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Quantum biosensensors could detect SARS-CoV-2

Quantum technology takes advantage of scientific phenomena that are only accessible on the smallest of scales, such as the concept of superposition: where a system exists in a combination of possible states rather than in a single one. This unique characteristic of quantum systems is quite fragile—when a quantum system in superposition interacts with its environment in any way, its superposition “collapses” and it exists in one state instead of many. Quantum sensing, however, takes that fragility and makes it an advantage. If the superposition of a system can be disturbed by a single molecule, a single atom, or even a single photon, that system can be turned into a sensor for these individual particles.

 

Many important phenomena in biology originate from single atoms, like the motion of an individual ion or a small change in the electric charge of a protein. These processes, however, are currently incredibly difficult or even impossible to measure. Quantum biosensing offers a way to investigate these biological events with unprecedented sensitivity.

 

The potential applications of quantum biosensing range from tracking a drug through the membrane and across the cytoplasm of a single cell, to precise demarcation of tumor margins during surgery. Quantum sensors might even be able to record critical biological processes like protein folding and the movement of particles through ion channels in cellular membranes, as well as the transmission of electrical signals through neurons.

 

“Quantum sensing allows you to measure quantities that are traditionally hard to measure at those scales, such as temperature, pressure, or electromagnetic fields,” says UChicago molecular engineering professor Peter Maurer. Maurer’s research lab can use quantum sensors to track temperature changes across a single cell, which is important for understanding how cells respond to different kinds of stress.

 

NV-Assisted Current and Thermal Biosensing in Living Cells

Electromagnetic field sensing is of the utmost importance for several applications in current scientific research, fostering the search for novel high sensitivity sensors. Several innovative electromagnetic field sensors emerged in the last years, whose main goal is revealing less and less intense fields with an increased spatial resolution. In particular, high sensitivity sensing coupled to high resolution is of the utmost relevance in biological research, especially, for instance, in studies of human brain cell currents, which are typically extremely faint.

 

Localized monitoring of neuronal fields would allow not only the investigation of brain currents during cognitive processes in order to improve neurological diagnostic systems also identifying the early stages of neurodegenerative disease, like Parkinson’s, Alzheimers’s disease and other forms of dementia.

 

Among the various sensing devices that have emerged over the years, promising sensors for the detection of biological fields are color centers in diamond.  Color centers are impurities in the crystalline matrix that, when stimulated, emit fluorescence. In particular, the nitrogen-vacancy (NV) complex is by far the most promising due to its level structure.  The NV defect is a natural complex of impurities in the diamond crystalline matrix. This complex is composed of a substitution nitrogen atom and a vacancy-type defect, located in adjacent reticular sites.

 

This dependence allows the realization of techniques for optical initialization and spin readout by means of the optically detected magnetic resonance (ODMR) technique. Furthermore, its spin energy levels are sensitive not only to electromagnetic fields, but also to temperature variations. These exceptional properties, together with their photostability at room-temperature and the nontoxicity of diamond, promotes the NV complex as a very promising candidate for biological application.

 

The sensitivity can be improved by implementing specific experimental ODMR techniques, that are based on laser and microwave pulses of particular duration, synchronized appropriately. The CW ODMR is the simplest and the most widely employed magnetometry method with NV-based sensors, wherein the microwave driving and the optical polarization and readout (laser pumping) occur simultaneously.

 

Although this technique is easy to be implemented, the relative ODMR spectrum dips are affected by the broadening induced by the continuous exposure of the laser beam and microwave field on the sample. With pulsed ODMR techniques this broadening effect is substantially suppressed, allowing to obtain a narrower ODMR spectrum dips and therefore to improve the measurement sensitivity.

 

Quantum sensor could detect SARS-CoV-2

A quantum sensor based on nitrogen-vacancy centres in diamond could be used to detect viruses like SARS-CoV-2, which is responsible for the current COVID-19 pandemic. This is the finding of researchers at the University of Waterloo in Canada, who performed detailed mathematical simulations to show that the new technique would make it faster and cheaper to detect viruses with high accuracy.

 

Since November 2019, there have been more than 400 million reported cases of COVID-19 worldwide and nearly six million deaths. This huge toll highlights the importance of rapid and cost-effective tests that detect infection with low false negative rates (FNRs). Such tests allow preventive measures (such as asking infected individuals to isolate) to be taken early, when they are most effective. In the absence of treatments, testing also provides vital clues to help epidemiologists track the virus’s spread and contain outbreaks.

 

At present, the most accurate and widely-used tests for the SARS-CoV-2 virus rely on a technique known as reverse transcriptase quantitative polymerase chain reaction (RT-PCR), which detects the presence of the virus’ genetic material, or RNA. Extracting and amplifying this RNA from samples can take several hours and requires trained personnel, special testing and analytical equipment. Even so, the FNR for this method can exceed 25% depending on the viral load of samples and how they are obtained. This is a problem, since infected people who receive false negative results may not isolate and could go on to infect others.

 

An alternative, faster, technique is antigen testing. This involves detecting specific viral proteins, such as spike proteins, found on the surface of the virus. Antigen tests are, however, even less accurate than PCR tests. What is more, they cannot quantify the amount of virus present.

 

NV centres are defects in the diamond lattice that occur when two adjacent carbon atoms in the lattice are replaced by a nitrogen atom and an empty lattice site. Together, the nitrogen atom and the vacancy behave as a negatively-charged entity with an intrinsic spin and three spin sublevels, denoted |ms = 0⟩ and |ms = ±1⟩. Illuminating this NV centre with a laser polarizes its spin into the |ms = 0⟩ sublevel, which fluoresces intensely. The system then relaxes to its thermal equilibrium state, which fluoresces less. This thermalization process occurs over a certain characteristic period of time known as the longitudinal relaxation time, T1, which depends on the magnetic field sensed by the NV centre in its environment. For this reason, NV centres can be used as highly sensitive magnetic resonance probes capable of monitoring changes to spins in a sample over distances of a few tens of nanometres.

 

The Waterloo team’s proposed device would be made by coating nanodiamonds containing NV centres with cationic polymers such as polyethyleneimine (PEI), which can form reversible complexes with viral complementary DNA sequences. Magnetic molecules such as Gd3+ (gadolinium) complexes could then be incorporated into the sequence to form hybrid c-DNA-Gd pairs.

 

In the presence of viral RNA, these pairs will detach from the nanodiamond surface thanks to a process called c-DNA and virus RNA hybridization. The newly formed c-DNA-Gd3+/RNA compound will then freely diffuse in solution, thereby increasing the distance between the magnetic Gd and the nanodiamond. As a result of this increased distance, the NV centres will sense less magnetic “noise” and thus have a longer T1 time, which manifests itself in a larger fluorescence intensity.

Quantum sensors based on NV centres

According to new work by Paola CappellaroMohammad Kohandel and colleagues, this is where quantum sensors could come into their own. Though still in the early stages of development, such sensors have emerged in recent years as powerful tools for detecting chemical and biological signals, and the Waterloo team have identified sensors based on nitrogen-vacancy (NV) centres in diamond as particularly promising.

 

Project BioSensing

Biosensors are considered among the most promising of tools for addressing a broad range of biomedical and public health concerns, including disease diagnosis, identification of multidrug-resistant organisms, early detection of burgeoning epidemics, and detection of low-concentration toxins and pathogens in food and drinking water. In fact, all of these applications are goals of current research programs.

 

Scientists and engineers working on these issues face enormous challenges, however. For instance, biosensors being developed to increase the reliability and efficiency of medical diagnoses must be sufficiently sensitive to detect even the smallest amounts of pathogens in blood or other biological fluids. At the same time, they should be able to identify even difficult-to-diagnose diseases in real time so that therapy can be deployed as early as possible.

 

Project BioSensing, a collaboration among two of Germany’s Fraunhofer institutes and Leiden University’s Institute of Physics (Leiden, Netherlands) was developed to overcome the limits of modern biosensors by applying quantum technology.

 

Project BioSensing focuses on a novel class of fluorescing biological nanomaterials called DNA-stabilized metal quantum clusters (QC-DNAs), which serve as “quantum biosensors.” In their simplest form, these biosensors consist of a short DNA sequence that encloses a group of six to 15 metal atoms (the so-called metal cluster).

 

The choice of DNA sequence determines the characteristics of the sensor—for instance, which disease it is able to detect. The basic structure of a quantum biosensor can be extended by adding specific biomolecules, which can enable the detection of selected biomarkers. The fluorescence properties of the metal cluster enable reporting: When the target is detected, the light emitted by the metal clusters shifts wavelength. A significant advantage of the technology is cost-effective production.  QC-DNA are suitable for the development of highly sensitive sensors in biological systems and provide solutions for an advanced, intelligent and affordable therapy.

 

But such a quantum biosensor not only responds to diseases (caused by germs or even mutations in the genome), but also to changing environmental conditions, such as an increase of salt concentrations. Further applications are possible such as the monitoring of food and forage or the use in environmental analysis. A significant advantage is the cost-effective production of quantum biosensors.

 

So far, tests were limited to the lab, but the project partners of Fraunhofer ISC, IME and Leiden University in the Netherlands have set themselves the goal of designing various quantum biosensors, scaling them up to pilot scale and preparing them for feasibility studies in university hospitals. In follow-up projects, the partners plan to develop a portable read-out device that works cost-effectively, highly sensitively, quickly and reliably and detects various pathogens, toxins or cancer cells.

 

By optically monitoring the change in relaxation time using a laser-based sensor, the researchers say they could identify the presence of viral RNA in a sample and even quantify the number of RNA molecules. Indeed, according to their simulations, Cappellaro, Kohandel and colleagues, who report their work in Nano Letters, say that their technique could detect as few as a few hundred strands of viral RNA and boast an FNR of less than 1%, which is much lower than RT-PCR even without the RNA amplification step. The device could also be scaled up so that it could measure many samples at once and could detect RNA viruses other than SARS-CoV-2, they add.

 

Developing new tools for manipulating sensors

To get the measurements researchers want, quantum biosensors have to be positioned at the exact locations where interesting biological events are happening. But the fragility of quantum technology often requires extremely controlled environments, like a vacuum chamber with near-zero temperature—in this sort of setting, biological processes can only be seen as frozen “snapshots.” To access the full potential of quantum biosensors, researchers are finding new ways to manipulate quantum sensors in warmer, less-controlled environments, so they can see “movies” of events rather than snapshots.

 

The go-to tool for controlling single molecules or particles are optical tweezers, which use highly focused laser beams to manipulate their targets. “But they can’t really trap anything smaller than a micron, unless you go to very low temperatures,” says UChicago molecular engineering professor Allison Squires. “That doesn’t really work for biology. Biology happens at room temperature, so these nanoscale processes take place in a wet and messy environment. To see those processes in action, we have to be able to work in that setting.”

 

Squires’ research lab is developing tools to manipulate and control quantum sensors in a biological system, including a technique that uses electric potentials as “walls” to keep the quantum sensor floating in one place without touching it. Squires expects this “arsenal” of nanoscale biophysical tools to provide new kinds of information.

 

Quantum sensors could measure the electric fields in a neuronal synapse, track a single ion moving through a cell membrane, or record the transfer of proteins between the smaller organelles inside a cell: all processes that are challenging to directly observe. Technology at the intersection of these two fields—quantum engineering and biology—has the potential to revolutionize our understanding of medical science at the smallest possible levels.

 

“I see quantum biosensing as pushing the limits of measurement resolution in the life sciences,” Maurer says. “By probing very sensitive systems in their physiological environment, this technology could produce invaluable tools.”

 

 

References and Resources also include:

https://www.techexplorist.com/understanding-biology-using-quantum-technology/42645/

https://chicagoquantum.org/news/quantum-biosensing-medicine-smallest-scales

https://physicsworld.com/a/quantum-sensor-could-detect-sars-cov-2/

About Rajesh Uppal

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