Research & Funding
Our research blends different conventional fields with emerging new areas. Broadly defined,
we are interested in RNA Structure and Function, Origin and Evolution of Life, Bioorganic Chemistry,
Novel Functional Molecule Discovery,
and Biosensors & Biomedical Applications. Our interdisciplinary research programs are built
on our strength in organic chemistry, biochemistry, molecular biology, and enzymology.
Novel Functional Molecule Discovery
Combining the powerful in vitro evolution techniques with
bioorganic synthesis , we are searching for artificial macromolecules
(with RNA as our current focus) with novel functions never known before. These functions either are of
great theoretical importance related to the origin and evolution of life or have potential biomedical
applications.
Using the strategy, we have successfully isolated a series of RNA enzymes (ribozymes) that can perform
biologically relevant chemical reactions. These reactions include RNA capping, RNA cap exchange,
phosphoryl coupling, pyrophosphate hydrolysis, synthesis of common coenzymes CoA, NAD, and FAD.
On this front, our current effort is directed towards isolation of ribozymes with several properties.
One RNA function of our great interest is to make thioesters and utilize them to build larger biomolecules (remember acetyl CoA's
core
position in the metabolic pathways?). Another interesting property of
RNA
we are trying to obtain is phosphorylation by polyphosphates (not
by ATP as
in current biology!). Both these properties have been speculated to have played important roles in the origin
and
early evolution of life. A third in vitro evolution project is
beginning
to produce novel RNA-RNA complexes of great stability, which may have significant implications in
extending
RNA capabilities beyond current knowledge.
RNA Structure and Function
Several of our isolated ribozymes have multiple catalytic functions, relative small sizes, and unique divalent
metal
ion requirements. A series of trans-active RNA enzymes have been engineered for the first time to be able
to bind
two small-molecule substrates, such as two nucleotides, and to build larger products between the two small-
molecule substrates. These ribozymes are excellent model systems to study RNA structure-function
relationship and
mechanism of ribozymes, both challenging questions in RNA catalysis. Furthermore, other fundamental
questions of
RNA catalysis are being addressed, such as how RNA catalysts are able to bind multiple small-molecule
substrates
and orient them at atomic precision so that reactions occur rapidly.
Funded by NSF, we are investigating (1) structural motif–function relationship, (2) spatial
arrangement
around RNA active centers, (3) metal ion and substrate binding sites within RNA, (4) RNA conformational
changes
upon metal and/or substrate binding, and (5) searching for reaction intermediates. A variety of chemicals
(such as
Pb2+, Fe(II)-EDTA,DMS, DEPC, CMCT, photocrosslinking agents, etc.) and enzymes (e.g., RNase T1,
nuclease
S1) are being used to probe the RNA conformation under different conditions. A large number of substrate
analogs
with probing groups attached are being chemically synthesized to aid this investigation.
Origin and Evolution of Life
Humans always wonder about the question: where did we come from? From ancient times to modern days,
philosophers, scientists, and ordinary people alike have been trying to find answers or clues. Due to the
extraordinary nature of this question, there are many religious beliefs and scientific views and attempts.
However,
no current theories are able to explain our past from the very early moment of the Earth.
I believe that life originated somewhere and at some time in the process of universe evolution. Life
(what
is life? Life has these basic properties clearly differentiating from non-living matters: self-organization at cost
of
external energy, growth, and reproduction) emerged when a series of natural processes produced a
collection of
molecules that coordinated their own reproduction. Although little is known about these processes and may
not be
possible to know what happened in the far past, we are not impeded to seek clues and excise our metal
power and
imagination. The advance of modern science is providing tools that may be used to search for plausible
answers
based on solid sciences instead of pure speculations.
Since the discovery of catalytic RNA by Cech and Altman in the early 1980's, a popular view that
RNA
proceeded our contemporary world is gaining support from different fields of science. This hypothesized
period in
the course of life evolution is termed an RNA World by Gilbert. Much of our lab's effort is directed towards
understanding RNA's structure and function and evaluating the plausibility of an RNA world before our
modern
world. In addition, we also consider other possible primordial living systems in which polyphosphates and
thioesters
might be the essential molecules.
Biosensors & Biomedical Applications
Our combinatorial approach (using both organic chemistry and enzymes) to generate novel functional
molecules can
also be applied to produce molecules with biomedical applications. Examples are aptamers, biosensors, and
enzymes. All of them can be fine tuned towards a specific target for the purpose of diagnostics and/or
biological
process interference. We are relatively new in this area. However, there is a lot of excitement coming out of the
field, and we predict that new diagnostic probes and drugs may evolutionize our current healthy care system and
improve the quality of people's life.
Research Facilities
Our lab is well equipped for our broad research effort. Major instruments within the lab include a Shimadzu
4-solvent system HPLC with a photodiode array detector, a BioRad phosphorimager system, a thermocycler,
and an array of centrifuges and gel electrophoresis apparatuses. Within our Center for Molecular and
Cellular Biosciences (CMCB) in Johnson Science Tower (JST), we have easy access to autoclave,
ultracentrifuge, UV spectrometer, fluorometer, scintillation counter, lyophilizer, and fluorescent microscope.
Our college of Science and Technology has electron microscope, atomic focusing microscope, high field
NMR. etc
Current Funding Agencies
Our research programs are funded by the following federal and state agencies:
National Science Foundation (NSF)
National Aeronautics and Space Administration
(NASA)
National Institute of Health (NIH)
University of Southern Mississippi (USM)