The penetrative power of neutron beams, combined with their non-destructive nature, provides an ideal tool for analyzing chemical and biological material. Our knowledge of biological systems has evolved thanks to the increasing power of imaging techniques, which could have the potential to revolutionize drug target identification.
Cancer is the second leading cause of death globally, accounting for approximately one in six deaths: an estimated 9.6 million people in 2018. Our understanding of the types, treatments, and biology of cancer has exponentially grown over the last century, though the disease has been found in human remains dating back to 1500 BC. Many theories have been recorded over the past few centuries for why cancer might develop, including ideas of parasites, trauma, or chronic irritation leading to tumor development. In the 20th century, the elucidation of DNA structure and subsequently the discovery of oncogenes and tumor suppressor genes opened our eyes to the endless potential causes of cancer, with scientific and technological advances in imaging enabling this deeper understanding. Great progress has been made in the characterization and treatment of cancer thanks to these technological advancements, and finding new leads to treat the illness is likely to continually rely on the optimization of analytical techniques.
Neutrons — the emerging heroes
The development of cancer is a complex process, which can result from minor mistakes in an otherwise well-functioning network of cellular processes. As such, it is essential that scientists have a clear picture of biochemical processes at an atomic level in order to gain an in-depth understanding of how various cancers occur and develop. One technique starting to gain recognition as a powerful tool is neutron crystallography. This is because it allows researchers to visualize the atomic structures of proteins, including the positions of the hydrogen atoms — key players in nearly all biochemical reactions and processes. In addition, neutrons do not damage the samples, so they allow structures to be determined at room temperature, close to physiological temperatures. This is in contrast to more common analytical tools, such as X-rays, where location of the all-important hydrogen atoms is generally not possible, and data collection is complicated by issues of radiation damage to the samples that can lead to alterations to the structure.
Galectin 3C — could crystallography lead to cure?
A study recently carried out of galectin-3, a member of the galectin family of proteins, demonstrates the ability of neutron crystallography to increase our understanding of proteins implicated in various cancers. Galectins are carbohydrate-binding proteins that attach to other proteins via the carbohydrates on their surface. When galectin-3 is overexpressed it can enhance the adherence of breast cancer cells to other cells in the human body, suggesting it plays a part in tumor development, and the way that cancer spreads through the body in a process called metastasis.
In collaboration with Lund University (Sweden), research carried out using the LADI-III instrument at the world’s flagship neutron facility, the Institut Laue-Langevin (ILL), as well as neutron instruments at Oak Ridge National Laboratory (ORNL) and Heinz Maier-Leibnitz Zentrum (MLZ), concentrated on understanding how galectin-3 binds to specific carbohydrates. Using neutron crystallography the researchers were able to visualize, for the first time, the key binding interactions in the protein’s active site: namely the hydrogen-bonds. The results of the study are significant because if galectin binding to malignant cells is a primary culprit in the progression of breast cancer, a drug that acts as an inhibitor of this binding may be effective as a therapeutic agent . Thus, knowledge of the key hydrogen-bonding interactions provides us with a better understanding of how to optimize the design of galectin-3 inhibitors.
Up to this point, our understanding of the binding processes have been based upon structures determined using X-ray crystallography, but even with the most high-resolution structures (better than 0.1 nm) it has been impossible to determine the positions of the hydrogen atoms that reveal the hydrogen-bonding interactions dictating how the sugar-binding occurs. Neutron crystallography, on the other hand, allowed the hydrogen atoms to be visualized even at modest resolutions (around 0.2 nm) at room temperature, and so really is the most powerful technique for revealing such critical interactions.
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