Understanding the viruses that kill cancer cells

Taking inspiration from virology to find better treatments for cancer

There are some viruses, called oncolytic viruses, that can be trained to target and kill cancer cells. Scientists in the field of oncolytics want to engineer these viruses to make them safer and more effective so they can be used to treat more people and different types of cancers. To achieve this, they first have to fully understand at the molecular level all the different ways that the virus has evolved to infect healthy cells and cause disease. A research team from Cardiff University set out to better understand how a protein on the surface of a virus often used to kill cancer, called an adenovirus, binds to human cells to cause an infection. Using X-ray crystallography, the team was able to determine the structure of one the key adenovirus proteins. Using this information and after extensive computational analysis, the research team realised the virus was not binding the receptor on the cells that was originally thought. This has important implications for the development of new virotherapies and engineering of viruses to treat cancer. The more thoroughly the researchers can understand how the adenoviruses interact with cancer cells at the molecular level, the more safe and effective treatments can be brought to clinical trial in the future.

>Read more on the Diamond Light Source website

Getting the timing right for molecular movies

Jitter effects measured at European XFEL

Scientists have long dreamed of being able to film the details of chemical and biological reactions by taking, and stitching together snapshots of these processes. Getting the timing of the individual shots of the movies just right is dependent on a number of factors including understanding the timing variation, or so-called ‘jitter’, of the laser beams used to take the images. In an experiment published now in the journal Optics Letters, scientists describe how they measured the jitter at the SPB/SFX instrument at European XFEL and demonstrate how this unavoidable and undesirable effect might be overcome. The knowledge gained from these movies could lead to new technological innovations and developments.
Biological and chemical reactions happen extremely quickly and filming them requires an extremely fast and precise camera. Much like a fast exposure time can be used to capture a series of images showing details of the movements a sprinter makes during a race, so the extremely short bursts of X-rays produced by facilities such as European XFEL are short and frequent enough to capture the sequence of molecular movements that happen during a reaction. To make a molecular movie, scientists can, for example, first kick-start the reaction they want to film by hitting their sample of choice with a laser. Then, the intense X-ray laser is used to take a sequence of images of the molecular process as it unfolds. Getting the timing of the two lasers just right is crucial for the success of these types of experiments, however, at these speeds, it is not trivial.

>Read more on the European XFEL website
Image: The SPB/SFX instrument at European XFEL.
Credit: European XFEL

Clear view of “Robo” neuronal receptor opens door for new cancer drugs

During brain development, billions of neuron nerve cells must find accurate pathways in the brain in order to form trillions of neuronal circuits enabling us to enjoy cognitive, sensory and emotional wellbeing.

To achieve this remarkable precision, migrating neurons use special protein receptors that sense the environment around them and guide the way so these neurons stay on the right path. In a new study published in Cell, researchers from Bar-Ilan University and Tel Aviv University in Israel, EMBL Grenoble in France and University of Exeter in the UK report on their discovery of the intricate molecular mechanism that allows a key guidance receptor, “Robo”, to react to signals in its environment.

One of the most important protein signaling systems that guide neurons consists of the cell surface receptor “Robo” and its external guidance cue, “Slit”. “Slit and Robo can be identified in virtually all animals with a nervous system, from a 1 mm-long nematode all the way to humans,” explains researcher Yarden Opatowsky, associate professor and head of the Laboratory of Structural Biology at Bar-Ilan University and who led the research.

>Read more on the European Synchrotron website

Image: A surface representation of the crystal structure of the extracellular portion of human Robo2. The yellow region represents the domain where dimerisation takes place. Here, we see it blocked by the other domains, meaning dimerisation cannot take place and that Robo2 is inactivated.
Credit: Y. Opatowsky.

What keeps spiders on the ceiling?

DESYs X-ray source PETRA III reveals details of adhesive structures of spider legs

Hunting spiders easily climb vertical surfaces or move upside down on the ceiling. A thousand tiny hairs at the ends of their legs make sure they do not fall off. Like the spider’s exoskeleton, these bristle-like hairs (so-called setae) mainly consist of proteins and chitin, which is a polysaccharide. To find out more about their fine structure, an interdisciplinary research team from the Biology and Physics departments at Kiel University and the Helmholtz-Zentrum Geesthacht (HZG) examined the molecular structure of these hairs in closer detail at DESY’s X-ray light source PETRA III and at the European Synchrotron Radiation Facility ESRF. Thanks to the highly energetic X-ray light, the researchers discovered that the chitin molecules of the setae are specifically arranged to withstand the stresses of constant attachment and detachment. Their findings could be the basis for highly resilient future materials. They have been published in the current issue of the Journal of the Royal Society Interface.

>Read more on the PETRA III at DESY website

Image: In order to find out why the hunting spider Cupiennius salei adheres so well to vertical surfaces, the interdisciplinary research team investigates the tiny adhesive hairs on the spider legs.
Credit: Universität Kiel, Julia Siekmann

Steering the outcome of photoionization in a molecule

An important step towards the understanding and control of photoinduced fragmentation processes in molecules has been achieved in an experiment on the H2 molecule taking advantage of the unique properties of the FERMI free-electron laser source in the vacuum ultraviolet (VUV) photon energy range.
Molecular dissociation, i.e., the breaking of a chemical bond, is governed by the coupling of electronic and nuclear motion and, once understood and controlled in large systems, e.g., by utilizing ultrashort light pulses, has the potential to impact tremendously photochemical and biochemical applications. A team of both experimentalists and theoreticians from France (CNRS, Université Paris-Sud, Université de Bordeaux), Spain (Universidad Autónoma de Madrid), Germany (European XFEL), and Italy (Elettra-Sincrotrone Trieste) has demonstrated that the outcome of dissociative (DI) and nondissociative (NDI) photoionization in the simplest of all molecules, H2, can be controlled exploiting nonlinear two-photon ionization with intense femtosecond pulses in the VUV.
The FERMI seeded free-electron laser is currently the only light source worldwide that provides external users access to bright femtosecond pulses at wavelengths in the VUV up to 100 nm, the energy regime required for studying nonlinear two-photon single-ionization in H2. The high spectral resolution and precise tunability of the 100-fs pulses provided by FERMI made it possible to selectively excite single vibrational levels in the neutral intermediate B state of H2 (blue line in Fig. 1). Absorption of a second VUV photon then leads to NDI or DI into the ionic H2+ ground state (green in Fig. 1) or to DI into the first excited H2+2p continuum (orange in Fig. 1). In single-photon single-ionization of H2, the yield of DI is very low – less than 2%. By contrast, recent ab initiocalculations suggest that the ratio of DI/NDI can be increased significantly in resonance-enhanced two-photon ionization and that it can be controlled by varying the pulse duration between 2 and 10 fs.

>Read more on the Elettra website

Image: (a) Schematic of resonant two-photon ionization viathe B intermediate state (12.51 eV). The grey shaded area shows the Franck-Condon region for one-photon absorption from the H2electronic ground state. The dashed purple arrows visualize the range for the absorption of the second FEL photon. The green (red) horizontal line shows the ionization threshold at 15.43 eV (dissociation limit at 18.08 eV). (b) The experimental photoelectron spectrum shows a clear separation of electrons correlated to NDI and DI. For DI, it is close to the prediction of the Condon-reflection approximation, i.e., the projection of the vibrational wavefunction onto the dissociative 2p continuum state. The infinite-time limit calculation (grey line for the convolution of the contributions from the two first ionization continua) reproduces the main features of the spectrum. The differences between experiment and calculation indicates that at FERMI a timescale between ultrafast dynamics and steady-state excitation is probed.

Snaphot of molecular mechanism at work in lethal virus

X-ray crystallography at the Australian Synchrotron contributed to major research findings.

Data collected on the macromolecular crystallography beamlines at the Australian Synchrotron has contributed to major research findings on two deadly viruses, Hendra and Nipah, found in Australia, Asia and Africa. The viruses can be transmitted to humans not directly by the bat which is the natural carrier but by an infected animal like horses or pigs.

Beamline scientist, Dr David Aragao (pictured above), a co-author on the paper in Nature Communications, said that obtaining a clear motion picture of key biological process at the molecular level of viruses is often not available with current biomedical techniques.
“However, using X-ray crystallography from data collected on both MX1 and MX2 beamlines at the Australian Synchrotron, we were able to obtain  8  ‘photograph-like’ snapshots of the molecular process that allows the Hendra and Nipah virus to replicate.“

Two authors of the paper, PhD students Kate Smith and Sofiya Tsimbalyuk, who are co-supervised by Aragao and his collaborator Professor of Biochemistry Jade Forwood of the Graham Centre for Agricultural Innovation Charles Sturt University, used the Synchrotron extensively collecting multiple data sets that required extensive refinements over two years to isolate the mechanism of interest.

>Read more on the Australian Synchrotron website

Image: Beamline scientist, Dr David Aragao.

Infrared beams show cell types in a different light

Berkeley Lab scientists developing new system to identify cell differences.

By shining highly focused infrared light on living cells, scientists at the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) hope to unmask individual cell identities, and to diagnose whether the cells are diseased or healthy.
They will use their technique to produce detailed, color-based maps of individual cells and collections of cells – in microscopic and eventually nanoscale detail – that will be analyzed using machine-learning techniques to automatically sort out cell characteristics.

Using microscopic color maps to unlock cell identity

Their focus is on developing a rapid way to easily identify cell types, and features within cells, to aid in biological and medical research by providing a way to probe living cells in their native environment without harming the cells or requiring obtrusive cell-labeling techniques.
“This is totally noninvasive,” said Cynthia McMurray, a biochemist and senior scientist in Berkeley Lab’s Molecular Biophysics and Integrated Bioimaging (MBIB) Division who is leading this new imaging effort with Michael Martin, a physicist and senior staff scientist at Berkeley Lab’s Advanced Light Source (ALS).
The ALS has dozens of beamlines that produce beams of intensely focused light, from infrared to X-rays, for a broad range of experiments.

>Read more on the Advanced Light Source website

Image: From left to right: Aris Polyzos, Edward Barnard, and Lila Lovergne, pictured here at Berkeley Lab’s Advanced Light Source, are part of a research team that is developing a cell-identification technique based on infrared imaging and machine learning.
Credit: Marilyn Chung/Berkeley Lab