Using NMR Spectroscopy to Untangle the Causes of Disease
Alzheimers, autism, cancer, autoimmune disorders – these are examples of disorders at the forefront of medical and pharmaceutical research. Complexity is a common hallmark among them. Each has a profile that seems to arise not from a single, discrete cause but from multiple complex factors such as environmental, genetic, and epigenetic interactions. Understanding these interactions, and how they relate to larger mechanisms like stress or inflammation response, will be key to developing better therapies for these disorders.
At the same time, infectious diseases continue to pose a major threat, in the form of emerging illnesses like Ebola, existing ones like HIV, and newly drug-resistant ones like MRSA and tuberculosis.
NMR – Proven Technology for Bioanalysis
Understanding these illnesses entails disentangling complex processes and determining the role played by each contributing factor on a molecular level. How cells react – or fail to react – to pathogens. How the digestive system absorbs nutrients. How the pancreas responds to sugar.
This is where nuclear magnetic resonance (NMR) spectroscopy comes into play. NMR has proven itself a valuable tool in areas of medical and pharmaceutical research in profiling and mapping complex diseases. For example, researchers recently used proton NMR spectroscopy to find metabolic biomarkers for Celiac disease, an autoimmune disorder triggered by eating gluten. The investigators showed differing serum lactate, valin, and lipid levels between people with Celiac disease and those without, pointing the way to both improved diagnostics and possible therapeutic targets. Another study by a different research group also looked at metabolites, this time in children with autism, employing a 2D-NMR approach to uncover several possible targets for further investigation and validation.
The unparalleled ability of NMR to characterize molecular structure also makes it an important method for drug development. For example, researchers have been seeking treatments for Ebola, a virulent hemorrhagic fever that recently caused crisis in several west African countries. In developing a compound that showed the ability to bind and block the virus’s protein coat, NMR was used to evaluate the drug-virus interaction at the structural level, and to screen analogues of the compound to find the most effective ones.
Other examples of NMR’s application in medical and pharmaceutical research include:
- Screening newborns for inborn metabolic diseases such as phenylketonuria
- Helping find new ways to boost immune response using a pathogen’s DNA instead of antigens
- Determining the structure and function of membrane proteins – prime drug targets – in diseases ranging from the 1918 influenza virus to the latest drug-resistant tuberculosis strain
- Identifying possible methods for inhibiting the development of the HIV virus
- Unraveling the metabolic pathways of tumor cells, another prime drug target
- Following the formation in the brain of the protein plaques that characterize Alzheimer’s disease
And as demonstrated by a study involving Italian centenarians, NMR spectroscopy can help us look at what can go right in the body, and not just at what can go wrong. Researchers used NMR to compare the urine and serum of the centenarians with that of an elderly control group and discovered unique changes in lipids biosynthesis in the over-100 group with 41 lipid species showing marked difference in abundancy from that of the elderly subjects.
NMR’s Robust Bioanalytical Toolbox
NMR spectroscopy has several advantages over other diagnostic methods. It is noninvasive and non-destructive; for example, NMR does not require the use of external tracer molecules, preserving samples for additional testing. Yet it is an effective probe that can be used to analyze a wide range of biological processes in systems as diverse as protein solutions, individual cells, isolated perfused organs, and tissues in vivo.
A Second Look with EPR
Electron paramagnetic resonance spectroscopy is a second, related technology that provides a sensitive, specific method for studying both radicals formed in chemical reactions and the reactions themselves. As such it is an excellent tool for exploring the effects of oxidative stress and the benefits, if any, of antioxidant therapies.
For example, recent improvements in EPR technology have enabled its use in the field to track the production rate of reactive oxygen species in everyone from sedentary individuals to ultra-marathon runners.