PATHOS Project (2019-2024).It is the purpose of PATHOS to pursue our potentially ground-breaking multidisciplinary effort in biomedical diagnostics. Starting from novel fundamental approaches to dynamical control, we seek to create new paradigms concerning control or guidance of spin evolutions in complex spin networks, so as to gear them to hitherto unforeseen MR applications in chemistry, biology and medicine. In a nutshell, PATHOS aims to further the very fruitful synergy pioneered by our partners towards developing new task-oriented comprehensive sensing strategies and exploring the new frontiers they entail for NMR, optical and MRI based analysis.
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PATHOS focuses on the theoretical and experimental investigations of new sensing tools optimizing the transfer of information from the environment/noise (to be probed) to the physical system (probe). In this context, methods as dynamical control, noise spectroscopy, and compressed sensing will be combined together to enhance the sensitivity of weak magnetic fields and temperature variations, and finally tested with very diverse but complementary experimental platforms as nuclei (MR), photons, and atoms (NV/ODMR). In all cases the probe will be manipulated by coherent driving and Zeno measurements, while the noise may be also correlated in space and in time. The shared goal is to have a higher signal-to-noise rate and/or a shorter acquisition time, with the future perspective of being applied in biomedicine diagnostics.
More specifically, the PATHOS shared objectives are:
The exploited complementary approaches are:
More specifically, the PATHOS shared objectives are:
- Develop advanced control schemes:
- polarization transfer/cooling
- control of interacting spin systems
- Characterize and mitigate effects of (possibly unwanted) non-classical noise
- Study and characterize non-classical effects in spin networks:
- Classify network topology in the context of:
- polarization/cooling
- quantum state transfer
- Develop high-resolution, high-sensitivity, high-bandwidth sensing
The exploited complementary approaches are:
- Combine closely theory with experiment:
- NMR, NV, Optics
- machine learning classification approaches
- compressed sensing
- Sensing:
- radical sensing/imaging
- super-resolution microscopy
- feedback schemes
PATHOS FOR THE GENERAL AUDIENCE
During the first half of the 20th century, physicists were able to unravel the basic properties of the constituents of matter and their interactions in what became known as the quantum revolution or simply the theory of quantum mechanics. Since then quantum mechanics has been firmly established as the fundamental theory of most fields of physics and its validity has been tested successfully in a vast array of different settings.
During the last decades, the second quantum revolution has emerged: with the foundations firmly established, scientists are discovering a range of opportunities where quantum mechanics offers improvements on existing technologies and generating fundamentally new ones, such as quantum communication and quantum computing. In the context of magnetic resonance imaging, quantum mechanics has always been essential for understanding the phenomenon. Now, we are learning how quantum mechanics can be harnessed to improve the sensitivity, resolution and information content of the imaging process. In extreme cases, such as the one shown in the image above, it is possible to obtain images with atomic resolution, using atomic systems such as the nitrogen-vacancy center in diamond to emit single quanta of light (photons) and provide detailed information at the atomic scale on material properties or important biological samples.
During the last decades, the second quantum revolution has emerged: with the foundations firmly established, scientists are discovering a range of opportunities where quantum mechanics offers improvements on existing technologies and generating fundamentally new ones, such as quantum communication and quantum computing. In the context of magnetic resonance imaging, quantum mechanics has always been essential for understanding the phenomenon. Now, we are learning how quantum mechanics can be harnessed to improve the sensitivity, resolution and information content of the imaging process. In extreme cases, such as the one shown in the image above, it is possible to obtain images with atomic resolution, using atomic systems such as the nitrogen-vacancy center in diamond to emit single quanta of light (photons) and provide detailed information at the atomic scale on material properties or important biological samples.
As part of our PATHOS research project, we have realised (at INRiM) a set-up for Optically Detected Magnetic Resonance (ODMR) techniques exploiting Nitrogen Vacancy (NV) centers in diamond, which is an emerging technique of extremely promising application in the fields of magnetometry and thermometry, especially in biosensing due to the perfect biocompatibility of nanodiamonds (hosting the NV centers) and the possibility of positioning them in close proximity to the cell membrane, thus allowing a nanometric spatial resolution down to the nano-scale
The first field of application of this technique concerns NV based thermometry. We have demonstrated magnetic sensing and temperature measurements, starting to work with living cells. The current sensitivity for temperature measurements is in line with the state of the art, normalized to the sensing volume, [PHYSICAL REVIEW APPLIED 13, 054057 (2020)]. We expect to demonstrate enhanced sensitivity in such scenarios using the techniques developed here.
Furthermore, besides the well known NV centers, affected by broadband spectral emission at room temperature, a quest for more bright and more monochromatic centers is ongoing. In the course of the project, new promising colour centres in diamond besides NV, such as Pb and F, are being investigated [New J. Phys. 23 (2021) 063032, Sci. Rep. 10 21537 (2020)].
The first field of application of this technique concerns NV based thermometry. We have demonstrated magnetic sensing and temperature measurements, starting to work with living cells. The current sensitivity for temperature measurements is in line with the state of the art, normalized to the sensing volume, [PHYSICAL REVIEW APPLIED 13, 054057 (2020)]. We expect to demonstrate enhanced sensitivity in such scenarios using the techniques developed here.
Furthermore, besides the well known NV centers, affected by broadband spectral emission at room temperature, a quest for more bright and more monochromatic centers is ongoing. In the course of the project, new promising colour centres in diamond besides NV, such as Pb and F, are being investigated [New J. Phys. 23 (2021) 063032, Sci. Rep. 10 21537 (2020)].
In parallel, at HUJI we have focused on a diamond-based platform, in which small (atomic) defects act as optically addressable quantum systems. We developed novel techniques for manipulating these quantum systems, enabling advanced sensing and control:
We developed an optical microscope based on diamond defects, which allows the direct, non-invasive measurement of radical concentrations, with high-sensitivity and resolution.
On a more general note, we developed and demonstrated advanced techniques to enhance our sensitivity based on “compressed sensing”. In this approach only part of the data is sampled in an informed way, such that along with specialized algorithms we can extract the signal with high fidelity in a short amount of time.
- Quantum sensing
We developed an optical microscope based on diamond defects, which allows the direct, non-invasive measurement of radical concentrations, with high-sensitivity and resolution.
On a more general note, we developed and demonstrated advanced techniques to enhance our sensitivity based on “compressed sensing”. In this approach only part of the data is sampled in an informed way, such that along with specialized algorithms we can extract the signal with high fidelity in a short amount of time.
- Polarizing (cooling) samples for MRI
Such alignment of the spins, called polarization (or cooling) is difficult to achieve in state-of-the-art techniques. We are working on novel techniques in which we can use a dense ensembles of diamond defects to polarize a contrast agent, e.g. for MRI. We proposed a scheme that improves over existing processes, and holds the promise of achieving enhanced polarization.
Moreover, INRIM, in order to reach the goal of performing quantum sensing of magnetic fields in living cells, has upgraded the setup in several ways. In particular, together with the already reported upgrades (high-power source, LIA, low noise amplifier, simultaneous driving of all three NV hyperfine peaks) recent upgrades consist of an optimised pulsed excitation source, and a trans-impedance amplifier for increasing measurement bandwidth. During the project, INRIM has developed ODMR sensing protocols with NV centres showing approximately 70 nT/Hz^1/2 magnetic sensitivity in continuous excitation and in biocompatible conditions [EPJ Quantum technology 7,13 (2020)]. This is in line with the state of the art for the investigated sensing volume (Adv. Quantum Technol. 2020, 2000066 (2020)). In order to furtherly increase the sensitivity, advanced pulsed techniques (Rabi, Ramsey, pulsed ODMR) are being investigated. In order to perform them a pulsed excitation source based on an acusto-opric modulator was implemented. Preliminary measurement show a promising improvement of the performance in terms signal-to-noise ratio of the measurement.
- Magnetic Resonance Imaging
Sensing via Zeno effects
A joint paper, involving INRIM, UNIFI and Weizmann Units, on the experimental study of (anti-)Zeno dynamics as proof of noise (anti-)correlations in quantum systems has been drafted and submitted to a high-profile scientific journal, and is now under consideration. Here we demonstrate, for the first time, the ability of a single photon, subjected to random polarisation noise, to diagnose temporal correlations within such a noise process. Specifically, a noise with positive temporal correlations makes our single photon undergo a dynamical regime characterized by the quantum Zeno effect, while noise characterized by negative correlations corresponds to regimes associated with the anti-Zeno effect.
Subsequently, a second experiment involving Zeno-dynamics for stochastic noise sensing in optical systems has begun. Suppose to have a system with D possible noise sources, stochastically distributed with different probabilities within our channel; the main purpose of this experiment is to reconstruct such noise probability distribution by performing a set of N Zeno-based samplings along the channel.
Subsequently, a second experiment involving Zeno-dynamics for stochastic noise sensing in optical systems has begun. Suppose to have a system with D possible noise sources, stochastically distributed with different probabilities within our channel; the main purpose of this experiment is to reconstruct such noise probability distribution by performing a set of N Zeno-based samplings along the channel.
Zeno to the rescue: Tackling the Covid Pandemic with advanced quantum physics
Covid-19 is a pandemic threat caused by a recently emerged coronavirus (CoV) containing a single-stranded positive-sense RNA genome encapsulated within a membrane envelope. The viral RNA offers valuable drug targeting opportunities, as its heterogeneous dynamic nature, opens numerous possibilities of locking it into non-pathogenic states. Nuclear Magnetic Resonance (NMR) is a tool that ideally posed to help in this task. NMR can “see” the environment of each atomic side in the RNA -or in proteins, or in sugars– by looking at the nuclear “spins”: a physical property whereby each atom behaves like a microscopic “quantum compass needles”. NMR is a powerful tool for screening pharmaceuticals and help in rational drug design and could be of decisive help in helping to defeat the pandemic and other diseases – provided it gets the sensitivity needed to tackle very large structures like the Covid virus. Unfortunately, NMR is a relatively insensitive technique. One of PATHOS’s main aims is to substantially increase NMR’s sensitivity, and it tries of doing so by “cooling” the spins –that is, by introducing a stronger alignment the “quantum compass needles” without using a bigger magnet, and of course while keeping the sample at physiological room temperature. To do so we rely on a variant of the Zeno effect; a phenomenon that finds its source in paradoxes that Zeno of Elea posed some 2500 years ago. According to Zeno’s paradox –which had to wait for calculus to appear in order to be fully resolved– multiple observations of a moving object would “stop” the object. As Ben Franklin said “A watched pot never boils”. These classical paradox finds a one-to-one translation in the quantum world: doing repetitive observations –projections, in quantum parlance– stops a system evolution. This is known as the quantum Zeno effect. The PATHOS network members have discovered, however, that the quantum world offers the possibility of a most counterintuitive “anti-Zeno effect” (AZE), whereby projective measurements actually speed up the time evolution of the system. The NMR experiments in PATHOS build on this quirky quantum effect, to sensitize by tens and hundreds of times the sensitivity per unit time of certain NMR experiments. In particular, it has developed a series of experiments that enables the study RNA regions taken from the SARS-CoV-2 virus. Our main goals include extending the power of AZE to other NMR experiments, including insight to facilitate the guided screening of small molecules’ binding to RNA, that could eventually support drug development campaigns.
For additional information on this project, see L. Frydman’s video in Bruker video interview: https://www.bruker.com/it/products-and-solutions/mr/make-mr-more-relevant/covid19-nmr-consortium.html, or written article in https://www.bruker.com/en/landingpages/bbio/resolution-in-a-new-dimension-for-solving-challenges-of-society/israeli-scientists-collaborate-to-speed-up-covid-19-rna-research-using-ultra-sensitive-nmr-techniques.html.
For additional information on this project, see L. Frydman’s video in Bruker video interview: https://www.bruker.com/it/products-and-solutions/mr/make-mr-more-relevant/covid19-nmr-consortium.html, or written article in https://www.bruker.com/en/landingpages/bbio/resolution-in-a-new-dimension-for-solving-challenges-of-society/israeli-scientists-collaborate-to-speed-up-covid-19-rna-research-using-ultra-sensitive-nmr-techniques.html.
A 3D heteronuclear-resolved version for structural NMR is introduced based on AZE-derived effects, where sensitivity is enhanced by ≈2-5x as compared to conventional counterparts. The enhanced signal sensitivity can greatly facilitate RNA assignments and secondary structure determinations, as demonstrated by Kim et al (JACS, 2021) with the analysis of genome fragments derived from the SARS-CoV-2 virus.
More details for Experts
As part of our PATHOS research project, we have focused on the experimental platform of nitrogen-vacancy (NV) defects in diamond. We developed novel techniques for manipulating and controlling NVs, in the context of open quantum dynamics, quantum sensing, compressed sensing and many-body dynamics:
We developed an optical microscope based on shallow NVs in a diamond substrate, in which the radical sample placed near the diamond modifies the NV charge state, leading to changes in the measured fluorescence spectrum. We have demonstrated this effect using hydroxyl radicals, exhibiting direct, non-invasive measurement of radical concentrations, with a sensitivity of and a spatial resolution of [Y. Ninio et. al., ACS Photonics, 8,1917-1921 (2021)].
We have further addressed the limited bandwidth of NV-based magnetic sensing in the large-field regime, by utilizing compressed sensing techniques to improve the accuracy of sub-sampling. We demonstrated significant improvements of the resulting measurement error, specifically for short-time measurements [G. Haim et. al., in preparation].
- Quantum sensing
We developed an optical microscope based on shallow NVs in a diamond substrate, in which the radical sample placed near the diamond modifies the NV charge state, leading to changes in the measured fluorescence spectrum. We have demonstrated this effect using hydroxyl radicals, exhibiting direct, non-invasive measurement of radical concentrations, with a sensitivity of and a spatial resolution of [Y. Ninio et. al., ACS Photonics, 8,1917-1921 (2021)].
We have further addressed the limited bandwidth of NV-based magnetic sensing in the large-field regime, by utilizing compressed sensing techniques to improve the accuracy of sub-sampling. We demonstrated significant improvements of the resulting measurement error, specifically for short-time measurements [G. Haim et. al., in preparation].
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- Spin bath cooling (hyperpolarization)
We analyzed these dynamics theoretically and developed a general framework for the control of interacting spin systems in the average Hamiltonian picture [K. Ben’Attar et. al., PRR 2, 013061 (2020)]. We then utilized this framework to develop and optimize a polarization transfer scheme which combines resonant transfer approaches (such as Hartmann-Hahn) with decoupling protocols. We showed that our approach can improve over existing methods in terms of achievable polarization level and speed of polarization transfer [K. Ben’Attar et. al., in preparation].
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Sensing via Zeno effects
Following the results of this work, after an initial feasibility study a second experiment involving Zeno-dynamics for stochastic noise sensing in optical systems is now ongoing. Suppose to have a system with D possible noise sources, stochastically distributed with different probabilities within our channel; the main purpose of this experiment is to reconstruct such noise probability distribution by performing a set of N Zeno-based samplings along the channel.
To do so, we exploit an optical setup in which a laser, collimated in a Gaussian mode and prepared in the polarisation state |+⟩=1/√2 (|H⟩+|V⟩), is sent to a series of N=6 steps, each composed of a pair of birefringent crystals and a polariser projecting the photons onto the |+⟩ state. In each step, a birefringent crystal pair (playing the role of our stochastic noise) can be chosen among a set of D=5 possible thickness entries (0, g, 2g, 3g, and 4g, being g the minimum thickness available). At the end of the optical path, photons are detected by an EM-CCD: from the final photon count distribution registered by the EM-CCD, we are able to extract the exact number and type of birefringent crystals encountered by the photons, i.e. the probability distribution of the D noise sources along our optical channel.
To do so, we exploit an optical setup in which a laser, collimated in a Gaussian mode and prepared in the polarisation state |+⟩=1/√2 (|H⟩+|V⟩), is sent to a series of N=6 steps, each composed of a pair of birefringent crystals and a polariser projecting the photons onto the |+⟩ state. In each step, a birefringent crystal pair (playing the role of our stochastic noise) can be chosen among a set of D=5 possible thickness entries (0, g, 2g, 3g, and 4g, being g the minimum thickness available). At the end of the optical path, photons are detected by an EM-CCD: from the final photon count distribution registered by the EM-CCD, we are able to extract the exact number and type of birefringent crystals encountered by the photons, i.e. the probability distribution of the D noise sources along our optical channel.
(Anti-)Zeno based noise diagnostics: results for positive (left), null (middle) and negative (right) noise temporal correlations, with (in blue) and without (in yellow) frequent measurement on the single photon.
AZE for Biomolecular NMR Improvements
The bulk of the magnetic resonance work done at Weizmann in this project’s WP1: Demonstrate anti-Zeno-effects (AZEs) for enhancing the sensitivity of homonuclear and heteronuclear transfer experiments. We have found significant successes when applying AZE concepts within the framework of in vitro NMR investigations –particularly within the framework of SARSCoV-2 biophysical elucidations. Indeed, it was foundusing AZE- related concepts that these approaches could lead to sizable enhancements in cross-peaks arising between exchangeable and non-exchangeable protons in crucial homonuclear experiments like NOESY or TOCSY. These enhancements are particularly strong for intrinsically for the rapidly exchangingimino, amino and hydroxyl sugar protons in sugars and in RNAs, as described in numerous recent PATHOS-acknowledging publications (Novakovic et al, “Hadamard magnetization transfers achieve dramatic sensitivity enhancements in homonuclear multidimensional NMR correlations of labile sites in proteins, polysaccharides and nucleic acids”, Nature Communications 11, 5317, 2020; Novakovic et al, “Magnetization transfer to enhance NOE cross-peaks among labile protons: Applications to imino-imino sequential walks in COVID-derived RNAs”, Angewandte Chemie, 60, 11884, 2021; Novakovic et al, “The Incorporation of Labile Protons into Multidimensional NMR Analyses: Glycan Structures Revisited”, J. Am. Chem. Soc.,143, 8935, 2021). This becomes particularly important in the elucidation of nucleic acids, including RNAs like those forming the genome of the SARS-CoV-2 viruses. We have recently observed that these AZE-related sensitivity enhancements can lead to ≥ 500-fold reductions in the effective acquisition times involved in observing NOE-derived cross-peaks involving imino protons. Such experiments are crucial in establishing the chemical identity and the structure of SARS-CoV-2 RNAs. Such sensitivity-enhancing performance maximizes at ultrahigh fields, opening up an even brighter future when implemented inmachines like the 1 GHz NMR that operates at the Weizmann. In this respect, we envision that the AZE-likeeffects facilitating these sensitivity enhancements will also be evidenced when using NMR to assay the binding of small molecules to larger constructs –with the dynamic on/off effects of the binding taking the role adopted by the labile imino protons. This means that binding studies of small molecules (e.g., drugs) to RNAs and proteins, will also be greatly facilitated by this new kind of methods. In addition to this progress entailing homonuclear correlations, we also tested the advantages of AZE-related concepts in heteronuclearpolarization transfer processes. Once again, our AZE proposals lead to distinct advantages that we have started to describe in PATHOS acknowledging publications (Kim et al, “3D Heteronuclear Magnetization Transfers for the establishment of secondary structures in SARS-CoV-2-derived RNAs”, J. Am. Chem. Soc., 143, 4942, 2021) utilizing again data collected on fragments derived from the SARS-CoV-2 RNA. This kindof experiments relate to WP1’s AZE to optimize heteronuclear polarization transfer milestone. This research is also particularly relevant for labile hydrogens in general and for RNAs imino and intrinsically disordered protein amide sites in particular; these are normally resolved thanks to heteronuclear correlation experiments to their bound 15N and, in effecting this, solvent exchanges act as a well-known, harmful source ofdecoherence. Using advanced quantum-mechanical simulations that incorporate both the NMR dynamics as well as relaxation and chemical exchange superoperators, we found that our hypothesis concerning thesuperiority of cross-polarization-related procedures for implementing these heteronuclear transfers over commonly-used INEPT counterparts, were well founded. We are now working on tailoring these experiments to imino RNA 1H-15N pairs, once again in the hope of bringing the enhancements afforded by theseconcepts into our coronavirus-related research efforts.
PATHOS Deliverables so far
|
Deliverable Number |
Deliverable
Title |
WP |
Lead
beneficiary |
Type |
Dissemination
Level |
Due
Date (in
months) |
|
D4.1 |
WEB |
4 |
UNIFI |
Web,
etc. |
Public |
2 |
|
D4.2 |
Data Management Plan |
4 |
Weizmann |
ORDP |
Public |
6 |
|
D4.9 |
Dissemination &
Exploitation Plan 1 |
4 |
Weizmann |
Report |
Confidential |
6 |
|
D2.5 |
Non-Markovian probes |
2 |
UNIFI |
Report |
Public |
11 |
|
D1.5 |
AZE heteronuclear |
1 |
Weizmann |
Report |
Confidential |
12 |
|
D1.6 |
AZD homonuclear |
1 |
Weizmann |
Report |
Public |
12 |
|
D3.5 |
NV imager |
3 |
HUJI |
Report |
Public |
12 |
|
D3.6 |
Optical CS imaging |
3 |
HUJI |
Report |
Public |
12 |
|
D2.6 |
DD Spectral density |
2 |
TUDO |
Report |
Public |
18 |
|
D1.1 |
AZE cooling |
1 |
Weizmann |
Report |
Public |
24 |
|
D2.1 |
DD probing |
2 |
UNIFI |
Report |
Public |
24 |
|
D3.1 |
NV-imaging + CS |
3 |
HUJI |
Report |
Public |
24 |
|
D3.7 |
ODMR neurons |
3 |
INRIM |
Report |
Public |
24 |
Public deliverable reports:
D4.1 WEB
D4.2 Data Management Plan
D2.5 Non-Markovian Probes
D1.6 AZD homonuclear
D3.5 NV imager
D3.6 Optical CS imaging
D2.6 Spectral density
D1.1 AZE cooling: Refs. 23-25, 33-34 in Dissemination
D2.1 DD probing
D3.1 NV-imaging+CS
D3.7 ODMR neurons
D4.1 WEB
D4.2 Data Management Plan
D2.5 Non-Markovian Probes
D1.6 AZD homonuclear
D3.5 NV imager
D3.6 Optical CS imaging
D2.6 Spectral density
D1.1 AZE cooling: Refs. 23-25, 33-34 in Dissemination
D2.1 DD probing
D3.1 NV-imaging+CS
D3.7 ODMR neurons
Work performed from the beginning of the project
During the first year of PATHOS project, we have advanced as planned and contributed to all our WPs towards the expected long-term objectives.
From the theory side, we have introduced conceptually novel approaches to the enhancement of heteronuclear spin-polarization transfer by means of repeated measurements, phase flips or spin-orientation flips for one of the spin species (alias the probe). Secondly, we have proposed new optics experiments for Zeno-based noise spectroscopy and studied several aspects of non-Markovian probes where the noise is correlated in time. Moreover, we have been working on the general formulation of the theory and practice of filtering environmental noise. Finally, we are also exploring a new path (not expected in PATHOS) where more recent deep learning techniques can improve the sensing properties of our classical and quantum probes.
From the experimental side, we have constructed a widefield NV-based magnetic microscope, to form the basis for the experimental demonstrations in this project. We have initiated studies of enhanced magnetic sensing capabilities through compressed sensing techniques. We have developed novel schemes for controlling dense, interacting spin ensembles, through robust pulses relying on rapid adiabatic passage, as well as generalized sequences based on the icosahedral symmetry group. Besides, we have studied spin bath coupling through advanced noise spectroscopy schemes, achieving both efficient bath characterization using uneven echo sequences, as well as detailed spectroscopy with modulated, continuous control (the gDYSCO scheme). In addition, we have improved the sensitivity of spectroscopy methods based on homonuclear mixing and recoupling in magnetic resonance experiments, and, as new and unexpected research direction, we have successfully applied these ideas into Coronavirus-related problems. Moreover, we have shown a spectral super-resolution reconstruction by using random lasers and also started preparing the setup for an optical experimental study of Zeno dynamics and related-sensing applications. Finally, we have upgraded our setups in several ways resulting in an increase of magnetic field sensitivity of ODMR-based magnetometry protocols ultimately for applications of sensing in biological systems.
These achievements have been disseminated in the scientific literature and via international conferences and non-specialist meetings, and form the basis for current efforts of studying quantum spatially and temporally correlated bath dynamics, further testing our theoretical results with our experimental platforms, proposing novel sensing protocols by further exploiting optimal control and compressed sensing, keeping enhancing the sensitivity of our biomolecular NMR, MRI and ODMR schemes, which follows the future plans of the project.
We have advanced during the second reporting (M13-M28) period as described below:
As part of WP1, at Weizmann we have performed further progress on the use Anti-Zeno effect (AZE) to optimize heteronuclear polarization transfer and we have developed a water-based activity aimed at enhancing NMR spectroscopy on RNA imino protons. In particular, we have found that AZE can lead to sizable enhancements in cross-peaks arising between exchangeable and non-exchangeable protons in Nuclear Overhauser Effect SpectroscopY (NOESY) experiments that are crucial for assigning protons in RNAs. These AZE-related sensitivity enhancements can lead to ≥500-fold reductions in the effective acquisition times. This becomes particularly important in the elucidation of nucleic acids, including RNAs like those forming the genome of the SARS-CoV-2 viruses. Therefore, given the Covid-19 worldwide-spread pandemic and since in our project we planned to later select some biomolecules to test our novel methods, we have decided to apply them to SARS-CoV-2 RNA fragments. Such experiments were actively being used and shared to establish these structures within an international COVID-oriented network, remarkably increasing the scientific and societal impact of PATHOS. In parallel, at HUJI we have built upon our novel control framework for interacting spin ensembles [K. Ben’Attar et. al., PRR 2, 013061 (2020)] to develop techniques for efficient spin bath cooling, combining resonant transfer with decoupling sequences [K. Ben’Attar et. al., in preparation]. This is part of MS1 and of D1.1. At INRIM we have upgraded the setup for ODMR sensing in several ways, including an optimised diamond sample with an optimised pulsed excitation source and a trans-impedance amplifier for increasing measurement bandwidth. Pulsed measurement protocols are being investigated via an excitation source based on AOM allowing to observe Rabi oscillations and Ramsey fringes together with the first preliminary results of pulsed ODMR, showing improved linewidth of the resonance dip. Preliminary measurements of living cells viability after nano-diamond internalization are currently being performed, with the perspective of measuring temperature variation in biological processes at the sub-cellular scale. Moreover, new promising colour centres in diamond, as alternatives to NVs are being investigated. Therefore, we have demonstrated temperature measurements, starting to work with cells. Parallel measurements with classical techniques were performed. We expect to demonstrate enhanced sensitivity in such scenarios using the techniques developed here. Finally, we have achieved the first milestone (MS1), concluding that the most promising cooling method for spin and oscillator baths should be a pulse sequence that combines “Alternating Dispersive and Resonant Transfer” (ADRT) and AZE features, which should be adapted to the bath spectrum, to interactions within the bath and the bath-probe coupling strength and variance.
As part of WP2, at HUJI we have developed and demonstrated enhanced magnetic and noise sensing using our diamond-based magnetic microscope, along with a novel optical scheme for radical concentration characterization [Y. Ninio et. al., ACS Photonics 8, 1917-1921 (2021)]. This development could have broad implications, and is being considered for exploitation (provisional patent). These results contribute to MS3 and MS4, as well as to D2.1 and toward D2.4. At INRIM we have completed the realization of an optical set up for quantum Zeno measurements (started during RP1), demonstrating the efficiency of such methods for noise measurements and leading to a joint paper, involving INRIM, UNIFI and Weizmann units. In particular, this novel noise diagnostic method assisted by repeated quantum measurements was shown through the ability of a single photon, subjected to random polarisation noise, to sense non-Markovian temporal noise correlations. Besides, we have started a new involving Zeno-dynamics for stochastic noise sensing, i.e. to reconstruct the noise probability distribution. Furthermore, while new dynamical decoupling (DD) pulse sequences have been proposed and experimentally tested in MRI systems at TUDO, we have also started to develop other optimization methods based on Machine Learning (ML) methods, e.g. supervised and reinforcement learning algorithms, to predict the unknown noise spectrum avoiding the very large sets of DD measurements. Then, we have found that the novel combination of DD schemes, optimal control theory, quantum Zeno effects and machine learning algorithms can allow us to select the best sensing protocols in a way that this combination can be accordingly adapted and tuned to the specific experimental platform, e.g. the photonic, NV-center, and MRI-based sensing systems, hence reaching the milestone MS3.
As part of WP3, at HUJI we have developed and demonstrated magnetic imaging with enhanced bandwidth, resolution and sensitivity using NV CS. This is detailed in D3.1, and contributes toward MS5 and D3.2. This technique could find varied applications, and further exploitation will be addressed (provisional patent etc.). In parallel, at INRIM we have upgraded our ODMR setup as described above for WP1 and exploited it for magnetic sensing, showing 40 nT/Hz^1/2 magnetic sensitivity in continuous excitation and 70 nT/Hz^½. As next steps, we expect to further improve it by means of the future developments discussed above, i.e. pulsed measurements and novel colour centres in diamond. Finally, at TUDO we have worked on NMR microimaging at fields of 8, 9.5 and 14 T to generate images of biological objects that use the interaction of spins with their environment as probes of the dynamic processes in which the molecules bearing the spins participate. Besides, we have started a new collaboration between UNIFI and TUDO to map classical images into quantum states and process these images in the quantum domain, in the context of the so-called quantum image processing. We are currently exploring how this technique can be applied to MRI images of biological samples.
As part of WP4, our achievements have been disseminated in the scientific literature and via international conferences and outreach activities, leading also to several open-access publications in international high-impact peer-review journals as Nature, JACS and APS.
PATHOS Objectives
Objective WP1: Achieving orders-of-magnitude improvement of imaging, spectroscopy and/or thermometry resolution/quality, by experimentally demonstrating the efficacy of conceptually innovative dynamically controlled cooling schemes, pioneered by our partners, based on alternating coherent and stochastic spin control pulses, towards realistic NMR/MRI medical diagnostic applications.
Objective WP2: Exploit optimal control theory to extract more information from the noise that the bio-system exerts on the probes, to be compared with the existing diagnostic schemes and tested with NV centre and NMR platforms.
Objective WP3: Develop and demonstrate novel data processing tools, and utilize information from environment correlations, combining the WP2 tools with CS schemes and testing them on NV, MRI and optical platforms.
In order to further proceed towards these objectives, we have implemented the expected tasks for each WP with an overall progress being well inline with PATHOS planned research activities.
Objectives achieved in this reporting period
During the first year of PATHOS project, we have advanced as planned and contributed to all our WPs towards the expected long-term objectives.
From the theory side, we have introduced conceptually novel approaches to the enhancement of heteronuclear spin-polarization transfer by means of repeated measurements, phase flips or spin-orientation flips for one of the spin species (alias the probe). Secondly, we have proposed new optics experiments for Zeno-based noise spectroscopy and studied several aspects of non-Markovian probes where the noise is correlated in time. Moreover, we have been working on the general formulation of the theory and practice of filtering environmental noise. Finally, we are also exploring a new path (not expected in PATHOS) where more recent deep learning techniques can improve the sensing properties of our classical and quantum probes.
From the experimental side, we have constructed a widefield NV-based magnetic microscope, to form the basis for the experimental demonstrations in this project. We have initiated studies of enhanced magnetic sensing capabilities through compressed sensing techniques. We have developed novel schemes for controlling dense, interacting spin ensembles, through robust pulses relying on rapid adiabatic passage, as well as generalized sequences based on the icosahedral symmetry group. Besides, we have studied spin bath coupling through advanced noise spectroscopy schemes, achieving both efficient bath characterization using uneven echo sequences, as well as detailed spectroscopy with modulated, continuous control (the gDYSCO scheme). In addition, we have improved the sensitivity of spectroscopy methods based on homonuclear mixing and recoupling in magnetic resonance experiments, and, as new and unexpected research direction, we have successfully applied these ideas into Coronavirus-related problems. Moreover, we have shown a spectral super-resolution reconstruction by using random lasers and also started preparing the setup for an optical experimental study of Zeno dynamics and related-sensing applications. Finally, we have upgraded our setups in several ways resulting in an increase of magnetic field sensitivity of ODMR-based magnetometry protocols ultimately for applications of sensing in biological systems.
These achievements have been disseminated in the scientific literature and via international conferences and non-specialist meetings, and form the basis for current efforts of studying quantum spatially and temporally correlated bath dynamics, further testing our theoretical results with our experimental platforms, proposing novel sensing protocols by further exploiting optimal control and compressed sensing, keeping enhancing the sensitivity of our biomolecular NMR, MRI and ODMR schemes, which follows the future plans of the project.
We have advanced during the second reporting (M13-M28) period as described below:
As part of WP1, at Weizmann we have performed further progress on the use Anti-Zeno effect (AZE) to optimize heteronuclear polarization transfer and we have developed a water-based activity aimed at enhancing NMR spectroscopy on RNA imino protons. In particular, we have found that AZE can lead to sizable enhancements in cross-peaks arising between exchangeable and non-exchangeable protons in Nuclear Overhauser Effect SpectroscopY (NOESY) experiments that are crucial for assigning protons in RNAs. These AZE-related sensitivity enhancements can lead to ≥500-fold reductions in the effective acquisition times. This becomes particularly important in the elucidation of nucleic acids, including RNAs like those forming the genome of the SARS-CoV-2 viruses. Therefore, given the Covid-19 worldwide-spread pandemic and since in our project we planned to later select some biomolecules to test our novel methods, we have decided to apply them to SARS-CoV-2 RNA fragments. Such experiments were actively being used and shared to establish these structures within an international COVID-oriented network, remarkably increasing the scientific and societal impact of PATHOS. In parallel, at HUJI we have built upon our novel control framework for interacting spin ensembles [K. Ben’Attar et. al., PRR 2, 013061 (2020)] to develop techniques for efficient spin bath cooling, combining resonant transfer with decoupling sequences [K. Ben’Attar et. al., in preparation]. This is part of MS1 and of D1.1. At INRIM we have upgraded the setup for ODMR sensing in several ways, including an optimised diamond sample with an optimised pulsed excitation source and a trans-impedance amplifier for increasing measurement bandwidth. Pulsed measurement protocols are being investigated via an excitation source based on AOM allowing to observe Rabi oscillations and Ramsey fringes together with the first preliminary results of pulsed ODMR, showing improved linewidth of the resonance dip. Preliminary measurements of living cells viability after nano-diamond internalization are currently being performed, with the perspective of measuring temperature variation in biological processes at the sub-cellular scale. Moreover, new promising colour centres in diamond, as alternatives to NVs are being investigated. Therefore, we have demonstrated temperature measurements, starting to work with cells. Parallel measurements with classical techniques were performed. We expect to demonstrate enhanced sensitivity in such scenarios using the techniques developed here. Finally, we have achieved the first milestone (MS1), concluding that the most promising cooling method for spin and oscillator baths should be a pulse sequence that combines “Alternating Dispersive and Resonant Transfer” (ADRT) and AZE features, which should be adapted to the bath spectrum, to interactions within the bath and the bath-probe coupling strength and variance.
As part of WP2, at HUJI we have developed and demonstrated enhanced magnetic and noise sensing using our diamond-based magnetic microscope, along with a novel optical scheme for radical concentration characterization [Y. Ninio et. al., ACS Photonics 8, 1917-1921 (2021)]. This development could have broad implications, and is being considered for exploitation (provisional patent). These results contribute to MS3 and MS4, as well as to D2.1 and toward D2.4. At INRIM we have completed the realization of an optical set up for quantum Zeno measurements (started during RP1), demonstrating the efficiency of such methods for noise measurements and leading to a joint paper, involving INRIM, UNIFI and Weizmann units. In particular, this novel noise diagnostic method assisted by repeated quantum measurements was shown through the ability of a single photon, subjected to random polarisation noise, to sense non-Markovian temporal noise correlations. Besides, we have started a new involving Zeno-dynamics for stochastic noise sensing, i.e. to reconstruct the noise probability distribution. Furthermore, while new dynamical decoupling (DD) pulse sequences have been proposed and experimentally tested in MRI systems at TUDO, we have also started to develop other optimization methods based on Machine Learning (ML) methods, e.g. supervised and reinforcement learning algorithms, to predict the unknown noise spectrum avoiding the very large sets of DD measurements. Then, we have found that the novel combination of DD schemes, optimal control theory, quantum Zeno effects and machine learning algorithms can allow us to select the best sensing protocols in a way that this combination can be accordingly adapted and tuned to the specific experimental platform, e.g. the photonic, NV-center, and MRI-based sensing systems, hence reaching the milestone MS3.
As part of WP3, at HUJI we have developed and demonstrated magnetic imaging with enhanced bandwidth, resolution and sensitivity using NV CS. This is detailed in D3.1, and contributes toward MS5 and D3.2. This technique could find varied applications, and further exploitation will be addressed (provisional patent etc.). In parallel, at INRIM we have upgraded our ODMR setup as described above for WP1 and exploited it for magnetic sensing, showing 40 nT/Hz^1/2 magnetic sensitivity in continuous excitation and 70 nT/Hz^½. As next steps, we expect to further improve it by means of the future developments discussed above, i.e. pulsed measurements and novel colour centres in diamond. Finally, at TUDO we have worked on NMR microimaging at fields of 8, 9.5 and 14 T to generate images of biological objects that use the interaction of spins with their environment as probes of the dynamic processes in which the molecules bearing the spins participate. Besides, we have started a new collaboration between UNIFI and TUDO to map classical images into quantum states and process these images in the quantum domain, in the context of the so-called quantum image processing. We are currently exploring how this technique can be applied to MRI images of biological samples.
As part of WP4, our achievements have been disseminated in the scientific literature and via international conferences and outreach activities, leading also to several open-access publications in international high-impact peer-review journals as Nature, JACS and APS.
PATHOS Objectives
Objective WP1: Achieving orders-of-magnitude improvement of imaging, spectroscopy and/or thermometry resolution/quality, by experimentally demonstrating the efficacy of conceptually innovative dynamically controlled cooling schemes, pioneered by our partners, based on alternating coherent and stochastic spin control pulses, towards realistic NMR/MRI medical diagnostic applications.
Objective WP2: Exploit optimal control theory to extract more information from the noise that the bio-system exerts on the probes, to be compared with the existing diagnostic schemes and tested with NV centre and NMR platforms.
Objective WP3: Develop and demonstrate novel data processing tools, and utilize information from environment correlations, combining the WP2 tools with CS schemes and testing them on NV, MRI and optical platforms.
In order to further proceed towards these objectives, we have implemented the expected tasks for each WP with an overall progress being well inline with PATHOS planned research activities.
Objectives achieved in this reporting period
- Novel control schemes for enhanced sensitivity and polarization transfer. The polarization transfer rate has been improved by over a factor of 2.
- Demonstration of NV magnetic sensing with compressed sensing, achieving improved bandwidth and sensitivity. Achieved bandwidth improvement (for similar sensitivity) of over a factor of 4.
- Study of multiple spin baths - characterization of radicals through noise on shallow NVs, demonstrating a sensitivity of ~10 nMol/Hz^½ with sub-micron resolution.
- AZE-related sensitivity enhancements up to ≥500-fold reductions in the effective acquisition times for NMR experiments involving RNA imino protons, like those forming the genome of the SARS-CoV-2 viruses.
- Temperature sensing (with possible application in biological samples) based on ODMR measurement (sensitivity 5 mK/Hz^½) in bulk diamond.
- ODMR sensing protocols with NV centres showing 40 nT/Hz^1/2 magnetic sensitivity in continuous excitation (70 nT/Hz^½ in biocompatible conditions).
- Discrimination between Markovian and non-Markovian noise sources via machine learning algorithms with a theoretically predicted classification mean absolute error of around 5% (that will be experimentally tested).
- Automatic assignment of MRI voxels to tissue / liquid with high fidelity.
- Efficient quantum state tomography for 2 spin qubits of NV center with the minimum number of measurements (16) and high fidelity (99%).
