A REVIEW OF NEUROBIOLOGICAL STUDIES ON
PLANARIANS
BY ALANA MOSKOWITZ
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INTRODUCTION
One of the defining features of humanity is the awareness of mortality; the knowledge that all
things inevitably come to an end. To many, it is a frightening notion. It is for that reason that mankind has
always longed for the unattainable immorality.
Though humans are more aware of their mortality, there are other organisms much closer to
mastering it. These organisms are called biologically immortal. According to expert Leonard Hayflick,
“The most stringent definition of immortality is a life form capable of indefinite survival in conditions
where no changes have occurred in molecular composition from some arbitrary beginning.” Hayflick
goes on to state that “A more liberal definition of biological immortality would be the indefinite survival
of a life form whose vital life processes function indefinitely” (Hayflick, 2013).
Modern scientists are studying the different organisms that fall under this definition of
immortality, hoping to understand the mechanisms that enable these organisms to live the way they do.
For example, scientists have long been observing the regenerative abilities of hydra. However, it was not
until fairly recently that the presence of stem cells was identified as the cause (Bosch, 2008). Scientists
have also been studying Turritopsis nutricula, otherwise known a the “Immortal Jellyfish”, in an effort
to understand its ability to avoid aging. The jellyfish begins life as a polyp, but when it reaches maturity,
it reverts back to the polyp stage, therefore escaping the ailments of aging (Carla, et al. 2003). As
fascinating as these organisms are, one of the most well known biologically immortal organisms is the
planarian, which is commonly used to study stem cell biology, embryonic development, and as a model
for neurobiology (Gentile, Cebria, and Bartscherer, 2011).
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Planarians are free living flatworms, belonging to the class Turbellaria of the phylum
Platyhelminthes. They are capable of reproducing either sexually or asexually, depending on the specie.
They are very simple organisms, but still have many distinct tissues and organs (Newmark and
SanchezAlvarado, 2002). This makes them ideal models for experimentation.
PLANARIANS AS BIOLOGICALLY IMMORTAL ORGANISMS
Planarians are classified as biologically immortal organisms because of their ability to create
endless telomerase, an enzyme that regulates the length of telomeres. Telomeres trigger cell death and
aging at a certain point, which is referred to as the Hayflick limit (Harley, et al., 1992). As a telomere
becomes shorter, a cell becomes less able to regenerate. The cell will begin to show signs of aging, until
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it eventually dies. This does not occur in planarians, enabling them to regenerate indefinitely and
preventing any signs of aging (Tan, et al., 2012).
HISTORY OF REGENERATION
Regeneration has been documented for thousands of years. Among the earliest known examples
of regeneration are included in the writings of the ancient Greek philosopher, Empedocles. His works
were passed down from generation to generation, describing incredible animals with “necks that would
grow new heads” (SanchezAlvarado, 2010). These writings eventually reached Aristotle, some
hundred years later, who was the first to document his observations of lizards growing new tails. During
the Middle Ages, the topic of regeneration became popular among alchemists hoping to create
regeneration in humans. Since alchemy was entirely discredited following the Renaissance period, the
study of regeneration all but stopped until the 1600’s.
During the late 1600’s, scientist Melchisédech Thévenot presented a live lizard before the
French Academy of Sciences. To the members horror, he cut off its tale, and asked the members of the
academy to write down any observations. In the coming days, the tail regenerated (SanchezAlvarado,
2010). This restored interest in the study of regeneration. Soon after, Abraham Trembley began his
study of polyps. He found that the polyps he found could regenerate any missing tissue. He dubbed
these polyps “Hydra”, named for the ancient Greek monster capable of regenerating its head. Sylvia and
Howard Lenhoff' translated Trembley’s findings in their book "Hydra and the Birth of Experimental
Biology” (SanchezAlvarado, 2010). These early regeneration studies inspired and paved the way for
scientists in later years.
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PLANARIANS AS MODELS FOR REGENERATIVE STUDY
In 1766, Peter Simon Pallas noted that planarians were able to generate an entirely new body
from no more than a fragment of the head (Newmark and SanchezAlvarado, 2001). This marked the
first study of regeneration carried out using planarian flatworms. Pallas’ findings were confirmed by
French naturalist Jacques Philippe Draparnaud who found that planarians undergo asexual reproduction
through fission. Planarians will reproduce by simply ejecting part of their body in order to create an
identical organism (Newmark and SanchezAlvarado, 2001). In 1814, J.G. Dalyell conducted one of
the first experiments regarding planarian regeneration, declaring them to be “immortal under the
knife”(Dalyell, 1814).
In 1898, the “Father of Genetics”,
Thomas Hunt Morgan published his
article “Experimental studies of the
regeneration of Planaria maculata”. In
his article, he describes some of the
various experiments he performed in
testing the regenerative abilities of
planarian flatworms. He found that
planarians has a natural sense of
polarity, enabling them to identify which way was “up” during regeneration. In addition, he found that
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planarians could be divided in any direction and still be able to regenerate. Not only could they be
divided in multiple directions, but they could be divided into numerous pieces 279, as Morgan
concluded (Morgan, 1898). The experiments conducted by T. H. Morgan inspired many scientists
during the turn of the century to experiment with planarians.
MECHANISMS OF REGENERATION
Scientists in the developmental biology field have been utilizing planarians flatworms as a way of
understanding the mechanisms of regeneration. This is because planarian flatworms contain pluripotent
stem cells called neoblasts throughout their body, which enable them to recreate any missing tissue
through the processes of epimorphosis and morphallaxis (Wagner, Irving, Wang, and Reddien, 2011).
During epimorphosis, undifferentiated cells, called neoblasts, form over a wound site. This mass
of cells is known as the blastema. Within the blastema, genetic information develops to meet the needs
of the wound a new tail or part of the head may regenerate from the initial wound site. (Agata, Saito,
and Nakajima, 2007). Morphallaxis differs from epimorphosis in that morphallaxis deals with the
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regeneration of an entire new body. During morphallaxis, a mass of undifferentiated cells will develop
into new tissue to replace absent tissue and create a new body. Within these undifferentiated cells,
genetic information develops and is eventually dispersed and made proportionate, thus creating new
cells and tissues (Reddien and Sánchez Alvarado, 2004).
The determining factor in the type of regeneration that a planarian undergoes is dependent on
the type of wound. Based on the wound type, the planarian will respond with one of two responses. It
determines which type of regeneration through a two wave mitotic response. The neoblasts emit two
different mitotic peaks, signaling to the body what the appropriate response is. The body will then act on
these signals and regenerate cells as necessary (Wenemoser and Reddien, 2010).
Many scientists believe that in regeneration, the way that cells are able to maintain polarity and
differentiate is by receiving chemical signals through signal pathways. In this way, information can be
transported throughout the body, and the body is able to respond to injury. These pathway are called
hedgehog (Hh) pathways (Rink, 2009, Ingham, Nakano, and Seger, 2009, Gurley, et al. 2010).
It is the theory of many scientists the RNA is a factor in cell replication and regeneration. This
idea originated from the controversial studies of James V. McConnell. A scientist in McConnell’s lab
suggested that RNA is involved in memory retention, using that as an explanation for how memories
were preserved through head regeneration. To test this, the scientists treated a conditioned planarian
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flatworm with ribonuclease, an enzyme that breaks down RNA, and cut it in two. The progeny resulting
from the tail end had no memory; the progeny from the head portion however, did. It was suggested
that some memory is stored in the central nervous system, and some is stored in RNA. In an attempt at
memory transfer, McConnell made unconditioned planarians eat the ground up remains of conditioned
planarians (McConnell, 1962). This practice was seen as unethical, the experiments proved difficult if
not impossible to repeat, there were no listed citations, and the article was never peerreviewed before
being released to the public. For these reasons, many scientists came to the conclusion that
McConnell’s findings were not to be taken seriously (Rilling, 1996).
Though McConnell’s works have been largely discredited, a few studies have shown a link
between RNA and regeneration. The article “Doublestranded RNA specifically disrupts gene
expression during planarian regeneration”, describes how dsRNA acts like a restriction enzyme,
preventing specific genes from being expressed during planarian regeneration. This shows how RNA
can be used to manipulate genes (SanchezAlvarado and Newmark, 1999). In addition, “Gene
Knockdown in Planarians Using RNA Interference” explains how by using RNAi, a type of RNA that
interferes with gene transcription, scientists have been able to study gene function during regeneration
(Oviedo, et al., 2007).
USE OF PLANARIANS IN BEHAVIORAL STUDIES
In the words of planarian experts, Philip A. Newmark and Alejandro SanchezAlvarado, “…
planarians have key anatomical features (mesoderm, central nervous system (CNS) and excretory
system) that might have been platforms for the evolution of the complex and highly organized tissues and
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organs found in higher organisms” (Newmark and SanchezAlvarado, 2002). In synaptic organization
and in many features of its neurons, the planarian brain is similar to the brain of a vertebrate organism.
The planarian central nervous system is typically compared to that of mice and flies, though it also shares
characteristics of the human brain. In fact, some scientists believe that the brain of the planarian flatworm
evolved into the human brain, as evidenced by the numerous homologues between human genes and
planarian genes, and the presence of enzymes in planarian brians found in human brains (Sarnat H.B.
and Netsky M.G., 1985).
The impact of drugs on the central nervous is currently being experimented with in regards to
planarians. In 2008, scientists at Temple University explored the addictiveness of cannabinoid, an
extract of cannabis, in comparison to that of cocaine and amphetamines. Ultimately, the scientists found
that abstinenceinduced withdrawal occurred with cocaine and amphetamines, but not with cannabinoid.
This conclusion suggested that cannabinoid is less addictive than some other drugs (Raffa, et al., 2008).
Scientists have also been looking into reversing the impacts of harmful drugs by using planarians
as models. One scientist in particular, Oné Pagan, has reversed the unusual behavior exhibited by
planarians exposed to cocaine (Pagan, 2008). He has also stopped nicotine withdrawal in planarians
given tobacco. This novel research could help lessen the effects of withdrawal and reduce addiction in
cases of drug abuse in humans (Pagan, 2009). Additionally, in 2014, an article was published describing
scientists using Schmidtea mediterranea as a model to understand nervous system development in
infants suffering from fetal alcohol syndrome.
PLANARIAN MEMORY STUDIES
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One of the most well known planarian experts is James V. McConnell. The experiments carried
out by McConnell during the early 1960’s are still discussed and debated by the scientific community
today because of their controversial nature. McConnell’s experiments began by conditioning planarians
to a certain response, something that had previously been thought to be impossible to do in
invertebrates. He did this by training the flatworms to find their way through a maze, guided by electric
shocks. McConnell called this process “worm running”. To test just how complete the regeneration of
the central nervous system was in planarian flatworms, he cut off their heads and then put them through
the maze again. To his surprise, after a very short amount of time, the worms were able to find their way
through the maze, suggesting that memory was retained through regeneration. This led to a string of
experiments involving memory retention through regeneration. McConnell believed that if the tail of a
conditioned worm was able to generate a head complete with the old head’s memory, memory was not
stored solely in the central nervous system (McConnell, 1962).
McConnell’s work is currently being looked into by behavioral scientists. The article “An
automated training paradigm reveals longterm memory in planaria and its persistence through head
regeneration” by Michael Levin and Tal Shomrat. The Tufts University scientists trained planarians to
become familiar with a specific environment. This was done through a complicated procedure involving
planarians natural sensitivity to light. Once the planarians had been properly conditioned, the scientists
amputated their heads. The regenerated offspring was then put into the same environment, and the
scientists tested their familiarity with that environment. What they discovered is that some memory is in
fact retained through head regeneration. While this study did not support all of McConnell’s claims, it is
a huge step in the study of memory retention in planarian flatworms (Levin and Shomrat, 2013).
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USE OF PLANARIANS
TO TEST IMPACT OF CAFFEINE ON LONG TERM MEMORY IN A NEWLY
DEVELOPED CENTRAL NERVOUS SYSTEM
Studies have been conducted showing a direct correlation between caffeine and long term
memory. By inhibiting adenosine production, memories are retained for longer periods of time (Kopf, et
al., 1999). In the article “Caffeine in floral nectar enhances a pollinator’s memory of reward”, bees were
conditioned to respond to a specific odor. Bees given caffeine were able to remember this odor and
responded appropriately three times longer than those which were not (Wright, et al., 2013). In mice,
not only has it been shown to improve long term memory by inhibiting adenosine, but it has been
suggested that when caffeine is given to an adult mouse, it can prevent alzheimers (Arendash G.W. and
Cao C., 2010). While caffeine has been tested on planarian flatworms to study regeneration, its effect
on long term memory has not been explored (Collins, 2007).
SIGNIFICANCE
Stem cells show a lot of promise for the future of medical research. Scientists involved
in developmental biology are constantly exploring new ways to study stem cells. By using planarians,
scientists are able to study not only stem cells, but developing central nervous systems. This enables
scientists to observe how stem cells impact a central nervous system in embryonic stages and also in
regeneration, the latter of which is becoming increasingly important. Some scientists suggest that stem
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cells will be used to treat neurodegenerative diseases, such as alzheimers (AbdelSalam, 2011). This
would involve the reconstruction of brain tissue, which could potentially be damaging to the patient. By
understanding the mechanisms of regeneration, long term memory retention, and the substances that
could improve memory, one would be able to potentially save many memories that could be lost in such
a procedure.
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BIBLIOGRAPHY
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"Observations on Some Interesting Phaenomena in Animal Physiology Exhibited by Several
Species of Planariae" written by J.G. Dalyell was published in Edinburgh in 1814.
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