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At NCCOS's Hollings Lab in Charleston , S.C.
Research from Atoms... to Ecosystems:
New NMR Technology Shows Great Promise
Scientists at NCCOS's Hollings Marine Laboratory (HML) in Charleston, S.C., have some powerful new technology available to them in the form of two just-installed world-class nuclear magnetic resonance (NMR) instruments.
The new technology is expected to be a focal point of the laboratory's plans to address a range of human health and coastal ocean research areas of prime importance to NCCOS and its HML partners. (See this feature from January 2005 for information on HML and its unique partnerships.)
“With this new facility, our scientists will be able to relate truly molecular-scale information to complex ecosystem issues,” according to NCCOS scientists Dan Bearden and Peter Moeller, whose enthusiasm for their new research potential is tangible. “Our new NMR capabilities will have the capacity to address most, if not all, of the key environmental stressors affecting the coastal ecosystem.”
What's so impressive about the new NMR capabilities is the breadth of the potential applications:
- Structural biology — involving the shape and function of large biomacromolecules having thousands of atoms (DNA, RNA, proteins, etc.);
- Metabolomics — involving the study of metabolites in an organism, the byproducts and small building blocks essential for life to go on;
- Natural products research — in which chemists look for commercially viable chemicals with interesting effects or properties from naturally occurring sources.
The new NMR capabilities will help scientists better investigate, for instance, climate change effects on organisms at the structural biology level and also at the functional level, providing insight into how organisms react to subtle environmental changes.
In keeping with HML's fundamental goal of facilitating complementary research among its five institutional partners, the new NMR capabilities will address both important human medical issues and also important marine ecosystem health issues. As one example, the Medical University of South Carolina's ongoing cancer research will benefit in new ways along with HML's marine research community, as both benefit from studies of anti-cancer compounds derived from marine sources and from potential uses of naturally occurring marine toxins (natural products and their applications).
At the same time, HML coastal ocean scientists will have access to tools of structural biology developed through the cancer research, bringing new insights to the marine community.
Making Sense of Simple, but Profoundly Important, Questions
NMR will help the scientists make sense of some seemingly simple — yet profoundly important and complicated — questions:
- What is this stuff? And how much is there?
- How is this material different from other things we know about?
- Have we manufactured or synthesized the right product?
- How does this chemical reaction happen precisely?
- Is this material pure?
- Can we make this drug work better?
- Is this person or animal sick? If so, what is the possible diagnosis? Is the treatment working?
Simple questions, with vital implications. For the trained clinician, chemist, or biochemist, the new NMR capabilities just now taking shape in Charleston can provide a wealth of valuable information in addressing those questions. They can lead to a better understanding of the “conceptual framework for understanding living organisms,” says Bearden. “The ultimate goal would be to bring together the knowledge to get an accurate picture of living organisms.”
Significantly, the NMR technology itself is non-destructive to the sample, meaning other potentially destructive tests can later be applied to the same sample. Furthermore, it is quantitative, so scientists can analytically determine the quantity of material in a sample, and it can provide very quick analyses and provide detailed data about the atomic connectivity in molecules. In addition, NMR can be used in studying the movements of atoms in solids, liquids and gases.
“It is really important to emphasize,” according to Bearden, “that NMR is essential for identifying and characterizing previously unidentified chemicals. There is enough information available in NMR data from organic compounds, for example, to identify the compound unambiguously, down to the details of the stereochemical structure.” While other technologies work well for known compounds, Bearden says, they often require extensive libraries or reference compounds for making positive identifications. “The non-destructive nature of NMR lets us look and re-look at novel molecules, asking all the pertinent questions we have,” Moeller emphasized.
Like any technology, NMR is better suited in some applications than in others. In most cases, NMR requires a sample of more than 100 nanograms for a low-molecular weight compound, and that much material can be difficult to come by in natural products chemistry, for instance. Even so, recent advances are bringing that limit down by a factor of 10, “opening new approaches which would have been neglected previously,” according to Moeller.
In some cases, techniques other than NMR may be more suitable, for instance in working with unknown crystalline substance, X-ray crystallography may provide a quick automated way to answer questions directly. Sensitive techniques like Gas Chromatography/Mass Spectrometry might be preferred in working with a known molecule at low concentrations in a complex mixture, if the molecule is volatile. Liquid Chromatography/Mass spectrometry is used if the molecule is less volatile. Again, however, those non-NMR techniques are destructive of the samples, and meticulous care is needed to avoid destroying the molecules' structure and avoid misinterpreting the resulting data.
Characterizing Specific Chemicals, Developing Population Assessment Tools
The Hollings researchers have on the drawing board detailed plans for developing profiles of known anthropogenic contaminants and impacts on marine organisms. For instance, by comparing responses of a pesticide with responses of other pesticides or contaminants, they hope to develop tools to characterize new chemicals of interest or perhaps develop new population assessment tools.
“As we develop this model for other classes of compounds,” Bearden explains, “we should be able to distinguish modes of action characteristic of the class of compound for that organism. We then hope to apply those techniques to other important species, developing corresponding models for exposure, and widening our ability to assess modes of actions for new compounds across numerous species.”
Another application: Focusing on rare, endangered, or protective organisms on which classical toxicological research is infeasible. Coordinating with marine mammal scientists, the HML scientists are obtaining samples of body fluids — urine, plasma, and stomach contents — and using NMR-based techniques to examine the samples. They are looking for patterns that may correlate with age, sex, geographic location, or apparent disease states.
Looking ahead, Bearden says that “The exciting thing about NMR-based research is that the technology and tools of NMR continue to evolve at an exciting pace that could not have been envisioned not so long ago. The utility of NMR has grown with the computer revolution, of course, but fundamental advances in the field continue apace.”
“Applying modern high-field NMR to marine issues can be risky, as with all cutting-edge science,” Moeller and Bearden say. “But the unexplored territory is vast, and if we are to address the complex issues of the 21 st Century, we need all the understanding we can manage.”
Calling it a “fool's errand” to try to guess just where the NMR technological capabilities may be just a decade from now, Bearden says that successfully managing human' interactions with the environment “must cover the scale of atoms to ecosystems. And NMR is a tool that can do that right now.”
