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Mark Shwartz, News Service (650) 723-9296; e-mail:

Creatures from the deep fight cancer and warn of environmental hazards

They are slimy, wormlike and sometimes brainless creatures, but the strange organisms that inhabit our oceans, lakes and streams may one day provide a cure for cancer -- or serve as an early-warning system for the subtle effects of toxic pollution.

That was the message delivered by two Stanford scientists at the recent international meeting of the American Chemical Society (ACS) in San Francisco.

Paul A. Wender, who holds the Bergstrom Professorship in Chemistry, presented his remarks during an ACS symposium on "New Prospects in Anticancer Agents for the 21st Century."

Researchers are scouring rainforests, deserts and ocean bottoms in search of wild plants and animals that produce regulators of enzymes capable of fighting diseases in humans.

Wender told his colleagues that isolating and synthesizing these exotic biochemicals has been a difficult yet exciting challenge.

"It's an absolutely fantastic time to be a chemist," he said, pointing to the large number of promising anti-tumor compounds recently discovered in ocean-dwelling invertebrates, such as sponges, sea hares, marine worms and bryozoa.

Of particular interest, he said, is a species of bryozoa called Bugula neritina found off the California coast.

This tiny, plantlike animal produces a remarkably potent chemical called bryostatin that appears to prevent the growth of tumors in a variety of human cancers, including melanoma, non-Hodgkin's lymphoma and renal cancer.

Bryostatin is being tested in more than 40 clinical trials in the United States, and so far, many cancer patients have shown marked improvement with relatively minor side effects.

But if bryostatin is eventually approved by the Food and Drug Administration, pharmaceutical companies will face another problem: a lack of supply.

It takes 14 tons of Bugula neritina harvested from the sea to produce less than one ounce of bryostatin, Wender noted, which has led to the creation of bryozoa farms in California.

A more practical solution than aquaculture, Wender said, would be to synthesize bryostatin in the laboratory -- currently a long and expensive process requiring 60 to 70 chemical steps.

The ultimate answer, he argued, is for chemists to create a simplified version of the bryostatin molecule that would be easier to manufacture in bulk and would perform better in the clinic.

"Maybe we can do better than bryostatin and get around some of the supply issues," Wender suggested.

The goal, he said, is to redesign bryostatin by removing segments of the molecule that have nothing to do with blocking tumors.

"Perhaps we can delete these unnecessary features in order to simplify the target and thereby streamline synthesis," he noted.

And that's exactly what he and his Stanford colleagues have begun doing.

First, they teach computers to create "bryologs" -- less complicated versions of the bryostatin molecule designed to maximize its cancer-blocking ability.

Then, a team of chemists use the 3-D, computer-generated models to synthesize actual bryolog molecules in the lab.

The results have been outstanding, according to Wender. He pointed to studies with the National Cancer Institute showing that designed, synthetic bryologs are significantly more effective than natural bryostatin in reducing tumors.

Wender predicted that the ocean will continue to be a rich source of disease-fighting agents, especially in coral reefs, which contain thousands of marine species.

And when a new compound is discovered, chemists now are prepared to make it therapeutically more effective.

"We can now take the wonderful inspirations nature has provided and engineer better molecules," he concluded. "We are able to design compounds that have not been on this planet before."

Toxic warning

Many scientists who attended the ACS meeting agreed that if we hope to extract new medical cures from the sea, then we must learn to protect the health of the oceans and their inhabitants.

Unfortunately, many synthetic compounds that are beneficial to humans end up harming aquatic organisms, said David Epel of Stanford's Hopkins Marine Station.

Epel, the Jane and Marshall Steel Jr. Professor of Marine Sciences, discussed his findings during an ACS panel on pharmaceutical and personal care products in the environment.

"You're probably glad that the person sitting next to you is wearing a deodorant," Epel told reporters. "And I know I am grateful for the cholesterol-lowering drug that I take every morning.

"But I'm not certain that the inhabitants of our lakes, oceans and rivers are cheering these inventions."

Epel warned that when people excrete drugs or throw away old cosmetics, toxic compounds end up in the environment in amounts that may threaten the delicate immune systems of freshwater and ocean-dwelling creatures.

"These organisms use a protection strategy that is basically a preventive medicine approach," Epel said.

"Instead of detoxifying any poisons that happen to get into the cells, they instead use a 'first line of defense' strategy, which is to keep the toxins out of the cell in the first place."

Epel and graduate student Nancy Eufemia study aquatic animals such as the mud-dwelling fat innkeeper worm found along California's Monterey Bay.

These animals have a relatively simple defense mechanism that consists of proteins called "efflux transporters" imbedded in the outer surface of their cells (see drawing).

Transporters work by kicking out toxins before they can enter the cell and cause damage.

Unfortunately, Epel noted, efflux transporters can be easily overwhelmed by minute levels of synthetic chemicals like those found in drugs and perfumes.

As a result, toxic compounds can enter the cell and eventually cause genetic or structural damage to the entire organism.

Little research has been done to determine how much pollution is being generated each year from discarded deodorants, cough syrups and medications.

But according to Epel, "It is urgent that we study these pharmaceuticals that are now appearing in the environment and determine whether they can affect this first line of defense."

He noted that while we may not observe large numbers of animals dying today, careless disposal of drugs and cosmetics might be having subtle and "profound consequences on reproduction and the long-term health of aquatic ecosystems."

Epel pointed out, however, that his laboratory at Hopkins Marine Station is one of the few trying to assess this "potential danger to the aquatic environment."


By Mark Shwartz

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