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DR. RUSSELL HILL - University of Maryland, Center of Marine Biotechnology (COMB)

The Research: The Role of Microbes in Marine Natural Product Production

Russell Hill's research focuses on microorganisms with a role in producing important compounds, especially those with potential as new drugs. Though Hill has certainly pursued other interests in his career, his work now is largely focused on symbionts of marine invertebrates, which he finds particularly interesting because a single sponge can have hundreds or possibly thousands of associated bacterial species. Hill is interested in both the more basic research aspects of how microbes and higher organisms interact, and also the potential pharmaceutical benefits of compounds produced by the microbes.

"The link between the basic research and the practical aspects is not a really direct one at this point and that I think is because we understand so little about these systems," says Hill. However, he hopes to increase understanding of interactions, for instance what sort of environment invertebrates are providing for microbial symbionts, to ultimately increase success in growing more of these microbes.

One of the problems Hill is addressing through his work is the serious drug development hurdle of establishing a supply of promising compounds to enable research on the compounds to continue and, if all goes well, to provide commercial quantities of a compound. Hill is excited that many important compounds are turning out to be produced by microbes living in invertebrates, rather than by the invertebrates themselves, because then researchers need only to learn to culture the microbe to establish a steady supply.

Hill allows that the pursuit of compound supply through microbe culturing in most cases still involves a number of critical "ifs" - if a microbe is making a given compound, if it can be grown in the laboratory, and if it continues to produce the compound when grown in the laboratory. No small questions these, but in many cases Hill has already generated some positive answers. In fact, his laboratory group is credited as being the first to ever isolate a microbe that produces a pharmaceutically important compound, and then to culture it in the laboratory in such a way that its production of the compound continues.

- VIDEO CLIP 1: "Research Interests of the Hill Lab"

Hill's most successful effort to date has been focused on the production of a group of compounds called manzamines, the first of which was discovered by a Japanese researcher in a sponge collected near Okinawa. Later, work by the Harbor Branch Oceanographic Institution identified a single compound, dubbed manzamine A, as being particularly interesting, biomedically-speaking. It has now been shown active against malaria, tuberculosis, and HIV, among other conditions. The most promising of these potential disease applications is malaria, an application that Mark Hamann of the University of Mississippi is exploring extensively.

Because manzamines have had been isolated from a number of unrelated sponge species in different oceans, researchers long suspected that microorganisms might be responsible for their production rather than the sponges themselves. So, Hill and his team traveled with Hamann to Indonesia to collect a sponge that grows there and produces especially high quantities of manzamine A.

In hopes of culturing a microbe responsible for the production, collected sponges were taken quickly to shore where a field laboratory had been established at the group's dive base. Sponges were ground and then "plated off," the process used to begin microbial cultures in Petri dishes. As many microbes as possible were isolated in this way and samples were also frozen and returned to Maryland for DNA extraction and molecular analyses.

The result of this work was the isolation of a microbe species Hill's team has called Microminospora sp. strain M42, which is part of the Actinomycetes family of bacteria. Actinomycetes are some of the most common microbes on the planet and produce about 70% of currently available antibiotics. The group has been able to culture M42 and, as important, the species continues to produce manzamine A in culture. Long a goal in the marine biomedical field, this appears to be the first time any group has ever accomplished such a culturing of a microorganism that produces a bioactive compound first discovered in an inevertebrate. "As a result, we hope we'll play a small part in the process where this compound can move forward and become a practical drug," says Hill.

- VIDEO CLIP 2: "The Manzamines: Sponge-Derived Anti-Malarial Compounds"

More Focus on the Little Things

Hill and his group are of course also pursuing microbes that produce other compounds of interest discovered in various sponges and even a mollusc. "We think that in all these cases, we are likely to find that the target compound that we are going after is actually produced by symbiotic bacteria rather than by the invertebrates themselves," says Hill.

The Center of Marine Biotechnology as a whole, Hill's lab included, has made the collective decision to forego almost any natural products screening work, which frees Hill to focus on other important aspects of microbiology. Instead, Hill works with collaborators such as Mark Hamman at the University of Mississippi, who screens compounds from his samples and also helps in identifying microbes that might prove the best targets for study. Hill considers this strict focus on microbiology a strength of his research program.

Hill's lab takes a somewhat unusual approach to new projects in that they work extensively to determine what microbe species might be present in a given organism before ever trying to grow any of the microbes from it. This is accomplished through molecular analyses of samples from a sponge or other target to sequence 16s ribosomal genes, widely used to identify species. These analyses are also used to determine where in the host organism microorganisms might be concentrated. Once the team has a good understanding of these community dynamics, they are able to use a more targeted approach to growing the microbes they think are particularly important.

A second factor guiding decisions about which microbes and compounds to focus on is track record. Actinomycetes, as already noted, are known to be good producers of pharmaceutical compounds, so when such organisms are present they present a logical target for study. Cyanobacteria are also known to produce many bioactive compounds and they are especially attractive because they can be found in many shallow water sponges at high concentrations. Though the lab has had mixed results in culturing cyanobacteria, Hill remains confident that his group will ultimately find novel cyanobacteria that make important compounds.

- VIDEO CLIP 3: "Mining the Diversity of Sponge Microbial Associates"

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