Since Congress mandated testing of new medicines and chemicals on animals
back in 1937, billions of laboratory animals have been subjected to a vast
number of chemicals and medicinal compounds — all under the entrenched
belief that this “safety testing” is translatable to human animals;
a concept known as the concordance assumption.
But a recent study
by a consortium of medical researchers (Seok et al) and published on the
Proceedings of the National Academy of Sciences website, throws the assumption
of concordance into serious doubt. To be sure, there has been a scattering
of previous studies* casting doubt on this concordance theory (and pharmaceutical
companies have know for quite some time that most new drug candidates first
tested on “animal models” fail to work when tested on humans),
but this most recent study is the most comprehensive yet conducted.
Its wider implications
cast serious doubt on seventy plus years of safety research upon which we
base our notions of “safe” medicines and chemicals verses unsafe
ones. The ramification of this most recent study are sure to have major
impact on the current testing practices of the medical, chemical, and pharmaceutical
Study Results in More Detail
This particular research
was prompted by an investigation of 150 clinical trials of drugs begin tested
for treatment of inflammatory diseases (such as diabetes, arthritis, asthma).
Investigators found (to date) a 100% failure rate of these anti-inflammatory
drugs in these trials; all of the drugs were originally tested on mice.
To understand why this
was happening, the consortium decided to conduct further studies of the
effects of various treatments (that produced inflammation) and compare results
between humans and mice.
Looking first at acute
inflammation in mice resulting from three types of stimuli (bacterial toxins,
burns, and trauma), the investigators quantified changes in gene activity
(i.e., increased or decreased gene expression) in response to the stimuli
in thousands of genes.
Using the concordance
assumption (that mouse gene activity changes would be concordant with similar
gene changes in humans), the investigators expected that the gene activity
changes seen in mice would enable accurate predictions of similar changes
in humans. Yet this was not what the investigators discovered. Instead,
changes in a particular mouse gene, following drug treatment, failed to
predict changes in the closest-related (homologue) gene in humans.
revealed another significant difference: in humans, similar patterns of
gene activity in response to the stimuli were noted, but not in mice. Each
type of treatment stimulus in mice resulted in distinct gene activity changes
— confirming the earlier findings that similar treatments resulted
in different (gene) responses between humans and mice.
These differences could
not be attributed to experimental “noise”, according to the
consortium, but rather, they were the result of fundamental physiological
differences between mice and humans in how each responds to the various
More Experimental Results
The consortium investigators
next tested key biological signalling pathways (i.e., sequences of signals
within cells that trigger various functions) after similar treatments. Once
again, dissimilar cell signalling responses between mice and humans were
observed. Further testing on other human/mouse models of inflammatory diseases
also showed low correlations.
The experiments by
Seok et al confirm that, physiologically, humans and mice have little in
common and that mouse models (and presumably other animal models) are of
little clinical relevance in testing new treatments for human inflammatory
diseases, which are quite prevalent in humans (and include various allergies,
celiac disease, asthma, RA and other autoimmune diseases).
The results would seem
to be valid for other categories of human disease as well. However, for
carcinogenicity studies, most researchers consider mice an appropriate test
Of Mice and Men…and other Animal Models
Many researchers have
previously noted that there is a 120 million year difference in evolutionary
(genetic) change between mice and humans. Consequently, mice have distinct
immune systems and suffer from different diseases; they lack a gall bladder,
menstrual cycles, and have different metabolic rates and lifespans (which
are functions of their smaller size).
Thus, in most ways,
these experimental results should not come as a great shock.
The General Medical Research Implications of the Findings
The general implication
of these findings is that they most likely hold for other laboratory animals
as well: rats, rabbits, and dogs being the most common examples. However,
the experiments by Seok et al were not conducted on primates — monkeys
and chimps — which are genetically and physiologically much more similar
The objection to using
primates — and especially chimpanzees — in medical research
is primarily one of ethics: should we subject our closest evolutionary relatives
to what amounts to cruel and unusual treatment, that is, the confinement
in cages and the introduction of experimental chemicals or disease-causing
While these results do not mean that medical testing as we know it is finished,
it will force medical researchers to reevaluate their assumption about the
validity of using animal models to test new medical treatments that will
ultimately be used to treat human diseases.
It will also, no doubt,
call into question the wisdom of spending billions of dollars every year
on animal model testing of new drugs, and this will have a serious impact
on future funding (and the careers of many laboratory scientists).
New chemical testing
methodologies are emerging, but are yet to be fully validated. Although
one cannot expect a complete ban on animal testing any time soon, on a more
basic level, these findings may mean medical researchers will have to rely
more on clinical observation, better gene analysis techniques, and better
in vitro (human) cell models (cultures). These latter models are still undergoing
validation studies, but there has been at least one recent advance here.
So, What About the Impact on Toxicology Testing?
Beyond the medical
field, these results have serious implications for toxicology testing, for,
if the concordance assumption is false —
granted that the above experiments were not performed with synthetic chemicals
(but see references, below) — then current toxicology testing on animals
to determine human safety levels is probably invalid as well.
Our every day lives
are permeated with household and environmental products containing a vast
assortment of synthetic chemicals — most all of which have been tested
on non-human animals prior to their approval for use by humans.
If non-human animals
are poor models for predicting disease treatment effects in humans, can
they be valid test models for toxicology safety?
If the failure of concordance
in animal medical testing is applicable to general chemical safety testing
(ironically, another form of concordance) then this would mean that our
homes, food and environment are flooded with a dizzying assortment of essentially
untested (or invalidly tested) chemicals.
Further, if the concordance
assumption is generally false, meaning it is scientifically invalid, then
the entire regulatory process upon which we base our confidence in chemical
safety is seriously flawed.
Indeed, a recent
National Research Council study supports the argument that many chemical
safety tests are not relevant to humans.
It is hoped that these
findings will spur investment and investigation into alternative forms of
chemical safety testing that will ultimately, be less costly to all concerned.
The recent effort to
develop a so-called ‘human
on a chip’ (an expanded in silico variant of ‘organ on a chip’)
technology holds some promise here, but is also awaiting full validation
as a replacement for animal testing.
Main scientific reference
for this post: Genomic
responses in mouse models poorly mimic human inflammatory diseases (Seok
et al, 2013)
source material for this post came form the Truthout.org article (repost
Science News): The
Experiment Is on Us: Science of Animal Testing Thrown Into Doubt’
by Pat Dutt and Jonathan Latham, PhD.
References for further academic reading:
HK et al, 2007. Gene
expression signatures that predict radiation exposure in mice and humans.
PLoS Med 4:4.
Greek CR, Swingle Greek, J (2003). Specious science: Why Experiments on
Animals Harm Humans. The Continuum International Publishing Group, Ltd,
Knight A (2007) Systematic
reviews of animal experiments demonstrate poor human clinical and toxicological
utility. ATLA 35: 641-659.
Mestas, J and Hughes, CCW, (2004) Of mice and not men: differences between
mouse and human immunology, The Journal of Immunology, 172: 5.
Stoloff L (1992) An
analysis of the 1987 list of IARC-identified human carcinogens and the correlated
animal studies. Regulatory Toxicology and Pharmacology 15: 10–13