing tool CRISPR is improving the process.

In CRISPR-based lineage tracing, researchers insert an array of CRISPR target sequences into cells’ genomes. The Cas9 enzyme then periodically cuts into these targets, triggering DNA-repair processes and leaving a genetic scar that acts as a unique identifier for a cell and its progeny. Unlike lentiviral barcodes, this system generates unique barcodes dynamically, potentially every time the cells divide, allowing researchers to reconstruct how different cells and their progeny are related 6 . “Changes accumulate over time,” says stem-cell biologist Alexander van Oudenaarden at the Hubrecht Institute in Utrecht, the Netherlands. “It’s fundamentally different from the lentiviral barcodes that were used earlier.”

Cancer research with a human touch

Another approach couples the sequence for a fluorescent protein to a repetitive piece of DNA — a long repeat of cytosine and adenine bases that cells see as problematic. As cells divide, they periodically ‘repair’ this repetitive sequence by trimming it, ultimately bringing the sequence for the fluorescent protein into a position in the genome where it can be expressed. This fix happens once in every 10,000 cells or so, Vermeulen says, sending up a tiny genetic flare that’s visible under the microscope. The advantage, he says, is that this sort of fluorescent label doesn’t require a chemical to activate it. “It’s a way of lineage tracing that leaves the cell completely untouched,” he says.

Each of these strategies has its pros and cons. Some CRISPR sequences are more prone to scarring than others, for instance, introducing bias into a theoretically unbiased process. And both microscopy and sequencing-based strategies require advanced computational and technical skills. Still, coupled with single-cell RNA sequencing, the labels provide powerful tools to assess the relative importance of individual cells in a tumour.

“If a tumour is driven by cancer stem cells, only a few labelled cells will proliferate and become large clones,” Vermeulen points out. “But in a tumour that depends on many cell types, most cells will expand. When the data are put into a mathematical model, you can actually identify to what extent it’s one mode of growth versus the other.”


The Collective Harms That Result from Misleading Animal Experiments

As medical research has explored the complexities and subtle nuances of biological systems, problems have arisen because the differences among species along these subtler biological dimensions far outweigh the similarities, as a growing body of evidence attests. These profoundly important𠅊nd often undetected𠅍ifferences are likely one of the main reasons human clinical trials fail. 63

𠇊ppreciation of differences” and �ution” about extrapolating results from animals to humans are now almost universally recommended. But, in practice, how does one take into account differences in drug metabolism, genetics, expression of diseases, anatomy, influences of laboratory environments, and species- and strain-specific physiologic mechanisms𠅊nd, in view of these differences, discern what is applicable to humans and what is not? If we cannot determine which physiological mechanisms in which species and strains of species are applicable to humans (even setting aside the complicating factors of different caging systems and types of flooring), the usefulness of the experiments must be questioned.

It has been argued that some information obtained from animal experiments is better than no information. 64 This thesis neglects how misleading information can be worse than no information from animal tests. The use of nonpredictive animal experiments can cause human suffering in at least two ways: (1) by producing misleading safety and efficacy data and (2) by causing potential abandonment of useful medical treatments and misdirecting resources away from more effective testing methods.

Humans are harmed because of misleading animal testing results. Imprecise results from animal experiments may result in clinical trials of biologically faulty or even harmful substances, thereby exposing patients to unnecessary risk and wasting scarce research resources. 65 Animal toxicity studies are poor predictors of toxic effects of drugs in humans. 66 As seen in some of the preceding examples (in particular, stroke, HRT, and TGN1412), humans have been significantly harmed because investigators were misled by the safety and efficacy profile of a new drug based on animal experiments. 67 Clinical trial volunteers are thus provided with raised hopes and a false sense of security because of a misguided confidence in efficacy and safety testing using animals.

An equal if indirect source of human suffering is the opportunity cost of abandoning promising drugs because of misleading animal tests. 68 As candidate drugs generally proceed down the development pipeline and to human testing based largely on successful results in animals 69 (i.e., positive efficacy and negative adverse effects), drugs are sometimes not further developed due to unsuccessful results in animals (i.e., negative efficacy and/or positive adverse effects). Because much pharmaceutical company preclinical data are proprietary and thus publicly unavailable, it is difficult to know the number of missed opportunities due to misleading animal experiments. However, of every 5,000�,000 potential drugs investigated, only about 5 proceed to Phase 1 clinical trials. 70 Potential therapeutics may be abandoned because of results in animal tests that do not apply to humans. 71 Treatments that fail to work or show some adverse effect in animals because of species-specific influences may be abandoned in preclinical testing even if they may have proved effective and safe in humans if allowed to continue through the drug development pipeline.

An editorial in Nature Reviews Drug Discovery describes cases involving two drugs in which animal test results from species-specific influences could have derailed their development. In particular, it describes how tamoxifen, one of the most effective drugs for certain types of breast cancer, “would most certainly have been withdrawn from the pipeline” if its propensity to cause liver tumor in rats had been discovered in preclinical testing rather than after the drug had been on the market for years. 72 Gleevec provides another example of effective drugs that could have been abandoned based on misleading animal tests: this drug, which is used to treat chronic myelogenous leukemia (CML), showed serious adverse effects in at least five species tested, including severe liver damage in dogs. However, liver toxicity was not detected in human cell assays, and clinical trials proceeded, which confirmed the absence of significant liver toxicity in humans. 73 Fortunately for CML patients, Gleevec is a success story of predictive human-based testing. Many useful drugs that have safely been used by humans for decades, such as aspirin and penicillin, may not have been available today if the current animal testing regulatory requirements were in practice during their development. 74

A further example of near-missed opportunities is provided by experiments on animals that delayed the acceptance of cyclosporine, a drug widely and successfully used to treat autoimmune disorders and prevent organ transplant rejection. 75 Its immunosuppressive effects differed so markedly among species that researchers judged that the animal results limited any direct inferences that could be made to humans. Providing further examples, PharmaInformatic released a report describing how several blockbuster drugs, including aripiprazole (Abilify) and esomeprazole (Nexium), showed low oral bioavailability in animals. They would likely not be available on the market today if animal tests were solely relied on. Understanding the implications of its findings for drug development in general, PharmaInformatic asked, “Which other blockbuster drugs would be on the market today, if animal trials would have not been used to preselect compounds and drug-candidates for further development?” 76 These near-missed opportunities and the overall 96 percent failure rate in clinical drug testing strongly suggest the unsoundness of animal testing as a precondition of human clinical trials and provide powerful evidence for the need for a new, human-based paradigm in medical research and drug development.

In addition to potentially causing abandonment of useful treatments, use of an invalid animal disease model can lead researchers and the industry in the wrong research direction, wasting time and significant investment. 77 Repeatedly, researchers have been lured down the wrong line of investigation because of information gleaned from animal experiments that later proved to be inaccurate, irrelevant, or discordant with human biology. Some claim that we do not know which benefits animal experiments, particularly in basic research, may provide down the road. Yet human lives remain in the balance, waiting for effective therapies. Funding must be strategically invested in the research areas that offer the most promise.

The opportunity costs of continuing to fund unreliable animal tests may impede development of more accurate testing methods. Human organs grown in the lab, human organs on a chip, cognitive computing technologies, 3D printing of human living tissues, and the Human Toxome Project are examples of new human-based technologies that are garnering widespread enthusiasm. The benefit of using these testing methods in the preclinical setting over animal experiments is that they are based on human biology. Thus their use eliminates much of the guesswork required when attempting to extrapolate physiological data from other species to humans. Additionally, these tests offer whole-systems biology, in contrast to traditional in vitro techniques. Although they are gaining momentum, these human-based tests are still in their relative infancy, and funding must be prioritized for their further development. The recent advancements made in the development of more predictive, human-based systems and biological approaches in chemical toxicological testing are an example of how newer and improved tests have been developed because of a shift in prioritization. 78 Apart from toxicology, though, financial investment in the development of human-based technologies generally falls far short of investment in animal experimentation. 79


Contents

The terms animal testing, animal experimentation, animal research, in vivo testing, and vivisection have similar denotations but different connotations. Literally, "vivisection" means "live sectioning" of an animal, and historically referred only to experiments that involved the dissection of live animals. The term is occasionally used to refer pejoratively to any experiment using living animals for example, the Encyclopædia Britannica defines "vivisection" as: "Operation on a living animal for experimental rather than healing purposes more broadly, all experimentation on live animals", [6] [7] [8] although dictionaries point out that the broader definition is "used only by people who are opposed to such work". [9] The word has a negative connotation, implying torture, suffering, and death. [10] The word "vivisection" is preferred by those opposed to this research, whereas scientists typically use the term "animal experimentation". [11] [12]

The following text excludes as much as possible practices related to in vivo veterinary surgery, which is left to the discussion of vivisection.

The earliest references to animal testing are found in the writings of the Greeks in the 2nd and 4th centuries BC. Aristotle and Erasistratus were among the first to perform experiments on living animals. [13] Galen, a 2nd-century Roman physician, performed post-mortem dissections of pigs and goats. [14] Avenzoar, a 12th-century Arabic physician in Moorish Spain introduced an experimental method of testing surgical procedures before applying them to human patients. [15] [16]

Animals have repeatedly been used throughout the history of biomedical research. In 1831, the founders of the Dublin Zoo were members of the medical profession who were interested in studying animals while they were alive and when they were dead. [17] In the 1880s, Louis Pasteur convincingly demonstrated the germ theory of medicine by inducing anthrax in sheep. [18] In the 1880s, Robert Koch infected mice and guinea pigs with anthrax and tuberculosis. In the 1890s, Ivan Pavlov famously used dogs to describe classical conditioning. [19] In World War I, German agents infected sheep bound for Russia with anthrax, and inoculated mules and horses of the French cavalry with the equine glanders disease. Between 1917 and 1918, the Germans infected mules in Argentina bound for American forces, resulting in the death of 200 mules. [20] Insulin was first isolated from dogs in 1922, and later revolutionized the treatment of diabetes. [21] On 3 November 1957, a Soviet dog, Laika, became the first of many animals to orbit the earth. In the 1970s, antibiotic treatments and vaccines for leprosy were developed using armadillos, [22] then given to humans. [23] The ability of humans to change the genetics of animals took a large step forwards in 1974 when Rudolf Jaenisch was able to produce the first transgenic mammal, by integrating DNA from simians into the genome of mice. [24] This genetic research progressed rapidly and, in 1996, Dolly the sheep was born, the first mammal to be cloned from an adult cell. [25] [26]

Toxicology testing became important in the 20th century. In the 19th century, laws regulating drugs were more relaxed. For example, in the US, the government could only ban a drug after a company had been prosecuted for selling products that harmed customers. However, in response to the Elixir Sulfanilamide disaster of 1937 in which the eponymous drug killed more than 100 users, the US Congress passed laws that required safety testing of drugs on animals before they could be marketed. Other countries enacted similar legislation. [27] In the 1960s, in reaction to the Thalidomide tragedy, further laws were passed requiring safety testing on pregnant animals before a drug can be sold. [28]

Historical debate Edit

As the experimentation on animals increased, especially the practice of vivisection, so did criticism and controversy. In 1655, the advocate of Galenic physiology Edmund O'Meara said that "the miserable torture of vivisection places the body in an unnatural state". [31] [32] O'Meara and others argued that animal physiology could be affected by pain during vivisection, rendering results unreliable. There were also objections on an ethical basis, contending that the benefit to humans did not justify the harm to animals. [32] Early objections to animal testing also came from another angle—many people believed that animals were inferior to humans and so different that results from animals could not be applied to humans. [32]

On the other side of the debate, those in favor of animal testing held that experiments on animals were necessary to advance medical and biological knowledge. Claude Bernard—who is sometimes known as the "prince of vivisectors" [29] and the father of physiology, and whose wife, Marie Françoise Martin, founded the first anti-vivisection society in France in 1883 [33] —famously wrote in 1865 that "the science of life is a superb and dazzlingly lighted hall which may be reached only by passing through a long and ghastly kitchen". [34] Arguing that "experiments on animals [. . .] are entirely conclusive for the toxicology and hygiene of man [. . . T]he effects of these substances are the same on man as on animals, save for differences in degree", [30] Bernard established animal experimentation as part of the standard scientific method. [35]

In 1896, the physiologist and physician Dr. Walter B. Cannon said "The antivivisectionists are the second of the two types Theodore Roosevelt described when he said, 'Common sense without conscience may lead to crime, but conscience without common sense may lead to folly, which is the handmaiden of crime. ' " [36] These divisions between pro- and anti-animal testing groups first came to public attention during the Brown Dog affair in the early 1900s, when hundreds of medical students clashed with anti-vivisectionists and police over a memorial to a vivisected dog. [37]

In 1822, the first animal protection law was enacted in the British parliament, followed by the Cruelty to Animals Act (1876), the first law specifically aimed at regulating animal testing. The legislation was promoted by Charles Darwin, who wrote to Ray Lankester in March 1871: "You ask about my opinion on vivisection. I quite agree that it is justifiable for real investigations on physiology but not for mere damnable and detestable curiosity. It is a subject which makes me sick with horror, so I will not say another word about it, else I shall not sleep to-night." [38] [39] In response to the lobbying by anti-vivisectionists, several organizations were set up in Britain to defend animal research: The Physiological Society was formed in 1876 to give physiologists "mutual benefit and protection", [40] the Association for the Advancement of Medicine by Research was formed in 1882 and focused on policy-making, and the Research Defence Society (now Understanding Animal Research) was formed in 1908 "to make known the facts as to experiments on animals in this country the immense importance to the welfare of mankind of such experiments and the great saving of human life and health directly attributable to them". [41]

Opposition to the use of animals in medical research first arose in the United States during the 1860s, when Henry Bergh founded the American Society for the Prevention of Cruelty to Animals (ASPCA), with America's first specifically anti-vivisection organization being the American AntiVivisection Society (AAVS), founded in 1883. Antivivisectionists of the era generally believed the spread of mercy was the great cause of civilization, and vivisection was cruel. However, in the USA the antivivisectionists' efforts were defeated in every legislature, overwhelmed by the superior organization and influence of the medical community. Overall, this movement had little legislative success until the passing of the Laboratory Animal Welfare Act, in 1966. [42]

Regulations and laws Edit

The regulations that apply to animals in laboratories vary across species. In the U.S., under the provisions of the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals (the Guide), published by the National Academy of Sciences, any procedure can be performed on an animal if it can be successfully argued that it is scientifically justified. In general, researchers are required to consult with the institution's veterinarian and its Institutional Animal Care and Use Committee (IACUC), which every research facility is obliged to maintain. [43] The IACUC must ensure that alternatives, including non-animal alternatives, have been considered, that the experiments are not unnecessarily duplicative, and that pain relief is given unless it would interfere with the study. The IACUCs regulate all vertebrates in testing at institutions receiving federal funds in the USA. Although the provisions of the Animal Welfare Act do not include purpose-bred rodents and birds, these species are equally regulated under Public Health Service policies that govern the IACUCs. [44] [45] The Public Health Service policy oversees the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC). The CDC conducts infectious disease research on nonhuman primates, rabbits, mice, and other animals, while FDA requirements cover use of animals in pharmaceutical research. [46] Animal Welfare Act (AWA) regulations are enforced by the USDA, whereas Public Health Service regulations are enforced by OLAW and in many cases by AAALAC.

According to the 2014 U.S. Department of Agriculture Office of the Inspector General (OIG) report—which looked at the oversight of animal use during a three-year period—"some Institutional Animal Care and Use Committees . did not adequately approve, monitor, or report on experimental procedures on animals". The OIG found that "as a result, animals are not always receiving basic humane care and treatment and, in some cases, pain and distress are not minimized during and after experimental procedures". According to the report, within a three-year period, nearly half of all American laboratories with regulated species were cited for AWA violations relating to improper IACUC oversight. [47] The USDA OIG made similar findings in a 2005 report. [48] With only a broad number of 120 inspectors, the United States Department of Agriculture (USDA) oversees more than 12,000 facilities involved in research, exhibition, breeding, or dealing of animals. [46] Others have criticized the composition of IACUCs, asserting that the committees are predominantly made up of animal researchers and university representatives who may be biased against animal welfare concerns. [49]

Larry Carbone, a laboratory animal veterinarian, writes that, in his experience, IACUCs take their work very seriously regardless of the species involved, though the use of non-human primates always raises what he calls a "red flag of special concern". [50] A study published in Science magazine in July 2001 confirmed the low reliability of IACUC reviews of animal experiments. Funded by the National Science Foundation, the three-year study found that animal-use committees that do not know the specifics of the university and personnel do not make the same approval decisions as those made by animal-use committees that do know the university and personnel. Specifically, blinded committees more often ask for more information rather than approving studies. [51]

Scientists in India are protesting a recent guideline issued by the University Grants Commission to ban the use of live animals in universities and laboratories. [52]

Numbers Edit

Accurate global figures for animal testing are difficult to obtain it has been estimated that 100 million vertebrates are experimented on around the world every year, [53] 10–11 million of them in the EU. [54] The Nuffield Council on Bioethics reports that global annual estimates range from 50 to 100 million animals. None of the figures include invertebrates such as shrimp and fruit flies. [55]

The USDA/APHIS has published the 2016 animal research statistics. Overall, the number of animals (covered by the Animal Welfare Act) used in research in the US rose 6.9% from 767,622 (2015) to 820,812 (2016). [56] This includes both public and private institutions. By comparing with EU data, where all vertebrate species are counted, Speaking of Research estimated that around 12 million vertebrates were used in research in the US in 2016. [57] A 2015 article published in the Journal of Medical Ethics, argued that the use of animals in the US has dramatically increased in recent years. Researchers found this increase is largely the result of an increased reliance on genetically modified mice in animal studies. [58]

In 1995, researchers at Tufts University Center for Animals and Public Policy estimated that 14–21 million animals were used in American laboratories in 1992, a reduction from a high of 50 million used in 1970. [59] In 1986, the U.S. Congress Office of Technology Assessment reported that estimates of the animals used in the U.S. range from 10 million to upwards of 100 million each year, and that their own best estimate was at least 17 million to 22 million. [60] In 2016, the Department of Agriculture listed 60,979 dogs, 18,898 cats, 71,188 non-human primates, 183,237 guinea pigs, 102,633 hamsters, 139,391 rabbits, 83,059 farm animals, and 161,467 other mammals, a total of 820,812, a figure that includes all mammals except purpose-bred mice and rats. The use of dogs and cats in research in the U.S. decreased from 1973 to 2016 from 195,157 to 60,979, and from 66,165 to 18,898, respectively. [57]

In the UK, Home Office figures show that 3.79 million procedures were carried out in 2017. [61] 2,960 procedures used non-human primates, down over 50% since 1988. A "procedure" refers here to an experiment that might last minutes, several months, or years. Most animals are used in only one procedure: animals are frequently euthanized after the experiment however death is the endpoint of some procedures. [55] The procedures conducted on animals in the UK in 2017 were categorised as –

  • 43% (1.61 million) were assessed as sub-threshold
  • 4% (0.14 million) were assessed as non-recovery
  • 36% (1.35 million) were assessed as mild
  • 15% (0.55 million) were assessed as moderate
  • 4% (0.14 million) were assessed as severe [62]

A 'severe' procedure would be, for instance, any test where death is the end-point or fatalities are expected, whereas a 'mild' procedure would be something like a blood test or an MRI scan. [61]

The Three Rs Edit

The Three Rs (3Rs) are guiding principles for more ethical use of animals in testing. These were first described by W.M.S. Russell and R.L. Burch in 1959. [63] The 3Rs state:

  1. Replacement which refers to the preferred use of non-animal methods over animal methods whenever it is possible to achieve the same scientific aims. These methods include computer modeling.
  2. Reduction which refers to methods that enable researchers to obtain comparable levels of information from fewer animals, or to obtain more information from the same number of animals.
  3. Refinement which refers to methods that alleviate or minimize potential pain, suffering or distress, and enhance animal welfare for the animals used. These methods include non-invasive techniques. [64]

The 3Rs have a broader scope than simply encouraging alternatives to animal testing, but aim to improve animal welfare and scientific quality where the use of animals can not be avoided. These 3Rs are now implemented in many testing establishments worldwide and have been adopted by various pieces of legislation and regulations. [65]

Despite the widespread acceptance of the 3Rs, many countries—including Canada, Australia, Israel, South Korea, and Germany—have reported rising experimental use of animals in recent years with increased use of mice and, in some cases, fish while reporting declines in the use of cats, dogs, primates, rabbits, guinea pigs, and hamsters. Along with other countries, China has also escalated its use of GM animals, resulting in an increase in overall animal use. [66] [67] [68] [69] [70] [71] [ excessive citations ]

Invertebrates Edit

Although many more invertebrates than vertebrates are used in animal testing, these studies are largely unregulated by law. The most frequently used invertebrate species are Drosophila melanogaster, a fruit fly, and Caenorhabditis elegans, a nematode worm. In the case of C. elegans, the worm's body is completely transparent and the precise lineage of all the organism's cells is known, [72] while studies in the fly D. melanogaster can use an amazing array of genetic tools. [73] These invertebrates offer some advantages over vertebrates in animal testing, including their short life cycle and the ease with which large numbers may be housed and studied. However, the lack of an adaptive immune system and their simple organs prevent worms from being used in several aspects of medical research such as vaccine development. [74] Similarly, the fruit fly immune system differs greatly from that of humans, [75] and diseases in insects can be different from diseases in vertebrates [76] however, fruit flies and waxworms can be useful in studies to identify novel virulence factors or pharmacologically active compounds. [77] [78] [79]

Several invertebrate systems are considered acceptable alternatives to vertebrates in early-stage discovery screens. [80] Because of similarities between the innate immune system of insects and mammals, insects can replace mammals in some types of studies. Drosophila melanogaster and the Galleria mellonella waxworm have been particularly important for analysis of virulence traits of mammalian pathogens. [77] [78] Waxworms and other insects have also proven valuable for the identification of pharmaceutical compounds with favorable bioavailability. [79] The decision to adopt such models generally involves accepting a lower degree of biological similarity with mammals for significant gains in experimental throughput.

Vertebrates Edit

In the U.S., the numbers of rats and mice used is estimated to be from 11 million [57] to between 20 and 100 million a year. [81] Other rodents commonly used are guinea pigs, hamsters, and gerbils. Mice are the most commonly used vertebrate species because of their size, low cost, ease of handling, and fast reproduction rate. [82] [83] Mice are widely considered to be the best model of inherited human disease and share 95% of their genes with humans. [82] With the advent of genetic engineering technology, genetically modified mice can be generated to order and can provide models for a range of human diseases. [82] Rats are also widely used for physiology, toxicology and cancer research, but genetic manipulation is much harder in rats than in mice, which limits the use of these rodents in basic science. [84]

Over 500,000 fish and 9,000 amphibians were used in the UK in 2016. [85] The main species used is the zebrafish, Danio rerio, which are translucent during their embryonic stage, and the African clawed frog, Xenopus laevis. Over 20,000 rabbits were used for animal testing in the UK in 2004. [86] Albino rabbits are used in eye irritancy tests (Draize test) because rabbits have less tear flow than other animals, and the lack of eye pigment in albinos make the effects easier to visualize. The numbers of rabbits used for this purpose has fallen substantially over the past two decades. In 1996, there were 3,693 procedures on rabbits for eye irritation in the UK, [87] and in 2017 this number was just 63. [85] Rabbits are also frequently used for the production of polyclonal antibodies.

Cats Edit

Cats are most commonly used in neurological research. In 2016, 18,898 cats were used in the United States alone, [57] around a third of which were used in experiments which have the potential to cause "pain and/or distress" [88] though only 0.1% of cat experiments involved potential pain which was not relieved by anesthetics/analgesics. In the UK, just 198 procedures were carried out on cats in 2017. The number has been around 200 for most of the last decade. [85]

Dogs Edit

Dogs are widely used in biomedical research, testing, and education—particularly beagles, because they are gentle and easy to handle, and to allow for comparisons with historical data from beagles (a Reduction technique).(citation needed) They are used as models for human and veterinary diseases in cardiology, endocrinology, and bone and joint studies, research that tends to be highly invasive, according to the Humane Society of the United States. [89] The most common use of dogs is in the safety assessment of new medicines [90] for human or veterinary use as a second species following testing in rodents, in accordance with the regulations set out in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. One of the most significant advancements in medical science involves the use of dogs in developing the answers to insulin production in the body for diabetics and the role of the pancreas in this process. They found that the pancreas was responsible for producing insulin in the body and that removal of the pancreas, resulted in the development of diabetes in the dog. After re-injecting the pancreatic extract, (insulin), the blood glucose levels were significantly lowered. [91] The advancements made in this research involving the use of dogs has resulted in a definite improvement in the quality of life for both humans and animals.

The U.S. Department of Agriculture's Animal Welfare Report shows that 60,979 dogs were used in USDA-registered facilities in 2016. [57] In the UK, according to the UK Home Office, there were 3,847 procedures on dogs in 2017. [85] Of the other large EU users of dogs, Germany conducted 3,976 procedures on dogs in 2016 [92] and France conducted 4,204 procedures in 2016. [93] In both cases this represents under 0.2% of the total number of procedures conducted on animals in the respective countries.

Non-human primates Edit

Non-human primates (NHPs) are used in toxicology tests, studies of AIDS and hepatitis, studies of neurology, behavior and cognition, reproduction, genetics, and xenotransplantation. They are caught in the wild or purpose-bred. In the United States and China, most primates are domestically purpose-bred, whereas in Europe the majority are imported purpose-bred. [94] The European Commission reported that in 2011, 6,012 monkeys were experimented on in European laboratories. [95] According to the U.S. Department of Agriculture, there were 71,188 monkeys in U.S. laboratories in 2016. [57] 23,465 monkeys were imported into the U.S. in 2014 including 929 who were caught in the wild. [96] Most of the NHPs used in experiments are macaques [97] but marmosets, spider monkeys, and squirrel monkeys are also used, and baboons and chimpanzees are used in the US. As of 2015 [update] , there are approximately 730 chimpanzees in U.S. laboratories. [98]

In a survey in 2003, it was found that 89% of singly-housed primates exhibited self-injurious or abnormal stereotypyical behaviors including pacing, rocking, hair pulling, and biting among others. [99]

The first transgenic primate was produced in 2001, with the development of a method that could introduce new genes into a rhesus macaque. [100] This transgenic technology is now being applied in the search for a treatment for the genetic disorder Huntington's disease. [101] Notable studies on non-human primates have been part of the polio vaccine development, and development of Deep Brain Stimulation, and their current heaviest non-toxicological use occurs in the monkey AIDS model, SIV. [102] [97] [103] In 2008 a proposal to ban all primates experiments in the EU has sparked a vigorous debate. [104]

Sources Edit

Animals used by laboratories are largely supplied by specialist dealers. Sources differ for vertebrate and invertebrate animals. Most laboratories breed and raise flies and worms themselves, using strains and mutants supplied from a few main stock centers. [105] For vertebrates, sources include breeders and dealers like Covance and Charles River Laboratories who supply purpose-bred and wild-caught animals businesses that trade in wild animals such as Nafovanny and dealers who supply animals sourced from pounds, auctions, and newspaper ads. Animal shelters also supply the laboratories directly. [106] Large centers also exist to distribute strains of genetically modified animals the International Knockout Mouse Consortium, for example, aims to provide knockout mice for every gene in the mouse genome. [107]

In the U.S., Class A breeders are licensed by the U.S. Department of Agriculture (USDA) to sell animals for research purposes, while Class B dealers are licensed to buy animals from "random sources" such as auctions, pound seizure, and newspaper ads. Some Class B dealers have been accused of kidnapping pets and illegally trapping strays, a practice known as bunching. [108] [109] [110] [111] [112] [113] It was in part out of public concern over the sale of pets to research facilities that the 1966 Laboratory Animal Welfare Act was ushered in—the Senate Committee on Commerce reported in 1966 that stolen pets had been retrieved from Veterans Administration facilities, the Mayo Institute, the University of Pennsylvania, Stanford University, and Harvard and Yale Medical Schools. [114] The USDA recovered at least a dozen stolen pets during a raid on a Class B dealer in Arkansas in 2003. [115]

Four states in the U.S.—Minnesota, Utah, Oklahoma, and Iowa—require their shelters to provide animals to research facilities. Fourteen states explicitly prohibit the practice, while the remainder either allow it or have no relevant legislation. [116]

In the European Union, animal sources are governed by Council Directive 86/609/EEC, which requires lab animals to be specially bred, unless the animal has been lawfully imported and is not a wild animal or a stray. The latter requirement may also be exempted by special arrangement. [117] In 2010 the Directive was revised with EU Directive 2010/63/EU. [118] In the UK, most animals used in experiments are bred for the purpose under the 1988 Animal Protection Act, but wild-caught primates may be used if exceptional and specific justification can be established. [119] [120] The United States also allows the use of wild-caught primates between 1995 and 1999, 1,580 wild baboons were imported into the U.S. Over half the primates imported between 1995 and 2000 were handled by Charles River Laboratories, or by Covance, which is the single largest importer of primates into the U.S. [121]

Pain and suffering Edit

The extent to which animal testing causes pain and suffering, and the capacity of animals to experience and comprehend them, is the subject of much debate. [122] [123]

According to the USDA, in 2016 501,560 animals (61%) (not including rats, mice, birds, or invertebrates) were used in procedures that did not include more than momentary pain or distress. 247,882 (31%) animals were used in procedures in which pain or distress was relieved by anesthesia, while 71,370 (9%) were used in studies that would cause pain or distress that would not be relieved. [57]

Since 2014, in the UK, every research procedure was retrospectively assessed for severity. The five categories are "sub-threshold", "mild", "moderate", "severe" and "non-recovery", the latter being procedures in which an animal is anesthetized and subsequently killed without recovering consciousness. In 2017, 43% (1.61 million) were assessed as sub-threshold, 4% (0.14 million) were assessed as non-recovery, 36% (1.35 million) were assessed as mild, 15% (0.55 million) were assessed as moderate and 4% (0.14 million) were assessed as severe. [62]

The idea that animals might not feel pain as human beings feel it traces back to the 17th-century French philosopher, René Descartes, who argued that animals do not experience pain and suffering because they lack consciousness. [55] [124] Bernard Rollin of Colorado State University, the principal author of two U.S. federal laws regulating pain relief for animals, [125] writes that researchers remained unsure into the 1980s as to whether animals experience pain, and that veterinarians trained in the U.S. before 1989 were simply taught to ignore animal pain. [126] In his interactions with scientists and other veterinarians, he was regularly asked to "prove" that animals are conscious, and to provide "scientifically acceptable" grounds for claiming that they feel pain. [126] Carbone writes that the view that animals feel pain differently is now a minority view. Academic reviews of the topic are more equivocal, noting that although the argument that animals have at least simple conscious thoughts and feelings has strong support, [127] some critics continue to question how reliably animal mental states can be determined. [55] [128] However, some canine experts are stating that, while intelligence does differ animal to animal, dogs have the intelligence of a two to two-and-a-half-year old. This does support the idea that dogs, at the very least, have some form of consciousness. [129] The ability of invertebrates to experience pain and suffering is less clear, however, legislation in several countries (e.g. U.K., New Zealand, [130] Norway [131] ) protects some invertebrate species if they are being used in animal testing.

In the U.S., the defining text on animal welfare regulation in animal testing is the Guide for the Care and Use of Laboratory Animals. [132] This defines the parameters that govern animal testing in the U.S. It states "The ability to experience and respond to pain is widespread in the animal kingdom. Pain is a stressor and, if not relieved, can lead to unacceptable levels of stress and distress in animals." The Guide states that the ability to recognize the symptoms of pain in different species is vital in efficiently applying pain relief and that it is essential for the people caring for and using animals to be entirely familiar with these symptoms. On the subject of analgesics used to relieve pain, the Guide states "The selection of the most appropriate analgesic or anesthetic should reflect professional judgment as to which best meets clinical and humane requirements without compromising the scientific aspects of the research protocol". Accordingly, all issues of animal pain and distress, and their potential treatment with analgesia and anesthesia, are required regulatory issues in receiving animal protocol approval. [133]

In 2019, Katrien Devolder and Matthias Eggel proposed gene editing research animals to remove the ability to feel pain. This would be an intermediate step towards eventually stopping all experimentation on animals and adopting alternatives. [134] Additionally, this would not stop research animals from experiencing psychological harm.

Euthanasia Edit

Regulations require that scientists use as few animals as possible, especially for terminal experiments. [135] However, while policy makers consider suffering to be the central issue and see animal euthanasia as a way to reduce suffering, others, such as the RSPCA, argue that the lives of laboratory animals have intrinsic value. [136] Regulations focus on whether particular methods cause pain and suffering, not whether their death is undesirable in itself. [137] The animals are euthanized at the end of studies for sample collection or post-mortem examination during studies if their pain or suffering falls into certain categories regarded as unacceptable, such as depression, infection that is unresponsive to treatment, or the failure of large animals to eat for five days [138] or when they are unsuitable for breeding or unwanted for some other reason. [139]

Methods of euthanizing laboratory animals are chosen to induce rapid unconsciousness and death without pain or distress. [140] The methods that are preferred are those published by councils of veterinarians. The animal can be made to inhale a gas, such as carbon monoxide and carbon dioxide, by being placed in a chamber, or by use of a face mask, with or without prior sedation or anesthesia. Sedatives or anesthetics such as barbiturates can be given intravenously, or inhalant anesthetics may be used. Amphibians and fish may be immersed in water containing an anesthetic such as tricaine. Physical methods are also used, with or without sedation or anesthesia depending on the method. Recommended methods include decapitation (beheading) for small rodents or rabbits. Cervical dislocation (breaking the neck or spine) may be used for birds, mice, and immature rats and rabbits. High-intensity microwave irradiation of the brain can preserve brain tissue and induce death in less than 1 second, but this is currently only used on rodents. Captive bolts may be used, typically on dogs, ruminants, horses, pigs and rabbits. It causes death by a concussion to the brain. Gunshot may be used, but only in cases where a penetrating captive bolt may not be used. Some physical methods are only acceptable after the animal is unconscious. Electrocution may be used for cattle, sheep, swine, foxes, and mink after the animals are unconscious, often by a prior electrical stun. Pithing (inserting a tool into the base of the brain) is usable on animals already unconscious. Slow or rapid freezing, or inducing air embolism are acceptable only with prior anesthesia to induce unconsciousness. [141]

Pure research Edit

Basic or pure research investigates how organisms behave, develop, and function. Those opposed to animal testing object that pure research may have little or no practical purpose, but researchers argue that it forms the necessary basis for the development of applied research, rendering the distinction between pure and applied research—research that has a specific practical aim—unclear. [142] Pure research uses larger numbers and a greater variety of animals than applied research. Fruit flies, nematode worms, mice and rats together account for the vast majority, though small numbers of other species are used, ranging from sea slugs through to armadillos. [143] Examples of the types of animals and experiments used in basic research include:

  • Studies on embryogenesis and developmental biology. Mutants are created by adding transposons into their genomes, or specific genes are deleted by gene targeting. [144][145] By studying the changes in development these changes produce, scientists aim to understand both how organisms normally develop, and what can go wrong in this process. These studies are particularly powerful since the basic controls of development, such as the homeobox genes, have similar functions in organisms as diverse as fruit flies and man. [146][147]
  • Experiments into behavior, to understand how organisms detect and interact with each other and their environment, in which fruit flies, worms, mice, and rats are all widely used. [148][149] Studies of brain function, such as memory and social behavior, often use rats and birds. [150][151] For some species, behavioral research is combined with enrichment strategies for animals in captivity because it allows them to engage in a wider range of activities. [152]
  • Breeding experiments to study evolution and genetics. Laboratory mice, flies, fish, and worms are inbred through many generations to create strains with defined characteristics. [153] These provide animals of a known genetic background, an important tool for genetic analyses. Larger mammals are rarely bred specifically for such studies due to their slow rate of reproduction, though some scientists take advantage of inbred domesticated animals, such as dog or cattle breeds, for comparative purposes. Scientists studying how animals evolve use many animal species to see how variations in where and how an organism lives (their niche) produce adaptations in their physiology and morphology. As an example, sticklebacks are now being used to study how many and which types of mutations are selected to produce adaptations in animals' morphology during the evolution of new species. [154][155]

Applied research Edit

Applied research aims to solve specific and practical problems. These may involve the use of animal models of diseases or conditions, which are often discovered or generated by pure research programmes. In turn, such applied studies may be an early stage in the drug discovery process. Examples include:

    of animals to study disease. Transgenic animals have specific genes inserted, modified or removed, to mimic specific conditions such as single gene disorders, such as Huntington's disease. [156] Other models mimic complex, multifactorial diseases with genetic components, such as diabetes, [157] or even transgenic mice that carry the same mutations that occur during the development of cancer. [158] These models allow investigations on how and why the disease develops, as well as providing ways to develop and test new treatments. [159] The vast majority of these transgenic models of human disease are lines of mice, the mammalian species in which genetic modification is most efficient. [82] Smaller numbers of other animals are also used, including rats, pigs, sheep, fish, birds, and amphibians. [120]
  • Studies on models of naturally occurring disease and condition. Certain domestic and wild animals have a natural propensity or predisposition for certain conditions that are also found in humans. Cats are used as a model to develop immunodeficiency virus vaccines and to study leukemia because their natural predisposition to FIV and Feline leukemia virus. [160][161] Certain breeds of dog suffer from narcolepsy making them the major model used to study the human condition. Armadillos and humans are among only a few animal species that naturally suffer from leprosy as the bacteria responsible for this disease cannot yet be grown in culture, armadillos are the primary source of bacilli used in leprosy vaccines. [143]
  • Studies on induced animal models of human diseases. Here, an animal is treated so that it develops pathology and symptoms that resemble a human disease. Examples include restricting blood flow to the brain to induce stroke, or giving neurotoxins that cause damage similar to that seen in Parkinson's disease. [162] Much animal research into potential treatments for humans is wasted because it is poorly conducted and not evaluated through systematic reviews. [163] For example, although such models are now widely used to study Parkinson's disease, the British anti-vivisection interest group BUAV argues that these models only superficially resemble the disease symptoms, without the same time course or cellular pathology. [164] In contrast, scientists assessing the usefulness of animal models of Parkinson's disease, as well as the medical research charity The Parkinson's Appeal, state that these models were invaluable and that they led to improved surgical treatments such as pallidotomy, new drug treatments such as levodopa, and later deep brain stimulation. [103][162][165]
  • Animal testing has also included the use of placebo testing. In these cases animals are treated with a substance that produces no pharmacological effect, but is administered in order to determine any biological alterations due to the experience of a substance being administered, and the results are compared with those obtained with an active compound.

Xenotransplantation Edit

Xenotransplantation research involves transplanting tissues or organs from one species to another, as a way to overcome the shortage of human organs for use in organ transplants. [166] Current research involves using primates as the recipients of organs from pigs that have been genetically modified to reduce the primates' immune response against the pig tissue. [167] Although transplant rejection remains a problem, [167] recent clinical trials that involved implanting pig insulin-secreting cells into diabetics did reduce these people's need for insulin. [168] [169]

Documents released to the news media by the animal rights organization Uncaged Campaigns showed that, between 1994 and 2000, wild baboons imported to the UK from Africa by Imutran Ltd, a subsidiary of Novartis Pharma AG, in conjunction with Cambridge University and Huntingdon Life Sciences, to be used in experiments that involved grafting pig tissues, suffered serious and sometimes fatal injuries. A scandal occurred when it was revealed that the company had communicated with the British government in an attempt to avoid regulation. [170] [171]

Toxicology testing Edit

Toxicology testing, also known as safety testing, is conducted by pharmaceutical companies testing drugs, or by contract animal testing facilities, such as Huntingdon Life Sciences, on behalf of a wide variety of customers. [172] According to 2005 EU figures, around one million animals are used every year in Europe in toxicology tests which are about 10% of all procedures. [173] According to Nature, 5,000 animals are used for each chemical being tested, with 12,000 needed to test pesticides. [174] The tests are conducted without anesthesia, because interactions between drugs can affect how animals detoxify chemicals, and may interfere with the results. [175] [176]

Toxicology tests are used to examine finished products such as pesticides, medications, food additives, packing materials, and air freshener, or their chemical ingredients. Most tests involve testing ingredients rather than finished products, but according to BUAV, manufacturers believe these tests overestimate the toxic effects of substances they therefore repeat the tests using their finished products to obtain a less toxic label. [172]

The substances are applied to the skin or dripped into the eyes injected intravenously, intramuscularly, or subcutaneously inhaled either by placing a mask over the animals and restraining them, or by placing them in an inhalation chamber or administered orally, through a tube into the stomach, or simply in the animal's food. Doses may be given once, repeated regularly for many months, or for the lifespan of the animal. [ citation needed ]

There are several different types of acute toxicity tests. The LD50 ("Lethal Dose 50%") test is used to evaluate the toxicity of a substance by determining the dose required to kill 50% of the test animal population. This test was removed from OECD international guidelines in 2002, replaced by methods such as the fixed dose procedure, which use fewer animals and cause less suffering. [177] [178] Abbott writes that, as of 2005, "the LD50 acute toxicity test . still accounts for one-third of all animal [toxicity] tests worldwide". [174]

Irritancy can be measured using the Draize test, where a test substance is applied to an animal's eyes or skin, usually an albino rabbit. For Draize eye testing, the test involves observing the effects of the substance at intervals and grading any damage or irritation, but the test should be halted and the animal killed if it shows "continuing signs of severe pain or distress". [179] The Humane Society of the United States writes that the procedure can cause redness, ulceration, hemorrhaging, cloudiness, or even blindness. [180] This test has also been criticized by scientists for being cruel and inaccurate, subjective, over-sensitive, and failing to reflect human exposures in the real world. [181] Although no accepted in vitro alternatives exist, a modified form of the Draize test called the low volume eye test may reduce suffering and provide more realistic results and this was adopted as the new standard in September 2009. [182] [183] However, the Draize test will still be used for substances that are not severe irritants. [183]

The most stringent tests are reserved for drugs and foodstuffs. For these, a number of tests are performed, lasting less than a month (acute), one to three months (subchronic), and more than three months (chronic) to test general toxicity (damage to organs), eye and skin irritancy, mutagenicity, carcinogenicity, teratogenicity, and reproductive problems. The cost of the full complement of tests is several million dollars per substance and it may take three or four years to complete.

These toxicity tests provide, in the words of a 2006 United States National Academy of Sciences report, "critical information for assessing hazard and risk potential". [184] Animal tests may overestimate risk, with false positive results being a particular problem, [174] [185] but false positives appear not to be prohibitively common. [186] Variability in results arises from using the effects of high doses of chemicals in small numbers of laboratory animals to try to predict the effects of low doses in large numbers of humans. [187] Although relationships do exist, opinion is divided on how to use data on one species to predict the exact level of risk in another. [188]

Scientists face growing pressure to move away from using traditional animal toxicity tests to determine whether manufactured chemicals are safe. [189] Among variety of approaches to toxicity evaluation the ones which have attracted increasing interests are in vitro cell-based sensing methods applying fluorescence. [190]

Cosmetics testing Edit

Cosmetics testing on animals is particularly controversial. Such tests, which are still conducted in the U.S., involve general toxicity, eye and skin irritancy, phototoxicity (toxicity triggered by ultraviolet light) and mutagenicity. [191]

Cosmetics testing on animals is banned in India, the European Union, [192] Israel and Norway [193] [194] while legislation in the U.S. and Brazil is currently considering similar bans. [195] In 2002, after 13 years of discussion, the European Union agreed to phase in a near-total ban on the sale of animal-tested cosmetics by 2009, and to ban all cosmetics-related animal testing. France, which is home to the world's largest cosmetics company, L'Oreal, has protested the proposed ban by lodging a case at the European Court of Justice in Luxembourg, asking that the ban be quashed. [196] The ban is also opposed by the European Federation for Cosmetics Ingredients, which represents 70 companies in Switzerland, Belgium, France, Germany, and Italy. [196] In October 2014, India passed stricter laws that also ban the importation of any cosmetic products that are tested on animals. [197]

Drug testing Edit

Before the early 20th century, laws regulating drugs were lax. Currently, all new pharmaceuticals undergo rigorous animal testing before being licensed for human use. Tests on pharmaceutical products involve:

  • metabolic tests, investigating pharmacokinetics—how drugs are absorbed, metabolized and excreted by the body when introduced orally, intravenously, intraperitoneally, intramuscularly, or transdermally.
  • toxicology tests, which gauge acute, sub-acute, and chronic toxicity. Acute toxicity is studied by using a rising dose until signs of toxicity become apparent. Current European legislation demands that "acute toxicity tests must be carried out in two or more mammalian species" covering "at least two different routes of administration". [198] Sub-acute toxicity is where the drug is given to the animals for four to six weeks in doses below the level at which it causes rapid poisoning, in order to discover if any toxic drug metabolites build up over time. Testing for chronic toxicity can last up to two years and, in the European Union, is required to involve two species of mammals, one of which must be non-rodent. [199]
  • efficacy studies, which test whether experimental drugs work by inducing the appropriate illness in animals. The drug is then administered in a double-blind controlled trial, which allows researchers to determine the effect of the drug and the dose-response curve.
  • Specific tests on reproductive function, embryonic toxicity, or carcinogenic potential can all be required by law, depending on the result of other studies and the type of drug being tested.

Education Edit

It is estimated that 20 million animals are used annually for educational purposes in the United States including, classroom observational exercises, dissections and live-animal surgeries. [200] [201] Frogs, fetal pigs, perch, cats, earthworms, grasshoppers, crayfish and starfish are commonly used in classroom dissections. [202] Alternatives to the use of animals in classroom dissections are widely used, with many U.S. States and school districts mandating students be offered the choice to not dissect. [203] Citing the wide availability of alternatives and the decimation of local frog species, India banned dissections in 2014. [204] [205]

The Sonoran Arthropod Institute hosts an annual Invertebrates in Education and Conservation Conference to discuss the use of invertebrates in education. [206] There also are efforts in many countries to find alternatives to using animals in education. [207] The NORINA database, maintained by Norecopa, lists products that may be used as alternatives or supplements to animal use in education, and in the training of personnel who work with animals. [208] These include alternatives to dissection in schools. InterNICHE has a similar database and a loans system. [209]

In November 2013, the U.S.-based company Backyard Brains released for sale to the public what they call the "Roboroach", an "electronic backpack" that can be attached to cockroaches. The operator is required to amputate a cockroach's antennae, use sandpaper to wear down the shell, insert a wire into the thorax, and then glue the electrodes and circuit board onto the insect's back. A mobile phone app can then be used to control it via Bluetooth. [210] It has been suggested that the use of such a device may be a teaching aid that can promote interest in science. The makers of the "Roboroach" have been funded by the National Institute of Mental Health and state that the device is intended to encourage children to become interested in neuroscience. [210] [211]

Defense Edit

Animals are used by the military to develop weapons, vaccines, battlefield surgical techniques, and defensive clothing. [142] For example, in 2008 the United States Defense Advanced Research Projects Agency used live pigs to study the effects of improvised explosive device explosions on internal organs, especially the brain. [212]

In the US military, goats are commonly used to train combat medics. (Goats have become the main animal species used for this purpose after the Pentagon phased out using dogs for medical training in the 1980s. [213] ) While modern mannequins used in medical training are quite efficient in simulating the behavior of a human body, some trainees feel that "the goat exercise provide[s] a sense of urgency that only real life trauma can provide". [214] Nevertheless, in 2014, the U.S. Coast Guard announced that it would reduce the number of animals it uses in its training exercises by half after PETA released video showing Guard members cutting off the limbs of unconscious goats with tree trimmers and inflicting other injuries with a shotgun, pistol, ax and a scalpel. [215] That same year, citing the availability of human simulators and other alternatives, the Department of Defense announced it would begin reducing the number of animals it uses in various training programs. [216] In 2013, several Navy medical centers stopped using ferrets in intubation exercises after complaints from PETA. [217]

Besides the United States, six out of 28 NATO countries, including Poland and Denmark, use live animals for combat medic training. [213]

Most animals are euthanized after being used in an experiment. [10] Sources of laboratory animals vary between countries and species most animals are purpose-bred, while a minority are caught in the wild or supplied by dealers who obtain them from auctions and pounds. [218] [219] [108] Supporters of the use of animals in experiments, such as the British Royal Society, argue that virtually every medical achievement in the 20th century relied on the use of animals in some way. [102] The Institute for Laboratory Animal Research of the United States National Academy of Sciences has argued that animal research cannot be replaced by even sophisticated computer models, which are unable to deal with the extremely complex interactions between molecules, cells, tissues, organs, organisms and the environment. [220] Animal rights organizations—such as PETA and BUAV—question the need for and legitimacy of animal testing, arguing that it is cruel and poorly regulated, that medical progress is actually held back by misleading animal models that cannot reliably predict effects in humans, that some of the tests are outdated, that the costs outweigh the benefits, or that animals have the intrinsic right not to be used or harmed in experimentation. [6] [221] [222] [223] [224] [225]

Viewpoints Edit

The moral and ethical questions raised by performing experiments on animals are subject to debate, and viewpoints have shifted significantly over the 20th century. [226] There remain disagreements about which procedures are useful for which purposes, as well as disagreements over which ethical principles apply to which species.

A 2015 Gallup poll found that 67% of Americans were "very concerned" or "somewhat concerned" about animals used in research. [227] A Pew poll taken the same year found 50% of American adults opposed the use of animals in research. [228]

Still, a wide range of viewpoints exist. The view that animals have moral rights (animal rights) is a philosophical position proposed by Tom Regan, among others, who argues that animals are beings with beliefs and desires, and as such are the "subjects of a life" with moral value and therefore moral rights. [229] Regan still sees ethical differences between killing human and non-human animals, and argues that to save the former it is permissible to kill the latter. Likewise, a "moral dilemma" view suggests that avoiding potential benefit to humans is unacceptable on similar grounds, and holds the issue to be a dilemma in balancing such harm to humans to the harm done to animals in research. [230] In contrast, an abolitionist view in animal rights holds that there is no moral justification for any harmful research on animals that is not to the benefit of the individual animal. [230] Bernard Rollin argues that benefits to human beings cannot outweigh animal suffering, and that human beings have no moral right to use an animal in ways that do not benefit that individual. Donald Watson has stated that vivisection and animal experimentation "is probably the cruelest of all Man's attack on the rest of Creation." [231] Another prominent position is that of philosopher Peter Singer, who argues that there are no grounds to include a being's species in considerations of whether their suffering is important in utilitarian moral considerations. [232] Malcolm Macleod and collaborators argue that most controlled animal studies do not employ randomization, allocation concealment, and blinding outcome assessment, and that failure to employ these features exaggerates the apparent benefit of drugs tested in animals, leading to a failure to translate much animal research for human benefit. [233] [234] [235] [236] [237]

Governments such as the Netherlands and New Zealand have responded to the public's concerns by outlawing invasive experiments on certain classes of non-human primates, particularly the great apes. [238] [239] In 2015, captive chimpanzees in the U.S. were added to the Endangered Species Act adding new road blocks to those wishing to experiment on them. [240] Similarly, citing ethical considerations and the availability of alternative research methods, the U.S. NIH announced in 2013 that it would dramatically reduce and eventually phase out experiments on chimpanzees. [241]

The British government has required that the cost to animals in an experiment be weighed against the gain in knowledge. [242] Some medical schools and agencies in China, Japan, and South Korea have built cenotaphs for killed animals. [243] In Japan there are also annual memorial services (Ireisai 慰霊祭) for animals sacrificed at medical school.

Various specific cases of animal testing have drawn attention, including both instances of beneficial scientific research, and instances of alleged ethical violations by those performing the tests. The fundamental properties of muscle physiology were determined with work done using frog muscles (including the force generating mechanism of all muscle, [244] the length-tension relationship, [245] and the force-velocity curve [246] ), and frogs are still the preferred model organism due to the long survival of muscles in vitro and the possibility of isolating intact single-fiber preparations (not possible in other organisms). [247] Modern physical therapy and the understanding and treatment of muscular disorders is based on this work and subsequent work in mice (often engineered to express disease states such as muscular dystrophy). [248] In February 1997 a team at the Roslin Institute in Scotland announced the birth of Dolly the sheep, the first mammal to be cloned from an adult somatic cell. [25]

Concerns have been raised over the mistreatment of primates undergoing testing. In 1985 the case of Britches, a macaque monkey at the University of California, Riverside, gained public attention. He had his eyelids sewn shut and a sonar sensor on his head as part of an experiment to test sensory substitution devices for blind people. The laboratory was raided by Animal Liberation Front in 1985, removing Britches and 466 other animals. [249] The National Institutes of Health conducted an eight-month investigation and concluded, however, that no corrective action was necessary. [250] During the 2000s other cases have made headlines, including experiments at the University of Cambridge [251] and Columbia University in 2002. [252] In 2004 and 2005, undercover footage of staff of Covance's, a contract research organization that provides animal testing services, Virginia lab was shot by People for the Ethical Treatment of Animals (PETA). Following release of the footage, the U.S. Department of Agriculture fined Covance $8,720 for 16 citations, three of which involved lab monkeys the other citations involved administrative issues and equipment. [253] [254]

Threats to researchers Edit

Threats of violence to animal researchers are not uncommon. [ vague ] [255]

In 2006, a primate researcher at the University of California, Los Angeles (UCLA) shut down the experiments in his lab after threats from animal rights activists. The researcher had received a grant to use 30 macaque monkeys for vision experiments each monkey was anesthetized for a single physiological experiment lasting up to 120 hours, and then euthanized. [256] The researcher's name, phone number, and address were posted on the website of the Primate Freedom Project. Demonstrations were held in front of his home. A Molotov cocktail was placed on the porch of what was believed to be the home of another UCLA primate researcher instead, it was accidentally left on the porch of an elderly woman unrelated to the university. The Animal Liberation Front claimed responsibility for the attack. [257] As a result of the campaign, the researcher sent an email to the Primate Freedom Project stating "you win", and "please don't bother my family anymore". [258] In another incident at UCLA in June 2007, the Animal Liberation Brigade placed a bomb under the car of a UCLA children's ophthalmologist who experiments on cats and rhesus monkeys the bomb had a faulty fuse and did not detonate. [259]

In 1997, PETA filmed staff from Huntingdon Life Sciences, showing dogs being mistreated. [260] [261] The employees responsible were dismissed, [262] with two given community service orders and ordered to pay £250 costs, the first lab technicians to have been prosecuted for animal cruelty in the UK. [263] The Stop Huntingdon Animal Cruelty campaign used tactics ranging from non-violent protest to the alleged firebombing of houses owned by executives associated with HLS's clients and investors. The Southern Poverty Law Center, which monitors US domestic extremism, has described SHAC's modus operandi as "frankly terroristic tactics similar to those of anti-abortion extremists," and in 2005 an official with the FBI's counter-terrorism division referred to SHAC's activities in the United States as domestic terrorist threats. [264] [265] 13 members of SHAC were jailed for between 15 months and eleven years on charges of conspiracy to blackmail or harm HLS and its suppliers. [266] [267]

These attacks—as well as similar incidents that caused the Southern Poverty Law Center to declare in 2002 that the animal rights movement had "clearly taken a turn toward the more extreme"—prompted the US government to pass the Animal Enterprise Terrorism Act and the UK government to add the offense of "Intimidation of persons connected with animal research organisation" to the Serious Organised Crime and Police Act 2005. Such legislation and the arrest and imprisonment of activists may have decreased the incidence of attacks. [268]

Scientific criticism Edit

Systematic reviews have pointed out that animal testing often fails to accurately mirror outcomes in humans. [269] [270] For instance, a 2013 review noted that some 100 vaccines have been shown to prevent HIV in animals, yet none of them have worked on humans. [270] Effects seen in animals may not be replicated in humans, and vice versa. Many corticosteroids cause birth defects in animals, but not in humans. Conversely, thalidomide causes serious birth defects in humans, but not in animals. [271] A 2004 paper concluded that much animal research is wasted because systemic reviews are not used, and due to poor methodology. [272] A 2006 review found multiple studies where there were promising results for new drugs in animals, but human clinical studies did not show the same results. The researchers suggested that this might be due to researcher bias, or simply because animal models do not accurately reflect human biology. [273] Lack of meta-reviews may be partially to blame. [271] Poor methodology is an issue in many studies. A 2009 review noted that many animal experiments did not use blinded experiments, a key element of many scientific studies in which researchers are not told about the part of the study they are working on to reduce bias. [271] [274] A 2021 paper found, in a sample of Open Access Alzheimer Disease studies, that if the authors omit from the title that the experiment was performed in mice, the News Headline follow suit, and that also the Twitter repercussion is higher. [275]

Most scientists and governments state that animal testing should cause as little suffering to animals as possible, and that animal tests should only be performed where necessary. The "Three Rs" [63] [135] are guiding principles for the use of animals in research in most countries. Whilst replacement of animals, i.e. alternatives to animal testing, is one of the principles, their scope is much broader. [276] Although such principles have been welcomed as a step forwards by some animal welfare groups, [277] they have also been criticized as both outdated by current research, [278] and of little practical effect in improving animal welfare. [279]

The scientists and engineers at Harvard's Wyss Institute have created "organs-on-a-chip", including the "lung-on-a-chip" and "gut-on-a-chip". Researchers at cellasys in Germany developed a "skin-on-a-chip". [280] These tiny devices contain human cells in a 3-dimensional system that mimics human organs. The chips can be used instead of animals in in vitro disease research, drug testing, and toxicity testing. [281] Researchers have also begun using 3-D bioprinters to create human tissues for in vitro testing. [282]

Another non-animal research method is in silico or computer simulation and mathematical modeling which seeks to investigate and ultimately predict toxicity and drug affects in humans without using animals. This is done by investigating test compounds on a molecular level using recent advances in technological capabilities with the ultimate goal of creating treatments unique to each patient. [283] [284]

Microdosing is another alternative to the use of animals in experimentation. Microdosing is a process whereby volunteers are administered a small dose of a test compound allowing researchers to investigate its pharmacological affects without harming the volunteers. Microdosing can replace the use of animals in pre-clinical drug screening and can reduce the number of animals used in safety and toxicity testing. [285]

Additional alternative methods include positron emission tomography (PET), which allows scanning of the human brain in vivo, [286] and comparative epidemiological studies of disease risk factors among human populations. [287]

Simulators and computer programs have also replaced the use of animals in dissection, teaching and training exercises. [288] [289]

Official bodies such as the European Centre for the Validation of Alternative Test Methods of the European Commission, the Interagency Coordinating Committee for the Validation of Alternative Methods in the US, [290] ZEBET in Germany, [291] and the Japanese Center for the Validation of Alternative Methods [292] (among others) also promote and disseminate the 3Rs. These bodies are mainly driven by responding to regulatory requirements, such as supporting the cosmetics testing ban in the EU by validating alternative methods.

The European Partnership for Alternative Approaches to Animal Testing serves as a liaison between the European Commission and industries. [293] The European Consensus Platform for Alternatives coordinates efforts amongst EU member states. [294]

Academic centers also investigate alternatives, including the Center for Alternatives to Animal Testing at the Johns Hopkins University [295] and the NC3Rs in the UK. [296]

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Cancer Biology

Faculty in this research area share a strong interest and broad expertise in molecular and clinical aspects of the prevention, development, diagnosis and treatment of cancer. Some are clinicians treating pets at the Flint Animal Cancer Center and collaborating with the human medical field to translate research discoveries into new treatments for both people and animals. Others leverage molecular and genetic approaches to define the molecular mechanisms underlying genetic instability associated with cancer. Nutrition and other environmental influences, particularly radiation, are also a major focus for cancer biology researchers in CMB.

Faculty

J Lucas Argueso
Associate Professor (Environmental & Radiological Health Sciences)
Molecular mechanisms of Copy Number Variation (CNV) and other chromosomal rearrangements. Genomics of industrial yeast strains

Susan M. Bailey
Professor (Environmental & Radiology Health Sciences)
Role of dysfunctional telomeres in tumorigenesis. NASA Twins Study.

Jennifer G. DeLuca
Professor (Biochemistry & Molecular Biology)
Mechanisms of Mitotic Chromosome Segregation.

Steven W. Dow
Professor (Microbiology, Immunology & Pathology and Clinical Sciences)
Developing new immunotherapies to treat cancer, including cancer vaccines, repurposed immunotherapy drugs, and checkpoint targeted immunotherapies. Rodent models, dog cancer clinical trials, and collaborative studies in human clinical trials.

Dawn L. Duval
Associate Professor (Clinical Sciences)
Molecular mechanisms of carcinogenesis and metastasis in osteosarcoma and breast cancer .

Nicole Ehrhart
Professor (Clinical Sciences)
Limb preservation musculoskeletal sarcoma orthopaedic oncology bone regeneration, and tissue engineering.

David D. Frisbie
Professor (Clinical Sciences)
In vitro and in vivo approaches to diagnostic and therapeutic musculoskeletal disease.

Daniel L. Gustafson
Professor (Clinical Sciences)
Cancer pharmacology, pharmacokinetics and toxicology.

Jeff Hansen
Professor (Biochemistry & Molecular Biology)
Higher order chromatin structure and chromatin architectural proteins.

Takamitsu Kato
Associate Professor (Environmental & Radiological Health Sciences)
DNA damage and repair after environmental stress including ionizing radiation, ultraviolet light, heat, mutagenic and carcinogenic compounds.

Steven Markus
Assistant Professor (Biochemistry & Molecular Biology)
Mechanisms regulating motor based transport in cells during mitosis

Jean Peccoud
Professor (Chemical & Biological Engineering)
Predictive models of the phenotype encoded in natural and synthetic DNA sequences.

Dan Regan
Assistant Professor (Microbiology, Immunology & Pathology)
Interplay between the immune system and tumor stroma. Resistance to therapy.

Elizabeth Ryan
Associate Professor (Environmental & Radiological Health Sciences)
Interactions of food components with gut microbiota and the immune system.
.

Douglas H. Thamm
Professor (Clinical Sciences)
Signal transduction and its inhibition in comparative cancer models.

Henry J. Thompson
Professor (Horticulture & Landscape Architecture)
Biochemical and molecular approaches to cancer prevention preclinical models and clinical investigations.

Tiffany Weir
Associate Professor (Food Science & Human Nutrition)
Role of microbes in ecosystems ranging from soils to processed food products to the human gut.

Claudia Wiese
Assistant Professor (Environmental & Radiological Health Sciences)
Molecular mechanisms of DNA repair, genome integrity, and cancer avoidance.

TingTing Yao
Associate Professor (Biochemistry & Molecular Biology)
Regulation of gene expression and chromatin dynamics by the ubiquitin – proteasome pathway.

Affiliate Faculty

Affiliate Faculty serve as committee members or participate in the program in other ways but are not currently taking CMB students in their labs.

James R. Bamburg
Professor (Biochemistry and Molecular Biology)
Regulation of the cytoskeleton in neuronal growth and pathfinding signal transduction pathways regulating actin dynamics abnormalities in actin behavior in neurodegenative diseases.

Robert Cohen
Professor (Biochemistry & Molecular Biology)
Regulation of ubiquitin – dependent signaling, protein degradation, and deubiquitination.

Charles S. Henry
Professor (Chemistry)
Bioanalytical chemistry chemical separations and chemical nature of disease.

Susan Kraft
Professor (Environmental & Radiological Health Sciences)
Cancer imaging, Magnetic Resonance Imaging and spectroscopy, radiation therapy and neuroradiology.

Susan M. LaRue
Professor (Environmental & Radiological Health Sciences)
Experimental therapeutics hyperthermia tumor physiology tumor cytogenetics.

Paul J. Laybourn
Professor (Biochemistry and Molecular Biology)
The mechanism of transcription regulation in a chromatin context.

Amy MacNeill
Associate Professor, (Microbiology, Immunology & Pathology)
Isolation and characterization of canine and feline tumor cells and the study of poxviruses as anticancer agent

Jac A. Nickoloff
Professor (Environmental & Radiological Health Sciences)
Cellular processes that maintain eukaryotic genome stability, including homologous recombination, nonhomologous end – joining and other DNA repair processes.

Rodney Page
Professor (Clinical Sciences)
Director of the Flint Animal Cancer Center.

Ashok Prasad
Associate Professor (Chemical and Biological Engineering and School of Biomedical Engineering)
Mathematical and computational modeling of biological processes.

Sandra L. Quackenbush
Professor, (Microbiology, Immunology & Pathology)
Viral pathogenesis, particularly viral – induced oncogenesis.

Laurie A. Stargell
Professor & Chair (Biochemistry & Molecular Biology)
Mechanisms of transcription initiation in yeast

Michael M. Weil
Professor (Environmental & Radiological Health Sciences)
Genetic susceptibility to radiation – induced cancers.

Coursework

ERHS / VS 510 Cancer Biology
ERHS 611 Cancer Genetics
ERHS 733 Environmental Carcinogenesis
VS 780 Cancer Biology Clinical Practicum

ERHS 530 Radiological Physics and Dosimetry I
ERHS 630 Radiological Physics and Dosimetry II
ERHS 550 Principles of Radiation Biology
ERHS 701 Advanced Diagnostic Imaging Modalities
EHRS 714 Radiation Therapy Physics

Resources & Facilities

CMB Students

Joseph Stewart (ArguesoLab)
(PhD, 2019 Cohort)
LinkedIn

Sam Brill (Thamm Lab)
NIH Medical Scientist Training Fellowship
LinkedIn

Katie Cronise (Duval Lab)
PRSE Fellow, Summer 2020

Suad Elmegerhi (Kato Lab)
LinkedIn

Alissa Mathias (Regan Lab)
Summer 2019 Cancer Biology & Comparative Oncology Fellow
LinkedIn

Sean Merriman (Argueso Lab)
LinkedIn

Lisa Schlein DVM (Thamm Lab)
CCTSI – TL1 – TOTTS Fellow 2018 – 19
LinkedIn

Platon Selemenakis (Wiese Lab)
LinkedIn

Alumni

Ilham Alshiraihi (Brown Lab)

Taghreed Al Turki (Bailey Lab)
Post-doctoral fellow at UNC Lineberger in the Griffith Lab

Matt Dilsaver (Markus Lab)
Scientist at Sartorius laboratory
LinkedIn

Amy Hodges (DeLuca Lab)

Jared Luxton (Bailey Lab)
Summer 2019 Cancer Biology & Comparative Oncology Fellow
LinkedIn

Elena Pires (Wiese Lab)
Completing DVM at Colorado State University

Nouf Alyami (PhD 2019, Duval Lab)

Nora Jean Nealon (PhD 2019 Ryan Lab) – Completing DVM at Colorado State

Genevieve Hartley (PhD 2018 Dow Lab) – Post-doctoral Fellow at MD Anderson Cancer Center

Lyndah Chow (PhD 2018 Dow Lab) – Post-doctoral Fellow at Colorado State University

Hailey Sedam (PhD 2018, Argueso Lab) – Post – doctoral Fellow, University of New Mexico

Nadia Sampaio (PhD 2018, Argueso Lab) – Post-doctoral Fellow Boston University

Tymofiy Lutsiv (MS 2018, Thompson Lab) – PhD program at Loyola University

Miles McKenna (PhD 2017, Bailey Lab) – Bioscience Specialist at Nikon Instruments

Christopher Nelson (PhD 2017, Bailey Lab) – Post – doctoral Fellow Children’s Medical Institute, Sydney, Australia

Melissa Edwards (PhD 2016, Brown Lab) – Associate Director, Office of Undergraduate Research and Artistry, CSU


Cancers of the Blood and Hemopoietic and Lymphatic Systems

Leukemias can be detected in the living animal by examining blood samples for the presence of circulating cancer cells or changes in the cellular constituents of the blood. Increases in circulating tumor cells or changes in blood constituents can forecast the onset of clinical symptoms. When human leukemia cells are engrafted into immunodeficient mice, the number of circulating human cancer cells is less predictive of either the onset or severity of clinical symptoms. In the absence of reliable laboratory-based assays, animals with leukemia or lymphomas should be observed for early clinical signs such as anemia, loss of condition or weight, and enlargement of the spleen and lymph nodes. Scientific endpoints should precede limiting clinical signs such as consistent weight loss, clinical anemia, apathy, impaired respiration, or death.


  • Maria L. Cayuela, Hospital UniversitarioV. De La Arrixaca-IMIB-FFIS, Murcia, Spain
  • Martin Distel, Children’s Cancer Research Institute, Wien, Austria
  • Claudia Legerke, DBM, Universitätsspital Basel, Switzerland
  • Burkhard Luy, Karlsruhe Institute of Technology, Germany
  • Victor Mulero, University of Murcia, Spain
  • Sergio Roman Roman (Institut Curie, Paris) and the UM Cure Consortium
  • Alex Rosch, Universitätsklinikum Essen, Germany
  • Dirk Sieger, Centre for Neuroregeneration, The University of Edinburgh, U.K.
  • Uwe Strahle, Karlsruhe Institute of Technology, Germany

Mayrhofer M, Gourain V, Reischl M, Affaticati P, Jenett A, Joly J.S, Benelli M, Demichelis M, Poliani P.L, Sieger D, Mione M*. A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth, Disease Models & Mechanisms 2016 : doi: 10.1242/dmm.026500

Anelli V, Mione M*. Melanoma niche formation: it is all about melanosomes making CAFs. Pigment Cell Melanoma Res. 2016 Oct 23. doi: 10.1111/pcmr.12545. [Epub ahead of print]

Schutera M, Dickmeis T, Mione M*, Peravali R, Marcato D, Reischl M, Mikut R, Pylatiuk C. Automated phenotype pattern recognition of zebrafish for high-throughput screening. Bioengineered. 2016 Jul 37(4):261-5. doi: 10.1080/21655979.2016.1197710.

Mayrhofer M, Mione M*. The toolbox for conditional zebrafish cancer models. In: Cancer and Zebrafish: Mechanisms, Techniques and Models. Ed. Langenau, Springer, Adv Exp Med Biol. 2016916:21-59. doi: 10.1007/978-3-319-30654-4_2

Arbizzani F, Mayrhofer M, Mione M*. Novel transgenic lines to fluorescently label clathrin and caveolin endosomes in live zebrafish. Zebrafish. 2015 Apr12(2):202-3

Mione M*, Bosserhoff A. MicroRNAs in melanocyte and melanoma biology. Pigment Cells & Melanoma Research 2015 May28(3):340-54

Alghisi E, Distel M, Malagola M, Anelli V, Santoriello C, Herwig L, Krudewig A, Henkel C, Russo D, Mione MC* Targeting oncogene expression to endothelial cells induces proliferation of the myeloerythroid lineage by repressing the notch pathway. Leukemia, 2013, 27(11):2229-41

Mione M*, Zon LI: Cancer and inflammation: an aspirin a day keeps the cancer at bay. Curr Biol. 2012 Jul 1022(13):R522-5.

Feng Y, Santoriello C, Mione M*, Hurlstone A*, Martin P.* Live imaging of innate immune cell sensing of transformed cells in zebrafish larvae: parallels between tumor initiation and wound inflammation. PLoS Biol. 2010 Dec 148(12):e1000562.

Santoriello C, Gennaro E, Anelli V, Distel M, Kelly A, Köster RW, Hurlstone A, Mione M.* Kita driven expression of oncogenic HRAS leads to early onset and highly penetrant melanoma in zebrafish. PLoS One. 2010 Dec 105(12):e1517

Mione MC*, Trede NS. The zebrafish as a model for cancer. Dis Model Mech. 2010 Sep-Oct3(9-10):517-23.​

Anelli V, Santoriello C, Distel M, Köster RW, Ciccarelli FD, Mione M.* Global repression of cancer gene expression in a zebrafish model of melanoma is linked to epigenetic regulation. Zebrafish. 2009 Dec6(4):417-24.


Additional Information on Humane Endpoints

  • Ulcerated, necrotic tissue is one of the most common findings in tumor models. Ulcerated or necrotic tissue may result in a continuous seepage of body fluids and predisposes to infection. It is inconsistent with sound research to allow the tumor to proceed to the point of ulceration and necrosis unless this is the phenomenon under study.
  • Weight loss/cachexia: Implanted or naturally occurring tumors may cause weight loss in the host animal due to their nutritive demands or due to loss of well-being causing anorexia. A recommended humane endpoint is a body weight loss of no more than 20% of pre-procedural weight in adult rodents. In the live animal, this has to be estimated, since the tumor cannot be weighed apart from the host. Animal on tumor studies must be weighed at least weekly and documented and records available for veterinary staff.
  • Restlessness/inability to get comfortable is an indication of severe pain and requires immediate attention either with administration of analgesics or euthanasia.
  • Self-mutilation lack of grooming behavior rough/unkempt hair coat is an indication that the animal is not well and requires daily monitoring and attention
  • The professional judgment and decision of the attending veterinarian is final.

References

  1. Boston University IACUC Policy on Tumor Guidelines for Rats and Mice
  2. NCI Frederick ACUC Guidelines Involving Experimental Neoplasia Proposals in Mice and Rats, 2006.
  3. Wallace, J. (2000). Humane Endpoints and Cancer Research. ILAR 41(2).
  4. Humane Endpoints and Cancer Research. ILAR 41(2), 2000.

BU IACUC Approved November 2008, Revised January 2014
Post-Procedure Monitoring Form

  • Procedures
    • Adjuvants
    • Administration Of Drugs and Experimental Compounds in Mice and Rats
    • Ascites
    • Blood Collection Guidelines
    • Biological Materials in Rodents
    • Body Condition Scoring for Mice
    • Collection of tissues for genotyping
    • Irradiation of Rodents
    • Osmotic Pumps in Mice and Rats
    • Search for Alternatives (IACUC)
    • Surgery: Aseptic
    • Surgery: Rodent
    • Thioglycollate
    • Tumor Policy for mice and rats
    • Use of Pharmaceutical-grade chemicals and other substances (IACUC)

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