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Home » Page 355

Quantum teleportation expands beyond neighbouring nodes

Physicists in the Netherlands have shown for the first time that quantum information can be reliably teleported between network nodes that are not directly connected to each other. According to the researchers, who created the world’s first three-node quantum network at QuTech (a collaboration between the Delft University of Technology and TNO) in 2021, the latest work marks a further step towards a scalable quantum Internet.

Quantum networks offer a super-secure way of transferring information between different locations, or nodes. While these nodes can be connected using ordinary optical fibres, photon losses within the fibres limit the quality, or fidelity, of the connection: when a photon is lost, its quantum information is lost, too. Using quantum entanglement to teleport information directly from one node to another removes this loss mechanism, making it desirable for a future quantum Internet.

The three-node network demonstrated at QuTech in 2021 used quantum bits, or qubits, made from nitrogen-vacancy (NV) centres, which are defects within diamond’s lattice of carbon atoms. Each node contained a communication qubit, and one node also incorporated a memory qubit (made from an adjacent carbon atom) that could store the node’s quantum information. The building blocks for entangling three nodes were thus already present, but the system was far from reliable at teleporting states consistently.

Quantum teleportation

The first step in teleporting quantum information from a sender to a receiver is to establish entanglement between their respective qubits. Performing a so-called Bell state measurement (BSM) on the sender’s qubit causes its quantum state to teleport – meaning that it disappears from the sender’s node and appears, in encrypted form, at the receiver’s node. The quantum state can then be decrypted using the BSM outcome that is sent to the receiver via a classical channel (such as an optical fibre).

Previously, this had only been done with two adjacent network points, traditionally called Alice and Bob. Adding a third point, Charlie, is no easy task, as the entanglement between Alice and Charlie needs to be created via Bob, the intermediate node. It also requires a high fidelity to make the teleportation functional.

Optimization steps

To achieve this high fidelity, the QuTech researchers carried out several upgrades. In their previous system, the “heralding” signals that indicate entanglement came from the same photodetectors that detected the photons used for entanglement. This, however, can lead to false heralding signals due to various undesired processes generating a second photon. To avoid this, the team set up an additional detection path that flags the false heralding signals by catching the second photon.

Photo showing a sample of diamond connected with wires
Qubits up close: Nitrogen-vacancy centres within a diamond sample are used as qubits in the teleportation experiment. (Courtesy: QuTech)

Another problem the researchers addressed is spectral diffusion, which causes the qubits to come out of phase, lowering the fidelity of transmission. This process has more impact for photons emitted at later times, so the team shortened the detection window.

A final set of improvements concerned the memory used to store quantum information. First, the team protected the memory qubit from interactions with neighbouring nuclear spins. To do this, they integrated a magnetic field pulse into the entangling sequence that flips the memory qubit at set time intervals, thereby averaging out the effects of these unwanted interactions. They also improved their ability to read the memory qubit. Because one of the memory qubit’s states has a more favourable fidelity, its readout is not symmetric. By repeating the readout process, the team filtered out “bad” readouts, ultimately increasing the fidelity.

Beam me up

Following these improvements, the researchers were able to teleport quantum information between the non-adjacent nodes of Charlie and Alice. First, they entangled Alice’s qubit and Charlie’s via Bob’s. Charlie then stored its part of the entangled state at its memory qubit and prepared the quantum state to be teleported. Applying the BSM at Charlie teleports the state to Alice. The researchers then sent the BSM outcome to Alice and retrieved the state with a fidelity of 71% – higher than the classical bound of ⅔, proving that the teleportation was successful.

Ronald Hanson, the QuTech researcher who led the study, says that the team’s next step will be to expand the number of memory qubits, making it possible to run more complex protocols. Another objective is to get the technology working outside a lab environment, for example by using already-deployed optical fibres within a real network. “We are also cooperating with computer scientists to develop the quantum network control stack – a similar stack of control layers that currently run the Internet we all use today,” he tells Physics World.

Hugues de Riedmatten, a researcher at ICFO in Barcelona, Spain, who was not involved in the study, says that quantum teleportation over non-neighbouring nodes is a significant milestone. In his view, the team’s biggest achievement was to combine several challenging experiments – all of which need to be fully optimized to reach the required fidelity for quantum teleportation – into a single demonstration. de Riedmatten notes that the current set-up can use only a small percentage of the emitted photons, which limits its remote entanglement rate. However, he adds that this could be fixed by embedding the NV centres in an optical cavity to collect more photons, or by using other emitters.

Rodney Van Meter at Japan’s Keio University also praises the work, describing it as the fundamental difference between a simple channel connecting two parties and an actual network. One of the difficulties, he notes, will be to scale up to large numbers of qubits at each node, but other teams around the world have been working on this problem for NV-centre qubits. With the Delft team already planning to increase the number of nodes in its network, he is, he says, “looking forward to seeing what they produce next”.

The research is described in Nature.

Portable MRI diagnoses stroke at the patient bedside

Portable MRI (pMRI), a new type of very low-field MRI scanner that does not require dedicated shielding, can effectively diagnose stroke and detect blood clots in the brain as small as 4 mm in size. In a study of 50 patients with ischaemic stroke treated at Yale New Haven Hospital, intracranial imaging with pMRI detected ischaemic infarcts in 90% of patients. The prospective study, described in Science Advances, is the first to demonstrate that the 0.064 T Swoop portable MRI system can be used to definitively diagnose and assess stroke at a patient’s bedside.

The ability to rapidly distinguish ischaemic stroke, where a blockage cuts off the blood supply to the brain, from haemorrhagic stroke, in which there is bleeding in the brain, is critical to expedite effective clinical treatment. Ischaemic stroke, the most common type of stroke, is usually treated with thrombolytic “clot busting” treatment. This approach, however, is not appropriate for haemorrhagic strokes.

As such, both the European Society for Cardiology and American Heart Association advise that all stroke patients receive rapid brain imaging on hospital arrival to rule out intracranial haemorrhage. CT is the imaging method of choice for diagnosing haemorrhagic stroke, with radiation-free MRI becoming increasingly popular; but access to stationary MRI machines can be limited.

The Hyperfine Swoop
Portable MRI: The Hyperfine Swoop. (Courtesy: Hyperfine)

Low-field pMRI scanners could prove the ideal approach for point-of-care diagnosis. The Swoop pMRI scanner, which incorporates an eight-channel radiofrequency head coil, operates from a standard electrical outlet, does not require cryogenics and integrates electromagnetic interference rejection, removing the need for a shielded room.

Its compact size (140 cm high and 86 cm wide) enables use in inpatient or emergency department settings, and it does not require a specialized MRI technician for operation. Importantly, the pMRI is not affected by and does not compromise the functionality of nearby hospital equipment.

“A mobile, bedside solution for portable MRI-based imaging opens the doors for re-imagining how we can deliver high-quality care, reach patients and communities across the globe, and further understand the basis for neurological injury and health,” says principal investigator Kevin Sheth from Yale School of Medicine.

For the study, the researchers used low-field pMRI to perform bedside intracranial imaging for 50 patients with ischaemic stroke. The pMRI scans were performed an average of 37±60 hr after the patient’s last known normal time (unknown for five patients). Six patients underwent pMRI in the emergency department, 40 in a neuroscience intensive care unit (ICU) and four in a COVID-19 ICU.

The team acquired a total of 50 T2-weighted, 51 fluid-attenuated inversion recovery (FLAIR) and 56 diffusion-weighted imaging (DWI) images, with a mean exam time of about 25 min. Each of the 50 patients had an ischaemic infarct detected by standard-of-care neuroimaging – high-field MRI or non-contrast CT – within 36 hours of the pMRI exam.

Sheth and colleagues evaluated and compared each low-field pMRI with the conventional MRI or CT scan acquired closest to the time of the pMRI exam. The pMRI was considered to have correctly detected an ischaemic infarct (which appeared as a hyperintense region) if at least one sequence showed the same infarct as seen on the standard exam.

The pMRI detected infarcts in 45 patients across cortical, subcortical and cerebellar structures. The researchers report that “stroke volume measurements were consistent across pMRI structural sequences and pMRI measurements were in agreement with conventional MRI measurements”. They also note that pMRI stroke volumes significantly correlated with stroke severity at the time of exam and functional outcome at patient discharge.

Sheth believes that the team’s results are just the beginning for pMRI. “Hardware and software improvements, algorithm development and image quality improvements, and the science of interpretation and utility must be developed urgently in order to unlock the potential of this approach,” he tells Physics World. “That development needs careful validation from the clinical and scientific community.”

“We’ve seen progressive improvement in imaging resolution and scan times, which will expand access to timely neuroimaging,” adds co-author W Taylor Kimberly from Massachusetts General Hospital. “Due to the portability, this technology can be considered for a variety of scenarios where MR imaging was not previously available. We’re looking forward to continuing to advance the clinical application and validate its use for stroke.”

Writing in an accompanying commentary, Peter Basser from the National Institutes of Health describes pMRI as a milestone in medical imaging. “Owing to their reduced cost and portability, these scanners could be deployed in a myriad of new settings, such as sporting events or rock concerts, rural health care centres, emergency rooms and assisted living facilities,” he writes.

Basser notes that the portability and ease-of-use of this type of device could make medical imaging more widely available in resource-limited environments. “If urgent care facilities or local hospital emergency rooms offered portable low-field brain MRI as readily as they offer ultrasound imaging, for instance, then it would help bridge this gap in patient access to emergency medical care,” he explains. “Overall, deploying portable, low-cost and easy-to-use brain imaging systems could democratize the delivery of critical medical imaging services and resources.”

Web of confusion

Nobody is perfect and errors do, inevitably, creep in to even the best publications. In the February issue of Physics World, David Marshall was right to highlight this problem in the context of school textbooks, but these mistakes are as nothing compared with the persistent misinformation that floods the Internet. The problem is particularly acute at the intersection between science and popular culture.

A few months back, my year 8 students (13–14 year olds) were trying to get to grips with energy in food. Teenagers are far more familiar with calories than joules in the context of food, but they were thrown into confusion by the bombshell that what people often call “calories” are actually kilocalories. “So does that mean somebody who eats a thousand calories is really eating a million calories?” a student asked. “That’s so wrong,” another countered. “If you ate a million calories you would be huge.”

To explore this issue, we turned to the Internet. Our first search told us that an apple contains 14 calories. I said that’s way too low and the class told me my mistake was to use Bing (the school’s default search engine): apparently I have to look on Google. Here the top hits revealed that an apple typically contains around 50 calories. The students were much happier with the higher number, but I pointed out that’s hardly any better and the right answer is probably 50 kcal. As it happens, the NHS website gives 47 kcal (196 kJ).

My heart sank when another student asked, “Aren’t calories and kilocalories the same thing?” Thankfully, a few of them were starting to correct this error among themselves, and I reiterated that the two units – as written on the side of the cereal box I was showing them – are not the same thing and that the problem is with our everyday language.

“The whole Internet can’t be wrong,” insisted one pupil, trying to resolve what had become a very animated debate. Then another student joined in to ask, “What about a McDonald’s chicken mayo?” We turned again to the great god Google and the first hit told us that this favoured treat contains 413 calories. I scrolled down because a link to McDonald’s own website had caught my eye, where a mayo chicken is declared to contain 319 kcal. “So McDonald’s has got it right,” somebody observed, to my great relief. But with so much inconsistency and inaccuracy online, is it any wonder that students struggle to separate true facts from accepted norms?

Try searching for diagrams showing “the dispersion and recombination of white light through a pair of prisms”. Sadly, the vast majority of images returned are fundamentally flawed

This was a particularly productive classroom debate, and there would be a good case for saying that a lot of learning took place in that lesson, but try searching for diagrams showing “the dispersion and recombination of white light through a pair of prisms”. That’s pretty specific, so you would expect to get a suitable calibre of hits showing a symmetrical arrangement of prisms and spectra, separated by a biconvex lens, as sketched by Isaac Newton in part II of his First Book of Opticks, Proposition XI. Sadly, the vast majority of images returned are fundamentally flawed.

A lot of the diagrams show the two prisms pointing in opposite directions, relatively close to each other with no lens in between. While this set-up can appear to recombine the light, close inspection would reveal that the “recombined” light is actually a rainbow. In some of the images, the spectrum between the two prisms has beams of parallel colours, which at least provides the symmetry expected from the reversibility of ray diagrams in geometric optics. Other diagrams correctly show the emerging spectrum diverging from the first prism, as is the common result when searching for the effect of a single prism, but then have some colours magically refracting beyond the normal to achieve recombination inside the second prism. Contrary to my student’s suggestion, the Internet clearly can be wrong – and overwhelmingly so.

One answer would be to direct students towards reliable websites, such as BBC Bitesize and NASA, but this is akin to running a library based on books from only two publishers, which would be unhealthy. Encouraging students to look at the domain name of a website before accepting its information as accurate is a good step forward but this requires a certain level of web literacy (which most have) and a willingness to look past the first few results (which is rarer).

Adding inurl:ac.uk can be a very useful filter for A-level students who are seeking high-quality sources but this isn’t often helpful for those who are just starting out on their voyages of scientific discovery. Dedicated search engines and portals that return hits from reliable and accessible sources are very thin on the ground (refseek.com being one) but they are not Google so, no matter how good such services may be, few students will remember to use them.

Of course, there are many cases where learning has to be simplified to make it accessible. Nevertheless, there is a difference between simplification and persistent errors. I am curious to know how prevalent these problems are and I would therefore be interested to hear if other readers have their own examples of common online misinformation.

As for the numerous incorrect representations of the dispersion and recombination of white light, maybe they all stem from Pink Floyd’s cover for Dark Side of the Moon and somebody deciding to flip a mirror image? Whatever the reason, Isaac Newton would surely be turning in his grave, if only he had access to the Internet.

Fifth force could explain puzzling orbits of dwarf galaxies

New physics, in the form of a “fifth force”, could be responsible for the odd and unexplained arrangement of dwarf galaxies orbiting the Milky Way and other large galaxies – according to new research done it the UK. The new force could also shed light on the nature of dark matter, a mysterious substance that accounts for about 85% of the matter in the universe.

The Standard Model of cosmology describes the universe in terms of three components: dark energy, dark matter and normal matter. The model says that large galaxies like the Milky Way were formed in a flurry of mergers of smaller galaxies that occurred inside an immense halo of dark matter.

Some of these dwarf galaxies remain distinct to this day and they surround the Milky Way and other large galaxies. But rather than being distributed throughout the dark-matter halo, the dwarfs preferentially orbit the centre of the Milky Way in a plane. Similar planes exist around other nearby large galaxies, such as Andromeda. How long-lived these planes are, and whether the Standard Model can explain their existence, has been a source of great debate among researchers.

New scalar field

Now, astrophysicist Aneesh Naik and particle physicist Clare Burrage at the University of Nottingham propose that a new scalar field and associated fifth force could be the cause of these planes of satellite dwarf galaxies.

Our current understanding of particle physics involves four fundamental forces: electromagnetism, gravity, the strong force and the weak force. However, this model is known to be incomplete – it has no adequate description of dark matter, for example. As a result, researchers are developing “new physics” to attempt to create a better understanding of nature.

In this latest work, Naik and Burrage have delved into the world of scalar fields to develop their new physics. A scalar field refers to an energy field where every point in space can have a unique value. For example, a temperature map of the Earth, where different locations have different temperatures, is a familiar example of a scalar field.

When the universe began, the duo’s scalar field would have adopted the same minimum energy level everywhere. But, as the universe expanded, the density of the matter distribution in space became greatly reduced.  Naik and Burrage’s scalar field is tightly coupled to matter, so below some critical density threshold, the scalar field changes and adopts two possible minimum energy solutions. These solutions are described as positive and negative, although their exact values depend upon the parameters of the scalar-field model, which have yet to be nailed down.

Symmetry breaking

“This is what we call symmetry breaking,” Naik tells Physics World. “In different regions of the universe the scalar field will adopt the positive solution and in other regions it will adopt the negative solution.”

The boundary between these positive and negative regions is referred to as a domain wall, and Naik and Burrage propose that domain walls have sliced through the Milky Way and other galaxies, creating the planes of satellites.

A domain wall would act as a fifth force, attracting satellite galaxies to the plane. Although they admit that their model is simplified at the moment, the duo was able to broadly replicate the Milky Way’s plane of satellites, and even the Andromeda galaxy’s bi-modal plane, where some of the dwarfs orbit within a plane, while others are randomly distributed off the plane.

Geraint Lewis, who is an astrophysicist at Australia’s University of Sydney, describes the work as “interesting,” and he agrees that it provides a “possible mechanism for shaping satellite distributions into planes”. However, he cautions that the idea is only at the proof-of-concept stage. “It is a limited exploration and while it makes something that looks like a plane, it’s hard to assess how generic this result is and whether the resultant planes match those observed in galaxies.”

Short-lived and coincidental

Meanwhile, proponents of the Standard Model of cosmology still believe it can explain dwarf-galaxy planes. Earlier this month, a preprint was posted that argues that the Milky Way’s plane of satellites is consistent with the Standard Model. The authors’ simulations suggest that the plane is short-lived and coincidental, but Lewis is not convinced by it. “This is another ‘post-diction’ and so I am not too swayed, especially if the planes are long-lived structures.”

Naik and Burrage’s scalar-field model and fifth force could also have something to say about the nature of dark matter. Naik explains, “It’s a new fundamental force because it’s a force that’s mediated by a new scalar particle, in the same way that the electromagnetic force is mediated by the photon”. This particle goes by numerous names in the various scalar field models developed by researchers, but one common name is the symmetron.

The models suggest that the symmetron would be a massive particle. “It could – potentially – be dark matter,” says Naik.

Naik and Burrage will now finesse their model and perform more sophisticated N-body simulations.

A preprint of the duo’s paper is available on arXiv.

Graphene ‘drums’ pick up vibrations from individual bacteria

Ultrathin carbon sheets known as “graphene drums” can pick up vibrations created by the nanoscale movements of individual bacteria, giving researchers a sensitive new way of probing their behaviour. As well as advancing our understanding of the mechanobiology of bacterial cells, the technique might be used to screen the effectiveness of antibiotics in a rapid and simple way, say the researchers at TU Delft in the Netherlands who developed it.

Graphene – a sheet of carbon just one atom thick – has many unique properties, including high mechanical strength and exceptional electrical conductivity. It is also extremely sensitive to external forces, explains nanomechanical engineer Farbod Alijani, who led the research. When an object such as a bacterium sticks to the surface of a graphene drum – which is made from graphene sheets – it generates oscillations with amplitudes as small as nanometres. These oscillations can be detected using laser light.

In the case of bacteria, the oscillations predominantly come from the motion of flagella<, which are tail-like structures on the microorganisms’ surface that help propel them through the aqueous environments in which they live. These flagella beat on the graphene drums with a force of up to 6 nN – around 10 billion times less than the force of a boxer’s punch on a bag, Alijani says. These beats can then be converted into “soundtracks” that researchers can monitor.

Detecting antibiotic resistance

The researchers performed their experiments in a cuvette containing live E. coli bacteria in growth medium. They used laser light to determine how the bacteria deflected off the surface of the graphene drum. “The outcome of our first measurements was striking,” Alijani tells Physics World. “We were able to detect the babbles from individual bacteria.”

These “bacteria babbles” appeared as a noisy signal with a spectrum that suggested contribution from biological processes occurring at different times scales, with a major input from bacterial flagella, he says. This is the first time a technique has been shown to be capable of detecting the sound generated by a single bacterium in its aqueous growth environment.

The technique could be used to detect antibiotic resistance, say the researchers. If the bacteria are resistant to an antibiotic, the oscillations would continue at the same level. If they were killed by the drug, however, the vibrations would decrease over a period of one or two hours before completely disappearing. This is fast compared to conventional antibiotic sensitivity tests that require at least 24-48 hours, explains Alijani. The graphene drums are also sensitive enough to detect such phenomena in just a single bacterium.

Alijani says the team is now optimizing its single-cell graphene antibiotic sensitivity platform to validate it against a variety of pathogenic samples, with the aim of bringing the technology closer to market. The research is detailed in Nature Nanotechnology.

Nanoparticle ‘tracers’ reveal quantized vortices in superfluid helium

Semiconducting nanoparticles can become trapped along structures called quantized vortices in superfluid helium-4, allowing them to act as “tracers” in studies of vortex dynamics. This finding, from researchers at Osaka University and Osaka Metropolitan University in Japan, could improve our understanding of quantum fluids and materials, including superconductors, while also shedding more light on turbulence.

When helium-4 is cooled to about 2 K, it transforms from a liquid into a quantum state of matter with zero viscosity. In this supercooled state, the material can, in principle, flow forever without losing any kinetic energy, which gives it several curious properties. It can climb up the walls of a container, for one, and it also supports the existence of excitations known as vortices. These structures, which are created by turbulence, look like tiny cyclones and occur over large scales in the superfluid. Importantly, they are quantized, meaning that each vortex carries a fixed amount of angular momentum.

The quantized nature of the vortices means that a system that is initially chaotic will become more ordered and structured as increasing amounts of energy are supplied to it. This result is somewhat counterintuitive, yet vortices of this type have been observed in systems ranging from soap films to atmospheric flow on planets, with the best-known example being Jupiter’s Great Red Spot. Visualizing them in experiments has, however, proved difficult.

Nanoparticles as tracers

Researchers led by Yosuke Minowa of Osaka University’s Graduate School of Engineering Science have now succeeded in doing just that by using silicon nanoparticles as tracers, with the vortices revealing themselves through the behaviour of nanoparticles trapped along their cores. The researchers also used their technique to study vortex reconnection, which is a process in which vortices coalesce and exchange parts of their structures.

Minowa and colleagues prepared their silicon nanoparticles using a technique called laser ablation, which involves directing a high-energy laser pulse onto the surface of a piece of solid silicon material located within the superfluid helium. In this fashion, they were able to suddenly melt, vaporize and cluster the material. “This drastic process leads to the immediate ejection of the melted vaporized/clustered materials,” explains Minowa. “The ejected particles are then quickly cooled and we end up with many nanoparticles distributed in the superfluid helium.”

The researchers observed that the nanoparticles clustered along a curved line, confirming that they were trapped inside the vortices. They also compared the patterns they observed with theoretically expected vortex dynamics and saw an excellent agreement between the two.

“We have developed a new tool for studying quantized vortex properties that will help us better understand the science of turbulence,” Minowa tells Physics World. “Our technique could also be applied to different materials and different sizes of nanoparticles to investigate the details of the nanoparticle-vortices interactions.”

Minowa says he and his colleagues are now planning to manipulate quantized vortices using optical forces. They detail their present work in Science Advances.

Paper-based semiconductor aids the drive for sustainable electronics

A new paper-based semiconductor could herald the advent of sustainable electronics made entirely from plant-based materials. The material, developed by researchers at the universities of Osaka, Tokyo, Kyushu and Okayama in Japan, could be used to make sensors for wearable devices or as an electrode in a glucose biofuel cell, and could even power a small light bulb.

Led by Hirotaka Koga, the researchers crafted three-dimensional-network-structured semiconducting materials using cellulose nanofibres derived from wood pulp as building blocks. The result is a semiconducting paper that could be made with surface areas of more than 20 cm in diameter.

According to the team, the new semiconducting cellulose nanopaper (CNP) can be tailored for a variety of applications. The paper itself can be shaped into different designs and the material’s electrical conduction properties can be tuned from 1012 to 10–2 Ω cm – values that exceed those of previously-reported 3D semiconducting materials – by changing the concentration of charge carriers (electrons and holes) in it. This means it is suitable for use in many devices, from water vapour sensors to electrodes in enzymatic biofuel cells.

nanocellulose-derived nano-semiconductor
The wood nanocellulose-derived nano-semiconductor with customizable electrical properties and 3D structures. (Courtesy: 2022 Koga et al. Nanocellulose paper semiconductor with a 3D network structure and its nano−micro−macro trans-scale design. ACS Nano)

Paper folding cutting

Koga and colleagues fabricated their nanocellulose paper semiconductor from a nanocellulose/water dispersion using a combination of paper folding (origami) and paper cutting (kirigami) techniques. They also applied an iodine treatment to their material to protect its nanostructure.

To demonstrate the material’s capabilities, the researchers fabricated several differently-shaped structures, including a bird and a box by folding and an apple and snowflakes by punching out pieces of the paper. They also produced more intricate structures using laser cutting.

The team say that the electrical and chemical properties of the CNP semiconductor might be altered further by modifying its molecular structure using techniques such as doping with other species of atoms. “We will be further tuning the electrical and chemical properties of the new semiconductor as well as its fine patterning,” Koga tells Physics World.

In their paper, which is published in ACS Nano, the researchers say that their study is a milestone in manipulating the functionality and practicality of semiconducting nanomaterials for various electronic applications. “As such CNP semiconductors can be prepared from ubiquitous and abundant biological resources, our strategy might be used to produce sustainable electronics,” they write.

Cancer-killing bacteria evade the immune system

Bacterial therapies, in which living bacteria are used to deliver drugs or other payloads to kill cancerous cells, could provide an alternative treatment for a wide range of cancers. When bacteria infiltrate the human body, the immune system triggers a fighting mechanism against the foreign substance, with the aftermath of such events dependent on the potency of the bacterium. However, some probiotic bacteria, such as Escherichia coli Nissle 1917 (EcN), easily resist the immune system’s lines of defence. This could be problematic if such bacteria are being considered for therapeutic applications.

Living bacteria can be engineered to kick back against the immune system, resulting in two potential outcomes: a compromise in the immune system after bacteria delivery; and the living bacteria causing toxicity to its host cells. Over the past decade, researchers have explored the reduction of toxicities from live bacteria by genetically deleting the parts of the bacterium that can cause toxicity; but this can lead to unwanted mutations in the bacterium itself and may substantially decrease therapeutic efficacy.

Tunable surface modulation
Tunable surface modulation: Programmable encapsulation enables bacteria to evade immune attack. (Courtesy: CC BY 4.0/Nat. Biotechnol. 10.1038/s41587-022-01244-y)

A team of engineers from Columbia University has now determined an effective approach to enhance the delivery of living engineered bacteria into cells, while maintaining the bacterium’s integrity and minimizing toxicity. Reporting their findings in Nature Biotechnology, the researchers describe a way of coating engineered bacteria with an inducible capsular polysaccharide (iCAP) that responds in a smart manner when delivered into the body.

Capsular polysaccharide (CAP) is a layer of water molecules that coats the surface of natural bacteria and acts as a shield against foreign infections. By converting CAP into iCAP, the researchers could apply programmable external stimulus that enables the engineered bacteria to evade immune attack, survive for a considerable duration in the host environment and deliver a tolerable therapeutic dose.

Guiding the bacteria

Cancer cells possess a natural ability to evade the immune system, which is one of the significant hallmarks of cancer. Since engineered bacteria are also required to evade immune attack, targeting bacteria to tumours becomes a herculean task, requiring a highly sophisticated design to enable adequate localization of the bacteria in the tumours.

The researchers leveraged synthetic gene circuits to dynamically control how the bacteria interact with their surrounding environment using the iCAP. As well as protecting against environmental pressures and forming a barrier for the bacteria wall, CAP has also been reported to play important roles in sensing immune responses. To control CAP expression, the authors introduced a small-molecule inducer termed IPTG. Induction of the CAP with IPTG modulated the bacteria’s interactions with circulating antimicrobials, bacteriophages, acids and the host immune system.

The iCAP system for cancer applications

While bacterial therapies for cancer continue to advance, developing a robust system for killing all tumours might seem insurmountable. As a starting point, however, the researchers demonstrated that the iCAP system can control the therapeutic delivery in mouse models.

To investigate the efficacy of iCAP, the researchers first examined the bacterial viability in human whole blood. They found that the engineered bacteria survived significantly longer than bacteria with natural CAP. Furthermore, after administering mice with iCAP bacteria, they observed lower inflammatory responses compared with the non-engineered bacteria.

Bacterial biodistribution
Bacterial biodistribution: Bioluminescence images show the distribution of engineered bacteria in various mouse models. White arrows depict the location of bacterial injection, black arrows show bacterial translocation after administration of IPTG. (Courtesy: CC BY 4.0/Nat. Biotechnol. 10.1038/s41587-022-01244-y)

In tumour-bearing mice, iCAP also enabled the translocation of therapeutic bacteria to multiple distal tumours throughout the body, with increased trafficking compared with natural bacteria. Additionally, delivering an EcN iCAP construct engineered to produce an anti-tumour toxin led to a reduction in tumour growth in the mice, demonstrating its therapeutic efficacy.

Tal Danino, senior author of this study, now plans to further explore the use of iCAP and other bacterial-based therapeutics to accelerate clinical translation in the future.

‘Warm glow’ of Unruh effect could be seen in the lab using accelerated electrons

An obscure quantum-mechanical phenomenon involving a warm glow visible only to accelerated observers, long thought almost impossible to detect, should be measurable in the laboratory after all. So say three physicists in Canada and the US, who reckon that the “Unruh effect” could be seen by accelerating an electron along a very well-defined path while showering it with microwaves. Evidence for the effect, they calculate, should become available after just a few hours of observations – in contrast to the signature from an unirradiated particle, which would take longer than the history of the universe to emerge.

The special theory of relativity, which Albert Einstein unveiled back in 1905, applies to observers who are not accelerating – those in “inertial” frames of reference. It tells us that some very unusual effects occur when one observer moves relative to another at close to the speed of light – including the fact that time and velocity are no longer absolute quantities but depend on the observer’s frame of reference. However, the theory has little to say about the effects of acceleration.

Theorists investigated this problem in the 1970s, seeking to work out what an accelerated observer would experience as they move through the vacuum of deep space. William Unruh, Stephen Fulling and Paul Davies worked out that while an inertial observer would see nothing in particular, the accelerating individual would be basked in a (relatively) warm glow of particles from the quantum vacuum – slightly increasing the temperature in their frame of reference from zero to some finite amount.

Extreme acceleration

However, the effect is extremely small. To measure a temperature rise of just 1 K, an observer would have to accelerate at 1020 m/s2 – unimaginably higher than anything a human being could achieve. Such accelerations can be attained by electrons thrust along inside powerful particle accelerators, but even then, the odds of detecting the (probabilistic) phenomenon are tiny – just one in 1018 per second.

In the latest work, Barbara Šoda and Achim Kempf of the University of Waterloo in Canada take a new approach to calculating the quantum effects of acceleration. In particular, they consider how to boost the chances of a particle experiencing the Unruh effect by exposing it to electromagnetic radiation as it is accelerated. They explain that the amplification of the “stimulated” Unruh effect relative to the conventional, spontaneous variety is comparable to the difference between the spontaneous and stimulated emission of light by atoms – the latter being used in laser technology.

Doing the algebra, they conclude that the probability of seeing the stimulated Unruh effect rises in proportion to the number of photons in the stimulating radiation (compared with the spontaneous effect). As such, they argue, it should in principle be possible to slash the time needed for observing the effect by sending an accelerated electron through an intense electromagnetic field. Pointing out that state-of-the-art microwave cavities can store some 1015 photons, they reckon that a measurable effect could be seen after just a few hours of observation.

Unwanted absorption

There is a snag in that their calculations reveal a second quantum effect that should be experienced by an accelerating particle. This is resonant absorption, of the kind that any atom would undergo when exposed to radiation of the right frequency. But the researchers believe that this shouldn’t be a showstopper, arguing that given just the right trajectory an accelerated particle would experience the stimulated Unruh effect while undergoing practically no absorption.

A suitable experiment to generate such an acceleration is currently being developed by Vivishek Sudhir and colleagues at the Massachusetts Institute of Technology in the US. Sudhir, who collaborated with Šoda and Kempf on this latest research, says the idea is to use a “cryogenic ‘table-top’ microwave cavity” to trap and accelerate a single electron and then measure the mechanical recoil of the electron in the lab frame of reference as it emits and absorbs Unruh photons in its own accelerated frame. But he is reluctant to provide details about the acceleration method and on how he and his colleagues intend to achieve the necessary measurement sensitivity.

Indeed, Anatoly Svidzinsky of Texas A&M University in the US doubts that the Unruh effect can be directly detected experimentally. He says that a paper published by himself and some colleagues last year anticipated the current work, using the notion of negative frequency (or energy). He argues that stimulation without absorption could in principle be achieved without an external photon source, but relying instead on self-amplification – the fact that Unruh emission from one or more of a group of accelerated atoms in their ground state should stimulate other atoms within the group to do the same thing (energy conservation dictating that the photons can’t be absorbed). But he cautions that the effect would be miniscule in any realistic experiment.

If the newly proposed experimental scheme does see the light of day, the result might have implications beyond the Unruh effect itself. As Šoda and Kempf point out, the local equivalence of acceleration and gravity implies that the Unruh effect is closely related to Hawking radiation – which is the heat black holes are thought to emit from beyond their event horizons. Given the new findings, they suggest that Hawking radiation might also be stimulated – not by any lab-based photon source but by naturally-occurring ambient radiation near black holes.

The research is described in Physical Review Letters.

A glimpse into the future of radiation therapy

Which innovations will have the greatest impact in radiotherapy by 2030? That was the question posed in the closing session of last week’s ESTRO 2022 congress; and five experts stepped up to respond.

As often seen in debate-style ESTRO sessions, competition was intense and gimmicks were plentiful, with all talk titles based on movies and a definite sci-fi twist. Before battle commenced, the audience voted for their preferred innovation based on the presentation titles. This opening vote put personalized inter-fraction adaptation as the winner. But could the speakers change the audience’s mind?

I, Robot

First up was Yatman Tsang from Mount Vernon Cancer Centre in the UK, who was tasked with arguing that by 2030, automation will have replaced humans in most aspects of the radiotherapy pathway.

“When I was first given the topic, I put ‘I, Robot’ into Google. I decided that instead of doing my slides, I’d rewatch the movie, to look for insight for my talk,” he admitted. “Then I thought, actually my job is quite easy, I’ll just present the facts and they will vote for me.”

So Tsang began by highlighting the prevalence of automation in our everyday routines. A wide range of technologies are available to reduce human intervention and increase efficiency in various tasks. Examples include sensors that control lights or escalators to save energy, or contactless payment cards. “All of this automation is already embedded in daily life and we are very familiar with it,” he said.

Moving onto automation in radiotherapy, Tsang explained that the radiotherapy pathway – a series of processes performed to deliver treatment – is extensive, complicated and involves a lot of people in different roles. He suggested that automation and robotics could take on some of the time-consuming tasks in this pathway, freeing up people’s time to invest elsewhere.

Tsang noted that automation in radiotherapy is a popular topic, with the number of published studies on this theme increasing from 30 in 2011 to 381 in 2021, and many talks in this area at the ESTRO congress. He conceded that some colleagues are less keen on the idea of automation, thinking that machines may not perform tasks as well as humans. “But we are the ones that decide what, when and how we want to use automation,” he emphasized. “We should let the machines do the time-consuming tasks that we design for them.”

“Automation is everywhere,” he concluded. “And as the other panel members give their talks, I want to point out that automation will be the greatest innovation to help all of these four achieve the results that they want to achieve.”

Inter(fraction)stellar

The second speaker, Stine Korreman from Aarhus University in Denmark, proposed that in the future, every target, every plan and every fraction will be adapted to individual risk and response models.

Korreman began by sharing an image taken with a new imaging modality, containing a lot of new, hard-to-interpret information. It was, in fact, the first image sent back to Earth from the James Webb telescope. She explained that the same type of situation can arise in the medical field when encountering new modalities or other new information that’s difficult to interpret and unclear how to use.

“We can take two paths,” she said. “The Interstellar path, where we look at these as opportunities: so much information, so much to explore. Or the Don’t Look Up path: ‘this is a lot of information, we don’t understand it, let’s stick to what we know’. Of course, I’d like to propose the Interstellar path.”

Patients want to know how the tests performed on them are used to personalize their treatment, whether the scans taken every day are used to improve their plan, and whether the measured tumour response is accounted for. “At the moment, we are not really doing this,” said Korreman. “Our objective should be fully personalized radiotherapy in which we do risk profiling for every patient’s initial prescription, risk-based target definition, including microscopic spread, and dose painting to target every part of the patient with exactly the correct amount of dose.”

Citing the ESTRO 2022 programme, she noted that many researchers are already developing adaptation and personalization for every part of the radiation treatment chain. Ultimately, combining all of this research will enable the full chain of personalized radiotherapy, with every target, plan and fraction adapted to each patient.

“We have the choice of following the Interstellar path, exploring and putting it to the test, or to not look up and just stick to what we know,” Korreman concluded. “I say let’s not have all the information disappear into a black hole. Instead, even though it may be hard to use and difficult to interpret, use this information to personalize radiation therapy at every level for every patient.”

Rogue One (to five) 

Next, Alison Tree from the UK’s Royal Marsden/Institute of Cancer Research explained why all radiotherapy should be delivered in a maximum of five fractions.

Aiming to sway the audience vote, Tree let the infamous Star Wars opening crawl argue the case for her, introducing the idea of a war against unnecessarily long radiation treatment. Instead, the crawl explained, we should use the force in just three to five days, to provide a new hope: a world where cancer can be cured in less than a week.

Tree explained that the idea of fractionation originated almost 100 years ago, when Claudius Regaud studied whether irradiation could cause sterility in rams. He observed that after delivering one large radiation dose, sperm were still produced, but that lots of small doses of radiation effectively stopped spermatogenesis. “That would be fine if our objective was to prevent rams having babies, but actually we’re trying to cure cancer,” she pointed out.

What’s more, today’s radiotherapy technologies can deliver dose so precisely that the α/β ratios defining the dose sensitivity of the tumour and healthy tissues don’t really matter. So why do patients still receive radiotherapy over more than five days, travelling to hospitals every weekday for weeks on end?

Tree cited the large body of evidence showing that hypofractionation is effective and feasible in most common tumour types. Breast radiotherapy can be performed safely in five fractions, for example, and prostate treatments using fewer fractions are just as effective.

And how low can we go? Teams at the Royal Marsden and elsewhere are studying two-fraction prostate stereotactic body radiotherapy, with MR-guided adaptation for all fractions. “It’s early days, but so far so good,” said Tree. Studies are also starting on single-dose ablative radiotherapy in oligometastases and primary lung cancer. “That would be a real step change, to be able to see, diagnose and treat the patient all in one day,” she noted.

Tree concluded by urging the audience to think of the polar bears. “We modelled that if you dropped from 20 to five fractions, just in the UK and just for prostate cancer, you would save 3.5 million kilogrammes of CO2 over one year. Hypofractionation will make a difference to patients by 2030 and save the planet.”

FLASH (Gordon)

Speaker number four, Pierre Montay-Gruel, from the University of Antwerp and the Iridium Network in Belgium, presented a talk entitled FLASH: He’ll save every one of us. “Since I was given this title, I’ve had this song in my head,” he said.

For ESTRO, however, FLASH is defined as radiotherapy delivered extremely fast at ultrahigh dose rate using electrons, photons or particles. “What is amazing about FLASH is that it does not induce classical radiation-induced toxicity patterns on normal tissues, but has a high tumour efficacy,” Montay-Gruel explained. “That may make it possible to increase the therapeutic window in radiation therapy, and that’s what everybody in the room here has been trying to do for years.”

It was 2014 when Vincent Favaudon and colleagues first demonstrated that increasing the dose rate can protect normal tissue without impairing anti-tumour efficacy. “Now FLASH is everywhere and everyone is talking about it,” said Montay-Gruel, pointing out the large number of FLASH talks at ESTRO this year, with attendees spilling out of the auditoriums. “FLASH makes people talk, discuss, brainstorm, be curious, and that’s what we need in the field.”

Importantly, FLASH is already in clinical trials, with the first patient treated for skin lymphoma in 2019, at Lausanne University Hospital. Current trials are examining proton FLASH for bone metastases, electron-beam FLASH for skin metastases, and other trials are planned, such as breast cancer treatment using intraoperative radiotherapy.

But many questions remain. Radiobiologists, for example, need to investigate normal tissue toxicity and tumour kill mechanisms, and assess which models to use. Physicists must focus on dosimetry, designing new irradiation systems and optimizing treatment planning. Clinicians, meanwhile, must decide which treatment modality to use and which tumour types to treat. “We’ve got a lot of work to do, but we have a very powerful research tool,” said Montay-Gruel. “FLASH radiation therapy is a new tool for clinicians, but also for researchers, and that’s amazing”

Circling back to FLASH “saving every one of us”, Montay-Gruel defined “us” as radiation oncology professionals, whom FLASH will save by renewing the research field and triggering creativity, and also the patients, who may perhaps be saved from cancer. “Let’s be honest, FLASH will not replace 100 years of radiotherapy techniques,” he said. “But I hope it will help us renew those techniques and one day help us treat cancer.”

The Matrix

The session’s final speaker was Jean-Emmanuel Bibault, from Université de Paris in France, who argued that in the future, treatment decisions and optimal steering of radiotherapy will be based on big data and cloud computing. “I’m going to be talking about the matrix –  basically that’s just cloud computing for optimal treatment decision,” he explained.

Today, there are numerous new therapies and new biomarkers available and its essential to choose the right ones to treat each patient optimally. We are also entering the era of big data, said Bibault, and here we are only scraping the surface. “We have lots of treatments and are going to have a have huge amount of data and no idea what we should be doing with it,” he said.

With the human brain only able to make optimal decisions when considering up to five variables, our brains are already saturated, Bibault pointed out. Thankfully, we have cloud computing. “We are currently building systems that are able to take much better decisions than us. Our responsibility is we have to use them for patients,” he explained. “We can’t simply reject AI or cloud computing because we are afraid to lose our jobs.”

The transition to cloud computing will no doubt face obstacles along the way. Bibault noted that some physicians are afraid that they will end up with no choices to make, just functioning as some kind of robots. But he emphasized that radiotherapy already works within sets of guidelines, which are essential for the patients, and predicted that the situation will not be so different from today.

By 2030, Bibault admitted, it’s likely that all radiotherapy will be automated, personalized and hypofractionated, and that FLASH will save us. “But the innovation piloting all that is going to be treatment decision and cloud computing,” he said. “Just like Neo learnt Kung Fu with a single button, I want to learn how to treat my patients with a single click of a button.”

Use the data
Big data: As we enter the era of big data, explains Jean-Emmanuel Bibault, we are not yet using all of the available information. (Courtesy: iStock/loops7)

Following the five presentations, the ESTRO attendees were invited to reconsider their earlier selections. The results revealed that Alison Tree may have used the force to change the audience’s minds, with hypofractionation clearly winning the final vote. Tree was rewarded with a prize of a Lego Millennium Falcon Microfighter. I look forward to seeing what ESTRO comes up with next year in Vienna.

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