A recent editorial called "Why Science Needs Female Mice" by the New York Times Editorial Review Board relies on a new study published in Nature Neuroscience by Robert Sorge and his colleagues titled "Different immune cells mediate mechanical pain hypersensitivity in male and female mice."
The abstract for this essay reads: "A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research."
While I have some expertise in the matters raised by the Times editorial, my co-author on this essay, Dr. Hope Ferdowsian, has considerably more, thus, I'm pleased to write this piece with her. The Times editorial notes that the study by Dr. Sorge and his colleagues suggests that experiments involving male animals may not hold up in women. What the editorial and the journal article neglect to note is that numerous experiments on male and female non-human animals (animals) fail to reliably hold up in humans, and many prominent researchers have argued we need to develop non-animal models in order to learn more about serious diseases from which numerous humans suffer.
"To understand sepsis, you have to go to the patients"
Let's look at some of the data. In the past several years, one story after another has revealed the failures in translating animal experiments to human health benefits. Systematic reviews and meta-analyses have shown that findings in animals are not reliably replicated in human cardiovascular, neurological, and infectious disease clinical research (please see Hackam and Redelmeier 2006); Perel et al. 2006; Bailey 2008) -- among other areas of research. In 2013, Massachusetts General Hospital's Dr. H. Shaw Warren published a landmark report exposing how mice experiments are misleading for at least three major killers -- sepsis, burns, and trauma. Dr. Warren's concerns were summarized in an essay by Gina Kolata, also published in the New York Times in February 2013, called "Mice Fall Short as Test Subjects for Some of Humans' Deadly Ills."
Ms. Kolata's piece summarized a study by a large group of researchers that showed how genomic responses in mouse models poorly mimic human inflammatory diseases. She notes, "The group had tried to publish its findings in several papers. One objection, Dr. Davis [the lead researcher] said, was that the researchers had not shown the same gene response had happened in mice." Furthermore, she writes, "'They were so used to doing mouse studies that they thought that was how you validate things,' he [Dr. Davis] said. 'They are so ingrained in trying to cure mice that they forget we are trying to cure humans.'" And, "The drug failures became clear. For example, often in mice, a gene would be used, while in humans, the comparable gene would be suppressed. A drug that worked in mice by disabling that gene could make the response even more deadly in humans."
Dr. Richard Hotchkiss, who studies sepsis at Washington University (St. Louis), stressed, that the above study argues strongly, "To understand sepsis, you have to go to the patients."
"We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans"
The failure of animal models is rather widespread, and other prominent researchers have also noted the problems with using animals in psychiatric research. Even former National Institutes of Health (NIH) Director Elias Zerhouni, a prominent physician and researcher, commented on the problem of relying on animal experiments -- including "knock-out" mouse experiments -- stating: "We have moved away from studying human disease in humans...We all drank the Kool-Aid on that one, me included...The problem is that it hasn't worked, and it's time we stopped dancing around the problem...We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans." Most vaccines and medicines available today have been tested on animals because of legal and regulatory requirements. However, suggestions that experiments on animals have causally advanced successful treatments for humans have come under increased scrutiny in recent years, based on empirical evidence, evolutionary theory, and our broadening knowledge of how genetic factors are influenced by the environment.
Many diseases introduced into animals do not sufficiently mimic disease processes seen in humans. Within species, natural selection pressures result in organizational complexity and very specific adaptive changes. As a result, some animals are either resistant to certain diseases or they have different mechanistic responses to diseases. Humans and other animals share abstract qualities, such as those required for survival, but there are differences in molecular mechanisms and pathways that commonly determine how diseases manifest, and which therapeutics work. Though humans share genetic material with other animals, even subtle differences in gene location and sequence and gene-environment interactions can result in substantial differences in gene expression and regulation.
Even experiments involving similar nonhuman species have shown that studies in mice, rats, and rabbits agree only a little more than half of the time (please see Hartung and Rovida 2009). Findings like these have led to a shift in the practice of toxicology, toward a more evidence-based standard that relies on human data, in vitro studies, and computational methods that more accurately predict toxic effects in humans. And, although scientists try to control animals in laboratories, the unnatural environment of a laboratory introduces the confounding influence of stress, which can affect disease development and how animals respond to various interventions.
Attitudes toward animals are also changing, and now is the time for action. As per a recent nonpartisan Pew Research Poll, a solid 50 percent of people surveyed now oppose the use of animals in laboratory experimentation -- an all-time high in the public opinion research literature.
The use of billions of mice and other "lab animals" continues despite what we know about their advanced cognitive and emotional capacities. Mice, for example, display empathy and are highly sentient beings. So too are rats and other commonly used lab animals. Yet, The federal Animal Welfare Act does not recognize them as animals. Dr. Ferdowsian and I realize that some might be incredulous to learn that mice and rats aren't animals but a quote from the federal register does in fact read, "We are amending the Animal Welfare Act (AWA) regulations to reflect an amendment to the Act's definition of the term animal. The Farm Security and Rural Investment Act of 2002 amended the definition of animal to specifically exclude birds, rats of the genus Rattus, and mice of the genus Mus, bred for use in research" (Vol. 69, no. 108, 4 June 2004).
We all should be very concerned with the continued use of a wide variety of animals in biomedical research, not only because billions of sentient beings suffer a good deal of harm and death, but also because of the reliability of the data that are amassed. And, as we've noted above, numerous prominent researchers agree it's time to move on and to use non-animal techniques that are currently available and to develop new techniques that do not use other animals and to focus on those that will produce results that actually help humans. There are numerous non-animal alternatives that are extremely reliable (please also see), and it's about time they are used. We really don't need to use mice of either sex to help humans.