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DR. MARK HAMANN - Director, Marine Natural Products Program,
University of Mississippi Department of Pharmacognosy
The Research: Marine Biotech, Mississippi-Style
Though more than 150 miles from the ocean, the University of Mississippi has one of the most extensive marine natural
products programs in the world. Mark Hamann came to Mississippi in 1993 to found and run the program, which is part of
both the University's Department of Pharmacognosy, and the USDA -funded Center for Natural Products Research, both of
which are in the School of Pharmacy.
The program's overall goal is to identify novel natural products from invertebrates that have either pharmaceutical or
agrichemical potential. Key interests for the department include infectious diseases, such as malaria and AIDS, and
anti-fouling compounds such as those that might be used to combat zebra mussels in the Great Lakes and elsewhere.
Collection work is currently focused on Jamaica, Egypt, and Indonesia, because of unique relationships the group has
established in those areas. The Ole Miss researchers also collaborate with PharmaMar, to study compounds that may be active against cancer.
Research in Hamann's lab is currently focused on a group of alkaloid compounds called the manzamines that were initially
pursued for anti-cancer potential but have more recently shown efficacy in fighting malaria.
 - VIDEO CLIP 1: "Research In the School of Pharmacognoscy"
 Collection Sites
The Mississippi program evaluates samples from diverse locations. The group has labored to establish relationships with
the governments of Jamaica, Indonesia, and Egypt to acquire the necessary permits for biomedical collection. In each
country they have also established collaborations with local scientists and divers to both assist the Mississippi
scientists in doing their own collections as well as to collect additional material for the group. The team makes
collections using conventional scuba, as well as rebreathers that allow access to sites as deep as 500 feet. Typically
the researchers target areas within a few hours of land, allowing them to work from relatively small boats and venture
out to dive on day trips. The group is also studying samples collected from deep reefs in Alaska's Aleutian Islands
region that have been supplied to them by NOAA researchers for screening.
- VIDEO CLIP 2: "Current Research Projects"
Deep Access Using Rebreathers
While scuba diving, a diver breathes in air from a tank and then exhales this air into the water. Rebreathers instead recapture most or all
of a diver's exhaled air and then remove carbon dioxide and add oxygen so that the air can be reused for extended periods of time, often as
long as eight hours. This allows divers to stay underwater and safely venture much deeper than they normally would with scuba, because
comparable dive durations with scuba would require that additional gas tanks be carried or placed at accessible locations in the water,
which is logistically complex and dangerous.
The Hamann team has been working with rebreather systems now for several years. They were initially attracted by a desire to venture deeper
on reefs to collect samples and to simply have more time on the bottom to collect samples. The researchers have done most of their
rebreather work in Jamaica, routinely working as deep as 350 feet. Hamann says they focus especially on areas between 150 and 250 feet that
are especially productive, with invertebrates there yielding higher quantities of secondary metabolites than their shallower counterparts.
This may be due to the fact that invertebrates in this depth range tend to be more mature, allowing them to put more energy toward
production of these products and less toward growth, according to Hamann.
"It's certainly been a steep learning curve going from traditional scuba to rebreathers, but a fantastic opportunity," says Hamann.
- VIDEO CLIP 3: "Sample Collection on Deep Reefs"
Discovery Approach: Start With the Ending
Unlike many groups, which focus most of their attention on collecting and screening new products for bioactivity then zeroing in on those
that show the most potential in their natural form, the Mississippi group takes a somewhat different approach. They do collect and screen
new products extensively, but a key focus is on seeking products that have qualities similar to those of successful existing drugs, such as
good metabolic stability, even if these new products do not exhibit exceptional bioactivity. Once such compounds are identified, the group
works to first isolate gram or in some cases even kilogram quantities of them. This material is then subjected to a series of synthetic
modifications to produce hundreds to thousands of analogs of the original natural product with the goal of enhancing and improving the
compounds initial properties. These analogs are then screened to identify which ones might have greater pharmaceutical potential than the
original, and in some cases to also identify additional applications.
With those products the group targets, they also work to identify a sustainable production source, mainly by seeking a microbial producer
for a given product that could then be fermented in large quantities to produce a steady, economical supply. This process ensures that
compounds identified as the best drug candidates can be produced in large quantities, and, because the group focuses on synthetic analogs of
the natural products, that they will offer a strong patenting opportunity. "Our goal is to look at all of these things early in the
process," says Hamann. "By doing that, we've immediately focused our attention on compounds that we know that we can produce on a
significant scale, so there's no issues downstream as far as insufficient availability of the molecule to develop it," says Hamann. The
process also allows the group to avoid the increasing difficulty of finding truly novel products, because they can work with known products
or product groups to develop extensive and diverse libraries of semi-synthetic, novel products. "Our marine program has taken the lead as
far as recognizing the fact that we really need to be more creative in how we utilize natural products," says Hamann, "if we're going to
generate successful drug candidates.
- VIDEO CLIP 4: "Looking For a Few Good Molecules"
Manzamines
One of Hamann's key research interests is exploring the use of a group of compounds called the manzamines in treating malaria. These
compounds were first discovered in a sample collected near Okinawa, Japan and pursued as a potential cancer treatment. Their malaria
potential has only recently become evident. To date the compounds have shown promising activity in animal models, exhibiting even in very
small doses the ability to completely clear the malaria parasite. The mechanism of action also appears to be unique at this point.
The development of malaria drugs has been greatly hindered by their relative lack of commercial potential as compared to treatment for
diseases such as cancer . This is because malaria cases are concentrated in developing countries, afflicting mainly people who would not be
able to afford even moderately expensive treatment.
Nonetheless, malaria has a major impact on global health, claiming nearly two million lives each year. Children are especially hard hit
because their immune systems are less developed. Chloroquin, the most commonly used treatment, is inexpensive but has several drawbacks,
including emerging resistance to it by the malaria parasite in many areas.
"It's not a very lucrative area to be working in," says Hamann, "but as far as global human health goes, it's a tremendous issue and a real
concern."
The manzamines have shown strong activity even against chloroquin-resistant malaria strains. Like most natural products, though, the
compounds are not flawless as they exhibit higher than desirable toxicity. So, the Hamann group is focusing significant effort on synthetic
modification of the natural forms with the goal of producing analogs that retain as good or better malarial activity without any harmful
side effects.
The manzamines are also of particular interest in the marine biotech field because they are one of the first, if not the first, product
initially isolated from a sponge whose microbial producer has been identified. This isolation work, by Russell Hill's lab at the University
of Maryland [LINK], suggests that the manzamines could be produced relatively cheaply and efficiently through fermentation of the identified
microbe, which would dramatically improve the chances of sustainable commercial production.
Industry Potential
Hamann is convinced that there is a wealth of interesting opportunities within the field of marine natural products, and in marine
biotechnology in general. He believes that increasing enthusiasm within the pharmaceutical industry for marine natural products would, of
course, be dramatically increased with some success stories of major, successful drug products derived from the ocean. He says the industry
already recognizes that marine natural products offer numerous unique structural classes and outstanding drug candidates, but a key step
toward greater attention to ocean potential will be proving that products can be produced by a microbial source, as sustainable, economical
production remains one of the greatest hurdles in advancing the field. "I think the pharmaceutical industry recognizes the potential, but
they just have not embraced marine natural products because of the issues regarding sources and then also the issue of the effort required
to optimize and produce a real drug candidate from a lead," says Hamann.
- VIDEO CLIP 5: "Opportunities and Need for Marine Natural Products"
Education
Hamann is convinced that there is a wealth of interesting opportunities within the field of marine natural products, and in marine
biotechnology in general. He believes that increasing enthusiasm within the pharmaceutical industry for marine natural products would, of
course, be dramatically increased with some success stories of major, successful drug products derived from the ocean. He says the industry
already recognizes that marine natural products offer numerous unique structural classes and outstanding drug candidates, but a key step
toward greater attention to ocean potential will be proving that products can be produced by a microbial source, as sustainable, economical
production remains one of the greatest hurdles in advancing the field. "I think the pharmaceutical industry recognizes the potential, but
they just have not embraced marine natural products because of the issues regarding sources and then also the issue of the effort required
to optimize and produce a real drug candidate from a lead," says Hamann.
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