DR. AMY WRIGHT - Harbor Branch Oceanographic Institution
Director, Division of Biomedical Marine Research

The Research: Going Deep for Cures

Amy Wright is a natural products chemist and head of the Harbor Branch Oceanographic Institution's Division of Biomedical Marine Research (DBMR). The group's focus is on finding potential new therapeutics for cancer and infectious diseases, mainly from deepwater marine invertebrates and the microbes that live in association with them. The Harbor Branch team includes a microbiology group that focuses primarily on infectious diseases by testing compounds' ability to block the growth of bacteria and fungi; a cell biology group that works primarily on cancer treatments but also works on Alzheimer's and Parkinson's; and a natural products chemistry group that purifies active compounds and determines their structure. The biomedical group is also working in conjunction with Harbor Branch's Aquaculture Division to explore the potential of farm-raising sponges or other organisms that produce important pharmaceutical compounds.

The Harbor Branch group does scuba collections, but for the majority of its exploration relies on the institution's two Johnson-Sea-Link submersibles. Harbor Branch has worked extensively throughout the Caribbean and at a wide range of locations around the world in the Pacific and Atlantic. Over the last few years, thanks to strong support from the State of Florida, the team has had the opportunity to focus on exploration of highly diverse deepwater reefs off Florida. In the process of exploring for new pharmaceuticals, the group has also discovered a number of ecologically important deep-water reefs, some of which are now being reviewed as potential Marine Protected Areas.

Since the early 1980s the group has discovered over 250 bioactive compounds. At any given time, the Harbor Branch researchers have about 10-12 compounds in various stages of development. One compound the team discovered, discodermolide, made it to stage one human clinical trials. For a number of other promising finds, the group is either completing preliminary studies, negotiating licensing, or seeking licensors.

Harbor Branch has amassed a collection of over 32,000 marine sponges, corals, and other animals, and over 17,000 samples of microorganisms. It also has thousands of extracts prepared from these samples that are made available to other research groups for screening. This collection is housed in a large -80°C (-112°F) freezer in a hurricane-proof bunker, which was tested multiple times by hurricanes that hit the institution in 2004 and 2005.

Wright's main research interest is the purification and structure identification of naturally occurring compounds that could help treat cancer. She holds 16 U.S. patents on marine natural products as well as numerous foreign patents, and has been the chief scientist on countless expeditions around the world.

- VIDEO CLIP 1: "Capabilities And Goals Of HBOI BMR"

Using Submersibles

Success Stories: Dictyostatin and the Lasonolides

Due to strong funding support in the area from the National Institutes of Health, Harbor Branch has been able to strongly focus on developing treatments for pancreatic cancer. One of the most promising finds to date in this search is a compound called dictyostatin, first found in a deepwater sponge collected in Jamaica by researchers in Arizona. Harbor Branch later re-purified the compound and discovered that its mechanism of action is very similar to that of Taxol®, which blocks cells from undergoing mitosis. Dictyostatin is being tested in an animal model and Harbor Branch is hoping to identify a pharmaceutical partner to license and continue dictyostatin's development. Harbor Branch already partnered with Ian Patterson at Cambridge University, who developed a synthesis method for dictyostatin and who has also made a series of dictyostatin analogs. "That's a project that's quite far along and that has real potential for being useful in the treatment of pancreatic cancer," says Wright. For now, Patterson's synthetic production method will have to suffice because although Harbor Branch researchers have worked to identify dictyostatin's biosynthetic production path, they were not able to do so because only very small sample quantities of the compound have so far been available. As yet, the team has not had the opportunity to return to Jamaica with the submersible for further collections.

Another DBMR drug discovery success story centers on the sponge-derived lasonolides. This story is explored in detail in an MBT Research Spotlight article elsewhere on the website.

- VIDEO CLIP 2: "Promising Anticancer Compounds: Dictyostatin And The Lasonolides"

Success Story: Topsentins

The topsentins, found in deep-sea sponges, were one of Harbor Branch's earliest discoveries, simultaneously found by a group of European researchers. They were first identified as antiviral and anti-tumor agents, but their greatest potential did not become clear until later. Harbor Branch sent samples of the topsentins to Bob Jacobs at the University of Santa Barbara, who specializes in inflammation. He and his colleagues discovered the topsentins to have powerful activity against inflammation associated with nerve tissue, known as neurogenic inflammation, and also against immunogenic inflammation. Further research at Harbor Branch has led to a method for synthesizing a simpler version of one of the topsentin compounds that retains these anti-inflammatory properties. This has greatly accelerated research on the products by reducing the need for sponge collection using a submersible.

- VIDEO CLIP 3: "Other Promising Compunds: Topsentins And More"

Florida Finds

"The State of Florida has, over the last few years, really taken an interest in the development of marine natural products," says Wright. One major initiative that Harbor Branch has been a part of is the Center of Excellence in Biomedical and Marine Biotechnology. This research consortium, based at Florida Atlantic University, provided two years of funding for expeditions, equipment, and research, to expand biotechnology in the state. The State of Florida has also provided some direct funding to Harbor Branch to promote further exploration of Florida waters for drug discovery and to support associated research. Collectively, the state funding has provided the first opportunities ever for exploration of a number of Florida deep-water reefs, work that has led to a number of important discoveries. One particularly interesting area is known as the Miami Terrace. "No one ever realized the incredible diversity of deep-water fish and corals that are down there, and that [Miami Terrace] plateau runs for about forty miles," says Wright. "As we dive all along it we're just finding incredible species diversity." Besides drug discovery work, the group also documents the areas they explore and, in the case of Florida, they have created a database of this information that can be accessed by those working to improve coastal management.

One of the group's more recent promising Florida finds, and one that is yet to be named, was actually first discovered in the Bahamas in a very small sponge sample. The group was excited that a compound isolated from the sponge appeared to be a powerful mitosis blocker in pancreatic cancer cell lines, but they did not have enough sample to fully explore the compound's potential. On a later dive at the Miami Terrace, off Florida, the researchers rediscovered the sponge. Not only was the species fairly abundant, but also the Florida samples had ten times higher concentrations of the target compound. That has allowed the team to decipher the compound's structure using NMR, and they are still working to discover its specific method of action.

Work is already simultaneously underway to identify a sustainable means of producing the novel compound. The team is working to determine if the compound is produced by a microorganism that might be culturable, and is also exploring the possibility of culturing the sponge at a newly established biomedical aquaculture facility at Harbor Branch. Wright is especially excited about the compound because the discovery of the sponge off Florida means that collecting more samples to fuel further research will be relatively easy. The recent Florida expeditions have also led to the discovery of a number of other compounds that have shown promising activity in pancreatic assays as well as a new colon cancer assay the group has begun using.

- VIDEO CLIP 4: "Collaborative Marine Biotechnology In Florida; History Of DBMR"

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Around the Caribbean and Well Beyond

Wright and the Harbor Branch team have worked at almost every major island in the Caribbean during more than 20 years of exploration, and have had a special focus on the rich deep and shallow-water reefs of the Bahamas, which are relatively close to their Ft. Pierce base. Work funded by the NOAA Office of Ocean Exploration enabled work in the Gulf of Mexico and off northern Florida, Georgia, and South Carolina. Other expeditions, mostly with a submersible but also at times with scuba alone, have taken the team to Honduras, the Galapagos, Cuba, Panama, Madeira, the Mediterranean, the Canary Islands, Western Africa, and even the North Sea, though Wright left that trip to others on the team because, she says, the diving was going to be just too cold.

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Letting the Ones with the Guns Veto Sampling Sites

Wright has countless tales from her extensive scuba and submersible experiences, but recalls one particularly interesting event during her fieldwork that happened at the surface. During a Bahamas expedition, she and a few other divers had used one of the ship's small boats to head in toward an island to explore the mangroves in search of sea squirts and other samples. "I love to work in mangroves," says Wright, but maybe not so much this time.

As they were approaching a mangrove channel, another boat with men wielding guns met them. This was the 1980s and the height of the drug trade between Florida and the Bahamas. "They came and said, "You're not going to snorkel here," and we said, 'OK, we're not going to snorkel here," recalls Wright with a laugh. "We just turned around and left," she says, "and we weren't shot. They had something in those bushes they didn't want us to snorkel upon."

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Developing New Target-Based Assays

Harbor Branch's in-house program focuses on assays for cancer and infectious diseases. They work with pancreatic, breast, lung, and colon tumor cell lines as well as some drug resistant lines and antimicrobial assays. The team also has newer target-based assays they are in the process of developing and that are now a primary focus. Rather than measuring cell toxicity, these assays detect effects on proteins involved in the growth of cancerous tumors and that are not present in healthy cells. The goal is to identify compounds that reduce the levels of those proteins or block activation of the genes responsible for their production, with overall goals of finding treatments with minimal side effects or that can overcome various forms of resistance.

Using such a test, the researchers recently identified important new activity in a known compound. Work is underway to determine if the compound can be used against drug-resistant tumors to overcome the resistance and render their cells susceptible to the toxicity of other treatments. "We're developing a whole series of those types of assays that will be much more cancer-specific and cancer-selective and hopefully less toxic therapies," says Wright. All of these new assays are cell-based, meaning any activity identified takes place within cells so that the compound has to penetrate the cell membrane„as it would need to do in any treatment application. This helps to identify compounds most likely to be of pharmaceutical use. Another possible approach is to look at bioactivity against purified enzymes, but Wright says the group has found at least in its own work with natural products that such tests are less diagnostic of potential new treatments.

- VIDEO CLIP 5: "The Compound Purification And Screening Process"

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Education: A Love of Marine Science from the Start

When Wright set out to pick a major in college, she thought about taking a path toward becoming a medical doctor, but realized she wasn't all that fond of biology and probably wasn't well suited in general to medicine. "All those cadavers and things, and then real people, forget it!" says Wright.

So, with an affinity for math and the physical sciences, she decided on chemistry as a major at Cal State, Dominguez Hills. Her next educational stop was influenced by a longstanding interest in the marine science, fostered through years working as a volunteer at the Cabrio Beach Marine Museum in San Pedro, California. At the museum she led tours, whale-watching boat trips, and museum activities focused on the area's yearly grunions runs when countless small grunion fish come onto the beaches to lay their eggs. Wright chose the University of California's Riverside campus, where she worked on marine algae and also plant pathology, which gave her the chance to study bacterial systems as well. This broad background prepared her well for marine biomedical work, she says, so from Riverside she went directly to Harbor Branch and has been there ever since. "Here I am and here I stay," says Wright, "there's a giant freezer full of tons of work still to be done."

- VIDEO CLIP 6: "Educational Background"

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