Research Project 3: Pharmaceutical Lead and Pharmacological Probe
Discovery
Team
Thomas Hemscheidt, Ph.D., Project Leader
Marla Berry, Ph.D., Co-Investigator
Patricia Lorenzo, Ph.D., Co-Investigator
Kelly Gabrielson, Research Associate
Domonkus Feher, Research Assistant
Benjamin Philmus, Research Assistant
 Goal
The main goal of this research is the discovery of new natural
products with biological activity from marine microorganisms. In
collaboration with the Facilities
Core for Culture and Characterization of Marine Microbes, we will test the
hypothesis that new microbes found in the open ocean and in marine
biofilms can be brought
into culture by application of new methodology. We postulate that most of
the microbes isolated in the course of this work will be unrelated
to microorganisms
known hitherto and that this novel biology will be reflected in the chemical
diversity of the compounds they produce. This leads us to the hypothesis
that extracts from biomass of such organisms will show biological
activity in assays
with relevance to cancer, infectious diseases and neuroscience. Moreover,
bioassay-guided fractionation of such extracts will result in the
discovery of new, useful compounds
that can serve as leads for treatments combating these diseases.
Specific Aims
The specific aims of this project are:
- To prepare hydrophilic and lipophilic extracts
from microorganisms mass-cultured in the laboratory.
- To screen the extracts for biological activity
in molecular and cell-based assays with relevance to cancer,
infectious diseases and as antioxidants
with neuroprotective activity and to further develop molecular assays
to medium- and high-throughput format.
- To isolate by bioassay-guided fractionation biologically
active components from crude extracts displaying significant
activity, to determine
the chemical structure of active compounds by spectroscopic methods and
to make larger quantities of the active agents available for
further
testing via mass
culture/isolation or chemical synthesis.
Innovative Approach
We
will combine recent significant discoveries of biodiversity in
the ocean and in marine microbial
biofilm communities with new technology to bring newly discovered organisms
into
culture. We will screen extracts from these cultured organisms in a range
of molecular and cellular assays of proven significance. The advantage
of this
approach is that the isolation effort is directed from the beginning towards
the discovery
of molecules that “hit” proven, clinically relevant targets. This
represents a significant departure from the classical approach in which the mechanism
of action of a compound is determined long after the material is first described.
Moreover, in classical natural products drug discovery programs cytotoxicity
was used as the sole endpoint. We will use instead some contemporary molecular
assays, which allow the identification of compounds hitting oncoproteins without
having cell death as a necessary consequence. Synthetic drugs of this type are
coming on the market (Gleevec®) demonstrating the validity of this approach
in a very practical sense. These new screens will be complemented by proven
mechanism-based cellular assays for other cancer related targets as well
as those with relevance
to infectious disease and neuroscience.
Much of what we are proposing to do is beyond what can be covered
competently by a single investigator, even with the help of an
occasional collaborator
with a different skill set. It could also not be funded under the existing
programs
at the established funding agencies since health-related research and oceanography
are not covered by one agency. Thus, this program represents an exciting
opportunity for the members of the Natural Products Program at
Cancer Research Center of Hawaii to
interact with an organized group in Oceanography with an almost
orthogonal
skill
set.
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