Genomic responses in mouse models poorly mimic human inflammatory diseases.
Beth Clifton collage
National Institutes of Health finding in 2013 presaged Wellcome
Foundation decision to close the Sanger Institute genetically modified mouse
lab by 2022
WASHINGTON D.C. (March 2013) Bluntly stated the headline in the February 11,
2013 edition of Proceedings of the National Academy of Sciences, “Genomic
responses in mouse models poorly mimic human inflammatory diseases.”
Echoing an article of faith prevailing among anti-vivisectionists for
several centuries, though not validated to biomedical researchers’
satisfaction by mouse studies, the report in this instance came from 10
years of investigation by 39 leading biomedical researchers, funded by the
U.S. National Institutes of Health––long the world’s leading sponsor and at
times the leading defender of animal-based research.
150 successes in mice failed in humans
Blogged NIH director Francis Collins, “If it works in mice, so we
thought, it should work in humans. But,” Collins recounted, “150 drugs that
successfully treated sepsis in mice later failed in human clinical trials.
Sepsis, a life-threatening systemic infection, can be caused by a variety of
pathogens, including bacteria, viruses, and fungi. Serious consequences
occur when tissues damaged by infection produce proteins sometimes called
‘alarmins’ that send the immune system into overdrive. Traumatic injuries
involving extreme blood loss or burns can set off the same dangerous
response.
“To probe the molecular response to all of these triggers,” Collins
explained, “the authors [of the study] took periodic blood samples from 167
trauma patients; 244 patients with burns over at least 20% of their body;
and four healthy volunteers who had been injected with a low-dose bacterial
toxin. Then they studied the activity of the genes in the white blood cells.
They found that of the 5,500 or so genes that responded to traumatic injury,
91% also played a role in burn response and recovery. About 45% of these
same genes were involved in recovery from the bacterial toxin exposure.
Mice use different genes to fight sepsis
“Mice, however, apparently use distinct sets of genes to tackle trauma,
burns, and bacterial toxins,” Collins continued. “When the authors compared
the activity of the human sepsis-trauma-burn genes with that of the
equivalent mouse genes, there was very little overlap. No wonder drugs
designed for the mice failed in humans: they were, in fact, treating
different conditions!
“But that doesn’t mean studying mice is useless,” Collins added. “Mice are
more resilient to infection and mount a much more regulated immune response
to pathogens than humans. Perhaps this is because mice nose around in some
filthy places and can’t afford to overreact to every microbe. If we knew how
these rodents limit the drama of their immune response, it might be useful
for us humans.
“But this study’s implications may well go beyond mice and sepsis,” Collins
allowed. “It provides more reason to develop better and more sophisticated
models of human disease.
Beth Clifton collage
“30% of all drugs successfully tested in animals fail in humans”
“More than 30 percent of all drugs successfully tested in animals fail in
human trials. The NIH plans to commit $70 million over the next five years,”
Collins announced, “to develop miniature 3-D organs made with living human
cells to help predict drug safety and efficacy. Though this is high-risk
research,” Collins acknowledged, “these ‘tissue chips’ may ultimately
provide better models of human disease and biology than the use of animals.”
Reported New York Times science writer Gina Kolata, “Sepsis afflicts 750,000
patients a year in the United States, kills one-fourth to one-half of them,
and costs the nation $17 billion a year. It is the leading cause of death in
intensive-care units.”
Skeptics
Despite the importance of the “Genomic responses” finding, however,
co-author Ronald W. Davis of Stanford University told Kolata that the team
tried for more than a year to publish their paper. “They submitted it to the
publications Science and Nature, hoping to reach a wide audience. It was
rejected from both,” Kolata wrote.
Scientific journal peer reviewers, said Davis, “were so used to doing mouse
studies that they thought that was how you validate things. They are so
ingrained in trying to cure mice that they forget we are trying to cure
humans.”
“When I read the paper, I was stunned by just how bad the mouse data are,”
University of California at Los Angeles sepsis expert Mitchell Fink told
Kolata. “I think funding agencies are going to take note,” Fink predicted.
“Until now, to get funding, you had to propose experiments using the mouse
model.”
“I would not consider the mouse as first choice model”
Two leading biomedical researchers told ANIMALS 24-7 that they had already
questioned the applicability of mouse studies to sepsis, burns, and trauma
in human patients.
“I can only say that I would not consider the mouse as first choice model
for the study of burns, since the anatomy of the mouse skin, and the gross
physiology of the mouse have less similarities to humans then, for instance,
the pig, and in particular the miniature hairless pig,” offered Gad Simon,
past editor of the Israel Journal of Veterinary Medicine and for more than
20 years a member of the Animal Experimentation Review Committee at the
Israel Institute for Biological Research.
“At least as far back as 1959 people were using mice for such studies,
dropping them in boiling water and then examining them for blisters and
toxins and God knows what. I saw such work with my own eyes,” recalled
Colorado State University at Fort Collins virologist Charles Calisher, who
said he had explosively disapproved of it even then, when animal studies
were much less often questioned.
“As to what the findings will mean for the future of mouse studies in
general, I do not know, of course. Mice are small and inexpensive, which I
presume are the reasons anyone uses them as models in the first place,”
Calisher said.
Millions of mice
Even if the findings in the “Genomic responses” paper influence only studies
of bacterial infection involving mice, mice are used in experiments so often
compared to all other animals that eliminating just 10% of mouse use would
spare as many animals as if all use of other species stopped entirely.
“Clearly ‘Genomic responses’ is very significant, and the New York Times was
right to report it on the front page,” American Anti-Vivisection Society and
Alternatives Research & Development Foundation president Sue Leary told
ANIMALS 24-7.
“This paper represents a trend,” Leary continued. “Similar studies have
looked at animal research methods for particular diseases and have found
problems almost as dramatic as the complete failure in inflammatory disease
research.
Forgot findings from Alzheimer’s research?
“The predominant mouse types used in Alzheimer’s research were shown to be
useless to the point that leading researchers were sent ‘back to the drawing
board.’ Comparable situations have been exposed recently in research on
stroke, multiple sclerosis, and asthma.
“At the Eighth World Congress on Alternatives & Animal Use in the Life
Sciences in 2011,” Leary recalled, “nearly 1,000 attendees agreed to the
‘Montreal Declaration,’ which is designed to examine the validity of
individual research proposals using animals and is gaining momentum.
“The important lesson [from ‘Genomic responses’] is that everyone needs to
challenge the assumptions behind routine approval of funding for research
and testing that uses animals. We saw that done successfully with the
publication in 2007 of the National Academy of Sciences report ‘Toxicity
Testing in the Twenty-first Century: A Vision and A Strategy.’
Beth Clifton collage
More investment in alternatives
“That comprehensive examination of the problems of the current, animal-based
methods in chemical safety assessment was commissioned by the Environmental
Protection Agency. Since then,” Leary said, “the EPA and other federal
agencies have invested much more in alternative technologies to be used
instead of animals.
“When AAVS and the Alternatives Research & Development Foundation conducted
our push in 1999 to ban the use of mice to produce monoclonal antibodies,
which are widely used in all kinds of research,” Leary recounted, “we drew
upon a growing scientific consensus about the benefits of alternative
methods. NIH ultimately declared that researchers should use in vitro
methods to produce monoclonal antibodies, unless they could provide a
detailed justification. Our understanding is that this development has
prevented the use of up to one million mice a year.”
Other medical fields
Researchers in some areas relatively far removed from sepsis, trauma, and
burns took immediate note of “Genomic responses.”
“A very interesting paper and I suspect sound. Of course it has to be tested
and validated by other researchers, but it smells correct,” Louisiana State
University epidemiology professor emeritus Martin Hugh Jones told ANIMALS
24-7.
“Really mind-blowing!” said Jack Woodall, a cofounder of the International
Society for Infectious Diseases’ Program for Monitoring Emerging Diseases.
Woodall recalled that for decades virologists injected extracts of blood and
tissues from humans, livestock and wildlife directly into the brains of baby
mice to isolate viruses, before tissue cultures were developed in the 1990s
that produced faster and more accurate results. “Baby mice were before that
[believed to be] the most sensitive system––it had nothing to do with
whether they reacted like people,” Woodall explained.
Alternatives
“The Humane Society of the U.S. and Humane Society International have urged
similar critiques of other areas of animal research,” said HSUS president
Wayne Pacelle. “For example, we have argued that there are major problems
with chimpanzee research and this was finally confirmed by the Institute of
Medicine last year. Leading research journals have published studies.
However,” Pacelle added, “it is important that we not simply focus on the
failures of the current animal research paradigm, but that we also encourage
the development of non-animal alternatives. We have launched the Human
Toxicology Project Consortium to make this vision a reality,” Pacelle said.
Commented Procter & Gamble toxicologist Harald Schlatter, “The ‘Genomic
responses’ finding is interesting, and needs to be verified over the coming
years in terms of its relevance and impact––primarily for drug development.
“However, I don’t think this impacts or relates directly to P&G, as we do
not test on sepsis, trauma, and burns,” Schlatter added. “We only explore
testing for very selected endpoints for which no alternatives exist yet.
Even for these, we are working to develop non-animal alternatives. We have
spent the last few decades investing over $300 million in the development of
over 50 alternative tests that are now used throughout the industry,
resulting in where we are today, with over 99% of our safety assessments
worldwide being conducted without animals.”
Education
Interniche representative Nick Jukes has for more than 10 years traveled the
world introducing non-animal teaching methods. The “Genomic responses”
findings, Jukes told ANIMALS 24-7, are “about pure research and the testing
of drugs, not a pedagogical issue. So it doesn’t directly correspond to our
work.
“However, there are of course connections between these fields,” Jukes
said. “The findings are another reminder that within human medicine we
should be focusing on human bodies and human tissue, and that is also true
within university-level education of medical students and within
professional training of doctors.”
The findings also “makes very clear that a lazy acceptance of convention is
far from scientific,” Jukes added.
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