Quantum Effects and Measurement Techniques in Biology and Biophotonics

Human exhaled breath contains more than 1,000 volatile organic molecules (biomarkers), combinations of which reflect metabolic processes in the human body. Spectroscopic detection of these biomarkers may be the basis for early diagnosis of various medical conditions. Our detection method, dual-comb spectroscopy (DCS) through the ultra-wideband, 1–100 THz (3–300 µm), spectral range, which targets the strongest vibrational and rotational molecular absorption resonances, relies on optical rectification of few-optical-cycle laser pulses to create mid-IR/THz frequency combs that are subsequently detected by electro-optical sampling (EOS), where the electric field of mid-IR/THz transients induces a change of polarization state of the near-IR probe pulse in the EO crystal. With this technique, we simultaneously achieved superior spectral resolution (via resolving comb lines), real-time detection, broadband (near octave) instantaneous coverage, and massive parallelism of data acquisition. Theoretically, EOS method is sensitive enough to detect vacuum fluctuations, which opens up wide opportunities for the study of quantum effects in biology.

This talk reflects a collaboration between Ye/Nesbitt groups to use of broad-band, ultrastable infrared frequency comb light sources in the 3-5 and 5-10 m IR fingerprint region with high finesse resonant cavities to probe small molecule content in exhaled human breath. These methods offer as much as a 100-million-fold enhancement in sensitivity x spectral throughput over conventional approaches, which in combination with machine learning algorithms have permitted encouraging first successes in real time identification of COVID disease state.

Cancer remains a significant global health challenge, necessitating the development of innovative diagnostic tools to improve patient outcomes and quality of life. We set out to address two critical challenges in oncology: ultra-early detection of cancer and early detection of chemotherapy-related cognitive impairments ("Chemo-Brain" or CB). Leveraging ultraweak photon emissions (UPE), very weak light emitted by biological tissues, we developed a novel, non-invasive, and portable optical diagnostic platform to passively detect cancer and predict cancer-related cognitive impairments earlier than current methods. UPEs provide non-invasive readouts of cell state and behavior as they are correlated to metabolism and molecular activity. Unlike current imaging techniques, UPE-based diagnostics use portable optical sensors without the need to use harmful ionizing radiation. We present our recent advances that show promising associations between UPE fluctuations, early cancer growth, and changes to functional brain states. The identification of endogenous light-based biomarkers represents a major advance in biomedical imaging for precision oncology and brain health.

The XX century brought a huge variety of measurement techniques exploring the quantum nature of photons. One of them, X-ray diffraction, facilitated major breakthroughs in understanding both crystal structures and compositions of specific molecules, including biological ones. In this talk, I will discuss how this approach can be extended to living tissues. The goal is to characterize quasiperiodic components of the extracellular matrix (ECM) to reveal the pathology-induced and, especially, pathology-causing aberrations. I will present preliminary experimental results on animal and human samples, including nails (keratin) and mammal glands (collagen and adipose), and show that our methodology can lead to very early cancer diagnostics. I will also discuss our future theoretical studies to understand the physical mechanisms both for structural changes of ECM and for the effects of these changes on cell dynamics, including quantum effects.

Quantum states of light allow for highly sensitive biosensing configurations, surpassing the limitations imposed by shot-noise. In this theoretical study, we focus on optical plasmonic sensors, which have extensive applications in disease diagnostics, including detection of diseases like HIV and TB. Our investigation involves simulating the impact of quantum states of light, such as the NOON state and squeezed states, on enhancing the limit of detection in a plasmonic phase-sensing biosensor, surpassing coherent light states' shot-noise limit. Specifically, we explore the use of quantum states to improve the limit of detection in phase-based biosensors for HIV detection, operating below the shot-noise limit. Through our analysis, we demonstrate that incorporating quantum states of light in surface plasmon resonance (SPR) biosensing leads to enhanced performance compared to classical states. Moreover, we take into account the impact of environmental losses in the biosensing setup, considering the real-world challenges in practical implementation. Our findings emphasize the potential of quantum SPR biosensors in the development of novel disease diagnostics devices.

Enzymes are the workhorses of the cell and catalyze their reactions with enormous rate enhancements. The role of H-tunneling has been identified in a wide range of such reactions and shown to be dependent on a directed interplay between the extended protein scaffold and site of reactivity.

Weak magnetic fields affect a multitude of biological processes including cell metabolism and are hypothesized to be a result of magnetic field-sensitive spin-selective radical-pair reactions. To provide much needed visualization of this process, we demonstrate the use of a custom-built multimodal nonlinear optical imaging system capable of measuring the redox state of cells through multi-photon-excited autofluorescence and autofluorescence lifetime of metabolic cofactors. We demonstrate a custom multi-axis Helmholtz coil system to apply time-varying magnetic fields across the sample during imaging. This imaging platform allows for characterization and optimization of the effects of magnetic fields on live cells and tissues.

Microtubules are self-assembling biological helical nanotubes made of the protein tubulin that are essential for cell motility, cell architecture, cell division, molecular signaling, and intracellular trafficking. It has been hypothesized that this hollow molecular nanostructure may support optical transitions in photoexcited tryptophan, tyrosine, or phenylalanine amino acid lattices to function as a light-harvester in similar fashion as photosynthetic units; this ability coupled with its shape is analogous to a quantum wire. In support of this, recent experimental work demonstrates that electronic energy can diffuse across microtubules in a manner that cannot be explained by conventional Förster theory making them effective light harvesters. Here we present theoretical work of energy transfer between amino acids in tubulin via dipole excitations in the presence and absence of a chemical perturbation. Results demonstrate the potential for chemical manipulation of the optical properties of aromatic amino acid lattices in microtubule protein structures.

Small migratory songbirds are extraordinary navigators: weighing less than 30 g, they fly thousands of kilometres between their breeding and wintering grounds, alone and at night. To do so they use the sun and the stars, olfaction and landmarks, but it is clear that they can also perceive the direction of the Earth’s magnetic field. Despite more than 50 years of research, the biophysical mechanism of this remarkable magnetic sense remains obscure. In this talk, I will discuss the proposal that the birds’ magnetic compass relies on a quantum mechanism in their eyes. Specifically, the unique properties of light-induced radical pairs in cryptochrome proteins in photoreceptor cells could allow chemical sensing of magnetic interactions orders of magnitude weaker than might otherwise be thought possible.

Melanopsin, a tri-stable photopigment found in intrinsically-photosensitive retinal ganglion cells (ipRGCs), drives circadian rhythms and other non-image forming functions in the nervous system. Despite increased understanding of the biomolecular and spectroscopic properties of melanopsin, its multiphoton and ultrafast optical absorption properties remain underexplored. We demonstrate the effects of two-photon absorption of melanopsin using 900-1160 nm optical stimulation. Excitation in this bandwidth causes consistent increases in calcium levels in transfected HEK293T cells. Our results demonstrate the first reported nonlinear optical properties and corresponding functional responses of two-photon excitation of melanopsin in vitro, along with the effects of spectral-phase modulation on activation.

Base stacking is fundamentally important to the stability of double-stranded DNA. However, few experiments can directly probe the local conformations and conformational fluctuations of the DNA bases. Here, we report a new spectroscopic approach called two-photon excitation (2PE) two-dimensional fluorescence spectroscopy (2DFS) to investigate the local conformations of DNA bases using the UV-absorbing fluorescent guanine analogue, 6-methyl isoxanthopterin (6-MI). Our results indicate that 2PE-2DFS experiments can provide information about the electronic-vibrational spectrum of the 6-MI monomer, in addition to the conformation-dependent exciton coupling between adjacent 6-MI monomers within a (6-MI)2 dimer. In principle, this approach can be used to determine the local base-stacking conformations of (6-MI)2 dimer-substituted DNA constructs.

Previously we have found that the two-photon absorption (2PA) spectra of red fluorescent proteins have enhanced vibronic transitions and are about twofold broader, compared to the corresponding one-photon absorption (1PA) spectra. We explained these observations by the dependence of the permanent dipole moment change (Deltamu) on a particular vibrational coordinate (in the Herzberg-Teller spirit). Here we demonstrate that this effect is responsible for the 2PA spectral shapes of many fluorescent dyes including rhodamines, ATTO dyes, fluorescein, oxazines, acridines, pyronines, resorufin, and thionine. By measuring the two-photon polarization ratio as a function of excitation wavelength in these dyes, we were able to separate the transitions with Deltamu perpendicular to the long molecular axis (“FC”-type) and parallel to it (“HT”-type). We have found the previously undetected “HT-ghost” transitions under the pure electronic envelope. These are the 0-0 transitions of the "HT" progression build on the BLA frequency that are non-vanishing if the corresponding Huang-Rhys factor is not zero.

Quantum light allows imaging with sensitivity, speed and resolution beyond the reach of other techniques. Applications in biology are particularly important, because the best conventional microscopes are often severely constrained by photodamage to the specimen. Here, I will present experiment work from my lab applying squeezed light, a form of quantum light, to imaging of molecular vibrations. If time permits, I will also discuss work on quantum single-molecule imaging.

The rate of two-photon absorption of time-frequency-entangled photon pairs has been the subject of much study for its potential to enable quantum-enhanced molecular spectroscopy and imaging. We closely replicated recent experiments that reportedly observed such enhancement and have found that in the low-photon-flux regime the signal is below detection threshold. Using an optical parametric down-conversion photon-pair source that can be varied from the low-gain spontaneous regime to the high-gain squeezing regime, we observe two-photon absorption with a molecular sample in solution for the high-gain regime but not for the low-gain regime. The observed rates are consistent with theoretical predictions and indicate that time-frequency photon entanglement does not yet provide a practical means to enhance spectroscopy or imaging with current techniques.

We discuss advances in ultrasensitive Raman-spectroscopic probing of various biosamples. Our approach is based on laser spectroscopy aided by plasmonic nanoantennas, as for example in tip-enhanced Raman spectroscopy. An additional enhancement in sensitivity and speed is obtained by employing quantum molecular coherence driven either by pump and Stokes pulse pair or a direct infrared drive field.

Many current microscopy techniques require high fluences that result in photobleaching and photo-damage of biological samples. This is especially true with respect to imaging of amino acids which require excitation with higher energy photons, and which are commonly used for native excitation of highly studied proteins. As such, it is important that we investigate an efficient way to gently excite native amino acids in proteins. Currently, this is carried out with direct ultra-violet (UV) excitation or multiphoton excitation, both of which can cause photodamage to the material under study. Entangled light has been proposed as a low intensity alternative to classical two-photon excitation. Our aim with this work is to test whether amino acids can be excited, and its fluorescence induced with entangled two-photon absorption. This will provide a technique for label-free fluorescence detection with low intensity localized light, exciting UV transitions without direct UV excitation. This can then be employed for bioimaging studies with bioenergy applications.

Next generation single-photon detectors are becoming available. Research grade SPAD arrays promise camera-like detectors with dozens to hundreds of thousands of pixels, providing both spatial and temporal information about single photon events. Concurrently, other detector technologies are under development, such as crossed-delay line detectors. We evaluate the application of SPAD arrays and NCam, a crossed-delay line detector, towards quantum ghost imaging applications. We discuss implementation challenges and performance differences in the context of ghost imaging.

Modal imaging can provide unprecedented resolution for imaging point sources, such as single-molecule fluorescent tags used to study biological samples. Among different modal imaging techniques, image inversion interferometry, where the input field is separated into symmetric and antisymmetric components, in principle allows for resolving two point sources near the quantum limit. We investigate the implementation of inversion interferometry for superresolving point sources in fluorescence microscopy. Our work focuses on the integration of this technique with microscopes used in superresolution microscopy for imaging broadband point sources and fluorophores commonly used to tag proteins in cells.

We present progress towards demonstrating multi-passed stimulated Raman scattering microscopy and multi-passed transmission electron microscopy. A multi-pass microscope interrogates a sample multiple times in a cyclical and deterministic fashion. This can lead to a metrological advantage for imaging weak scatterers. The enhanced sensitivity can yield a significant reduction in damage imparted to biological samples or can reduce image acquisition time. The approach compares favorably with imaging techniques using squeezed or entangled probe states, but avoids the technical complexity associated with the production of such states.

Dynamic 3D imaging of freely moving bacteria and cells is an enduring need in biological imaging. The most common approaches involve scanning the sample or beam and capturing multiple 2D images to be stacked into a volume. Unfortunately, these techniques can introduce loss in time resolution. Alternatively, two 2D sensors could simultaneously capture the scene from multiple perspectives with time-resolution limited only by the acquisition rate of each sensor. In principle, because each sensor can share a spatial axis, the information can be used to recreate the 3D scene; in practice however, correlating the information over a single axis can pose its own challenges. We describe how a quantum entangled light source can be used as a low-flux approach to generate 4D information which contains both spatial and temporal correlations. We characterize experimental possibilities of this approach including resolution target testing, the use of fluorescence correlations, and scattering correlations. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

Photosynthetic light harvesting in vivo displays near unit quantum efficiency under ultra-weak illumination conditions. A new generation of experimental and theoretical studies using quantum light sources and coincidence counting now allows explicit study of the absorption of individual photons. First generation experiments reveal a cycle of single photon absorption and single photon fluorescent emission that validates the microscopic interpretation of conventional bulk measurements of quantum efficiency. I shall discuss how these techniques and related theoretical studies can probe the spatiotemporal dynamics of photosynthesis in a new and fundamental manner.

Networks of interacting molecular optical dipoles play an important role in photosynthetic light harvesting, and also hold significant promise for future artificial technologies. In this presentation I will give an overview of our recent theoretical work taking inspiration from biological structures and processes, with the aim of designing systems that utilise bio-inspired collective quantum optical effects. These could, for instance, enable quantum-enhanced light harvesting, the charging of Dicke quantum batteries through superabsorption of light, and achieving efficient long-range energy transport.

We developed an ultrabroadband 2D electronic spectrometer that can measure ultrafast photophysics across the visible range. We apply this technique to explore the dissipative photophysical processes in the major light-harvesting protein in green plants, a mechanism by which plants protect against photooxidative damage.

2D Electronic Spectroscopy (2DES) was used to characterize the ultrafast relaxation dynamics of Fucoxanthin (Fx) and chlorophyll (Chl) chromophores in the Fucoxanthin Chlorophyll Protein (FCP) extracted from Cyclotella meneghiniana. Evidence was found for ultrafast delocalization of excitation among the Chls and the Fx within <20 fs, indicating interactions lasting only for the first femtoseconds, supporting predictions based on structural information. Additionally, the peculiar coherent dynamic behavior attributed to vibrational modes of Fx suggests that the nuclear degrees of freedom of Fx may play a functional role in the redistribution of energy between chromophores.

Using a photon-counting quantum light spectroscopy that probes photosynthetic light harvesting with a single photon at a time, we experimentally demonstrated that photosynthesis begins and proceeds with a single quantum of energy. We report the observation of individual single-photon absorption and emission events in spatially distinct regions in photosynthetic systems. The experiments were carried out on an ensemble of pigment-protein complexes light-harvesting 2 from purple bacteria Rhodobacter sphaeroides under ambient conditions in vitro.

The use of quantum resources can enhance measurement sensitivity beyond the standard quantum limit (SQL). Quantum metrology aims to achieve these enhancements in practical devices, requiring compatibility with existing quantum resources within the SQL. Plasmonic sensors are promising candidates for such enhancements, extensively used in biochemical sensing and disease diagnostics applications. They respond to small index variations, inducing resonance shifts that affect the probing light's amplitude and phase. Quantum states of light, like NOON states, squeezed states, or Fock states, can lower the measurement noise floor, enabling sub-SQL signal detection. In this study, we compare two quantum plasmonic sensing configurations: phase-based and amplitude-based. By considering the limit of detection for both, we demonstrate the phase-based configuration's superior exploitation of available quantum resources. The advantage stems from the plasmonic sensor's heightened sensitivity to refractive index changes and its lower loss operation. This work can assist in the development of biosensors which offer the best limit of detection in diagnostics experiments.

The mechanisms underlying the therapeutic effects of lithium (Li) in bipolar disorder remain elusive despite its clinical use for nearly half a century. Previous studies have shown that Li isotopes have different effects on animal behavior and neuronal electrical response. Li pathways in organisms are not fully understood, but there are studies linking Li with sodium (Na), potassium (K), and calcium (Ca) channels. Using calcium-induced fluorescence and inductively coupled plasma mass spectrometry (ICP-MS) we studied effects of Li isotopes is the mitochondrial sodium/calcium/lithium exchanger (NCLX), identified as a potential molecular target for Li. Our results showed that there was no difference in Ca efflux depending on the different Li isotopes and that is no selectivity between Li isotopes in permeation through mitochondrial membrane. Our findings suggest that there is no Li isotope differentiation in mitochondria and/or it does not affect Ca efflux via NCLX.

There is great promise in utilizing shallow paramagnetic luminescent defects such as NV- centers in conjunction with spin-labeled receptor proteins in biological and chemical sensing. One of the major challenges is the accurate and efficient placement of the receptor protein in the close vicinity of the luminescent center deposited within the host material. We analyze the FRET-driven functionalization of the surface, where the emission of the luminescent center serves as a donor of the excitation, and the photolabile group on the surface as the acceptor. The efficiency of biological detection with a combination of a spin-labeled protein receptor and a shallow NV- center is considered.

Quantum diamond microscopy (QDM) is a technique for wide field-of-view diffraction-limited imaging of a thin and dense layer of negatively charged nitrogen-vacancy (NV) defects in engineered diamond crystals. In the recent past, QDM has enabled imaging of a diverse class of samples with microscopic magnetic field profiles, for example, biological cells with magnetic nanoparticles and current flow profiles in thin quantum materials. A challenging extension of the technique is to perform spatially resolved magnetic field imaging from in-vitro 2D or 3D cultures of mammalian neurons. This potential development can lead to an alternative magnetometry-based neuronal imaging technique, with advantages over conventional scattering-limited multi-photon in-vivo calcium imaging.In this talk I will describe our path toward volume imaging of neurons with QDM.

The development of fluorescent molecular sensors for imaging voltage changes in biological systems has revolutionized neuroscience, providing a tool to capture neuronal activity over large areas with sub-neuron resolution both in vitro and in vivo [1–3]. However, the poor photostability of molecular voltage sensors limits recording times to a few minutes [1–3], posing problems for longitudinal studies of network evolution and disease processes. Here, we present an alternate non-invasive platform for sensitive high resolution voltage imaging using fluorescent, charge-sensitive defects in a transparent diamond substrate [6]. Using these charge state sensors, we establish an all-optical diamond voltage imaging microscope (DVIM) capable of sub-millisecond voltage imaging with sub-millivolt sensitivity. Our work open new pathways for the study of 2D neuronal network cultures as well as 3D brain organoids.

Magnetic signals from the heart and brain (MCG and MEG) can carry information not available with conventional electric measurements. However, biomagnetism in general is extremely weak and requires highly specialized sensors to be detectable. Quantum sensors based on Nitrogen Vacancy centers in diamond can reach the required sensitivity levels while still operating at room temperature and without magnetic shielding. Further, they are robust, relatively cheap, and can be manufactured at scale. Qnami is developing this technology with the goal of enabling improved quality diagnostics and point of care biomagnetism measurements.

FRET (Forster resonance energy transfer) has been known as the main mechanism of energy transfer between Quantum dot (QD) and other fluorescent protein resulting in photo luminescence quenching of donor and sensitization of acceptor. There are a few suggestions about quantum biological electron tunneling between nanomaterials (e.g. gold nanoparticles) and biomolecules, and its application for monitoring cellular function. However, there was little systematic study and understanding of mechanism about QD and metalloprotein in terms of energy transfer or electron transfer. Here, we developed QD and nanoparticle-based probe and explored the nanoparticle-mediated efficient energy transfer that is beyond traditional FRET and potential electron tunneling effect. We explore the nanoparticle-metalloprotein coupling study using steady state and time-correlated optical properties changes under varied environmental conditions.

Natural devices, such as those involved in photosynthesis, can display intriguing characteristics linked to the complexity of their architecture and operation. They have therefore emerged as avenues towards a renewed understanding of biological functions and bioinspired technological alternatives to semiconductor-based nanoelectronics. Such is the case of the Fenna-Matthews-Olson (FMO) complex, one of the simplest natural light-harvesting systems found in bacteria and renowned for its high efficiency of photon-to-electron conversion. With the aim of reproducing artificial FMO counterparts, we have developed a framework suitable for exciton quantum transport using the non-equilibrium Green's function formalism. We have investigated the role of the particular geometry of FMO architecture and the coupling of excitons to vibrations in alternative architectures inspired from the FMO complex. The investigation shows how both transport coherence and coupling to local vibrations can combine to improve the yield of exciton extraction from the designed antenna.

Quantum sensing tools have emerged as a compelling means to study nanoscale chemical and biological processes with high sensitivity and spatial resolution, promising wide impact in a variety of fields ranging from chemical synthesis to bioengineering. Recently there has been expanded interest in assay-like quantum sensing approaches that can yield high-fidelity analyte discrimination for practical applications. In this work, we introduce a novel high-throughput, in-flow, quantum sensing platform based on droplet microfluidics. Quantum sensors based on nanodiamonds hosting Nitrogen Vacancy (NV) centers are incorporated within monodisperse phase separated droplets which serve as picoliter containers for both the sensors and for analytes of interest. Such controllable micro-compartments allow for strong sensor-analyte interaction, and allow for the rapid, high throughput (~10kHz), quantum sensing of numerous droplets. We demonstrate a novel method for noise-suppression in the fluorescence-based optically detected magnetic resonance (ODMR) measurements exploiting droplet flow, and use it to carry out high sensitivity assay detection of several analytes of biological importance.

Iron is an essential yet toxic redox active element that is found in many cells, including neurons and glial cells. Several techniques have been used to quantify iron in neurons and cells; however, most are incapable of high-resolution imaging inside a single cell. Magnetic field sensors based on diamond nitrogen vacancy (NV) centers have emerged as a powerful tool for detecting magnetic signal in iron-containing biological samples with a good combination of spatial resolution and sensitivity. In this study we use NV based T1 relaxometry technique to map iron in cytochrome C (Cyt C) proteins. Cyt C plays an important role in the electron transport chain of mitochondria and it is in the Fe(III) paramagnetic state under ambient conditions. We measure Cyt C under different concentrations and locations of the 10-nm NV doped diamond chip. We show a reduction of the NV T1 from few milliseconds to hundreds of microseconds, explained by the spin noise from the intracellular iron spins in the Cyt C protein. Additionally, we perform imaging of Cyt C proteins on a nanostructured diamond chip.

We demonstrated single-photon emission from hBN color centers embedded inside live cells and their application to cellular barcoding. Each color center can exist in one out of 470 possible distinguishable states. A combination of a few color centers per cell can be used to uniquely tag virtually an unlimited number of cells. This barcoding technique is superior to others in almost all respects, including ease of production by a single-step procedure, biocompatibility and biodegradability, emission stability, no photobleaching, small size and a huge number of unique barcodes.

The future global quantum internet will require high-performance matter-photon interfaces at scale. The highly demanding technological requirements indicate that the matter-photon interfaces currently under study all have potentially unworkable drawbacks, and there is a global race underway to identify the best possible new alternative. For overwhelming commercial and quantum reasons, silicon is the best possible host for such an interface. Silicon is not only the most developed integrated photonics and electronics platform by far, isotopically purified silicon-28 has also set records for quantum lifetimes at both cryogenic and room temperatures [1]. Despite this, the vast majority of research into photon-spin interfaces has notably focused on visible-wavelength colour centres in other materials. In this talk I will introduce a variety of silicon colour centres and discuss their properties in isotopically purified silicon-28. Some of these centres have zero-phonon optical transitions in the telecommunications bands [2], some have long-lived spins in their ground states [3], and some, including the newly rediscovered T centre, have both [4] and can be integrated into silicon photonics chips at scale [5]. [1] K. Saeedi, S. Simmons, J.Z. Salvail, et al. Science 342:830 (2013). [2] C. Chartrand, L. Bergeron, K.J. Morse, et al. Phys. Rev. B 98:195201 (2018). [3] K. Morse, R. Abraham, A. DeAbreu, et al. Science Advances 3:e1700930 (2017). [4] L. Bergeron, C. Chartrand, A.T.K. Kurkjian, et al. PRXQuantum 1:020301 (2020). [5] D. Higginbottom, A.T.K. Kurkjian, C. Chartrand et al. Nature 607:266 (2022).

The deoxyribose moiety of a nucleotide in the DNA molecule can act as a quantum logic gate, in which the enantiomeric shift between the C2-endo and C3-endo conformations of each nucleotide, occurs within a logically and thermodynamically reversible situation of electron spin qubits, that are coherently held within the topologically insulating DNA crystalline nanostructure, and that are coherently conducted along the delocalized electrons of the pi-stacked nucleotide base pairs. The enantiomeric symmetry between the C2-endo and C3-endo conformations is logically and thermodynamically reversible because it functions as a symmetry-breaking Szilard engine that is effectively built out of the physicality of the information by which it functions, and therefore does not require information erasure to maintain function. Such a quantum logic gate is analogous to a Toffoli gate which operates across an energy barrier appropriate to the Landauer limit, to roll the DNA base pair and thereby break the pi-stacking coherence along a segment of the DNA molecule, thus effecting quantum-to-classical transition of information.

This study focuses on the quantum simulation of photon-tissue interactions to determine the scattering and absorption cross sections of biological tissues as a function of tissue depth. By leveraging the absorption and scattering coefficients, we aim to characterize the optical properties of the tissue. Such information holds the potential to discern between healthy and diseased tissues, as well as monitor changes in tissue composition over time. For instance, variations in absorption can unveil the presence of specific chromophores like hemoglobin or melanin, whereas scattering properties offer insights into tissue microstructure. We propose a novel quantum algorithm designed to calculate the quantities of scattered and absorbed photons across various tissue layers. Our quantum algorithm aims to offer a more efficient simulation of backscattered photon intensity, setting it apart from conventional classical algorithms.

In this talk, I will introduce metasurface-enhanced multiplexed nanospectroscopy and molecular diagnostics. First, we report metasurfaces-driven hyperspectral imaging via multiplexed plasmon resonance energy transfer to probe biological light-matter interactions, which can detect quantum biological electron transfer. We conduct real-time and label-free monitoring of reactive oxygen species (ROS) from different types of cells. We used three different cells, normal cells, tumor cells, and drug-treated tumor cells, and quantitatively analyzed ROS production in real-time. Second, we scalably fabricate a low-power-consuming metaphotonic PCR device composed of a metamaterial perfect absorber that can rapidly go through thermocycling steps using a single infrared LED. We demonstrate an ultrafast photonic reverse transcription PCR (RT-PCR) with 30 thermocycles achieving 21.9 °Cs-1 heating rate and 7.8 °Cs-1 cooling rate. Furthermore, we would like to utilize the metaphotonic PCR chip for quantitative quantum enzymology.

The constant advancements in single-photon technologies have led to the development of detectors with amazingly low jitter, that can play an important role in quantum measurements. A major limitation to their full-exploitation in practical applications is represented by the timing electronics that should possess both low jitter characteristics, as well as good speed, linearity and full-scale range (FSR) performance. In this talk, we propose a new TAC-based single-channel timing system that features a state-of-the-art jitter of 4.5 ps FWHM, along with a peak-to-peak DNL of 1.5 % LSB and a speed of 12 Mcps, over a wide full-scale range of 12.5 ns. Thanks to the promising results achieved in experiments with SNSPDs, we are extending the system to eight-channels, as to leverage converter parallelization to further reduce timing jitter below 2 ps.

Confocal fluorescence microscopy is a common imaging technique for biomedical applications such as tumor characterization, precision resections, etc... However, the imaging process is limited by photo bleaching of samples and optical scattering limits imposed by wavelength limitations of traditionally used detection technologies. Here we show that by leveraging the high detection efficiency and large spectral range of superconducting nanowire single-photon detectors, it is possible to image deeper into tissue with a significant reduction in laser excitation power compared to the same technique using silicon photo-multipliers.

Many quantum applications will benefit significantly from photon number resolving detection. However, photon number resolving detectors have been largely experimental devices implemented in laboratory settings. Recent advances in superconducting nanowire device fabrication and readout techniques have enabled the implementation of photon number resolution in widely deployable commercial single-photon detection systems. We will discuss progress in implementing photon number resolved detection with commercially produced superconducting nanowires using spatially multiplexing of indpendently instrumented detectors and photon number dependent rise-time changes in single-elment nanowire devices.

We've discovered a simple, nontoxic, biocompatible way to control the brightness of GFP-like fluorescent proteins via modest magnetic fields (~10 mT). Fluorescent proteins which seem magnetically inert (e.g. EGFP, mScarlet) become magnetoresponsive in the presence of an appropriate cofactor (e.g. EGFP-FlavinTag, or an mScarlet/FMN solution). This method works at room-temperature and body-temperature, in vitro, in E. coli and in cultured mammalian cells. The GFP-family magnetoresponse is weak (ΔF/F≈1%), but shows the hallmarks of evolvability. This suggests exciting technological possibilities, both short-term (e.g. lock-in detection, multiplexing) and long-term (e.g. optically-detected MRI, magnetogenetics). We've also discovered weak magnetoresponse from a member of the LOV-domain family. This suggests the possibility that magnetoresponse is a general feature of fluorescent proteins, and not unique to the cryptochrome/photolyase family.

The study of decoherence in biological systems has become an essential area of research for quantum mechanics. Fluorescence quenching is a physiochemical process that causes the decrease in fluorescence intensity of a fluorescent sample. Changing the surrounding environment of fluorescent proteins (FPs), by adding a fluorescence quenching agent could potentially have a large impact on the dynamical processes within these biological systems. Environmental influence on protein-protein interactions is not a well understood process, when looking at energy transfer dynamics of FPs. we attempt to establish the impact on the energy transfer dynamics between fluorophores by introducing varying concentrations of external quenchers to the FPs environment. We examine the photophysical properties and spectral changes of the FPs, after adding external quenchers to both the monomeric and dimeric structures to further characterise the energy transfer dynamics.

Quantum mechanics has significantly advanced our understanding of fundamental properties. While biological studies have traditionally been assumed to be governed by classical physics, recent studies have shown that coherent excitonic coupling between two chromophores in a homodimer of the yellow fluorescent protein, Venus, is possible at room temperature [Y. Kim et al., Biophys. J., 2019, 116, 1918-1930]. In this study, we present a genetically encoded sensor, inspired by recent finding of the ultrafast photoinduced energy transfer between dimeric enhanced green fluorescent proteins (dEGFPs), to monitor hydrophobic environmental changes [A. Sanchez-Pedreno Jimenez, et al., Phys. Chem. Chem. Phys., in press]. This sensor can be used to investigate the spatial and temporal dynamics biocondensates in cells. This biosensor offers an innovative approach to unravel the dynamics of biocondensates, to elucidate their biological functions and potential implications in health and disease. Experiments are being conducted to test this sensor in living cells.

DNA ‘breathing’ refers to spontaneous fluctuations of the sugar-phosphate backbones and bases of DNA, which are thought to mediate protein-DNA interactions central to the assembly of biomolecular complexes. Nevertheless, few experimental methods are currently available that can directly probe DNA breathing and provide molecular level details about their mechanisms. Here we describe a new method called polarization-sweep single-molecule fluorescence (PS-SMF) microscopy to monitor the local fluctuations of DNA fork constructs, which are site-specifically labeled with exciton-coupled cyanine [(iCy3)2] dimer probes. These systems exhibit spectroscopic signals that are sensitive to the local conformations adopted by the sugar-phosphate backbones and bases immediately surrounding the dimer probe label positions. We analyze our data using a kinetic network model, which we use to parametrize the free energy surface of the system. In addition to observing DNA breathing at and near ss-dsDNA junctions, the approach can be used to study the effects of proteins that bind and function at these sites.

Fluorescence spectrum, intensity and decay measurements are techniques for analyzing molecular structure and energy transition in cellular biology and cytometry. To address the challenge of measuring nanosecond order fluorescence decay times, single photon detection technology has been developed using pixel-coupled Silicon Photo Multiplier (SiPM), GHz electronics and waveform analysis. “Successive molecular fluorescence decay (SMFD)” and “Time-correlated multi-photon counting (TCMPC)” techniques were developed to detect multiple PE pulses during fluorescence decay in one START-STOP time interval. These new techniques for analyzing single molecule behavior and structure will be powerful tools to understand the quantum nature of biology.