The Role Elasmobranchs and Other Marine Animals Play in the Search for the
Cure for Cancer
Jocelyn Cercone
4-10-07
Abstract
Today, the ocean remains a relatively mysterious place that is worth exploring for
potential cures for human diseases. Currently, scientists in the field of marine
biomedical research have adopted elasmobranchs (sharks, skates, and rays) as
a primary subject for this important research. These animals have a very low
incidence of cancer, due to their lack of a bony skeleton as well as the extra
tissues their bodies devote to the production of immune cells. Scientists are in
the process of pinpointing exactly which cells play a key role in protecting the
elasmobranch body against cancer, and are hoping to apply this knowledge to
humans in the near future. Other marine animals besides the sharks, skates,
and rays have also been explored for potential anti-cancer drugs. Many of them,
like nudibranchs, sea whips, and others, have unique chemical defenses against
competing marine creatures that can be used in mammals to inhibit the growth of
tumor cells. The only problems standing in our way are the inconvenience of
collecting the large numbers of creatures needed for study, and obtaining the
funding for a relatively new subset of research projects that do not yet have many
published papers to back them up. Thus, the ocean holds many exciting new
prospects in this most important area of modern research that humans can take
advantage of, as long as we allot enough time, effort, and money to developing
the technologies needed in order to do so.
The critical role the ocean plays in our lives is undeniable. It takes up 50%
more of our earth than the land on which we live, yet we know comparatively little
about it. The main reason for this relative lack of knowledge is our inaccessibility
to many of the wonders the ocean holds. Although, with the advent of NITROX-
based scientific diving, ROVs (Remotely Operated Vehicles), and deep sea
submersibles, humans can now explore the undersea ecosystems to a larger
extent than ever, this is still not sufficient enough for us to be able to take full
advantage of the resources the earth’s oceans have to offer. Today, in the
twenty-first century, with the incidence of cancer and other diseases of the
immune system on the rise, scientists are trying even harder to uncover the
mysteries of the highly specialized immune responses of marine organisms that
humans can presently only envy.
Elasmobranchs (sharks, skates, and rays) are a very successful group of
marine animals, shown by the extraordinarily long time for which they have
survived in the cutthroat world of competition that is the ocean. They fill a unique
immunological niche in that they are the first group of vertebrates to have
developed an adaptive immune system. They were the first to make use of
immunoglobin, T-cell receptors, the major histocompatibility complex, primary
and secondary lymphoid tissues, and other important components of a
successful immune system (Walsh et al, 2006) Therefore, they have had a long
period of time over which to develop an immune system that works very well in
their environment.
Ever since the early 1800s, says Dr. Carl Luer, scientist and manager of the
Marine Biomedical Research Program at Mote Marine Laboratory in Sarasota,
FL, it has been observed that sharks have a relatively low incidence of disease,
particularly cancer. In the 1960s, he says, a registry was formed of tumors in
lower animals (non-mammalian, non-avian species). When observing all the
data collected from the 1960s to present, it can be seen that there are recorded
tumors in elasmobranchs, but not nearly as many as documented in the other
lower animals. According to Dr. Luer, many of these tissues once reported as
tumors in elasmobranchs were in fact not actually tumors at all, but neoplasms,
which could have been a fibrous response to a wound, parasitic infestation, or
even goiters misidentified as thyroid adenomas. So, the incidence of cancer in
these animals is actually lower than what was once thought.
Dr. Luer came to Mote Marine Laboratory in 1978 to help further explore the
possibility that elasmobranchs do have something unique about their immune
systems that causes this low incidence of cancer. In other words, he sought to
find out whether it was just that the scientists were not able to see the tumors in
the animals, or that there was actually something in the bodies of the sharks,
skates, and rays, that was resisting the tumor formation. Beginning in the 1980s,
Luer and his colleagues have spent their time attempting to expose sharks and
skates to carcinogens under controlled conditions. (per comm. Carl Luer)
Specifically, he uses nurse sharks and clearnose skates for the research.
Nurse Shark http://www.richard-seaman.com/Underwater/Belize/FishYouMightNotWantToMeet/NurseShark.jpg
Nurse sharks are one of the few shark species that do not need to swim in order
to breathe, so they can live relatively sedentary lifestyles. They are also not very
aggressive compared to other shark species and are generally slow-growing.
Therefore, they can be kept for three to four years before they become too large
for laboratory tanks and have to be released. Unfortunately, however, it takes
nurse sharks about twenty years to become sexually mature, so tests cannot
usually be performed on nurse sharks of reproductive age. For this reason, Dr.
Luer has another, more manageable elasmobranch species that he uses
regularly in his research in conjunction with the sharks: the clearnose skate.
Clearnose Skate http://www.mote.org/clientuploads/killing_cancer1.jpg
Their biochemistry and physiology are very similar to that of the sharks, and they
are easy to breed and maintain in captivity throughout their entire lifespan. With
these animals, Dr. Luer has been able to establish a controlled population with a
complete genetic history. (Self, 2005)
Both the nurse sharks and clearnose skates are exposed to chemical
carcinogens, namely aflatoxin B1 (a naturally occurring toxin produced by molds)
and methylazoxymethanolacetate (MAM). Most carcinogens, Dr. Luer says,
target the liver cells because it is the organ in which chemicals are detoxified.
Thus, the liver is the primary site in which Dr. Luer and colleagues normally look
to find possible tumors. They also scour the rest of the body, however, to make
sure no cancer has manifested itself in any other areas. Since isolating tumors in
humans and injecting them into the elasmobranchs would not be an effective
method of testing for tumor growth (due to the large differences in the biological
makeup of humans versus sharks and skates), Dr. Luer makes use of the next
best method by exposing the animals to carcinogens known to cause tumors in
both humans and lower animals. When exposed to the aforementioned
chemicals, the sharks and skates did not develop any tumors. While this study
was going on, another experiment using the same methodology, only on bony
fish, was also performed. Interestingly, tumors did appear in these species. (per
comm. Carl Luer)
Rather than attempting the relatively impossible task of exposing the
elasmobranchs to all possible chemical carcinogens, Dr. Luer and colleagues
followed the trend of the times and turned toward more immunological-based
research. (In recent years, it has been discovered that many more diseases than
we thought have their basis in the immune system, especially diseases on the
front-line of the world’s most pressing medical issues, like AIDS.) Before Dr.
Luer began this type of research, there was not much known about the immune
systems of elasmobranchs. This made for an interesting research situation, he
says, because the scientists were asking very basic questions, yet at the same
time performing cutting-edge cancer research. It was also somewhat of a cause
for frustration because, due to the lack of previous research to back it up, it is
difficult to get funding for these new immune system-based projects. (per comm.
Carl Luer)
Since shark skeletons are composed of cartilage only and contain no bone
marrow, it was originally thought that the major site of antibody production in the
shark must be the spleen. Before research done by Dr. Luer and colleagues,
scientists had not been able to locate a thymus (site of T-cell production) in
sharks, so it was thought for a long time that they did not have one. Dr. Luer,
however, was able to finally locate the thymus in a shark and determined that the
elasmobranchs, in addition to their spleen and thymus, have one to two other
tissues dedicated solely to protecting immune cells. (per comm. Carl Luer) That
is, they have specific Lymphomyeloid sites called the epigonal and Leydig
organs, associated with the gonads and esophagus, respectively. (Walsh et al,
2006) Interestingly, the epigonal organ has a composition similar to bone
marrow and is often referred to as “bone marrow equivalent” tissue. Currently,
Dr. Luer is focusing a lot of his attention on the epigonal organ and what its exact
role and function are in the immune system. Mote scientists are also currently
collaborating with scientists in St. Petersburg, Florida in identifying exactly what
types of immunoglobins elasmobranchs produce. (per comm. Carl Luer)
Right now, the main focus of the Mote studies, though, is the cellular
component of the immune system, namely the cells that the epigonal organ
produces. Dr. Luer has spent time learning how to put these cells into short-term
culture, which has been valuable because it allows scientists to isolate specific
cells and learn more about their respective functions without having to deal with
complicating factors within the shark body. It turns out that these cells secrete
substances when in culture that Dr. Luer is analyzing for their immunoregulatory
activity, including their ability to inhibit the growth of tumor cells. (per comm. Carl
Luer)
What is especially fascinating about elasmobranchs is that they manufacture
the same types of immune cells as humans, but they make them in different
proportions. Whereas, in humans, the immune cell found in highest
concentrations is a granulocyte cell called a neutrophil, in sharks the highest
concentrations are of lymphocytes. This presents an interesting situation for the
scientists. Since lymphocytes are made up of primarily B-cells and T-cells, this
tells us that these particular components are probably most important in their
immune system. Because the shark cells are isolated in culture in the laboratory,
however, it is difficult to know how exactly they function when in the body of the
shark, and even more difficult to know how they function in humans. In order to
do the latter, Dr. Luer and colleagues must change the conditions in culture from
those most optimal for the growth of shark cells to those best for growing human
cells, without harming the shark cells in the process. Before applying the
knowledge to humans, of course, Mote scientists must design a way to determine
how the immune cells function in the sharks themselves. The more funding
obtained for these endeavors, Luer says, the faster the answers will be
determined.
So far, of the different species in which Dr. Luer and colleagues have looked
at secretions of the epigonal organ, the bonnethead sharks seem to have the
highest potency of immunoregulatory components.
Bonnethead Shark taken at Mote Marine Aquarium, Jocelyn Cercone
This species is convenient for scientific study because it is in plentiful supply and
thus has lenient restrictions on collection for scientific purposes. The animal
itself would never actually be used as a source for the immunoregulatory
components, however. It would merely be used to isolate the particular cells and
devise a way to either clone the isolated gene or genetically engineer it into a
vector cell for testing on humans. (per comm. Carl Luer)
Although elasmobranchs are probably the most popular and exciting
contributors to marine cancer research, anti-cancer components have also been
found in many other organisms inhabiting the marine environment. Yuzuru
Shimizu, a natural-products chemist at University of Rhode Island, Kingston,
began studying the bioactive metabolites of microalgae. After screening various
types of microalgae against cancerous cell lines in tissue culture, he became
particularly interested in the dinoflagellates, a single-celled phytoplankton that
contributes to red tide blooms. Shimizu put together a culture that contained only
dinoflagellates without impurities, ground them up, and tried to isolate different
compounds, using chromatography techniques. He and a colleague, Bristol-
Myers Squibb, then tested the various compounds for their anti-cancer
properties. The results showed that a compound called carbenolide-I shrank
tumors when tested in vivo in mice with leukemia. (May, 1998)
After collecting dinoflagellates from the genus Amphidinium, Shimizu isolated
a compound from them called amphidinolide B.
Amphidinium sp. http://www.hokudai.ac.jp/pharma/tennen/homeres2/Y5.jpeg
It was able to kill cultures of both a mouse leukemia and a human carcinoma cell
line. The problem with these cultures is that the dinoflagellates must be collected
in extremely large quantities in order to be beneficial for future studies. It is also
very difficult to obtain a pure mixture of amphidinolides. Thankfully, Shimizu was
able to purify one eventually from his samples. Thus, he determined its structure
and was able to start a synthesis. Now, Shimizu and his colleagues must
synthesize the starting pieces atom by atom, come up with its four main
components, and close amphidinolide B’s large chemical ring. Through this
detailed synthesis, they hope to eventually be able to replicate the natural
products for use in humans. (May, 1998)
In addition to dinoflagellates, nudibranchs (a diverse group of mollusks lacking
a shell) have also been used in anti-cancer drug research.
Dolabella auricularia Hexabranchus sanguineus
http://www.seaslugforum.net/images/m11978.jpg http://www.ukdivers.net/life/rs/spanish_dancer.jpg
These unique animals often make use of noxious chemicals for defense. They
may either produce their own or, more commonly, recycle chemicals produced by
other animals. For example, many nudibranchs feed on sponges and make use
of their chemicals to produce toxic glandular secretions, or store the chemicals in
the more vulnerable parts of their bodies. Using a species of nudibranch called
Dolabella auricularia, scientists have already developed an anti-cancer drug
called Dolastin 10. Other compounds with anti-tumor properties have also been
isolated from the egg ribbons produced by the nudibranch species Hexabranchus
sanguineus. (Karacsonyi, 2003)
Another organism used for similar purposes is a marine macroalgae called
Bugula neritina.
Bugula neritina http://www.dnr.sc.gov/marine/sertc/images/photo%20gallery/Bugula%20neritina.jpg
Scientists have used its chemical compounds to develop an anti-cancer drug
called Bryostatin I, particularly effective against cancers of the blood. It is
currently being tested, in conjunction with the standard anti-cancer drugs, in
many human trials in America. A sea whip, Ecteinascidia turbinate, found in
mangrove swamps in the Caribbean, contains a chemical that has been effective
against mouse leukemias and human breast cancers.
Ecteinascidia turbinate http://www.hno.harvard.edu/gazette/2002/05.23/photos/10-seasquirt2-450.jpg
Ecteinascidin 743, the drug produced from this organism, is currently in Phase I
clinical trials in America, which test for safety. Another exciting development in
current biomedical science is the attempt scientists are making to create new
drugs by mixing together enzymes from different marine bacteria, in order to
hopefully create a compound more effective than either of the parent enzymes.
This is called semisynthesis. (Mestel, 1999)
Thus, marine organisms present an exciting new component in the ubiquitous
search for the cure for cancer. The endless ocean contains a myriad of
creatures humans know little or nothing about. Thus, in the twenty-first century,
marine scientists have a new responsibility of being extra-observant when
studying new ecosystems. They must look for the most uniquely well-adapted
creatures inhabiting our oceans, that is, the creatures that appear to be most
vulnerable to the human eye, but who have developed innovative chemical
defense systems for survival. These are the creatures that could potentially hold
the cure. In addition to exploring new solutions to the pervasive problem of
human cancer, however, both marine and biomedical scientists must also
continue to concentrate their efforts on the already established, and potentially
very successful projects, like the elasmobranch cancer research going on at
Mote Marine Laboratory and other locations. Taking advantage of the
remarkably diverse marine world that surrounds us is one of the most beneficial
and promising paths we humans can take towards eradicating one of the most
universally devastating and growing issues affecting us all.
Bibliography
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May, Mike. "Drugs From Dinoflagellates." Environmental Health Perspectives
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Mestel, Rosie. "Drugs From the Sea." Discover 20 (1999): 70-75. 4 Apr. 2007.
Self, Donna. "Killing Cancer?" Mote Magazine 2005. 6 Apr. 2007
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Walsh, Catherine J., Carl A. Luer, A B. Bodine, Clayton A. Smith, Heather L.
Cox, David R. Moves, and Maur Gasparetto. "Elasmobranch Immune Cells as a
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