Health Sciences Report Winter 2003

Diving Deep
By Phil Sahm

Photos by Steve Leitch; sponges, courtesy of Chris Ireland, Ph.D.

In the vast, merciless ocean, few creatures appear as defenseless as a sponge.

These simplest of multicellular organisms are consigned to lives of hugging shells and rocks on coral reefs and the ocean floor, with no visible means of protection against predators flashing razor smiles and gaping maws.

But those who might make a meal of sponges need beware: more than a half-billion years of evolution, since the pre-Cambrian era, have given sponges and other sea creatures ample ability to defend themselves by secreting toxins when would-be attackers come nosing around. If that's potentially deadly news for predators, it may be good news for people, because some of those toxins, found only in marine organisms, hold the tantalizing possibility of fighting cancer.

Two University of Utah College of Pharmacy faculty members find this possibility alluring enough to join the search for anticancer agents in the ocean's medicine chest; although they're approaching the challenge from different, yet complementary, avenues.

Chris M. Ireland, Ph.D., professor and chair of medicinal chemistry, has spent 20-plus years traveling the world to identify potential anticancer agents in the toxins of sea organisms such as sponges, ascidians, and mollusks. Ireland's goal is to understand the mechanisms by which these unique toxins work to see if they can be applied to stopping cancer. But there's a hitch: the amount of bioactive material that can be taken from marine animals is almost infinitesimally small, making it difficult to test these compounds for their chemical properties, let alone make drugs from them. So, while Ireland and others plumb the world's oceans to identify potential medications, researchers such as Eric W. Schmidt, Ph.D., assistant professor of medicinal chemistry, are trying to figure out how to make drugs through biosynthesis. This requires isolating the DNA in the genes of marine organisms that are responsible for the synthesis of toxins. If he and others identify and learn how to clone the genes that produce toxins, it may be possible to make anticancer drugs in the laboratory in viable quantities and at reasonable costs.

Ireland and Schmidt are fortunate in one respect: they each entered a field that was relatively new and fertile for discovery. Nonetheless, it's not work for someone in a hurry: thousands of compounds are discovered each year in marine organisms and sifting through them for potential drugs is a huge job.

"You're lucky if, in a lifetime, you get one drug into clinic," Ireland said.

Scientists formally started studying the biochemistry of marine organisms in the 1960s, when anticancer drugs were based solely on toxicity and the ability to kill cells. As researchers learned about the toxins of sponges and other ocean denizens, they realized the potential for new cancer medications.

In 1977, when marine biochemistry was still an emerging field, Ireland received his Ph.D. in oceanography from Scripps Institution of Oceanography at the University of California, San Diego. He'd planned to devote his research to studying how marine organisms communicate with one another using chemicals. But after serving a couple of fellowships, including one in Hawaii, Ireland's career path wound toward the search for anticancer drugs. After a stint at the University of Connecticut, he came in 1983 to the U of U to teach medicinal chemistry.

Sponges, ascidians, mollusks, soft corals, and other simple metazoans earn their living by filtering seawater for organisms to feed on. These organisms harbor bacteria, which help sea creatures process waste and absorb nutrients. But researchers suspect these organisms, called symbionts because they feed off of their host, also may interact with their host to create toxins. Laboratory tests have confirmed these toxins work by inhibiting growth factor pathways in other organisms. Because cancer involves mutations that switch cellular growth factor pathways permanently "on,"which allows tumors to grow; researchers conjectured that these toxins might act as 'off' switches to close these pathways and inhibit cancer progression.

In two decades of research, with $12 million in National Institutes of Health (NIH) grants, Ireland estimates he has identified 500 new chemicals from marine compounds that are toxic to tumors. About 25 of those agents showed anticancer activity in mouse models, and five are in preclinical evaluation against multiple tumors in mice. One of those five agents, naamidine A, has the potential for human trials against skin cancer, and by Ireland's measure, that's a pretty good batting average.

"I'd be happy if that one made it [into human trials],' he said.

A number of compounds from marine organisms already are in various stages of clinical trials. These include bryostatin 1, which comes from tiny invertebrates that form colonies in the ocean, and is being tested against leukemia, lymphomas, skin cancer (epidermal carcinomas), and tumors.

Ireland's lab has found that naamidine A, derived from a Leucetta sponge near the island of Fiji, inhibits the growth factor that causes skin cancer with a 96 percent tumor reduction in mice. Ireland also is studying another sponge, Stylissa massa, which produces a compound that inhibits the most frequently overexpressed growth factor pathway in solid tumors. He and his lab workers are investigating other promising toxins as well.

In addition to his work at the U, Ireland also leads a National Cancer Institute-funded consortium of three university teams of researchers. The consortium, called a National Cooperative Drug Discovery Group, has a compound in clinical trials at the Cleveland Clinic and the University of Chicago.

There literally is an ocean of promise in deriving possible drugs from marine organisms, but getting anticancer medications from the sea to the market is a monumental task. Even if drugs can be derived from toxins, harvesting these chemicals in large quantities would require huge, if not prohibitive, numbers of sponges and other creatures, making it too costly both environmentally and financially. Aquaculture "growing marine organisms for their toxins" is being tried, but with limited success, according to Ireland.

The best hope for deriving cancer drugs from ocean toxins in usable quantities, in Ireland's view, lies in the work of researchers such as Eric Schmidt. To make cancer drugs that are commercially viable, science must find a way to reproduce marine toxins in the laboratory.

The remarkable advances in molecular biology and bioinformatics in recent years have allowed scientists to sequence and analyze thousands of genes. Schmidt, who also received his Ph.D. in oceanography at Scripps, under the same advisor as Ireland, and came to the U in the summer of 2001, is applying these leaps in knowledge to study how sponges and ascidians, another ocean invertebrate, create toxins.

"We're looking at their biosynthetic pathways," Schmidt said. "Our goal is to clone these biosynthetic genes to go after the genes behind the production of compounds."

Schmidt is studying the biosynthetic reactions of compounds produced by organisms such as plants and bacteria. The sequences of proteins that cause those reactions have been well studied and are similar to those in ascidians and sponges. Based on the biosynthetic reactions of those terrestrial organisms, Schmidt can use DNA to search for similar genes in marine life. Once he identifies those genes, Schmidt hopes to isolate their DNA, transfer it to organisms that can be cultured in the laboratory, and clone the genes that make toxins from which drugs can be derived.

But Schmidt and others first must determine whether sponges, ascidians, and other marine creatures produce these toxins, or whether the microorganisms they harbor as symbionts create the compounds. There's strong evidence that the compounds come from bacteria, but that hasn't been proved. Researchers also have to figure out how the enzymes make the compounds, so they can be manipulated to produce them in the laboratory.

The amazing diversity and complexity of sea life make the search for anticancer drugs all the more formidable. Yet, this same diversity and complexity hold the potential for great discovery that sends Ireland and Schmidt to far-flung places for fieldwork.

Last October, just as winter settled on the Salt Lake valley, they traveled to the warm waters off Papua New Guinea to dive for sponges and ascidians. Ireland collected organisms to examine their chemistry for potential drugs, while Schmidt extracted DNA samples for his pursuits in the laboratory.

What they discover is anyone's guess. But it's an ocean, and the possibilities are vast.

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