In 1966, a
Scottish farmer caught a mouse in his barn. This, by itself, was not an
altogether rare or even strange occurrence. What made this particular event
noteworthy was that this mouse had no hair whatsoever, no fur, no whiskers,
nothing. Befuddled, the farmer brought his discovery to the local university,
hoping to gain some insight regarding any potential dangers to his crops or
livestock. Instead he contributed to the discovery of what has perhaps become
one of the most under-appreciated tools in medical research. Everyone has heard
of PCR and CAT-scans and gene-arrays are all the rage in today's research
environments. But the nude mouse marries the complexity of a whole, living
organism, to the ability to grow and treat an entire milieu of different
conditions from parasite infections to cancer in a single
model.
The
existence of the nude mouse results from the mutation of a single gene. This
mutation leads to abnormal keratinization of hair within the animal's
follicles, but more importantly to the malformation of an endocrine and
immunoactive organ called the thymus.
Lack of a functioning thymus is what makes the nude
mouse so interesting for immunological research, since this abolishes the
rejection reflex - the tendency of organisms to immunologically reject foreign
tissues introduced into them.
Before the advent of the nude mouse, the study of human tumors
was conducted either in naturally occurring or artificially created systems.
Artificially created systems, such as tissue culture - growing tumor cells in
flasks full of well defined growth media - are the least desirable of the two,
since information to be derived from them is limited by their very nature,
nevertheless, they are cheap, easy and quick to implement. Naturally occurring
systems, such as pharmacologically induced tumors in animals yield far more
detailed information, but raise different issues, such as just how applicable
results obtained in animals are to human disorders, at the same time that they
are difficult to control and expensive to conduct
thoroughly.
If
neither growing and treating tumor cells in culture nor inducing tumors in
animals are suitable model systems for studying treatment of human cancers, a
more complete model had to be described.
While the nude mouse was first described in 1966, the
absence of a thymus in this animal was not shown until 1969. This immediately
sparked interest in cancer research and immunology laboratories that had been
struggling with inferior growth models. The idea of monitoring the growth of
human tumors in a biological system as complex as a living mammal became a
reality in the nude mouse.
Since the nude mouse lacks a thymus, it also lacks the
T-cell-mediated rejection reflex. Because of this, human cancer cells can be
injected into the nude mouse, where they grow into full tumors. The most
important aspect of this is that, while the host organism for the tumor is a
mouse, albeit nude, the tumor remains human. This is a distinct departure from
past animal models that were based on inducing animals to produce their own
tumors.
This
opened the door to countless possibilities for drug therapy research. Suddenly,
we could study the true growth characteristics of human tumors. For the first
time, we could personalize care to patients based on how their mouse-bound
tumors reacted to available or even experimental pharmaceuticals, without
having to experiment blindly on the patient himself. At last, drug regimens
that had been considered too risky to try in patients could be tested in a
viable system with appreciable results.
In the very beginning, immunologists
were the most interested in the potential of the nude mouse. They used the nude
mouse to show that in certain parasitological diseases, like trypanosomiasis,
death was caused not by the parasite itself, but through the immune response to
the parasite. In fact, if a thymus were transplanted into nude animals infected
with Trypanosoma, effectively reconstituting a whole animal, that animal would
soon die, a victim of its own immune system.
When first described, the nude mouse seemed like a
perfect model for studying leprosy, since Mycobacterium leprae (the pathogen
that causes leprosy) is inhibited by the action of T-lymphocytes, which are
produced by the thymus gland. At the time, however, the animals available for
research were too sickly and too short-lived for the research to show any
significant difference in the infection rates of the nude mouse as compared to
its normal counterpart. Discouraged, leprosy researchers decided that nude mice
were not appropriate for their research, until, in 1976, investigators at St.
George's Hospital Medical School in London demonstrated that animals surviving
beyond six months showed significant worsening of the induced infection as well
as dissemination to multiple distant organs. This discovery sparked a flood of
new studies that have, in the intervening years, led to the partial control of
this horrible wasting disease.
Researchers at Memorial Sloan-Kettering Cancer Center in New
York used the nude mouse as a model for pneumonia caused by Pneumocystis
carinii in compromised hosts, such as patients with primary immune-deficiency
diseases or cancer patients receiving immune-suppressant therapy. They managed
to model it superbly in the nude mouse and because of this it has since been
able to be treated much more successfully than before.
Primary interest in the nude mouse was as a model for
human cancers. When introduced to the scientific community as a significant
improvement on contemporary methods of cancer research, several steps had to be
taken to show that results obtained using this new tool were clinically
relevant to humans. First, it had to be demonstrated that the tumors growing in
the animals were actually human. Differentiating between human and mouse
proteins accomplished this. The results in the mouse then had to be shown to
mimic those obtained in human studies. This last was demonstrated both at the
patient level and at the global level in massive studies undertaken in the
early 1980s, showing that 80-85% of tumors grown in the nude mouse responded in
the same way as they did in human patients when exposed to some of the major
chemotherapeutic agents available at the time.
Since the development of the nude
mouse model for cancer studies, we have grown, tracked and treated hundreds of
different tumors in the mice. This is important because human tumors grown in
the mouse do not cease to be human. They may be growing in a murine host, but
the tumor cells are still human and can still be affected by everything that
would affect them in the patient's body. By using these experiments,
researchers are able to tailor drug use to the specific needs of their
patients. There is a great likelihood that any given patient will respond to a
drug or drug combination that successfully treated their tumor after it had
been injected into nude mice. In addition non-traditional drug regimens and
combinations can be experimented with to provide the highest likelihood of
success when treating the patient.
Before new types of drugs are introduced to the
market, before they are even brought close to human subjects or patients, they
have to be tested on animals. The drugs are tested first for toxicity and
subsequently for efficacy against the disease they are designed for. This
process is doubly important for cancer chemotherapeutic drugs, since they are,
as a rule, much more toxic than most other pharmaceutical agents. For these
drugs it is imperative to study the effects on human tumor cells, but the
untested pharmaceutical is too dangerous to administer to patients. The answer
to this dilemma was found in the nude mouse. Now drug developers were able to
test their drugs against actual human tumors while in a system complex enough
to approximate human physiology without having to endanger human lives to do
so.
Because of its
resounding success as a tumor research and treatment tool, some failings of the
nude mouse were also uncovered. While some types of tumors, like melanomas,
colon and lung cancers, were able to take and grow very easily in the nude
mouse, other types were much more difficult to grow: only 6% of tested breast
cancers took, while virtually no leukemias were able to proliferate. Lymphomas
grew only in the brain of the nude mouse, except for Burkitt lymphomas that
grow easily wherever they were implanted.
Another confounding factor in nude mouse cancer
research is that the animals may develop spontaneous tumors themselves, mostly
late in life. There is about an 8% spontaneous tumor rate in nude animals,
mostly lymphomas and pulmonary adenomas, which can mislead researchers
investigating human tumors.
Some of these issues have led researchers to try to improve on
the paradigm introduced with the nude mouse. A severe combined immune
deficiency (SCID) has been genetically introduced to a group of mice, but
proved to be a very 'leaky' mutation, i.e. it was not inherited in a stable
manner and the researchers who used it had to always be on guard to make sure
that the animals they were working with were expressing the SCID
character.
In the
Triple Deficient (TripleD) mouse, three distinct genes have been engineered to
give the animal a much greater immune deficiency than the nude mouse, whose
immune deficiency is mediated by a single gene. The TripleD mutations are
stably inherited from generation to generation of mouse, but, strangely, the
percentages of tumors that take in the mouse are no greater than those apparent
in the nude mouse. This information would seem to point towards a response
other than the rejection reflex mediated by the thymus being responsible for
whether tumor cells are able to proliferate in immunologically distinct
hosts.
Many
laboratories today are targeting immune response genes to produce genetically
engineered mice or rats that are deficient in these areas. In this way,
specific animals can be produced which would suit the needs of whatever
research is being conducted at any given time.
The nude mouse has now become a staple
of medical research. Its existence has furthered our understanding of disease
processes, such as leprosy, pneumonia, immune deficiency and cancer. Thanks in
part to work done in the nude mouse, the 16th International Leprosy Congress
announced, "the prospect of eliminating leprosy from every country in the world
is tantalizingly close." Cancer research conducted using the nude mouse has
become such a reliable tool that the Food and Drug Administration now requires
any prospective oncological drug to supply pre-clinical response data in this
model.
And to
think that all this began when a farmer brought a strange looking animal into a
university laboratory.
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