Diving Deep For New Drug Therapies

Summer 2018

HUMANS HAVE RELIED ON A VARIETY OF NATURAL COMPOUNDS from plants, fungi, and other organisms for their medicinal properties for many thousands of years.

The search for new medicines to treat diseases has long relied on these natural products, so much so that approximately 75 percent of the medicines in use are believed to have originated from molecules extracted from wild species.

The most widely used breast cancer drug, for instance, was developed with elements from the bark of the Pacific yew tree, and the anti-inflammatory agent in aspirin is derived from the bark of the willow tree. Penicillin, codeine, quinine, and many other well-known medicines originated in this way as well.

Only about 10 percent of the world’s biodiversity has been evaluated for its potential for medicinal use, however, and the challenge has become how to access likely candidate species, especially those in the oceans.

David Rowley has accepted that challenge, which some have described as a global scavenger hunt. The professor of biomedical and pharmaceutical science at the University of Rhode Island College of Pharmacy is leading the search for potential medicinal agents from microorganisms in the ocean. He has collected and tested samples from water bodies around the world— from Narragansett Bay to the South Pacific—and he collaborates with scientists who travel to even more extreme realms.

(Above starting left) URI researchers David Nelson, Kathleen Castro, Marta Gómez-Chiarri, and David Rowley search for microorganisms that will prevent disease in farm-raised oysters. Photo by Jesse Burke.

“The marine environment is the biggest source of biodiversity on the planet, and the tiny microorganisms there produce some truly novel chemistry,” he says. “I’ve always been fascinated by those molecules [they produce] and the fact that they’ve been produced for a purpose, though that purpose is often unknown.”

Rowley knows that the drug development process takes many years from the initial research to an approved drug, and his research is the very first step in that process. But he enjoys imagining what might be possible with newly discovered molecules, such as curing antibiotic-resistant infections, which Rowley says are one of the world’s biggest health threats. Much of his research has focused on finding microorganisms from the ocean with antibiotic properties.

“With our current challenge of trying to overcome drug resistance … the marine environment is one area we need to explore more fully if we’re going to come up with the next generation of antibacterial agents to combat disease,” he says.

What he’s looking for are interesting chemical interactions between microorganisms.

“If we just went out into the environment and isolated lots of bacteria—in an average milliliter of water there’s probably a million molecules of bacteria—we’d fail far more often than we succeed. So we want to focus our attention where we feel chemistry is involved in the competition between organisms.”

URI has a long and rich history of research into the biomedical applications of marine organisms. Heber Youngken, the founding dean of the URI College of Pharmacy, studied the medicinal properties of plants, and he believed that the next frontier of drug discovery would come from the world’s oceans. He hosted the country’s first conference on marine natural product chemistry in 1967, and two years later he hired the university’s first faculty member to study the subject, Yuzuru Shimizu.

A pioneer in the search for potential anti-cancer agents in the oceans, Shimizu spent more than 30 years studying marine microalgae, especially the toxins produced by red tides. Believing that those toxins might make good drugs, he partnered with the Bristol- Meyers Squibb Pharmaceutical Research Institute and discovered numerous molecules with medicinal properties.

“Drugs and poisons can sometimes be synonymous,” he said in a 2001 interview. At the time, his lab contained room after room of test tubes, jars, and jugs growing various species of microalgae from around the world.

Professor Yuzuru Shimizu was the first URI faculty member to study the potential of marine organisms for biomedical applications.

As Shimizu prepared to retire in the early 2000s, he sought to ensure that the international reputation he helped establish at the College of Pharmacy would continue, so he initiated a search for his replacement. That’s when Rowley was hired. “I came here because URI was one of the most important homes for marine drug discovery and marine exploration,” Rowley says. “It was Shimizu’s success that drew me to URI.”

As a child, Rowley dreamed of becoming an oceanographer, but he wasn’t sure how to do so. When he enrolled in college, he discovered that he enjoyed organic chemistry. Later, while working for a biotechnology company synthesizing molecules, he took a class in natural products chemistry and was inspired by it.

“That’s when I first found people studying marine natural products, and it brought me full circle to combine my interests in organic chemistry and oceanography,” he says.

Matthew Bertin had a similar epiphany, but his occurred among coral reefs while working as a photographer for the state of Florida. Every time he went scuba diving, he became increasingly curious about the chemical ecology of the reef systems and how many corals were being stressed by diseases carried by marine microbes.

Now an assistant professor of biomedical and pharmaceutical sciences at URI, he studies the compounds produced by blooms of marine cyanobacteria—the mats of blue-green algae that are among the most ancient organisms on Earth.

“The compounds are thought not to be made for growth or reproduction but instead for defense, to ward off grazers or other competitors,” says Bertin. “And because marine cyanobacteria are so old, they’ve had a long time to have their genes mutated and duplicated and diverge, so they make all of these interesting molecules.”

Like Rowley, Bertin aims to extract new molecules from these blooms of cyanobacteria and test them for potential therapeutical use against a wide range of diseases. He and colleagues from Texas A&M University are collecting buckets of algae from the Gulf of Mexico, where the blooms are largely cyanobacteria, for analysis in his URI lab. He has already identified 21 new molecules and has begun testing them for anti-cancer properties.

Bertin is also curious about the genetic architecture of the chemical compounds he is working with. He believes their structure will help him learn more about how the cyanobacteria produce them.

“When you look at some of the molecules … from the bloom, they have the same general carbon backbone, the same core structure, but then they have little deviations,” he says. “I’m fascinated by what’s controlling it, and I’m quite certain it’s genetically controlled.”

A better understanding of that molecular architecture may enable scientists to engineer uniquely structured genes to build new compounds that could be used as therapies for a variety of diseases.

But it all begins with collecting and analyzing these buckets of blooming algae. So Bertin is seeking partnerships with scientists in distant corners of the globe who could regularly collect samples for him.

He is particularly interested in finding partners whose work takes them to the waters off Australia and in the Red Sea, where cyanobacteria commonly bloom. He is already collaborating with scientists in Italy who identified molecules in a sponge in the Mediterranean Sea that were very similar to some of the molecules he found in the Gulf of Mexico.

“The ultimate goal is to build a library of pure compounds and then try to … see where they might be therapeutically relevant,” Bertin says.

Probiotics could serve to combat disease common to shellfish.

While the research by Bertin and Rowley primarily focuses on seeking marine microbes that may help combat human diseases, they are also addressing diseases that affect creatures living in the marine environment.

One of Rowley’s newest projects aims to manage or prevent diseases common to shellfish.

He says that diseases are one of the most significant limiting factors in the successful farming of shellfish.

And while some aquaculture farms use antibiotics to reduce disease outbreaks, their use can lead to the same kind of antibiotic-resistant bacteria that are causing so many problems for people. So he is trying to identify naturally occurring microbes that could serve as probiotics to combat disease.

“Probiotic agents are microorganisms—most often a bacterium—that can promote the health of a host organism,” Rowley explains. “It might do that by breaking down molecules or providing nutrients to the host or by promoting disease resistance. In aquaculture, it might even help to promote water clarity.”

Working with URI professors Marta Gómez-Chiarri and David Nelson and research associate Kathleen Castro, Rowley is seeking to understand the mechanisms by which these organisms provide a benefit to their hosts and how best to provide the organisms to farmed shellfish.

According to Gómez-Chiarri, the process is somewhat simple. Using a sterile swab, she rubs the shell of an oyster and cultivates whatever bacteria are collected. Then she drops a small amount of the various bacteria on a plate with a disease-causing pathogen, and any bacteria with antibiotic properties will kill the pathogen around it.

The researchers have identified two microorganisms—one collected from healthy oysters in Narragansett Bay and one from a sponge found in the Narrow River, which flows through North Kingstown, South Kingstown, and Narragansett—that could be used as probiotics against the common oyster disease vibriosis.

“We tested [the probiotic] with the larvae of oysters because they’re especially susceptible to the disease,” says Gómez-Chiarri. “We treated them with the probiotic and then introduced the pathogen, and we had a high survival rate. The next step is to try to understand how they do it. It’s not clear how probiotics work.”

The other challenge is that the probiotics have to be alive to do what they do, which will make mass production difficult.

“It’s one thing to produce enough of the probiotic to test in the lab, but at a hatchery it has to be administered every day, so we need to produce a lot of it and figure out how to preserve it,” Gómez-Chiarri explains.

“The one from the sponge survives well when dried and made into a powder, but the other one is more complicated. We’ve applied for a grant to produce it in larger quantities and test it at commercial hatcheries.”

Similar studies of probiotics for disease prevention at shrimp farms are also promising, though early efforts targeting the shell disease that infects wild lobsters in southern New England have not yet proved successful.

All the researchers agree that there will not be just one solution to the problems of antibiotic resistance, infectious diseases, or disease outbreaks in aquaculture farms. Each problem will probably require numerous approaches from a wide variety of scientists from different disciplines.

“But at the end of the day, I hope the research we conduct here is going to contribute to finding solutions to some of the problems we face today and those we may face in the future,” Rowley says.

Besides the outcomes of the research itself, “the work we do is … training the next generation of scientists who will be responsible for the well-being of our planet and our people into the future.”

 By Todd McLeish

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