Last year, a cutting edge scientific imaging technology called cryo-electron microscopy earned a Nobel Prize for chemistry, lauded by the committee as ushering in a "revolution in biochemistry." The technique allows scientists to visualize biomolecules in their natural state for the first time ever, and one year on is already opening up some exciting possibilities. Now, scientists have used it to image a high-potential cancer-killing virus in unprecedented detail, allowing them to now ponder how it might be genetically modified to better do the job.
According to the Nobel statement accompanying the announcement last year, cryo-electron microscopy has allowed scientists to "visualise processes they have never previously seen." It relies on a careful freezing method that turns water inside cells into a solid to preserve their cellular structure, along with a modified electron microscope that blasts it with weakened beams for that very same reason.
This, paired with pioneering mathematical algorithms, has already enabled scientists to use cryo-electron microscopy to probe the secrets of poisonous bacteria, polio-fighting plant viruses and the immune-regulating effects of tick saliva. Now, scientists at the University of Otago and the Okinawa Institute of Science and Technology (OIST) are using it to explore the potential for designer viruses that kill off cancer.
"Cryo-electron microscopy is one of the most vibrant fields in life sciences today, a fact recognized by the 2017 Nobel Prize," study co-author Mihnea Bostina tells New Atlas. "We are now able to fix in vitreous ice (i.e. in near native conditions) our molecule of interest, and we can use advanced microscopes to collect thousands of very high resolution images, which we can analyze with complex algorithms. So we have a good method to preserve the sample, to image it and to analyze it. The result is that we can inspect in atomic detail the architecture of important molecular actors."
Bostina, who is the director of the Otago Centre for Electron Microscopy, and his fellow researchers focused on the makeup of the Seneca Valley Virus. This, like other anti-cancer viruses, is seen as a potentially powerful weapon against cancer because it selectively targets tumor cells while leaving healthy cells unharmed. These abilities have already been demonstrated in phase I and II clinical trials concerning pediatric solid tumors and small-cell lung cancers.
Seneca Valley Virus is seen as a particularly promising anti-cancer virus because it latches onto a receptor called ANTXR1, which happens to be found in almost two thirds of human cancers. What piqued the interest of the team was that the virus binds so wilfully to ANTXR1 on the tumor cells, while showing no apparent interest in a close relative called ANTXR2, which appears only in healthy tissues. This high degree of selectivity has been hard to replicate.
"Until now it was very difficult to target ANTXR1 specifically, because the drugs would not distinguish well enough between the two receptors," Bostina explains.
One other drawback of Seneca Valley Virus as a form of virotherapy for cancer treatment is that because it is a virus, it triggers an immune response from the patient that effectively kills it off within a few weeks. In theory, it is needed for much longer. So this is where cryo-electron microscopy comes in, and its benefits are two-fold.
By using it to image Seneca Valley Virus, the scientists hoped to home on the unique features that enable it to selectively bind to ANTXR1, and then improve on those features so that it can also evade the immune system long enough to finish the job. Their reconstruction of the virus revealed previously unknown features in its outer shell that dovetail perfectly with structural features of ANTXR1, but which aren't found on ANTXR2.
"The components must fit together like a key in a lock – this is a highly evolved system where everything fits perfectly," says OIST's Matthias Wolf, co-senior author on the study.
Bostina refers to these components as residues, and with this new knowledge of the role they play, he says scientists can start to explore how the virus can be enhanced for cancer-fighting purposes.
"Our work shows exactly which residues are important for receptor recognition, and we can keep these residues intact and mutate residues at the surface of the virus so it escapes the immune system attack, a strategy already employed by all viruses," he says.
The beauty of the breakthrough is that it could have implications for many avenues of cancer research, given the widespread nature of the ANTXR1 and Seneca Valley Virus' ability to open many doors. The new in-depth knowledge of how it works might also provide the basis for viral therapies that are tuned to latch onto different kinds of receptors as a way of treating different kinds of cancers.
"An enormous advantage for using Seneca Valley Virus is that its receptor is over expressed in over 60 percent of the human cancers," says Bostina. "This means that we have a virus acting as 'master-key' which can unlock different types of tumours. Now, we are trying to understand how the virus replicates in specific cancer cells and how we can use this knowledge to make the virus 'stronger.' We want to see how different types of cancer react to the infection, what is specific and what can be used to our advantage. It is an exciting horizon of new possibilities made possible by this study."
The team has published its research in the journal Proceedings of the National Academy of Sciences, and produced a short video demonstrating how the virus interlocks with the tumor, which can be viewed below.
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