>>NARRATOR: A vast expanse of liquid hope,

the oceans are part of America's newest medical frontier.

Its underwater organisms are teeming with potential cures.

>>Sponges are providing real chemicals, real pharmaceuticals.

>>About 70% of the drugs that we use now have their origin

in some natural product.

Most of them are plant-derived.

So can you imagine how much more there is

when two-thirds of the world is covered by water?

The potential is unlimited.

>>NARRATOR: The latest medical gold rush

takes place beneath the waves.

Marine creatures may hold the key

to unlocking the secrets of our own biology.

>>The horseshoe crab and its eyes

are really quite remarkable.

They become about a million times more sensitive at night

than they are during the day.

>>We've used that information to be able to get a better sense

of how human eyes work.

>>Aplysia fits the niche for a basic animal

that can be used to study memory and learning.

>>The compound that comes from a shallow water sponge

can help to block the spread of cancer.

>>NARRATOR: Scientists view this saltwater wilderness

as a treasure chest of promise for human medicine.

>>I still feel like I'm a kid in a candy store,

because marine natural products are amazing.

They have such potential to really be new drugs,

and yet we have just scratched the surface.

>>NARRATOR: The ocean's medical mysteries

are as deep as its trenches.

What breakthroughs have its sea life revealed?

Are there cures that lie beneath the waves?

>>Major funding for this program was provided

by the Batchelor Foundation,

encouraging people to preserve and protect

America's underwater resources.

>>NARRATOR: For centuries, man has looked to the oceans

for organic remedies to alleviate human illness.

In 1987, a chemical isolated from a Caribbean sponge

was the first drug approved for treatment of the HIV infection.

Toxins from a venomous cone snail

offer relief to those suffering from severe chronic pain.

Once again, the seas are proving to be

a valuable resource for medical research.

>>Over the last ten to 20 years,

we've been doing more and more research in this environment,

looking at the marine environment,

looking at shallow waters, going into deep waters.

And with our work,

we're looking at things which are associated

with invertebrates.

>>NARRATOR: In Florida, a team of scientists

at Harbor Branch Oceanographic Institute

are testing sea sponges

for their potential anticancer properties.

>>Our main focus right now is pancreatic cancer,

because it is the fourth leading cause of death

of cancer in the U.S.,

and it is one of those that only has a 5% survival rate.

So that means only 5% of the patients make it past five years

of being diagnosed.

So the drugs that we have right now are not very effective,

and we desperately need new drugs for pancreatic cancer.

Normally, the way it goes, we go on the sub, you get a sponge,

the chemists make extracts and then we test different abilities

that these compounds might have to fight cancer.

>>NARRATOR: The Center for Marine Biomedical

and Biotechnology Research at Harbor Branch

houses invertebrate specimens that have been collected

throughout the world's oceans.

Explorers use state-of-the-art research vessels

and manned submersibles to gather sea-dwelling creatures.

>>So Harbor Branch has had the Johnson Sea Link submersibles,

and they dive to 3,000 feet of seawater-- or 910 meters--

and they are fully outfitted with a work platform

that allows us to collect different organisms.

>>NARRATOR: Once an organism has been collected,

chemists break down the specimen

and begin the process of purification.

After an extract has been isolated,

scientists like Dr. Esther Guzman

perform a series of tests to determine

if the item shows activity against cancer cells.

>>Sponges cannot do much other than being in their little site,

so that makes them nice little chemical factories,

because everything that they want to do,

whether it's grow or expand

or attract another sponge to reproduce,

they do this by releasing things into the water.

That little sponge, as innocent as it looks,

it's making some very heavy chemicals.

If you put, for example, a drop of perfume in a glass of water,

you're going to lose that smell.

So think about how potent the signals of a sponge are,

because they are releasing it in more than a glass of water;

they are releasing it to the sea.

>>NARRATOR: One of these "chemical factories"

is the Caribbean barrel sponge.

It contains a compound called manzamine A,

which has drawn a lot of attention from scientists.

>>We've shown recently it can help to block

the spread of the cancer.

>>If you think about pancreatic cancer,

the reason it's very aggressive

is that normally when it's detected,

it has already migrated to another organ,

so it has already metastasized.

Manzamine A stops that process.

One of the characteristics of cancer cells

is that they don't need this cell-to-cell interaction.

They actually thrive on their own,

and that might be one of the characteristics also

that can lead to this spreading to another organ.

And if you put manzamine A in their midst at low doses,

it kind of returns the cell-to-cell interaction.

It also prevents the cells from migrating

from one organ to another.

>>NARRATOR: In addition to manzamine A,

another sponge extract that shows promise

for cancer therapies is discodermolide.

Initially developed as an immunosuppressant,

discodermolide, which comes from a Bahamian sea sponge,

functions similarly to Taxol,

a pharmaceutical commonly used to treat patients with ovarian,

breast or lung cancer,

as well as patients with AIDS-related Kaposi's sarcoma.

>>Taxol is one of the major drugs used to treat cancer,

and it was isolated from a yew tree.

The way Taxol works is that it freezes

or hyper-stabilizes tubulin.

Tubulin is a protein that is in all your cells.

and it helps to give cells shape.

It is very necessary when the cells are going to divide.

When you put Taxol in a cell that is dividing,

the cell can no longer align itself,

and so these cells will die.

There are certain tumors that do not respond to it,

and there are certain tumors that become resistant to it.

Discodermolide is about the same potency as Taxol,

but it is still effective on cells

that have become resistant to Taxol.

>>NARRATOR: Researchers at Harbor Branch

are also looking for chemical agents that can target

malignant cells efficiently

without suppressing healthy body systems.

>>One of the major problems that we have

with cancer treatments or with chemotherapies

is that you tend to kill normal cells

as much as you're killing cancer cells.

>>NARRATOR: A sponge found in Bahamian waters

contains a compound that may help reduce

patient side effects through cell selectivity.

Leiodermatolide, its chemical extract,

shows greater activity against cancer cells

than healthy cells.

>>Having this selectivity-- that it kills

6,000 times more cancer cells than normal cells--

is that then you will have less side effects,

because in certain senses you are weakening the patient

while you are trying to kill the cancer.

>>NARRATOR: The marine natural products from Harbor Branch

are in various stages of testing.

Getting drugs approved

by the U.S. Food and Drug Administration

is a lengthy process,

one that can take years before the public can gain access

to novel compounds such as these.

However, cancer biologists like Dr. Guzman

are still optimistic that sponges will one day

provide better medicines to treat pancreatic cancer.

They are living fossils.

Horseshoe crabs are curiously resilient

and unassuming creatures whose unique biology

has captivated the interest of man for decades.

More closely related to spiders and scorpions

than to true crabs, ancestors of horseshoe crabs

existed 350 million years ago,

long before the age of dinosaurs.

In the 1900s,

horseshoe crabs were commonly used in the farming industry

as crop fertilizers and as feed for livestock.

By the mid-1970s,

commercial fishermen began using them as bait

for eel and conch fisheries.

But it's the crab's "blue blood"

that revolutionized the medical industry.

>>They have a special chemical in their blood

that's used to detect the presence of bacterium.

>>That bacterium assay is used to screen everything

that goes into a human being and to test

the sterility of all the machines that are used

to deliver such products, like IV fluids.

>>NARRATOR: And that's not the only factor

that makes horseshoe crabs of interest to modern science.

Dr. Barbara Battelle from the University of Florida's

Whitney Lab for Marine Bioscience in Marineland

focuses on the animal's distinct visual system.

>>Well, it has ten eyes--

two compound eyes that are just like fly eyes.

These are the big eyes that you see on the sides of the carapace

or the upper part of the animal.

And the photoreceptors are very large,

among the largest in nature, so in experimental preparation,

they're really very useful.

>>NARRATOR: Horseshoe crabs have roughly

1,000 photoreceptors, or light-sensitive cells,

in each compound eye,

compared to the millions found in human eyes.

>>There are many people that have reduced vision,

and we don't have an explanation for it.

Why is vision going down?

How does that happen?

Well, in mammals it's difficult to study,

because our eyes are complex.

>>NARRATOR: In 1976,

researchers from Syracuse University discovered

that manipulation of an optic nerve that transmits signals

from the brain to the compound eyes of a horseshoe crab

mimics the visual function of circadian clocks.

>>Circadian clocks are internal clocks

that we have in our cells and in our brain

that make us change our physiology, day to night.

And we experience the effects of our circadian clocks

when we travel across time zones.

The circadian clock in your brain

doesn't only control your sleep-wake cycle;

it also controls how our eyes work.

>>NARRATOR: In 1967, Dr. Haldan Keffer Hartline

and his colleagues at the Marine Biological Laboratory

in Woods Hole, Massachusetts,

won the Nobel Prize for their work examining horseshoe crabs.

They identified lateral inhibition,

a visual process in animals and humans alike

that enhances contrast,

helping the eye to see borders and edges.

Scientists at the Whitney Lab

hope this species will provide even more clues

on the basic mechanisms of vision.

>>Oftentimes, our circadian rhythms degrade as we age,

and it could be that some of the reasons

for impaired vision as we get older

is that the signals from the circadian clock are degrading,

and the cells aren't getting the information they should get.

>>NARRATOR: To test this theory,

Dr. Battelle works with live specimens from her wet lab,

where a skylight provides

natural day- and night-time light patterns.

Tissue samples from the compound eye

are analyzed to detect any biochemical changes

that occur in response to internal or external stimuli.

>>We discovered a major protein in the photoreceptors.

So a protein is the part of the cell

that actually does the work of the cell.

So we found a major protein

that is changed in response to the signal

from the central 24-hour clock.

And we don't really know what that protein does yet,

but we think it has a major impact

on the way the photoreceptor cells function.

>>NARRATOR: By controlling circadian input

to the compound eye,

lab tests revealed concentrations

of the newly discovered protein, opsin 5.

Although similar proteins are far more abundant

during the night and day,

opsin 5 molecules may still impact photoresponse.

>>So we can see these proteins actually move around.

They're in different places depending on the time of day,

and that gives us some clue

about how the photoreceptor is changing its sensitivity,

day to night-- clock input, no clock input, and so forth.

So it gives us a clue of what's going on inside the cell.

>>NARRATOR: Studies indicate that light,

as well as the animal's circadian clock,

regulate opsin 5 differently

than other photosensitive proteins.

Experts suspect that changes in levels may underlie

some the dramatic day-night changes in photoreceptors.

>>The horseshoe crab and its eyes

become about a million times more sensitive at night

than they are during the day, and what's really interesting

is that we found the same kind of protein

in the photoreceptors of mammals.

And that's the way

the sort of comparative biology that we do works.

We find something in a simpler organism, and then we ask,

"Well, are we finding the same sorts of things

in other organisms?"

Basic mechanisms that go on in cells, regardless of species,

are similar.

And as we discover what this protein does

in the horseshoe crab eye, then we can begin to ask

more pointed questions about what it might be doing

in our own eyes.

So, if we can figure out how to make

cells more sensitive to light,

then the potential is that we can fix them.

>>NARRATOR: Marine invertebrates

are seemingly basic organisms.

Yet their simplistic anatomies offer great insights

into the way the human nervous system functions.

The larvae of starfish help researchers understand

how the body defends itself against disease.

The mechanisms by which nerve impulses travel

along nerve fibers was discovered via studies on squid.

In 2000, experiments with sea slugs won Eric Kandel

and his colleagues at Columbia University

the Nobel Prize in medicine

for their work on the cellular processes

of learning and memory.

The National Resource for Aplysia in Miami

is the only facility in the world

where sea slugs are raised for research purposes.

>> Aplysia californica has become an important model

for studying the development of the nervous system,

learning, behavior.

>>NARRATOR: In 1975, Thomas Capo joined Eric Kandel

at Columbia University, where he worked to improve

the availability of sea slugs, or aplysia,

for year-round studies.

>>Aplysia are an annual animal.

If you want to work with small animals in the late summer,

you can't find them.

Or, if you wanted to work with small animals in the winter,

they're not available.

So what we do here

at the University of Miami's Aplysia Resources,

we raise animals throughout the year.

>>NARRATOR: Before coming to Miami,

researchers moved to Woods Hole, Massachusetts,

where original aquacultural operations began

on Aplysia californica, a species commonly found

on the West Coast of the United States.

>>By 1978, we had moved to Woods Hole,

and it's there that we made the major breakthroughs

in getting large numbers of animals through the larval phase

and the metamorphic phases.

And once we were able to grow large numbers of animals,

it became obvious that we needed a larger facility,

a better facility, and there was a major problem

working in Woods Hole, and that was food supply.

And in Florida, at the University of Miami's

experimental facility on Virginia Beach

was the ideal place,

because not only did we have an abundant supply

of ambient seawater,

we also had warm weather to culture the algae.

And within two or three years of moving here in 1989,

we were able to culture over 300,

400 pounds of seaweed a week,

which was necessary to produce the animals.

And also, we had an abundant supply of raw seawater

which we could clean up, chill down

and grow our animals in.

The facility was initially set up

to produce around 10,000 animals,

but we've expanded several times over the years,

and now we produce anywhere

between 25,000 and 30,000 animals a year

for researchers around the world.

>>NARRATOR: One of those researchers, Dr. Leonid Moroz,

works at the University of Florida's Whitney Lab.

His studies focus on how individual nerve cells

function in relation to memory and learning.

>>Aplysia offers this opportunity,

because it has a relatively simple neurosystem,

with only about 100 cells per ganglion

and roughly 10,000 cells in the whole brain--

and, importantly, most of these neurons are giant.

You can study connections of the cells

and, most importantly, you can link everything to behavior.

>>NARRATOR: Aplysia neurons are so large,

they can be seen by the naked eye.

They possess nine groups of nerve cells, or ganglia,

within their bodies, distinct physical features

that help experimental scientists view aplysia

as a model organisms for neuroscience research.

>>Aplysia seem to be an interesting approach,

a reductionist approach whereby you look at an animal

with a small number of neurons

and basically get an understanding

of how the nervous system works.

>>If you remember your first kiss,

more likely what would happen in your brain--

or happened in your brain-- is that cell A and cell B

and cell C, they just talk to each other,

and synapses, the connections between cells, become stronger

and, more likely, they change shape.

So efficiency of these connections becomes better

or less better.

So if it's better, you will more likely remember something;

if it's weaker, you will lose this memory.

>>NARRATOR: Dr. Moroz examines how aplysia neurons

and synapses change as a result of memory formations.

Similar to Pavlov's famous salivating dogs experiment,

Dr. Moroz can elicit specific behaviors from sea slugs

through basic forms of learning.

>>You give to aplysia a simple task.

You produce tactical stimulation which is associated

with some kind of algae or juice.

In aplysia, you'll produce a feeding reaction

following this weak stimulus, which normally

they do not produce.

So you do, like, 40 repetitions, and aplysia will remember.

So this is a sort of elementary learning and memory.

It's called associative type of memory, when animals associate

to a type of stimulus, make connections,

and basically preserve those connections for quite a while.

So you count the number of synapses between cells

before and after memory formations.

So in older aplysia, this number of connections

becomes weaker,

and a similar process happens in the human brain

or a variety of neurological diseases.

So everything you learn and remember,

it's really linked to how one neuron talks to each other

and how they preserve this efficiency

of these communications.

So you can reduce complex memory process

to the level of only a few cells.

In fact, many people would be surprised

how many neurons would need to form

elementary forms of memory; only three cells is sufficient.

>>NARRATOR: By studying learning and memory

at the cellular level, Dr. Moroz hopes his experiments

will one day lead to solutions for neurodegenerative conditions

such as Alzheimer's and Parkinson's diseases.

>>I bet if you will solve the problem--

how in aplysia two neurons talk to each other,

how they modify the synapses-- it will be one or another way

to apply it to clinical studies or disease analysis.

>>NARRATOR: Scientists say it is important to study

a diverse group of species

to better understand complicated processes.

>>If everybody looked just at a rat or a mouse,

we'd know a lot about a rat or a mouse,

but we wouldn't have the full spectrum

of understanding about biology.

But by studying these simpler or less complex organisms,

we can learn a lot about basic processes,

and I think that remains critical to our understanding

of our own biology.

>>We know more about maybe rocks on the moon

than what lives in the ocean.

>>NARRATOR: Today's biomedical researchers

are diving into the deep blue,

hopeful the ocean's rich diversity of marine life

will reveal answers to man's greatest health issues.

>>One thing that's been very clear to us as marine scientists

over the last several decades

is that there are byproducts that we can extract

or get from many of these marine organisms

that can really benefit humans.

>>It holds so much wealth for us.

And we get our health from it.

We firmly believe there is a cure

down at the bottom of the sea.

>>Major funding for this program was provided

by the Batchelor Foundation,

encouraging people to preserve and protect

America's underwater resources.