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Inhibiting Cancer Cells Using NMR Spectroscopy

Andy Byrd, Chief of the Structural Biophysics Laboratory at the National Cancer Institute in Frederick, Maryland, shares his thoughts and explains how NMR spectroscopy can be applied to challenges in structural biology and cancer research.

My research these days is generally classified as structural biology, although as I trained in chemistry. I specialize in nuclear magnetic resonance (NMR) applied to biological problems. Our lab is very interested in studying mammalian proteins, particularly systems involved in cancer, in order to try to understand mechanisms to provide that information for our collaborators, and for the general knowledge of the community as well.

Which particular areas of research have you focused on?
Most recently, we’ve been working in two areas – the first one has somewhat come to an end, but it was very important clinically. This had to do with the protein molecule hepatocyte growth factor that works with the c-Met receptor. c-Met is an oncogene and it is directly involved in metastasis of cancer.

We, in collaboration with biologists, studied the structural biology of this protein, and using the fundamental information we obtained structurally, we were able to engineer variants of this molecule to make an antagonist that actually was clinically responsible in animals – not in humans yet, but in animals. The project was also broadened to also look at the vascular endothelial growth factor, or VEGF system, and so we generalized a principle of intervening with Heparin-based drugs.

Another area that’s particularly of interest to us is the proteasome degradation pathway that regulates the level of proteins in all human cells and, of course, that’s part of apoptosis and cell death. Our line of research is really to understand the mechanisms of the proteins that drive this process so they can be used therapeutically to manipulate or modulate that process.

How do you think your work will impact medical research?
What we hope from the basic knowledge that we generate is that it will drive new biology, and drive people to try new things, to test the hypotheses and the theories that we put out about function.

So, it’s really about structure and function relationships, both in the basic research with my molecular biology colleagues, but then leaning further to actually develop agents that interfere, either to enhance or to inhibit key cellular processes. That’s really the underlying point of trying to impact medicine.

At our level, it’s very basic research but it directly flows into what ends up happening in developing new therapies.

How important is instrumentation to structural biology?
Instrumentation plays a key role in our research because, as biophysicists and structural biologists, we rely on the ability to make detailed measurements about very complex protein systems and molecular systems.

While we’ve developed instrumentation and pushed the state of the materials in our labs, and other people have, the integration of that across the community with vendors and with individual labs, is key. So, getting that cutting edge, state of the art technology and new instrumentation is what enables us to break through barriers and to go to a whole new understanding of biology.

We primarily use nuclear magnetic resonance, or NMR, but we also use a variety of other tools – solution x-ray scattering, various biophysical tools to look at binding and complexes.

What technological improvements would have the biggest impact?
In the NMR field, which is really our specialty, the biggest key element has always been sensitivity. NMR is a very powerful tool and can lead to all kinds of information about structure and dynamics.

Usually we find, in human and mammalian proteins, is that we’re stuck fighting sensitivity all the time. Given sufficient sensitivity, spectroscopists can devise all kinds of new things. But sensitivity seems to be the holy grail.

About Dr Byrd
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Dr. Byrd has been prominent in developing NMR-based structural biology for the study of proteins, nucleic acids, polysaccharides, and protein complexes. Current research focuses on deciphering allosteric mechanisms in the ubiquitination pathway regulating protein degradation/homeostatis and the roles of ADP ribosylation factors and GTPase activating proteins in regulating membrane trafficking.

As Chief of the Structural Biophysics Laboratory and Head of the Macromolecular NMR Section, Dr. Byrd contributes to the development and impact of structural biology within the CCR and oversees an active, multidisciplinary research effort utilizing biophysics and NMR spectroscopy to provide mechanistic understanding of complex biological processes.