Open Space
Unsuspecting Collaborators in Research in Medicine
In the history of medicine, biomedical research has been playing an increasingly relevant role, particularly on the level of contribution towards a better understanding of the mechanisms associated to illness and to the development of new therapies.
The laboratory work in the field of research, although subjected to considerable evolution in the machinery, techniques and utensils, has benefited from a particularly valuable coadjuvancy, which has become as influential as the unstoppable progress of the new biomedical technologies.
Although it is not timely in the scope of this short article to deal with certain problematic associated to bioethics, it is becoming necessary, however, to also mention the role of our “unsuspecting collaborators in research in medicine” in the solving of some gaps, particularly those that have appeared after the deep crisis and public outcry over biomedical research as a result of criminal and abusive use of human beings during the Second World War.
These and many other issues of a practical, philosophical and deontological nature have accentuated the use of animal models in the laboratory, namely from the second half of the XX century on.
However, the average citizen does not know, for example, that some of the most popular ornamental fish are worthy of our respect and admiration, above all for the role they have played in countless laboratories in important research centres, including the Institute of Molecular Medicine (IMM), namely in the case of one of the examples dealt with here, as we will have the opportunity to discover further on.
Given the complexity of the issue, we will thus refer to only three types of fish that function as animal models and which are also popular fish-tank favourites.
The first example is closely connected to research into oncological diseases. The species in question have become especially important and suited to the comprehending and study of the mechanisms connected to the development and progress of tumours, including on a molecular and genetic level.
For analysis and research into the forming of melanomas “in vivo”, these models allow researchers better understanding of the intra-cell processes that are responsible for the transforming of healthy cells and with normal pigmentation into tumours.
Given that I am not at all qualified to go further into matters of a technical nature (and given the more informal and light intention of this article), let us move swiftly on to some no less interesting details about each case in particular.
This first protagonist is in fact an entire group.
Being recognised in the systematics and the taxinomy of living beings as the genre Xiphophorus (of the family Poeciliidae; subfamily Poeciliinae) means that we are not talking about a single fish, but that we are dealing with 23 potential species, some of which are already extinct or facing a grave threat of disappearing forever in the near future.
The 23 Xiphophorus may in turn be divided into three major groups, which are; the northern Swordtail, the southern Swordtail and the Platyfish. They are all from hydrographical basins that come down from the high lands of Central America towards the Atlantic ocean, namely in Mexico, Guatemala, Belize and the Honduras, although the majority of the species of this kind described by science are mainly found in Mexican hydrographical systems.
If the popular names “Sword” or “Platy” mean anything to you it is very probable that you have had one of these harmonious ornamental fish in your fish-tank, that you have come across them through literature or that someone has called your attention to them in a pet shop, given that three of these species in particular have been extremely popular among fish lovers for practically a hundred years.
One particular aspect which has made them common in captivity is the fact that they are ovoviviparous, that is, although they are not a true case of viviparism, they also give birth to fully developed young (almost exact miniature copies of the adults) after a variable period of gestation that depends a great deal on their diet and environmental factors such as water temperature, the respective chemistry or other less well understood stimuli.
Around the nineteen-twenties it was discovered that it was relatively easy to achieve hybrids between the different species of Xiphophorus. The most remarkable and unusual feature of these hybrids is the fact that they are fertile and consequently are capable of producing their own descendents.
But in what sense has that discovery contributed towards helping medicine?
Besides being a phenomenon common to certain specific populations, in hybrids in particular, an unknown pigmentation often occurs which has its origin in the genes of only one of the progenitors. Despite not appearing in any of the originating species, this particular aspect is shown in the respective hybrid descendants.
Researchers discovered then that some of these hybrids very easily develop melanomas, one of the most deadly skin cancers today. In the Xiphophorus, these melanomas result from irregular melanistic chromatic patterns that occur in some of the species, but above all with a high rate of incidence in many of the hybrids.
Study into the results of the crossings of the several different species started immediately, given that the scientists realised that they had discovered an animal model that would be extremely useful in research into this oncological disease. Indeed, the cells that develop melanomas in these fish are comparable to human cells (liable to the same process) in biochemical, morphological and physiological terms.
Much less well known and popularised as an aquarium fish in Portugal is, without any doubt, one of the species of Medaka, the Oryzias latipes (family Oryziinae).
The most common lineages in the laboratory were used for the first time in their country of origin, Japan, where the fish has been cultivated as an ornamental fish since at least the XVII century.
In 1994 this pleasant little fish was included on one of NASA’s space missions, on board the shuttle “Columbia”, during which it became the first vertebrate to procreate in orbit. The descendents from this experiment were perfectly healthy, and their lineage is still famous today. For those who are curious and wish to look deeper into this case, I recommend the link:
http://cosmo.ric.u-tokyo.ac.jp/SPACEMEDAKA/IML2/e/text/textcontents_E.html.
The laboratory career of this species, which is the most recent species of the Xiphophorus, is equally remarkable.
The Medaka is also linked to research into oncological diseases, but, unlike the Swords and the Platys, is used in a vast multitude of research fields such as genetics, study of fertilisation, embryology and development biology.
Besides supporting a thermal amplitude that is vastly more dilated that any Xiphophorus, (which makes the Oryzias latipes species a laboratory animal that is more suited to temperate climates), it has equally become a prized animal model due to its respectively short life cycle, its relative ease for reproduction in captivity and its small size in adulthood (about 4 cm).
Medaka mutations have also constituted a legendary case because it is through them that it has been possible to prove Mendel’s Laws for the first time in fish. Besides this particular aspect, it was also the first animal in which it was possible to achieve complete sexual reversals in both directions after administering sexual hormones still in a larval phase.
The third and final example is that of the Zebrafish (or simply the Zebra to its friends). Scientifically it is known as the Danio rerio and it is the only one of the “unsuspecting collaborators in research in medicine” that is (as far as I know) currently helping the researchers at the Institute of Molecular Medicine (IMM), where there is even a unit totally dedicated to it. (cf. http://imm.fm.ul.pt/web/imm/zebrafishfacility).
It is an old favourite of aquarium lovers, although its notoriety will probably never supplant the fame and popularity of the three best known Xiphophorus.
Yet in relation to the laboratory, although its “career” is more recent than any other of the noteworthy names in this article, its respective reputation has begun to take on startling proportions.
This little fish, about 4 to 5 cm long, is usually considered to be a tropical animal. In fact it is a species that possesses a vast geographical distribution, ranging from the north of India and Pakistan, Nepal, Bhutan and some outlying zones, covering certain regions of Bangladesh and Burma. One can thus conclude that at least some of the respective populations live in subtropical or even temperate climates, which is verisimilar and proven by the tolerance of most aquarium lineages to cold... as long as the temperature does not go down abruptly.
Among other illustrious collaborations with research in biomedicine, the Zebra is, just like the Medaka, often used as an animal model in studies related to embryology and development biology, given that the progress of its larval phases is comparable to the embryogenesis of the more complex vertebrates, including that of human beings. Its transparent eggs also allow a clear observation of the embryo development, which, in parallel with the speed of the process (all the internal organs are formed in 24 hours and eclosion takes place at the end of three days), becomes one of the points in favour of the use of this classic aquarium favourite in such studies. This and other characteristics allow it to even be one of the species chosen for the embryonic biological model, where it is possible to make genetic manipulation.
But the reputation and usefulness of our “unsuspecting collaborators in research in medicine in laboratory research is not just based on the most common and basic applications.
The Zebrafish, for example, was important news because it also became an interesting animal model in research into regenerative medicine, particularly when it was discovered that it had potential to reveal the secrets that one day might take sick human organs to regenerate on their own.
The major public divulging of this fact took place above all after a study showed that the animal produces new cells and totally regenerates its heart, even after 20% of the muscle had been removed.
As this is one of the few species of vertebrates with the capacity to totally recover parts of its body that have been affected by illnesses or have suffered amputations, our little Zebra friend is not just helping science when the researchers seek the genetic secrets that allow one to “reconstruct”... but also their contribution takes place on the level of research related to oncological, neurological, muscular and cardiovascular illnesses, as well as in the fields of inflammation, angiogenesis and osteoporosis.
To finish off, I am leaving some indications for later research on the relationships between these species and biomedical research:
Medaka EST database (Laboratory of Embryology, Graduate School of Science University of Tokyo) - http://medaka.lab.nig.ac.jp/
Medaka Fish Home Page - http://biol1.bio.nagoya-u.ac.jp:8000/
Medaka Genome Project - http://dolphin.lab.nig.ac.jp/medaka/
NBRP Medaka Mutant Stock Project - http://www.shigen.nig.ac.jp/medaka/
NIH Zebrafish Initiative - http://www.nih.gov/science/models/zebrafish/
The Zebrafish Model Organism Database - http://zfin.org/cgi-bin/webdriver?MIval=aa-ZDB_home.apg
Xiphophorus Genetic Stock Centre - http://www.xiphophorus.txstate.edu/
Zebrafish International Resource Center - http://zebrafish.org/zirc/home/guide.php
Zebrafish Models for Human Development and Disease - http://www.zf-models.org/
Miguel Andrade
Institute of Introduction to Medicine
mandrade@fm.ul.pt
ext. 44542
The laboratory work in the field of research, although subjected to considerable evolution in the machinery, techniques and utensils, has benefited from a particularly valuable coadjuvancy, which has become as influential as the unstoppable progress of the new biomedical technologies.
Although it is not timely in the scope of this short article to deal with certain problematic associated to bioethics, it is becoming necessary, however, to also mention the role of our “unsuspecting collaborators in research in medicine” in the solving of some gaps, particularly those that have appeared after the deep crisis and public outcry over biomedical research as a result of criminal and abusive use of human beings during the Second World War.
These and many other issues of a practical, philosophical and deontological nature have accentuated the use of animal models in the laboratory, namely from the second half of the XX century on.
However, the average citizen does not know, for example, that some of the most popular ornamental fish are worthy of our respect and admiration, above all for the role they have played in countless laboratories in important research centres, including the Institute of Molecular Medicine (IMM), namely in the case of one of the examples dealt with here, as we will have the opportunity to discover further on.
Given the complexity of the issue, we will thus refer to only three types of fish that function as animal models and which are also popular fish-tank favourites.
The first example is closely connected to research into oncological diseases. The species in question have become especially important and suited to the comprehending and study of the mechanisms connected to the development and progress of tumours, including on a molecular and genetic level.
For analysis and research into the forming of melanomas “in vivo”, these models allow researchers better understanding of the intra-cell processes that are responsible for the transforming of healthy cells and with normal pigmentation into tumours.
Given that I am not at all qualified to go further into matters of a technical nature (and given the more informal and light intention of this article), let us move swiftly on to some no less interesting details about each case in particular.
This first protagonist is in fact an entire group.
Being recognised in the systematics and the taxinomy of living beings as the genre Xiphophorus (of the family Poeciliidae; subfamily Poeciliinae) means that we are not talking about a single fish, but that we are dealing with 23 potential species, some of which are already extinct or facing a grave threat of disappearing forever in the near future.
The 23 Xiphophorus may in turn be divided into three major groups, which are; the northern Swordtail, the southern Swordtail and the Platyfish. They are all from hydrographical basins that come down from the high lands of Central America towards the Atlantic ocean, namely in Mexico, Guatemala, Belize and the Honduras, although the majority of the species of this kind described by science are mainly found in Mexican hydrographical systems.
If the popular names “Sword” or “Platy” mean anything to you it is very probable that you have had one of these harmonious ornamental fish in your fish-tank, that you have come across them through literature or that someone has called your attention to them in a pet shop, given that three of these species in particular have been extremely popular among fish lovers for practically a hundred years.
One particular aspect which has made them common in captivity is the fact that they are ovoviviparous, that is, although they are not a true case of viviparism, they also give birth to fully developed young (almost exact miniature copies of the adults) after a variable period of gestation that depends a great deal on their diet and environmental factors such as water temperature, the respective chemistry or other less well understood stimuli.
Around the nineteen-twenties it was discovered that it was relatively easy to achieve hybrids between the different species of Xiphophorus. The most remarkable and unusual feature of these hybrids is the fact that they are fertile and consequently are capable of producing their own descendents.
But in what sense has that discovery contributed towards helping medicine?
Besides being a phenomenon common to certain specific populations, in hybrids in particular, an unknown pigmentation often occurs which has its origin in the genes of only one of the progenitors. Despite not appearing in any of the originating species, this particular aspect is shown in the respective hybrid descendants.
Researchers discovered then that some of these hybrids very easily develop melanomas, one of the most deadly skin cancers today. In the Xiphophorus, these melanomas result from irregular melanistic chromatic patterns that occur in some of the species, but above all with a high rate of incidence in many of the hybrids.
Study into the results of the crossings of the several different species started immediately, given that the scientists realised that they had discovered an animal model that would be extremely useful in research into this oncological disease. Indeed, the cells that develop melanomas in these fish are comparable to human cells (liable to the same process) in biochemical, morphological and physiological terms.
Much less well known and popularised as an aquarium fish in Portugal is, without any doubt, one of the species of Medaka, the Oryzias latipes (family Oryziinae).
The most common lineages in the laboratory were used for the first time in their country of origin, Japan, where the fish has been cultivated as an ornamental fish since at least the XVII century.
In 1994 this pleasant little fish was included on one of NASA’s space missions, on board the shuttle “Columbia”, during which it became the first vertebrate to procreate in orbit. The descendents from this experiment were perfectly healthy, and their lineage is still famous today. For those who are curious and wish to look deeper into this case, I recommend the link:
http://cosmo.ric.u-tokyo.ac.jp/SPACEMEDAKA/IML2/e/text/textcontents_E.html.
The laboratory career of this species, which is the most recent species of the Xiphophorus, is equally remarkable.
The Medaka is also linked to research into oncological diseases, but, unlike the Swords and the Platys, is used in a vast multitude of research fields such as genetics, study of fertilisation, embryology and development biology.
Besides supporting a thermal amplitude that is vastly more dilated that any Xiphophorus, (which makes the Oryzias latipes species a laboratory animal that is more suited to temperate climates), it has equally become a prized animal model due to its respectively short life cycle, its relative ease for reproduction in captivity and its small size in adulthood (about 4 cm).
Medaka mutations have also constituted a legendary case because it is through them that it has been possible to prove Mendel’s Laws for the first time in fish. Besides this particular aspect, it was also the first animal in which it was possible to achieve complete sexual reversals in both directions after administering sexual hormones still in a larval phase.
The third and final example is that of the Zebrafish (or simply the Zebra to its friends). Scientifically it is known as the Danio rerio and it is the only one of the “unsuspecting collaborators in research in medicine” that is (as far as I know) currently helping the researchers at the Institute of Molecular Medicine (IMM), where there is even a unit totally dedicated to it. (cf. http://imm.fm.ul.pt/web/imm/zebrafishfacility).
It is an old favourite of aquarium lovers, although its notoriety will probably never supplant the fame and popularity of the three best known Xiphophorus.
Yet in relation to the laboratory, although its “career” is more recent than any other of the noteworthy names in this article, its respective reputation has begun to take on startling proportions.
This little fish, about 4 to 5 cm long, is usually considered to be a tropical animal. In fact it is a species that possesses a vast geographical distribution, ranging from the north of India and Pakistan, Nepal, Bhutan and some outlying zones, covering certain regions of Bangladesh and Burma. One can thus conclude that at least some of the respective populations live in subtropical or even temperate climates, which is verisimilar and proven by the tolerance of most aquarium lineages to cold... as long as the temperature does not go down abruptly.
Among other illustrious collaborations with research in biomedicine, the Zebra is, just like the Medaka, often used as an animal model in studies related to embryology and development biology, given that the progress of its larval phases is comparable to the embryogenesis of the more complex vertebrates, including that of human beings. Its transparent eggs also allow a clear observation of the embryo development, which, in parallel with the speed of the process (all the internal organs are formed in 24 hours and eclosion takes place at the end of three days), becomes one of the points in favour of the use of this classic aquarium favourite in such studies. This and other characteristics allow it to even be one of the species chosen for the embryonic biological model, where it is possible to make genetic manipulation.
But the reputation and usefulness of our “unsuspecting collaborators in research in medicine in laboratory research is not just based on the most common and basic applications.
The Zebrafish, for example, was important news because it also became an interesting animal model in research into regenerative medicine, particularly when it was discovered that it had potential to reveal the secrets that one day might take sick human organs to regenerate on their own.
The major public divulging of this fact took place above all after a study showed that the animal produces new cells and totally regenerates its heart, even after 20% of the muscle had been removed.
As this is one of the few species of vertebrates with the capacity to totally recover parts of its body that have been affected by illnesses or have suffered amputations, our little Zebra friend is not just helping science when the researchers seek the genetic secrets that allow one to “reconstruct”... but also their contribution takes place on the level of research related to oncological, neurological, muscular and cardiovascular illnesses, as well as in the fields of inflammation, angiogenesis and osteoporosis.
To finish off, I am leaving some indications for later research on the relationships between these species and biomedical research:
Medaka EST database (Laboratory of Embryology, Graduate School of Science University of Tokyo) - http://medaka.lab.nig.ac.jp/
Medaka Fish Home Page - http://biol1.bio.nagoya-u.ac.jp:8000/
Medaka Genome Project - http://dolphin.lab.nig.ac.jp/medaka/
NBRP Medaka Mutant Stock Project - http://www.shigen.nig.ac.jp/medaka/
NIH Zebrafish Initiative - http://www.nih.gov/science/models/zebrafish/
The Zebrafish Model Organism Database - http://zfin.org/cgi-bin/webdriver?MIval=aa-ZDB_home.apg
Xiphophorus Genetic Stock Centre - http://www.xiphophorus.txstate.edu/
Zebrafish International Resource Center - http://zebrafish.org/zirc/home/guide.php
Zebrafish Models for Human Development and Disease - http://www.zf-models.org/
Miguel Andrade
Institute of Introduction to Medicine
mandrade@fm.ul.pt
ext. 44542
