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It’s Time to Take Quantum Biology Research Seriously

  • Samueli School of Engineering, University of California, Los Angeles, Los Angeles, CA, US

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Imagine healing an injury by applying a tailored magnetic field to a wound. This outcome might sound fantastical, but researchers have shown that cell proliferation and wound healing, among other important biological functions, can be controlled by magnetic fields with strengths on the order of those produced by cell phones. This kind of physiological response is consistent with one caused by quantum effects in electron spin-dependent chemical reactions. However (and it’s a big however), while researchers have unambiguously established such reactions for in vitro experiments, they have not done so for in vivo studies. The barriers to in vivo experiments stem both from the absence of experimental infrastructure to perform true quantum measurements inside biological systems and from a misunderstanding of what quantum behaviors in biology are and why they matter. In my opinion, it is time to set the record straight so that we can legitimize work in this field. Quantum biology findings could enable the development of new drugs and of noninvasive therapeutic devices to heal the human body, as well as provide an opportunity to learn how nature builds its own quantum technologies.

Quantum biology researchers study the inherent quantum degrees of freedom of biological matter with the goal of understanding and controlling these phenomena. To a physicist, I’d describe quantum biology as the study of light–matter interactions, where the matter is living. Quantum biology is not the study of classical biology using quantum tools, nor is it the application of quantum computers or of quantum machine learning to drug discovery or healthcare big data processing, and it definitely has nothing to do with the manipulation of free will, with the origin of consciousness, or with other New Age buzzwords.

Experimental evidence consistent with quantum effects existing in biological systems has been around for more than 50 years. One example is the spin-dependent chemical reaction thought to allow birds to navigate using Earth’s weak magnetic field. Today, there is no doubt that such phenomena play important roles in laboratory biological systems—for example, it is uncontroversial that quantum superpositions can manifest in proteins in solution for long enough that they influence chemical processes. But as yet there is no unambiguous experimental evidence that a single living cell can maintain or utilize quantum superposition states within its molecules, as is required, for example, if birds truly use a quantum process as a compass.

This lack of experimental verification is one of the main reasons that the field is considered inconsequential by funders and by the established quantum and biophysics communities. Yes, sophisticated experiments have been performed with single molecules in solution and with whole organisms (birds and flies, for example). But these experiments only show correlation, not causation, between a molecule’s or an organism’s behavior and quantum physics. Bridging that gap will require performing truly quantum measurements inside biological matter using challenging combinations of quantum instrumentation and wet lab techniques.

Another reason quantum biology is not considered a legitimate field of science is the absence of a cohesive quantum biology community. That deficit is beginning to change, but further efforts are needed in that direction. In early 2020, people in my lab and in the Quantum Biology Doctoral Training Centre at the University of Surrey, UK, started an online seminar series called Big Quantum Biology Meetings. The seminars provide a forum for the more than 600 quantum biology researchers and enthusiasts signed up to our mailing list to meet informally once a week. Other efforts to create a cohesive community include establishing a Gordon Research Conference on Quantum Biology, the first of which happened earlier this year and was attended by 150 people, and the gaining of support from the National Science Foundation for a Research Coordination Network on “Instrumentation for Quantum Biology.”

A point of pride of the Big Quantum Biology Meetings series is the intentional incorporation of inclusive practices in the seminars. For example, each meeting starts with a short presentation from a trainee, which we define as anyone without a permanent position, giving them and their work exposure. The trainee is then the host and mediator for the rest of the meeting. The main speaker also gives a “DEIJ moment”—one slide on anything related to diversity, equity, inclusion, and justice that has impacted their scientific life.

A final reason why quantum biology struggles in being accepted as a stand-alone field is the continued presence of scientific silos at institutions. If cells and organisms are using quantum effects to function optimally, a cohort of interdisciplinary experts is needed to collaboratively explore the problem. In my opinion, this collaboration would ideally take place in a quantum biology-focused institute where scientists can easily and organically work together. Recently, in an example of this idea, Japan unveiled the Institute for Quantum Life Science, which brings chemists, biologists, engineers, clinicians, physicists, and others under one roof to work on quantum biology research questions. The development of a similar institute in the US could help in irrevocably establishing this field—which will have, I believe, radical consequences for the biological, medical, and physical sciences.

About the Author

Image of Clarice Aiello

Clarice Aiello is a quantum engineer interested in how quantum physics informs biology at the nanoscale. She is an expert on nanosensors that harness room-temperature quantum effects in noisy environments. Aiello received a bachelor’s in physics from the Ecole Polytechnique, France; a master’s degree in physics from the University of Cambridge, Trinity College, UK; and a PhD in electrical engineering from the Massachusetts Institute of Technology. She held postdoctoral appointments in bioengineering at Stanford University and in chemistry at the University of California, Berkeley. Two months before the pandemic, she joined the University of California, Los Angeles, where she leads the Quantum Biology Tech (QuBiT) Lab.

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New research area promotes both quantum computing and cognitive science

by Intelligent Computing

New research area promotes both quantum computing and cognitive science

Diving deep into quantum biology or cognitive science alone is challenging enough. That being said, a research team recently wrote a review article highlighting molecular quantum computing, a newly emerged research area that is likely to push the research boundaries of both. The review was published in Intelligent Computing .

Future theoretical breakthroughs may be achieved by connecting molecular quantum computing, the bridge research area, with cognitive science and quantum biology, the authors argue.

Cognitive science centers on exploring the learning mechanism, including whether neurons learn at the classical or quantum level. Quantum biology, on the other hand, seeks to address the biological questions that cannot be answered by classical mechanics alone. These puzzles may be solved through molecular quantum computing, which uses the special functions of molecules to process quantum information .

The review first covers the progress in molecular quantum computing, quantum biology, and cognitive science in general, then explains some basic terms in quantum physics before narrowing down to several key concepts to connect the dots.

One of the key concepts is quantum degrees of freedom, the bedrock of understanding and simulating quantum effects in biological systems . To simplify, quantum degrees of freedom generally describe how much "freedom" a qubit—the quantum equivalent of a classical bit—is allowed in storing and processing information in a given space.

Specifically, quantum degrees of freedom include orbitals, charges, spins, vibrations, rotations, photonic states, etc., and researchers could create different combinations of these to give different features to a quantum computing system.

In molecular quantum computing, the manipulation of molecular degrees of freedom, such as charge movement and spin states, is crucial for creating and maintaining quantum coherence. This coherence is a high-maintenance feature essential for the high performance of a quantum computing system, enabling electrons to function as qubits and transfer information across quantum circuits.

In quantum biology and cognitive science, degrees of freedom are also important. A single protein in a neuron is complicated enough to allow multiple degrees of freedom to create the quantum effect, which has already been observed in some biological processes like enzyme catalysis and photosynthesis and which may account for consciousness.

The quantum properties in enzyme catalysis are related to charge and orbital degrees of freedom , which could be used in performing molecular quantum computing and are presumed to be associated with microtubules and mitochondria—two key components inside a neuron cell.

In photosynthesis, the quantum effect largely involves opto-spins, an interplay between photon and spin. Opto-spins could provide insights into molecular quantum computing, where qubit performance could be enhanced by applying light to magnetic spins, and into cognitive science, where axons, another key component of neurons, might use bio-photons and spins to process information.

While many of the suggested connections remain unconfirmed or understudied, the research team hopes that further exploration could lead to "an extremely exciting science" appearing at the intersection of molecular quantum computing, quantum biology and cognitive science .

Provided by Intelligent Computing

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The future of quantum biology

Adriana marais.

1 Quantum Research Group, School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa

Betony Adams

Andrew k. ringsmuth.

2 Institute for Lasers, Life and Biophotonics, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1081, 1081 HV Amsterdam, The Netherlands

3 ARC Centre of Excellence for Engineered Quantum Systems, The University of Queensland, St Lucia 4072, Australia

Marco Ferretti

J. michael gruber, ruud hendrikx, maria schuld, samuel l. smith.

4 Cavendish Laboratory, University of Cambridge, Cambridge, UK

Ilya Sinayskiy

5 National Institute for Theoretical Physics, KwaZulu-Natal, South Africa

Tjaart P. J. Krüger

6 Department of Physics, Faculty of Natural and Agricultural Sciences, University of Pretoria, Hatfield, South Africa

Francesco Petruccione

Rienk van grondelle, associated data.

This article has no additional data.

Biological systems are dynamical, constantly exchanging energy and matter with the environment in order to maintain the non-equilibrium state synonymous with living. Developments in observational techniques have allowed us to study biological dynamics on increasingly small scales. Such studies have revealed evidence of quantum mechanical effects, which cannot be accounted for by classical physics, in a range of biological processes. Quantum biology is the study of such processes, and here we provide an outline of the current state of the field, as well as insights into future directions.

1. Introduction

Quantum mechanics is the fundamental theory that describes the properties of subatomic particles, atoms, molecules, molecular assemblies and possibly beyond. Quantum mechanics operates on the nanometre and sub-nanometre scales and is at the basis of fundamental life processes such as photosynthesis, respiration and vision. In quantum mechanics, all objects have wave-like properties, and when they interact, quantum coherence describes the correlations between the physical quantities describing such objects due to this wave-like nature.

In photosynthesis, respiration and vision, the models that have been developed in the past are fundamentally quantum mechanical. They describe energy transfer and electron transfer in a framework based on surface hopping. The dynamics described by these models are often ‘exponential’ and follow from the application of Fermi’s Golden Rule [ 1 , 2 ]. As a consequence of averaging the rate of transfer over a large and quasi-continuous distribution of final states the calculated dynamics no longer display coherences and interference phenomena. In photosynthetic reaction centres and light-harvesting complexes, oscillatory phenomena were observed in numerous studies performed in the 1990s and were typically ascribed to the formation of vibrational or mixed electronic–vibrational wavepackets. The reported detection of the remarkably long-lived (660 fs and longer) electronic quantum coherence during excitation energy transfer in a photosynthetic system revived interest in the role of ‘non-trivial’ quantum mechanics to explain the fundamental life processes of living organisms [ 3 ]. However, the idea that quantum phenomena—like coherence—may play a functional role in macroscopic living systems is not new. In 1932, 10 years after quantum physicist Niels Bohr was awarded the Nobel Prize for his work on the atomic structure, he delivered a lecture entitled ‘Light and Life’ at the International Congress on Light Therapy in Copenhagen [ 4 ]. This raised the question of whether quantum theory could contribute to a scientific understanding of living systems. In attendance was an intrigued Max Delbrück, a young physicist who later helped to establish the field of molecular biology and won a Nobel Prize in 1969 for his discoveries in genetics [ 5 ].

All living systems are made up of molecules, and fundamentally all molecules are described by quantum mechanics. Traditionally, however, the vast separation of scales between systems described by quantum mechanics and those studied in biology, as well as the seemingly different properties of inanimate and animate matter, has maintained some separation between the two bodies of knowledge. Recently, developments in experimental techniques such as ultrafast spectroscopy [ 6 ], single molecule spectroscopy [ 7 – 11 ], time-resolved microscopy [ 12 – 14 ] and single particle imaging [ 15 – 18 ] have enabled us to study biological dynamics on increasingly small length and time scales, revealing a variety of processes necessary for the function of the living system that depend on a delicate interplay between quantum and classical physical effects.

Quantum biology is the application of quantum theory to aspects of biology for which classical physics fails to give an accurate description. In spite of this simple definition, there remains debate over the aims and role of the field in the scientific community. This article offers a perspective on where quantum biology stands today, and identifies potential avenues for further progress in the field.

2. What is quantum biology?

Biology, in its current paradigm, has had wide success in applying classical models to living systems. In most cases, subtle quantum effects on (inter)molecular scales do not play a determining role in overall biological function. Here, ‘function’ is a broad concept. For example: How do vision and photosynthesis work on a molecular level and on an ultrafast time scale? How does DNA, with stacked nucleotides separated by about 0.3 nm, deal with UV photons? How does an enzyme catalyse an essential biochemical reaction? How does our brain with neurons organized on a sub-nanometre scale deal with such an amazing amount of information? How do DNA replication and expression work? All these biological functions should, of course, be considered in the context of evolutionary fitness. The differences between a classical approximation and a quantum-mechanical model are generally thought to be negligible in these cases, even though at the basis every process is entirely governed by the laws of quantum mechanics. What happens at the ill-defined border between the quantum and classical regimes? More importantly, are there essential biological functions that ‘appear’ classical but in reality are not? The role of quantum biology is precisely to expose and unravel this connection.

Fundamentally, all matter—animate or inanimate—is quantum mechanical, being constituted of ions, atoms and/or molecules whose equilibrium properties are accurately determined by quantum theory. As a result, it could be claimed that all of biology is quantum mechanical. However, this definition does not address the dynamical nature of biological processes, or the fact that a classical description of intermolecular dynamics seems often sufficient. Quantum biology should, therefore, be defined in terms of the physical ‘correctness’ of the models used and the consistency in the explanatory capabilities of classical versus quantum mechanical models of a particular biological process.

As we investigate biological systems on nanoscales and larger, we find that there exist processes in biological organisms, detailed in this article, for which it is currently thought that a quantum mechanical description is necessary to fully characterize the behaviour of the relevant subsystem. While quantum effects are difficult to observe on macroscopic time and length scales, processes necessary for the overall function and therefore survival of the organism seem to rely on dynamical quantum-mechanical effects at the intermolecular scale. It is precisely the interplay between these time and length scales that quantum biology investigates with the aim to build a consistent physical picture.

Grand hopes for quantum biology may include a contribution to a definition and understanding of life, or to an understanding of the brain and consciousness. However, these problems are as old as science itself, and a better approach is to ask whether quantum biology can contribute to a framework in which we can repose these questions in such a way as to get new answers. The study of biological processes operating efficiently at the boundary between the realms of quantum and classical physics is already contributing to improved physical descriptions of this quantum-to-classical transition.

More immediately, quantum biology promises to give rise to design principles for biologically inspired quantum nanotechnologies, with the ability to perform efficiently at a fundamental level in noisy environments at room temperature and even make use of these ‘noisy environments’ to preserve or even enhance the quantum properties [ 19 , 20 ]. Through engineering such systems, it may be possible to test and quantify the extent to which quantum effects can enhance processes and functions found in biology, and ultimately answer whether these quantum effects may have been purposefully selected in the design of the systems. Importantly, however, quantum bioinspired technologies can also be intrinsically useful independently from the organisms that inspired them.

3. Quantum mechanics: an introduction for biologists

At the beginning of the twentieth century, the success of classical physics in describing all observable phenomena had begun to be challenged in certain respects. In 1900, as a means to explain the spectral energy distribution of blackbody radiation, Planck introduced the idea that interactions between matter and electromagnetic radiation of frequency ν are quantized, occurring only in integer multiples of h ν, where h is the fundamental Planck constant. Five years later, Einstein further developed the notion of energy quantization by extending it to include the photon, a quantum of light. This concept is illustrated by the photoelectric effect where light incident on a material leads to the emission of electrons. It is, however, not the intensity of the light that determines this emission but rather its frequency. Even low-intensity light of a suitable frequency will lead to electrons being emitted whereas high-intensity light below this threshold frequency will have no effect. Einstein explained this by proposing that in this instance light behaves as a particle rather than a wave, with discrete energies h ν that can be transferred to the electrons in a material. Bohr’s 1913 model of the hydrogen atom, with its discrete energy states, and Compton’s 1923 work with X-rays all contributed to the beginning of a new era in modern physics. These ways of explaining blackbody radiation and the photoelectric effect, as well as atomic stability and spectroscopy, led to the development of quantum mechanics, a theory that has proved extremely successful in predicting and describing microphysical systems [ 21 , 22 ].

Whereas Planck and Einstein began the quantum revolution by postulating that radiation also demonstrates particle-like behaviour, de Broglie, in 1923, made the complementary suggestion that matter itself has wave-like properties, with a wavelength related to its momentum through Planck’s constant. This hypothesis suggested that matter waves should undergo diffraction, which was subsequently proved by experiments that demonstrated that particles such as electrons showed interference patterns. Schrödinger built on this observation in his formulation of quantum mechanics, which describes the dynamics of microscopic systems through the use of wave mechanics. The formulation of quantum mechanics allows for the investigation of a number of important facets of a quantum state: its mathematical description at any time t , how to calculate different physical quantities associated with this state and how to describe the evolution of the state in time [ 21 , 22 ].

An external file that holds a picture, illustration, etc.
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One of the more fascinating aspects of quantum theory is that for two quantum states | ψ 1 〉 and | ψ 2 〉 describing a system, a linear combination of these two states, α 1 | ψ 1 〉 + α 2 | ψ 2 〉, also describes the system. This combination or superposition of states constituting the Hilbert space is written more generally as

equation image

It is these specifically quantum properties such as superposition, coherence, entanglement and tunnelling that are described, in this review, as integral to a new understanding of biological phenomena as diverse as photosynthesis, magnetoreception, olfaction, enzyme catalysis, respiration and neurotransmission [ 25 – 27 ].

4. Transport processes

At a fundamental level, the dynamics in biological systems are associated with the transfer of energy and charge, the latter of which involves electrons, protons and ions. Excitation energy transfer and charge transfer in photosynthesis are the most well-established areas of quantum biology, and a more recent area of investigation is the study of enzyme catalysis, which often relies on the coupling of electrons and protons to control the transport of multiple charges.

4.1. Photosynthesis

A prolific class of organisms has been living on sunlight energy for over 3 billion years, using a process called photosynthesis to convert sunlight energy into forms useful for their survival. The overall efficiency with which photosynthetic organisms convert sunlight energy to biomass under typical conditions is fairly low (at best a few per cent [ 28 , 29 ]), since neither is all incoming sunlight absorbed, nor is all absorbed energy converted into biomass. However, the primary light-harvesting stage of photosynthesis proceeds with near-perfect quantum efficiency. This means that under optimal conditions (low light intensities and no stress) for almost every photon absorbed and transferred by the light-harvesting antennae, an electron is transferred within the photosynthetic reaction centre.

Light-harvesting antennae range from quasi-disordered self-assembled aggregates [ 30 ] to highly symmetric configurations of pigments bound to protein scaffolds [ 31 , 32 ]. The light-harvesting complexes that constitute the total antenna system are connected to a reaction centre, which is the single unit of the photosynthetic apparatus capable of carrying out a transmembrane charge separation [ 33 ].

Experiments performed by isolating both light-harvesting complexes and reaction centres from natural photosynthetic systems, whilst mimicking physiological environmental conditions, have shed much light on the in vivo functioning of the photosynthetic light-collecting system. It is well-established that the primary photosynthetic processes of energy and charge transfer exhibit essential quantum mechanical properties, such as delocalization, wavepackets, coherence and superradiance, and that classical models do not accurately describe the ensuing dynamics.

4.1.1. Excitation energy transfer

As early as 1938, Franck & Teller [ 34 ] proposed a quantum coherent mechanism for excitation energy transfer in photosynthesis. They considered the diffusion of a Frenkel exciton, which is a coherent superposition of the electronic excitations of the individual photosynthetic pigments ( figure 1 ). With the advent of femtosecond transient absorption spectroscopy in the early 1990s, long-lived vibrational coherences, lasting on the order of a picosecond, were detected for bacterial and plant light-harvesting complexes [ 35 – 40 ]. During the past 14 years, advanced ultrafast techniques, known as two-dimensional electronic spectroscopy (2D-ES), have been used to monitor the decay of coherent superpositions of vibrational states and vibronic (mixed excitonic–vibrational) states in light-harvesting complexes. The two-dimensional spectra revealed the presence of cross peaks [ 41 ] that oscillated in time [ 42 ]. A large number of studies associated the cross peaks with couplings between exciton states, while their oscillations were assigned to electronic quantum coherence, i.e. coherent superpositions between exciton states [ 42 ]. The first such study, which was conducted on the Fenna–Matthews–Olson (FMO) complex of green sulfur bacteria and published in 2007 by the Fleming group, revealed that particular coherences lasted surprisingly long (660 fs) [ 3 ]. In 2009, similar oscillatory signals were revealed for the main light-harvesting complex of higher plants (LHCII) and were interpreted as quantum-coherent energy transfer [ 43 ]. These initial results were obtained at cryogenic temperatures. An important development was the detection in 2010, independently by the Engel [ 44 ] and Scholes [ 45 ] groups, of similar coherent oscillations at physiological temperatures in FMO and light-harvesting complexes of two species of marine cryptophyte algae, respectively.

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Object name is rsif20180640-g1.jpg

A schematic illustrating the concept of excitation energy transfer in photosynthetic light-harvesting complexes. The ovals depict pigment clusters in which strong excitonic coupling occurs while the arrows represent incoherent transfer of the energy amongst the clusters. Within each cluster, the energy is delocalized over all pigments and is transferred coherently.

Generally, quantum coherence at physiological temperatures is observed to be fragile compared to that at cryogenic temperatures, since the environmental noise increases with increasing temperature, leading to shorter decoherence times. These results are therefore interesting, both from the perspective of quantum information processing, where a major challenge is to maintain quantum coherence in systems that unavoidably interact with an environment, and from the perspective of quantum biology, which investigates whether fundamental aspects of the functioning of living systems can only be explained quantum mechanically.

Inspired by the surprising phenomenon interpreted as long-living quantum coherence in warm, noisy, complex and yet remarkably efficient energy transfer systems, many models of environment-assisted quantum transport have been proposed. The aim has been to relate the phenomenon of quantum coherence across multiple chromophoric sites in photosynthetic pigment–proteins to the extreme efficiency of the excitation energy transfer process, typically within approximate spin-boson models of the system. Contrary to the intuition that noise will reduce the performance of a system, it has been found that interaction with an environment can result in increased transport efficiency [ 19 , 20 ]. Light-harvesting complexes consist of a number of pigments with generally differing site energies. If this energy difference is larger than the pigment–pigment coupling, then transitions will be suppressed. Dephasing noise can shift the site energies, thereby helping to overcome these energy gaps, and improving transport between sites without the loss of excitations from the system [ 46 ].

After much theoretical evidence both for and against long-lived (up to a few picoseconds) electronic coherence, very recent 2D-ES studies on the FMO complex have shown unambiguously that these long-lived coherences originate mainly from ground state vibrations and not from exciton–exciton superpositions [ 47 , 48 ]. It was found that quantum beatings related to electronic coherences have a small amplitude and decay within only 60–240 fs. However, experimental confirmation of excited-state vibronic coherence was also found [ 48 ] and its role in excitation energy transfer in photosynthesis remains to be determined.

One may then ask whether the role of quantum coherence—excitons as well as vibronic coherences—in light harvesting is optimized, or is simply a consequence of the proximity of pigments in pigment–protein complexes. The robustness of environmentally assisted transport with respect to variations in the system or environmental characteristics has also been investigated and results show that this robustness can be exploited in the design of highly efficient quantum transport systems [ 49 , 50 ]. The convergence of time scales in photosynthesis has been proposed as an example of the ‘quantum Goldilocks effect’: that natural selection tends to drive quantum systems to a parameter set where the resulting degree of quantum coherence is ‘just right’ for attaining maximum efficiency and optimal control [ 51 ].

In general, the observation of oscillatory dynamics is not sufficient to rule out classical descriptions of the same behaviour, and the quantum modelling of environment-assisted transport in photosynthesis has not been without controversy. However, more recent work [ 52 ] has shown unambiguously that the non-classical properties of environmental vibrational motions may assist excitation energy transfer in photosynthetic LHCs on the sub-picosecond time scale and at room temperature. These ideas should be verified experimentally by examining whether mutational variants of photosynthetic LHCs alter the degree of quantum coherence, the coherence lifetime, and consequently also the energy-transfer efficiency.

4.1.2. Charge transfer

Charge separation in photosynthesis is one of the most efficient phenomena in nature, with a quantum efficiency that approaches unity. The contributing processes happen on different time scales, from subpicoseconds to milliseconds, and involve the interplay between disorder and coherence, mediated by vibronic states (mixtures of vibrational and excitonic states). Charge separation represents a very good candidate for understanding the role of quantum physics in biology. Since charge separation happens on the microsecond time scale, quantum effects are generally not directly visible at such a macroscopic level. However, the charge separation mechanism can be represented by a chain of different processes, with the early steps on ultrafast time scales and involving only a few molecules, and the overall efficiency depending on each one of the steps.

In 1966, DeVault and Chance observed a temperature dependence of the electron transfer in purple bacterial reaction centres that could not be accounted for by classical physics [ 53 ]. They proposed the behaviour to show evidence of quantum mechanical tunnelling [ 54 ], and laid the foundation for the concept of electron and nuclear tunnelling in biology [ 42 ]. While Marcus’ theory of electron transfer neglects nuclear tunnelling [ 2 ], and can therefore underestimate the electron transfer rate at low temperatures, semi-classical Marcus theory can be extended to a fully quantum-mechanical treatment based on the theory of non-radiative transitions that includes nuclear tunnelling, and which gives a good prediction for the increasing rate of charge separation with decreasing temperature. If it is assumed that charge separation is strongly coupled to some harmonic vibrational mode, then the rate is given by the Jortner rate. However, this is based on the assumption that vibrational relaxation occurs on much shorter time scales than electron transfer, which is not the case for very fast transfer events. Ultrafast photoinduced electron transfer reactions are so quick that during the electron transfer from the donor to the acceptor complete vibrational relaxation does not occur. Vibrational relaxation usually occurs on a picosecond or sub-picosecond time scale, and ultrafast electron transfer reactions proceed on the same scale [ 55 ].

2D-ES experiments on the reaction centre of Photosystem II of higher plants have revealed long-lived oscillations of specific cross peaks, similarly as for light-harvesting complexes, and were interpreted as electronic coherences between excitons as well as between exciton and charge-transfer states ( figure 2 ) [ 56 ]. Strong correlation was observed between the degree of coherence and efficient and ultrafast charge separation [ 56 ]. The experimental results were reproduced quantitatively by a quantum coherent model featuring new energy transfer pathways that do not appear classically between a plethora of vibronic states [ 56 – 58 ]. Specifically, the simulations showed that the observed cross-peak oscillations can be maintained by specific vibrational modes, where the modes assisting the resonant transfer are primarily intrinsic to the pigment, while the pigment excitonic transitions are tuned mainly by the protein scaffold to match the energy of these modes. Therefore, while non-trivial quantum effects may appear hidden on a macroscopic level, they seem to contribute fundamentally to the biological machinery of charge separation. Charge transfer, therefore, represents a very good process for understanding the role of quantum physics in biology.

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Hence, experimental and theoretical evidence shows that single vibrational modes in a statically disordered landscape very likely assist transport in both light harvesting and charge separation in photosynthetic organisms, with the pigment excitonic transitions tuned by the protein scaffold to match the energy of the vibrational mode assisting the resonant transfer [ 52 , 56 ]. Nuclear–electronic (vibronic) coupling is an important mechanism in the light-induced function of molecular systems, in general, and in a specific designed system. The outcome of light-induced electron transfer has also been shown to be radically altered by mode-specific infrared excitation of vibrations that are coupled to the electron transfer pathway [ 59 ].

4.1.3. Single molecule spectroscopy

Single molecule experiments present an interesting and promising approach to investigate quantum features of photosynthetic complexes. Results of 2D-ES suggest an intimate role of the environment in the form of molecular vibrations on quantum coherent energy and electron transfer processes. This environment changes from complex to complex as well as on relatively slow time scales (milliseconds to minutes), as suggested by the distinct, time-varying energy transfer pathways reported in studies on single light-harvesting complexes [ 11 , 60 – 62 ]. Owing to this heterogeneity, generally termed ‘static disorder’, which originates from relatively slow protein conformational dynamic fluctuations, the decay of oscillations of spectral features is strongly affected by ensemble averaging. By avoiding ensemble averaging in single molecule experiments, quantum coherences could be scaled to the microscopic domain, which might shed more light on the physiological significance of this quantum phenomenon.

Static disorder also strongly affects the fate of an excitation in a light-harvesting complex by changing the probability of the excitation to be trapped in an energy sink [ 63 , 64 ] or by pigment clusters that are not neighbouring other complexes in the photosystem [ 65 ]. A detailed understanding of the fine control of the photodynamics by external influences on the light-harvesting complex, such as which occur during non-photochemical quenching, an important regulatory mechanism to dissipate excess energy in photosynthesis, is still missing. The role of vibration-assisted energy transfer and sampling of energy-transfer pathways may be clarified by single molecule coherent control experiments.

Recently, based on a series of experimental observations of magnetic field effects in the photosynthetic reaction centre, the direct role of the quantum-mechanical property of spin has been proposed in a quantum protective mechanism in photosynthesis [ 66 ]. Understanding regulatory and protective mechanisms in photosynthesis, as well as the resolution and control of these processes on time scales down to femtoseconds, has strong application in the investigation of crop failure under drought stress or conditions of high solar irradiation, as well as in the development of next-generation bioinspired solar cells.

A complementary way of accessing information about purely quantum-mechanical features in single molecules is to look for distinct quantum mechanical fingerprints, such as non-classical sub-Poissonian statistics in higher-order correlation functions or the statistics of some observable violating the Bell or Cauchy–Schwartz inequality. The non-classicality of initially thermalized vibrations has been shown to be induced via coherent exciton–vibration interactions and unambiguously indicated by negativities in the phase-space quasi-probability distribution of the effective collective mode coupled to the electronic dynamics, even with incoherent input of excitation. These results suggest that investigation of the non-classical properties of vibrational motions assisting excitation and charge transport, photoreception and chemical sensing processes could be a touchstone for revealing a role for non-trivial quantum phenomena in biology [ 52 , 67 ]. However, performing such investigations on the single molecule level is highly challenging due to the requirements for both ultrafast (femtosecond to nanosecond) time resolution and high photon counting rates.

4.1.4. Artificial photosynthesis

A claim from the field of quantum biology has been that developing a detailed understanding of photosynthesis on a microscopic scale, especially the primary stages thereof, will enable us to engineer biologically inspired artificial photosynthetic systems harnessing sunlight energy efficiently using Earth-abundant elements such as carbon, oxygen, nitrogen, etc. There have already been significant developments surrounding the design of such systems (e.g. [ 68 – 73 ]). A molecular approach to artificial photosynthesis is one among many contenders to convert solar energy into biofuel. Here, natural photosynthesis is investigated in order to extract design principles and then try to develop better photosystems based on these principles. A primary limitation of current systems is storage as well as the instability of their catalysts caused by an over-accumulation of charge. Counterbalancing of charge separation is essential, e.g. through coupled proton motion [ 74 ].

An important principle in quantum biologically inspired design is the presence of excitons: they are responsible for more efficient light absorption, faster energy funnelling (i.e. faster decay along the energy gradient), faster energy transfer and more efficient (irreversible) trapping of excitations by the reaction centre [ 75 ]. Moreover, their quantum behaviour is evident through their wave-like interference of different pathways and the way in which vibrational modes of the protein environment interact with the pigments (adding to the delocalization and extracting or absorbing vibrational energy) to facilitate the energy transfer in the complex.

Investigations of primary charge transfer in a prototypical artificial reaction centre have revealed correlated wave-like motion of electrons and nuclei on a time scale of a few tens of femtoseconds as a driving mechanism of the photoinduced current generation cycle [ 76 ]. It is important to include turnover in assessing such systems and not only efficiency. Resilient, stable systems are required for good turnover, which could perhaps be achieved via some kind of protective polymer wrapping around pigments [ 77 ]. For example, strategies for making artificial membrane-embedded proteins involving transmembranal BChl-binding protein maquettes have been investigated [ 78 ].

The challenges for the study of exciton transport in photosynthesis, including the disordered nature of the pigment networks, fluctuating exciton energy levels on similar time scales and coupled to exciton dynamics, also arise in other, non-biological settings. A specific example where insights and ideas that initially arose in quantum biology prove useful is in recent research into organic photovoltaics (PV). These are solar cells, made from a combination of two different man-made molecular semiconductors. The electron donor semiconductor is typically a polymer, while the acceptor is typically the fullerene derivative [6,6]-phenyl-C61-butyric acid methyl ester. Strongly bound Frenkel excitons are generated inside the device, which then diffuse until they reach an interface between donor and acceptor regions. The donor and acceptor have different chemical potentials, and this provides a driving force to dissociate excitons at the interface into free charges, which can then diffuse to opposite electrodes. However, since the Coulomb interaction is long-ranged, and organic materials have low dielectric constants, the electron and hole experience a binding energy 10 times deeper than k B T at room temperature, even after they have dissociated onto different molecules on either side of the interface. The overwhelming majority of devices consequently extract far fewer charges from the electrodes than are generated by the incoming light, leading to low power conversion efficiencies.

Yet in recent years, a small number of highly efficient devices have emerged, and near 100% charge extraction efficiencies have been reported [ 79 , 80 ]. A great amount of work has been done to identify the origin of efficient long-ranged charge separation in this subset. Experimental work has demonstrated that organic photovoltaics and photosynthesis share some striking coincidences. It was initially thought that charge separation at donor–acceptor interfaces would occur on picosecond to nanosecond time scales, which could be described by classical charge hops driven by thermal fluctuations. A number of experiments have observed that a substantial fraction of free charges are generated within just 100 femtoseconds of the exciton reaching an interface, just as femtosecond coherences and dynamics have been observed during photosynthetic exciton transport. Transport on such time scales is impossible to explain within classical Marcus ‘hopping’ models and the coherent transfer must explicitly be included [ 81 , 82 ].

Understanding these observations requires detailed modelling of charge transport near the donor–acceptor interface. Crucially, charges moving in organic semiconductors experience all three key properties of pigment–protein complexes listed above: high disorder, molecular fluctuations and reorganization. It is, therefore, perhaps not surprising that similar phenomena emerge. Theories of exciton transport in photosynthesis typically involve the interplay of partially delocalized states and noise-assisted transport, describing how transport through a network can be enhanced if the exciton or charge is coupled moderately strongly to molecular vibrational modes. It is increasingly the consensus view that partially delocalized states also arise in efficient organic photovoltaic systems, and it has also been argued that the charge separation process is enabled by noise within aggregated regions of the acceptor semiconductor. A number of theoretical groups working on organic photovoltaics now apply an open-quantum systems approach, using methods strongly influenced by early studies of photosynthetic light-harvesting complexes [ 83 – 86 ].

The potential for quantum biology to contribute to developing sustainable energy technologies is often claimed as a motivation for the field, and in particular for understanding quantum-coherent excitation energy transfer in photosynthetic systems. Progressing from this general claim to practical energy systems, however, requires more specific proposals for engineering quantum energy transfer into environmentally sustainable and economically scalable systems. Just as a foundational question in quantum biology itself asks how nanoscale phenomena can substantially affect macroscopic behaviour in an organism, the potential to exploit quantum-biological phenomena in engineered macroscopic energy systems depends on whether such phenomena can significantly influence system-scale operation under environmental and economic constraints. The development of existing renewable energy technologies such as silicon-based PV has taught that purely physical performance criteria such as energy-conversion efficiency are often less important than techno-economic performance measures such as life cycle analysis. Existing extremely efficient photovoltaic cells are too expensive for most practical applications and in some cases require elements with such low abundances that they would not be globally scalable even if affordable. Addressing these limitations has been a central concern in recent PV research, for example, through the development of organic PV materials.

Other global-scale considerations are important in assessing the potential of quantum biology in sustainable energy development. Globally, less than 20% of energy is consumed as electricity; almost all of the remaining 80% is consumed as fuel at final consumption. Although the share of energy consumed as electricity is steadily growing, fuel is likely to remain dominant within the time frame of tipping points in anthropogenic climate change and fossil-fuel depletion. There is, therefore, an urgent demand for renewable-fuel technologies such as engineered and/or artificial photosynthetic systems, rather than simply more efficient PV cells for electricity generation. Developing photosynthetic energy systems requires an integrated systems approach, with light-harvesting components being just one part of a complex (bio)physico-chemical system that should ideally be optimized for system-scale performance. The importance of quantum-dynamical effects in light harvesting within such a system can be fairly assessed only by balancing reductionistic analyses of subsystems against a holistic analysis of the overall system. Such considerations can help to focus the efforts of quantum-biology researchers whose main motivation is sustainable energy development. The key lesson is that an integrated systems approach is essential in order to relate global system-scale objectives to engineerable parameters across the spectrum of scales in the energy system, including at the nanoscale, where quantum-dynamical phenomena play an important role.

4.2. Enzyme catalysis

Enzymes are essential for cellular function through their catalysis of biochemical reactions that may have very low reaction rates otherwise. Understanding of the physical mechanism of the rate acceleration is a difficult topic of investigation. Transition-state theory has been used as the basis of explanations of enzyme catalysis, but recent theoretical and experimental developments have highlighted potential roles for quantum-mechanical tunnelling in enzyme-catalysed multiple-hydrogen transfer, and there has been a focus on depicting hydrogen transfer within a quantum-mechanical formalism [ 87 ]. Standard models for describing quantum tunnelling have been shown to explain experimental enzyme data, so long as one accounts for the fact that enzymes have many possible different structures [ 88 ]. Interesting and topical questions include whether local vibrational motions of the protein could provide the enzyme with catalytic advantage by coupling to the reaction coordinate and whether particular dynamical motions of the protein could have been selected to assist in the catalysis.

Enzymes often rely on the coupling of electrons and protons to control charge transport and catalysis [ 87 ]. In biological energy storage, the importance of proton translocation driven by electron transfer was first noted in 1961 [ 89 ], and since then, proton-coupled electron transfer mechanisms [ 90 ] have been shown to underlie amino acid radical generation and transport [ 91 ] along with the activation of most substrate bonds at enzyme-active sites [ 92 ].

Living systems are constantly updating internal processes based on information obtained from their sensing of the environment. Small changes in the environment can necessitate macroscopic changes in the functioning of the organism. There are proposals that several biological sensing mechanisms are so sensitive as to detect changes in the environment on a quantum level. These proposals are outlined in the subsections below.

5.1. Magnetoreception

The quantum theory of bird migration is not a new one. In its fourth decade since Schulten first proposed it [ 93 ], the radical pair mechanism is well established in both experimental and theoretical investigations of avian magnetoreception and is one of the main alternative (to photosynthesis) examples used as evidence for the field of quantum biology. The mechanism can be described in three steps ( figure 3 ). After an initial step where photoexcitation causes electron transfer and pair formation, the radical pair oscillates between singlet and triplet spin states before a final step of recombination and neural interpretation. It is the singlet–triplet mixing that experiences the influence of the Earth’s magnetic field and that has offered some way of explaining behavioural observations such as the light-dependence [ 94 ], inclination aspect [ 95 ] and resonance effects of the avian compass [ 96 , 97 ].

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The three steps of the radical pair mechanism. In the first step, a photon incident on the donor molecule causes one of the electrons of the pair to be donated to the acceptor to create the spatially separated but spin-correlated radical pair. In the second step, the radical pair oscillates between singlet and triplet states under the influence of the Zeeman and hyperfine effects. The third step is comprised of spin-dependent recombination into the chemical product.

The radical pair theory has given rise to numerous papers on compass coherence and entanglement and offers a convincing argument for compass behaviour (see [ 98 ] and references therein for a review of the subject). However, there remains some doubt as to whether the compass mechanism is truly a quantum phenomenon or can be described using a semi-classical framework. In response to this it has been suggested that the incredible accuracy of the compass is the result of avoided crossings of the spin energy levels of radicals formed in cryptochromes, a process that is genuinely quantum mechanical [ 99 ].

Progress has also been made in resolving the structure of the mechanism. Cryptochrome, the biological molecule proposed as the site of magnetoreception, is viable for various reasons. There is evidence that in plants, weak magnetic fields enhance cryptochrome responses [ 100 ]. That cryptochromes might mediate magnetic responses in animals has also been documented for the case of fruit flies [ 101 , 102 ]. It seems a logical next step to more complex living creatures, especially since four different types of cryptochrome have been confirmed in the eyes of migratory birds [ 103 ] and cryptochromes from the migratory garden warbler form radicals with millisecond lifetimes under the influence of the blue spectral range [ 104 ]. More recently, two studies have offered strong evidence for one of these four cryptochromes, Cry4, playing a role in the avian compass. Cry4 is expressed at a constant level rather than a cyclical pattern; this constancy is necessary for efficient navigation [ 105 ]. The double-cone localization of Cry4 as well as the fact that it is upregulated during the migration periods of migratory birds but not in chickens, is further confirmation that the molecule is viable as a magnetoreceptor [ 106 ].

The future of avian migration as a topic for quantum biology will then rely on a more detailed grasp of the spin dynamics of cryptochrome in an Earth-strength magnetic field and how this might explain some behavioural questions that have been posed, one of which is how to reconcile different observations of the disorienting effects of applied oscillating radiofrequency fields. Cryptochrome, among other things, is responsible for regulating circadian rhythms and closely resembles the DNA repair enzyme photolyase [ 107 , 108 ]. A better understanding of the interaction of cryptochrome with the Earth’s magnetic field could lead to further insight into other biological processes in more complex organisms which might display quantum effects.

5.2. Olfaction

Olfaction is the system by which living organisms ‘smell’ thousands of different molecules. How just several hundred different types of receptors that bind to odourants in humans, and several tens in fruit flies, result in such an amazingly sensitive molecular recognition system has remained a mystery. An intriguing theory, first proposed in 1928 [ 109 ], is that our sense of smell relies on the quantum-mechanical vibrational mode of the odourant molecule. In 1996, the theory was revived through the proposal that protein-coupled receptors are measuring molecular vibrations using inelastic electron tunnelling rather than responding to molecular keys fitting molecular locks, working by shape alone [ 110 ]. According to this theory, an electron will tunnel from a donor to acceptor site only when the energy difference between these sites is matched by the vibrational energy of the odourant. This vibrational theory of olfaction is reminiscent of phonon-assisted transport of excitons in photosynthesis, illustrating the fundamental role of quantized vibrations in quantum biology.

In support of the theory, experiments with fruit flies have indicated that shape and size of odourants are insufficient for detection. For example, the substitution with deuterium of hydrogen results in an odour change despite the fact that the two molecules have the same shape ( figure 4 ) [ 111 ]. Furthermore, molecules with similar vibrational frequencies have been observed to elicit similar reactions from fruit flies in spite of being unrelated chemically [ 111 ]. The physical viability and efficiency of the proposed mechanism using a simple but general theoretical model was shown in 2007 [ 112 ]. The next step is to engineer biologically inspired room-temperature molecular sensing devices.

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A schematic illustrating the possible role of quantum effects in olfaction. Where previously olfaction has been proposed to depend on the shape and size of odourants fitting a specific receptor, experiments with fruit flies have indicated that the substitution of hydrogen with deuterium results in an odour change in spite of their having the same shape. This suggests that vibrational frequency might play a role in the detection of odourants [ 111 ].

5.3. Cognition

The question of whether quantum physics could play a role in solving the yet unresolved body–mind problem of how the physiognomy of the brain accounts for conscious thinking is by no means new. Michael Lockwood’s Mind, body and the quantum from 1989 [ 113 ] or Henry Stapp’s 2009 Mindful universe [ 114 ] are examples of a number of monographs with a philosophical or popular science angle on the problem. A large amount of attention as well as criticism have also been levelled at the ideas of Roger Penrose and Stuart Hameroff, who proposed that parts of the cytoskeleton in neural cells, namely the microtubules, perform quantum computation based on what they call ‘orchestrated objective reduction’, a mechanism drawn from Penrose’s theory of ‘quantum gravity’ [ 115 ]. Another branch of science touches the question of the ‘quantum brain’ from a more pragmatic angle: quantum neural network research attempts to exploit quantum computation in order to improve artificial neural network models widely used in machine learning. These artificial neural network models are historically derived from the dynamics of biological neural nets [ 116 , 117 ], and are thus close to the question of the compatibility of quantum dynamics and neural computation. However, a crucial point has been made by Max Tegmark [ 118 ] who estimates decoherence time scales for ions involved in the propagation of action potentials to be 10 to 20 orders of magnitude smaller than relevant time scales of neural dynamics. In other words, quantum coherence of the ions involved in neural dynamics would be destroyed long before macroscopic dynamics could be influenced. A potential theory of quantum effects in biological neural networks would thus have to show how the macroscopic dynamics of biological neural nets can emerge from coherent dynamics on a much smaller scale. Promising research in this direction has been done by Matthew Fisher who has proposed that phosphorus can act as a neural qubit allowing quantum processing to occur in the brain, and that this quantumness is protected by so-called Posner molecules, which bind phosphate ions with calcium ions. Entangled Posner molecules then trigger non-local quantum correlations of neuron firing rates [ 119 ].

The study of anaesthetics leads to experimental roads to studying consciousness. So far, all we can say about consciousness is that it is ‘soluble in chloroform’ [ 120 ] and also in an array of molecules very different from one another. In a recent article on the study of consciousness [ 121 ] Turin and his co-workers discovered that a number of general anaesthetics reversibly increase the electron spin content in Drosophila , an effect absent from anaesthetic-resistant mutant flies. They propose that general anaesthetics change the structure of the highest occupied molecular orbital of certain molecules, facilitating electron transport between a donor and acceptor that puts the brain in an unconscious state. If this proves true, the changes in the structure of a molecule calculated by density functional theory, a tool from quantum theory, would have an impact on a macroscopic scale. Electron spin measurements have furthermore been crucial to observe the effects. Especially in a broader definition of quantum biology such findings are very encouraging and show the potential contribution the discipline could make.

6. Origins of life

The identification of quantum effects in primitive organisms such as bacteria has resulted in the successful application of open quantum systems models to energy and charge transfer processes in photosynthetic systems, as well as suggesting that quantum effects may have played an important role in the emergence of the very first living systems from the inanimate matter of which they are constituted.

The detection of the molecular precursors of life in interstellar ices suggests that the building blocks of life could possibly have emerged in space and been delivered to Earth by objects such as comets or meteorites. However, standard computational quantum chemistry cannot account for the variety and richness of chemistry occurring in the interstellar medium. For example, hydrogen cyanide (HCN) oligomers may have played a significant role in the synthesis of a wide range of prebiotic molecules [ 122 – 126 ], and recently, dimeric forms of HCN (cyanomethanimine) [ 127 ] have been detected in the interstellar medium. However, it has been found that interstellar gas-phase production routes are incapable of producing significant amounts of HCN [ 128 , 129 ], in spite of its detection.

The theoretical study of the spontaneous generation of prebiotic molecules in the interstellar medium is performed most fundamentally in the framework of open quantum systems. A low temperature interstellar icy environment strongly coupled to a simple molecular system such as HCN, and excited by incident UV radiation, can be investigated using appropriate well-known approximations from the field of quantum biology.

A much more difficult question is how the first living systems may have emerged from these prebiotic molecules, if at all. Despite remarkable work in viable DNA design [ 130 ], we have not yet been able to synthesize even a small functional peptide from basic components, and are still a long way from understanding exactly what distinguishes a collection of molecules from the collection of molecules that make up a living system, and what role quantum effects may have played in the origins of life.

7. Quantum biology and complexity

Complexity may be defined as the non-compressibility of the description of a system. If there is no basis set that simplifies the problem, the system is complex. Quantum features visible in macroscopic biosystems have to survive transition to high spectral densities. Chaotic fluctuations in the spectrum contain information about universal features of the dynamics of the system. The emerging field of quantum biology is concerned with interactions between dynamical phenomena at well-separated length and time scales, from femtosecond energy transfer processes in molecular assemblies at the nanoscale to survival and reproduction within ecosystems at the scales of overall organisms.

It is important to note that nature cannot select against the quantum-mechanical nature of chemistry. For example, it is not possible to design a plant with a light-harvesting complex that consists of compounds that defy quantum mechanical description. Biology describes systems that are evolutionarily selected for at the scales of entire organisms. The results of selection are mediated through genetic processes that can affect biological subsystems only down to a certain scale, and the physical details of what happens below that scale are immune to biological selection. Quantum biology then concerns whether or not quantum-dynamical processes that can be selected for—at the scales of proteins, for example—can affect macroscopic organismal dynamics. That is, if quantum behaviour at the nanoscale is to convey a selective advantage, it must be selectable and this selection takes place at the scale of the overall organism. We might claim, therefore, that only subsystems that can exist in quantum and classical variants are of interest, since one or the other can be selected by evolution. This trivializes the claim that all biology is quantum biology because it depends on chemistry and all chemistry is quantum at atomic and molecular scales; thus it is impossible for evolution to select anything other than quantum subsystems here. Precisely what range of length and time scales can be inhabited by subsystems of interest to quantum biology (because they could conceivably exist in quantum and classical variants) is an open question. The issue of scaling will prove important to the further progress of quantum biology [ 131 ].

8. Discussion and conclusion

The first book on quantum biology is entitled Physics of the mystery of organic molecules by Pascual Jordan [ 132 ]. Since its publication in 1932, however, many mysteries about the nature of life remain. It is clear that coarse-grained classical models fail to give an accurate picture of a range of processes taking place in living systems. The matter of ongoing debate then, is the extent to which quantum effects play a non-trivial role in such biological processes.

A useful path towards answering this question is through the engineering of biologically inspired quantum technologies that can outperform classical devices designed for the same purpose, for example, for energy harnessing or environmental sensing. If quantum effects on a macroscopic scale play a role in getting the job done better in certain processes perfected over billions of years at physiological temperatures and in immensely complex systems, then there exists a wealth of information in the biological world from which to draw inspiration for our own technologies.

In this direction, a prototype quantum heat engine, which clearly illustrates a quantum design principle whereby a coherent exchange of single energy quanta between electronic and vibrational degrees of freedom can enhance a light-harvesting system’s power above what is possible by thermal mechanisms alone, has been proposed. Its quantum advantage using thermodynamic measures of performance has been quantified, and the principle’s applicability for realistic biological structures demonstrated [ 133 ].

Quantum biology investigates biological function and regulation of this function, which is connected to static disorder. Single molecule spectroscopy gives us a unique, powerful lens on the role of static disorder, which connects biological function (i.e. projected onto the macroscopic/organismal scale) with quantum-mechanical phenomena. Quantum biology is also concerned with interactions between dynamical phenomena at well-separated length and time scales, from femtosecond energy transfer processes in molecular assemblies at the nanoscale to survival and reproduction within ecosystems at the scales of overall organisms.

While quantum biology is set to demonstrate in the next few decades the extent to which bioinspired quantum devices can outperform classical analogues, a deeper question is how quantum-dynamical phenomena at the nanoscale can provide a selective advantage to an overall organism. Addressing this question rigorously demands an account of how macroscale physical observables significant to organismal fitness can depend predictably on nanoscale quantum dynamical variables. Reciprocally, we must also account for how quantum subsystems at the nanoscale can depend on macroscale dynamics of organisms through evolution. Progress on this question may be assisted by a theoretical framework that allows organism-scale models to be parametrized by nanoscale models. This may be provided by the tools of multiscale analysis within the field of complex systems theory. We might also conceive of experiments in which wild-type organisms known to exhibit long-lived quantum-coherent processes at the nanoscale compete with genetically modified organisms in which such processes are known to be absent. Such an experiment—akin to those done regularly by biologists—may offer clear insight into whether quantum-biological phenomena can provide a selective advantage to organisms, as well add credibility to quantum biology as a field of biology.

Acknowledgements

We thank Andreas Buchleitner, Nathan Killoran, Alexandra Olaya-Castro, Bruno Robert, Elisabet Romero, Greg Scholes and Luca Turin for fruitful discussions at the Future of Quantum Biology Workshop in South Africa in December 2014.

Data accessibility

Authors' contributions.

F.P. and R.v.G. conceived the study. All authors discussed the results and wrote the manuscript.

Competing interests

We declare we have no competing interests.

A.M., B.A., I.S. and F.P. were supported by the South African Research Chair Initiative of the Department of Science and Technology and the National Research Foundation. M.F., J.M.G., R.H. and R.v.G were supported by the VU University Amsterdam, TOP grant no. 700.58.305 from the Foundation of Chemical Sciences part of NWO, and the advanced investigator grant no. 267333, PHOTPROT from the European Research Council. R.v.G. was additionally supported by the Royal Dutch Academy of Sciences (KNAW). S.L.S. acknowledges funding from the Winton Programme for the Physics of Sustainability. A.K.R. was funded by the ARC Centre of Excellence for Engineered Quantum Systems. T.P.J.K. was supported by the University of Pretoria’s Research Development Programme.

ScienceDaily

Bullseye! Accurately centering quantum dots within photonic chips

Traceable microscopy could improve the reliability of quantum information technologies, biological imaging, and more.

Traceable microscopy could improve the reliability of quantum information technologies, biological imaging, and more.

Devices that capture the brilliant light from millions of quantum dots, including chip-scale lasers and optical amplifiers, have made the transition from laboratory experiments to commercial products. But newer types of quantum-dot devices have been slower to come to market because they require extraordinarily accurate alignment between individual dots and the miniature optics that extract and guide the emitted radiation.

Researchers at the National Institute of Standards and Technology (NIST) and their colleagues have now developed standards and calibrations for optical microscopes that allow quantum dots to be aligned with the center of a photonic component to within an error of 10 to 20 nanometers (about one-thousandth the thickness of a sheet of paper). Such alignment is critical for chip-scale devices that employ the radiation emitted by quantum dots to store and transmit quantum information.

For the first time, the NIST researchers achieved this level of accuracy across the entire image from an optical microscope, enabling them to correct the positions of many individual quantum dots. A model developed by the researchers predicts that if microscopes are calibrated using the new standards, then the number of high-performance devices could increase by as much as a hundred-fold.

That new ability could enable quantum information technologies that are slowly emerging from research laboratories to be more reliably studied and efficiently developed into commercial products.

In developing their method, Craig Copeland, Samuel Stavis, and their collaborators, including colleagues from the Joint Quantum Institute (JQI), a research partnership between NIST and the University of Maryland, created standards and calibrations that were traceable to the International System of Units (SI) for optical microscopes used to guide the alignment of quantum dots.

"The seemingly simple idea of finding a quantum dot and placing a photonic component on it turns out to be a tricky measurement problem," Copeland said.

In a typical measurement, errors begin to accumulate as researchers use an optical microscope to find the location of individual quantum dots, which reside at random locations on the surface of a semiconductor material. If researchers ignore the shrinkage of semiconductor materials at the ultracold temperatures at which quantum dots operate, the errors grow larger. Further complicating matters, these measurement errors are compounded by inaccuracies in the fabrication process that researchers use to make their calibration standards, which also affects the placement of the photonic components.

The NIST method, which the researchers described in an article posted online in Optica Quantum on March 18, identifies and corrects such errors, which were previously overlooked.

The NIST team created two types of traceable standards to calibrate optical microscopes -- first at room temperature to analyze the fabrication process, and then at cryogenic temperatures to measure the location of quantum dots. Building on their previous work, the room-temperature standard consisted of an array of nanoscale holes spaced a set distance apart in a metal film.

The researchers then measured the actual positions of the holes with an atomic force microscope, ensuring that the positions were traceable to the SI. By comparing the apparent positions of the holes as viewed by the optical microscope with the actual positions, the researchers assessed errors from magnification calibration and image distortion of the optical microscope. The calibrated optical microscope could then be used to rapidly measure other standards that the researchers fabricated, enabling a statistical analysis of the accuracy and variability of the process.

"Good statistics are essential to every link in a traceability chain," said NIST researcher Adam Pintar, a coauthor of the article.

Extending their method to low temperatures, the research team calibrated an ultracold optical microscope for imaging quantum dots. To perform this calibration, the team created a new microscopy standard -- an array of pillars fabricated on a silicon wafer. The scientists worked with silicon because the shrinkage of the material at low temperatures has been accurately measured.

The researchers discovered several pitfalls in calibrating the magnification of cryogenic optical microscopes, which tend to have worse image distortion than microscopes operating at room temperature. These optical imperfections bend the images of straight lines into gnarled curves that the calibration effectively straightens out. If uncorrected, the image distortion causes large errors in determining the position of quantum dots and in aligning the dots within targets, waveguides, or other light-controlling devices.

"These errors have likely prevented researchers from fabricating devices that perform as predicted," said NIST researcher Marcelo Davanco, a coauthor of the article.

The researchers developed a detailed model of the measurement and fabrication errors in integrating quantum dots with chip-scale photonic components. They studied how these errors limit the ability of quantum-dot devices to perform as designed, finding the potential for a hundred-fold improvement.

"A researcher might be happy if one out of a hundred devices works for their first experiment, but a manufacturer might need ninety-nine out of a hundred devices to work," Stavis noted. "Our work is a leap ahead in this lab-to-fab transition."

Beyond quantum-dot devices, traceable standards and calibrations under development at NIST may improve accuracy and reliability in other demanding applications of optical microscopy, such as imaging brain cells and mapping neural connections. For these endeavors, researchers also seek to determine accurate positions of the objects under study across an entire microscope image. In addition, scientists may need to coordinate position data from different instruments at different temperatures, as is true for quantum-dot devices.

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  • Craig R. Copeland, Adam L. Pintar, Ronald G. Dixson, Ashish Chanana, Kartik Srinivasan, Daron A. Westly, B. Robert Ilic, Marcelo I. Davanco, Samuel M. Stavis. Traceable localization enables accurate integration of quantum emitters and photonic structures with high yield . Optica Quantum , 2024; 2 (2): 72 DOI: 10.1364/OPTICAQ.502464

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  • Review Article
  • Published: 03 February 2023

Quantum sensors for biomedical applications

  • Nabeel Aslam 1 , 2 , 3 ,
  • Hengyun Zhou 1 ,
  • Elana K. Urbach 1 ,
  • Matthew J. Turner 4 , 5 ,
  • Ronald L. Walsworth 4 , 5 , 6 ,
  • Mikhail D. Lukin 1 &
  • Hongkun Park   ORCID: orcid.org/0000-0001-9576-8829 1 , 2  

Nature Reviews Physics volume  5 ,  pages 157–169 ( 2023 ) Cite this article

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  • Confocal microscopy
  • Imaging and sensing
  • Nanosensors
  • Quantum metrology
  • Solution-state NMR

Quantum sensors are finding their way from laboratories to the real world, as witnessed by the increasing number of start-ups in this field. The atomic length scale of quantum sensors and their coherence properties enable unprecedented spatial resolution and sensitivity. Biomedical applications could benefit from these quantum technologies, but it is often difficult to evaluate the potential impact of the techniques. This Review sheds light on these questions, presenting the status of quantum sensing applications and discussing their path towards commercialization. The focus is on two promising quantum sensing platforms: optically pumped atomic magnetometers, and nitrogen–vacancy centres in diamond. The broad spectrum of biomedical applications is highlighted by four case studies ranging from brain imaging to single-cell spectroscopy.

Quantum sensors can detect magnetic fields and other physical quantities, with unprecedented spatial resolution and sensitivity, making them highly interesting for biomedical applications.

Optically pumped magnetometers offer new functionalities in clinical magnetoencephalography, with their wearable sensor helmet allowing the subject to perform tasks and move during the recording of brain activity.

Nitrogen–vacancy (NV)-centre-based magnetometry of single neurons and magnetic biomarkers, with subcellular resolution, opens new avenues in studying neuronal circuits and in rapid clinical testing.

Nuclear magnetic resonance based on NV centres in diamond enables microscale and nanoscale detection of single molecules and single cells, which could be applied in structure determination of transmembrane proteins and in metabolomics studies.

Nanodiamonds containing NV centres can locally probe temperature-dependent biological processes in cells and small organisms, such as cell development and endogenous heat generation.

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Introduction

Advances in biomedical sciences are often spurred by the development of tools with enhanced sensitivity and resolution, which allow detection and imaging of signals that are progressively weaker, more localized and/or biologically specific. Improvements in nuclear magnetic resonance (NMR) or magnetoencephalography (MEG) have resulted in tremendous progress in diagnostics and treatment, yet further progress in sensitivity and resolution seems to be challenging with conventional methods. However, a promising direction for a new generation of biomedical sensors with greatly enhanced performance comes from advances in quantum science and technology.

Control and measurement of individual quantum systems, which seemed impossible only a few decades ago, is now a reality in many laboratories worldwide. This achievement has generated much excitement in both academia and industry. Quantum computation and quantum communication have garnered great attention 1 , 2 , 3 , but quantum sensing, another pillar of quantum technology, is also advancing rapidly. One advantage of quantum sensors is the improvement in sensitivity that stems from quantum effects. Some quantum sensors are as small as a single atom and can consequently yield unmatched spatial resolution. These new capabilities could lead to a true ‘quantum leap’ in biomedical applications. First attempts have already been made, in the form of quantum-sensor-based brain imaging 4 and NMR at the scale of individual proteins and cells 5 , 6 . This is an exciting time for quantum sensing as it transitions from academic laboratories to commercial applications.

The focus of this Review is on two promising quantum platforms as exemplars of quantum sensors in biomedical applications: optically pumped magnetometers (OPMs) and magnetometry based on nitrogen–vacancy (NV) centres in diamond. An overview of the potential applications on the molecular, cellular and organism levels is given in Fig.  1 . We present four case studies, chosen among the many directions that are being actively explored. The first is MEG based on OPMs, with an emphasis on its advantages over conventional MEG based on superconducting quantum interference devices (SQUIDs). The second case study discusses how diamond sensor chips with an ensemble of NV centres can be used for magnetic sensing and microscopy of biological cells and tissue. The third is dedicated to NV-diamond sensing applied to nanoscale and microscale NMR imaging and spectroscopy. The final case study will discuss nanoscale thermometry with NV centres in nanodiamonds. For discussion of the principles of quantum sensing, we refer readers to other reviews 7 , 8 , 9 , 10 .

figure 1

Nitrogen–vacancy (NV) centres in diamond are suited for structure determination of single molecules. On the cellular scale, NV centres could help study metabolism and probe electrical activity of neurons. Such quantum sensors can also be integrated into nanodiamonds and serve as in vivo nanoscale temperature sensors. Detection of biomagnetic signal from animals and humans is another promising application of quantum sensors. In this regard, optically pumped magnetometers (OPM) are well suited due to their high magnetic field sensitivity.

What are quantum sensors?

Quantum sensors are individual systems or ensembles of systems that use quantum coherence, interference and entanglement to determine physical quantities of interest 7 . In what follows, we do not limit the discussion to entanglement-enhanced sensing, although there have been numerous early demonstrations of such capabilities in the field.

Quantum sensors have been realized in multiple systems with very different operating principles. This diversity makes them each suitable for different applications and allows them to be used in complementary ways. In the following, we give a brief overview of the most prominent examples of quantum sensors.

Superconducting circuits

One of the earliest quantum sensors is the SQUID. Based on superconducting Josephson junctions, SQUIDs can measure magnetic fields with sensitivities reaching 10 aT  Hz −1/2 in controlled laboratory settings 11 . Many SQUID sensors are commercially available and are, for example, applied in MEG, where they detect magnetic signals from the brain. However, SQUIDs require cryogenic operation, which necessitates bulky set-ups and limits the achievable spatial resolution for real-world applications.

Atomic ensembles

Alkali atom ensembles in vapour cells can be spin-polarized, and their magnetic field coupling can be probed through optical means (Fig.  2a ). Besides the absorption-based approach described in Fig.  2a , magnetic field detection can also be achieved by measuring d.c. and a.c. polarization rotation of the probe light 8 . These OPMs can achieve minute-long coherence times 12 and magnetic field sensitivities of 100 aT Hz −1/2 in the laboratory 13 . Spin-exchange relaxation-free OPMs are operated at elevated temperatures of 100 °C and near-zero magnetic field. The high temperature requires insulation from target samples, and the requirement for near-zero magnetic field necessitates additional coils to cancel out environmental magnetic fields. OPM cells have been miniaturized down to the millimetre scale, but with degradation in sensitivity, ultimately limiting the spatial resolution for a given sensitivity 14 . Entanglement-enhanced sensing has also been demonstrated with OPMs 15 , 16 . The combination of these properties has enabled OPM application in NMR 17 , MEG 4 , magnetocardiography (MCG) 18 and magnetic induction tomography 19 , 20 .

figure 2

a , In an OPM, rubidium atoms (as an example out of the various alkali atoms being used) in a glass cell are optically spin-polarized. In zero magnetic field, the transmission of a probe laser is at its maximum (left). The presence of a magnetic field leads to Larmor precession of the spins, which reduces transmission of the probe laser (right). b , The NV centre in the diamond lattice has its spin state initialized and interrogated via green excitation light, microwave (MW) resonant fields and red fluorescence, in the presence of magnetic fields ( B ). c , Optically detected magnetic resonance (ODMR) spectrum of the NV centre at zero field (left) and at B  = 1.2 mT (right), where  γ is the electron gyromagnetic ratio and |0 ⟩ , |±1 ⟩ stand for the electron spin states m s  = 0, ±1, respectively. Part a adapted with permission from ref. 4 , Springer Nature Ltd.

Solid-state spins

Electronic spin defects in semiconductors can also be used for quantum sensing. Diamond stands out as a special host material for optically addressable defects, owing to its large bandgap. Most notably, the NV colour centre in diamond has been widely studied as a quantum sensor 21 , 22 . Optical initialization and readout of the spin state has been demonstrated down to the single-NV level 23 (Fig.  2b ). Owing to low spin–orbit coupling, the NV’s ground-state spin can reach coherence times of ~1 ms under ambient conditions 24 . NV centres have been shown to function over large ranges of temperature (4 K to 625 K) 25 , magnetic field (up to 8.3 T) 26 and pressure (up to 13.6 GPa) 27 . These properties make the NV and other colour centres in diamond 28 attractive not only for quantum sensing but also for quantum information processing 29 and quantum communication 3 . For magnetometry, the photon shot-noise-limited sensitivity can be enhanced by a factor of 1/ \(\sqrt{N}\) by using an ensemble of N NV centres, with an experimentally achieved sensitivity of ~1 pT Hz −1/2 (ref. 30 ). In addition, NV centres can be used as a sensor for temperature 31 , electric fields 32 and pressure 27 .

NV centres exhibit a sensing bandwidth ranging from d.c. to gigahertz frequencies 33 . In wide-field imaging applications using NV ensembles, the spatial resolution is typically set by the diffraction limit of the optical microscope. However, by combining NVs with scanning techniques, such as atomic force microscopy, the spatial resolution can be improved to the few-nanometre level, mainly limited by the NV-to-surface distance 34 . It is also possible to create nanodiamonds containing NV centres, which can be functionalized and serve as local probes 31 . Other defects in diamond (such as silicon vacancy centres 28 ) and defects in different host materials (such as silicon carbide 35 or yttrium orthosilicate 36 ) are being actively investigated as quantum sensors. As yet, they do not show sensitivities comparable to the NV centres, owing to their limited coherence properties.

In this Review, we highlight biomedical applications of OPMs and diamond NV centres as an illustration of the broad operating regimes that quantum sensors can cover. The OPMs and NV centres have complementary strengths and weaknesses. The high sensitivity of OPMs makes them suitable for macroscopic detection of weak magnetic fields, such as those generated by the brain or the heart. Conversely, a major advantage of NV centres is the short sensor-to-sample distance, allowing high spatial resolution and high sensitivity to weak, microscopic signals. In addition, the NV centre is a multifunctional sensor (detecting a.c. and d.c. magnetic fields, temperature and so on) and operates under a wide range of conditions. This multifunctionality makes it attractive for spectroscopy and diagnostics on the cellular level.

OPM-based MEG

Monitoring and imaging biomagnetism from the human body is useful for diagnostic and treatment purposes 37 . For example, the brain produces magnetic fields through the flow of electric currents in neurons. These fields are detected by MEG and can be used to study brain injury 38 and brain disorders such as epilepsy 39 and dementia 40 .

Conventional MEG, as first demonstrated in the early 1970s, is based on SQUID sensors 41 , 42 and exhibits a noise level of fT Hz −1/2 . Despite considerable commercial and clinical adoption, the demanding operation conditions of MEG still pose severe limitations. For example, SQUID operation requires cryogenic temperatures, which makes the sensor array bulky (weighing over 400 kg for the helmet that holds the sensor array) and increases the sensor-to-subject distance. This distance not only limits signal-to-noise ratio and spatial resolution but also makes it infeasible for the subject to move during the recording. Moreover, the fixed MEG helmet’s size complicates brain imaging because the subject’s head profile can vary significantly, especially in the case of children.

The emergence of quantum sensing techniques has opened new avenues to tackle these limitations. Most promising are commercially available OPMs that can achieve sensitivities of ~10 fT Hz −1/2 (ref. 43 ), comparable to clinical SQUID devices. OPMs do not require low temperatures, thus simplifying the sensor architecture and allowing short sensor-to-sample distances. Another benefit of OPMs is their ability to detect vector magnetic fields 44 , 45 , 46 , whereas SQUIDs only measure the magnetic field component radial to the scalp surface. Such triaxial detection results in an overall higher signal strength and helps differentiate signal and background fields. Furthermore, progress in miniaturization of OPMs has enabled prototype OPM-MEGs to be built 4 (Fig.  3a ), paving the way towards real-world applications.

figure 3

a , Prototype wearable OPM-MEG. The subject can move their head during the measurement, as exemplified by the subject bouncing a tennis ball off a bat. b , Beta band oscillations recorded as a frequency spectrogram (left) and amplitude (right) during ball game and rest. c , Flexible wearable OPM-MEG helmet with 63 sensor mounts. d , SQUID-MEG (top) and OPM-MEG (bottom) recording of 11-year-old patient with refractory focal epilepsy. Left: superimposed data of multiple sensors showing filtered background brain activity and interictal epileptiform discharges (IEDs). Right: averaged IED data and magnetic field topography at the spike peak. e , OPM-magnetocardiography (MCG) measured at ambient conditions with a 87 Rb magnetic gradiometer. Parts a , b adapted with permission from ref. 4 , Springer Nature Ltd. Part c adapted with permission from ref. 149 under a Creative Commons licence CC BY 4.0 . Part d adapted with permission from ref. 53 , RSNA. Part e adapted with permission from ref. 51 , APS.

To detect the weak magnetic signal originating from the brain, it is crucial to suppress much stronger magnetic-field backgrounds. Such suppression is achieved through magnetic shielding and fast field compensation with electromagnetic coils 47 , 48 , 49 , 50 . This approach, combined with the light weight (about 1 kg) of an OPM-MEG helmet, has enabled head movement up to 10 cm during human MEG recording 4 . It also allowed the subject to bounce a ball off a bat or to rotate their head while a MEG signal was recorded 4 (Fig.  3b ). MEG detection has also been demonstrated at ambient conditions without magnetic shielding by combining two OPM magnetometers into a first-order gradiometer 51 .

Another key advantage of OPMs not needing cryogenics is that the MEG helmet can be made to fit any head size (Fig.  3c ). This possibility is especially helpful for neuroimaging of infants and enables long-term studies as the infants grow 52 . Subjects who are intimidated by the bulky SQUID-based MEG helmet, and others who cannot stay still during the imaging procedure, could also get access to MEG scans.

OPM-based MEGs are increasingly finding clinical application. OPMs have been applied to detect and localize focal interictal spikes in children with epilepsy 53 (Fig.  3d ). For many neuroscientific studies it is also important to detect signal from deeper within the brain. One example is the human hippocampus, which is crucial for navigation and has been studied with OPM-based MEGs 54 , 55 . Another proof-of-concept demonstration has been the detection of functional connectivity with a 50-channel OPM 56 , paving the way for studies of brain networks. Moreover, OPMs have successfully been used to measure human retinal activity 57 ; the use of OPMs is contactless, in contrast to the fibre electrodes currently used. Another exciting demonstration of OPM-MEG has been the detection of human visual gamma-band activity in the brain 58 . These high-frequency oscillations are assumed to play an important role in cognitive functions. The high spatial resolution of OPMs aids the localization of the active source areas, which is challenging with currently used techniques 58 . OPMs will also enable new possibilities in functional neuroimaging. For example, neuroscientists can now monitor brain activity while the subject moves and performs tasks of interest 4 . One can even envisage combining OPM-MEG with virtual-reality devices 59 .

OPM-MEG is a relatively new technique, and further improvements are required before it can achieve widespread use in hospitals. Currently, the noise floor measured with OPMs is higher than SQUIDs by a factor of three, negating the sensitivity increase coming from smaller sensor-to-sample distance. So far, <100 OPM sensors have been combined into an array for MEG measurements 60 ( https://www.cercamagnetics.com/cerca-opm-meg ), in contrast to typical SQUID-MEG arrays of ~300 sensors. Scaling up the OPM sensor array, to provide comparable or superior resolution to SQUID-based MEG, will require the suppression of crosstalk between individual OPMs. The OPM community is working on these challenges and moving towards commercialization.

Another notable application of OPMs is MCG 18 , 51 (Fig.  3e ). In this case, the measurement of magnetic fields from the heart allows diagnosis of diverse heart conditions associated with electrically active cardiac cells. The main advantages of OPM-MCG, relative to SQUID-based detectors, are its portability, low cost, and electrode-free application 61 . Some commercial OPM-MCG devices are already available ( https://genetesis.com ).

NV-based magnetic sensing and imaging of cells and tissues

Individual cells and tissues can produce magnetic fields, as exemplified by the fields produced by neuronal action potentials or by chains of magnetic nanoparticles (magnetosomes) in bacteria. Magnetic tags can also be introduced into living systems, in the form of magnetic nanoparticles (MNPs) or spin labels, for example. In all these cases, a biocompatible magnetometer with high sensitivity and high spatial resolution is required to measure the fields. One common method for such investigations uses a millimetre-scale diamond chip with a thin surface layer (micrometre scale) of ensemble NV centres 62 . Another commonly used modality is nanodiamonds containing NV centres, which can be injected or ingested into cells or tissues and functionalized, to target proteins of interest, for example.

Magnetic nanoparticle imaging

Labelling, detecting and targeting individual cells is useful for diagnostic applications, such as distinguishing cancer cells from healthy cells. Fluorescent markers are commonly used as labels, but often suffer from blinking, photobleaching and background autofluorescence. MNPs form the basis of magnetic immunoassay techniques, an emerging complementary diagnostic modality with potential advantages over fluorescent markers: long-term stability, negligible background signal and quantitative detection.

Diamond NV centres have been used for quantitative detection and wide-field imaging of MNPs in diverse biological samples, with micrometre-scale resolution and a millimetre field of view. In an early demonstration, NV-based magnetic microscopy was used to resolve and quantitatively characterize chains of MNPs (magnetosomes) that occur naturally in magnetotactic bacteria 62 . NV-based magnetic microscopy was also used to detect cancer biomarkers 63 (Fig.  4a , b ). In this study, SKBR3 cancer cells were labelled with HER2-specific MNPs (where HER2 is human epidermal growth factor receptor 2), allowing differentiation between healthy and cancer cells. The technique is now commercially available for diagnostic assessment of biomarkers in human blood and other samples ( https://qdti.com/ ). In another demonstration, NV-diamond magnetic microscopy was used to investigate malarial haemozoin nanocrystals, which serve as biomarkers for malaria 64 (Fig.  4c ). These nanocrystals are formed in human blood cells infected by Plasmodium falciparum . In this study, the paramagnetic nature of the haemozoin nanocrystals was confirmed, and a magnetic susceptibility of 3.4 × 10 –4 was measured, opening a possibility of drug screening against cells infected by Plasmodium .

figure 4

a , Wide-field NV-diamond microscope for magnetic imaging of cells. sCMOS, scientific complementary metal–oxide–semiconductor. b , Wide-field imaging of biomarkers. Left: bright-field image overlayed with fluorescence image of SKBR3 cancer cells labelled with magnetic nanoparticles (MNPs) and stained with fluorescence dyes. Right: same field of view showing NV magnetic imaging of MNP-labelled cells. Scale bar, 100 µm. c , Magnetic field image of natural haemozoin crystals acquired with a NV-diamond microscope. Field of view is 39 × 39 µm². d , Top: image of NV-diamond set-up for single-neuron action potential (AP) magnetic measurement of a living specimen of Myxicola infundibulum (worm). Bottom: time trace of the magnetic field signal coming from a single-neuron action potential of M. infundibulum detected with the NV-diamond set-up. Part a adapted with permission from ref. 62 , Springer Nature Ltd. Part b adapted with permission from ref. 63 , Springer Nature Ltd. Part c adapted with permission from ref. 64  under a Creative Commons licence CC BY 4.0 . Part d adapted with permission from ref. 66 , PNAS.

In another demonstration, NV-based magnetic microscopy was applied to detect concentrations of magnetically labelled protein, interleukin-6 65 , from patients hospitalized with COVID-19. Interleukin-6 is an endogenous cytokine associated with various diseases, such as severe COVID-19. The key idea was to detect the concentration of magnetic beads in the sample, and the results correlated well with the well-established Luminex assay technique. This success demonstrates the potential of NV-based microscopy for applications including rapid clinical testing.

Single-neuron action potential measurement

MEG is a powerful tool to investigate brain activity on macroscopic scales by interpreting effective current dipole sources in vivo. It would be desirable to understand how these effective current dipoles are related to underlying neuronal circuits. Such studies require minimally invasive magnetic measurements, ranging from single cells at the microscale to full neuronal circuits at the millimetre scale. NV-based microscopy has been used for a proof-of-concept measurement towards that direction. In this study, shallowly implanted diamond NV centres were used to measure the action potentials of single neurons from marine worms and squid 66 (Fig.  4d ). The study achieved a magnetic field sensitivity of ~10 pT Hz −1/2 . Importantly, the submillisecond time resolution of the technique allowed the direct measurement of the action potential waveforms, including the direction of action potential propagation along the neuron and detection in whole, live animals. These studies at both the single-neuron and neuronal-circuit levels would improve and validate assumptions used in MEG for current dipole source reconstruction and could potentially improve the resolution of MEG as a result.

Detection of spin labels with T1 relaxometry

The measurement of the longitudinal relaxation time (T1) of NVs is sensitive to magnetic noise at the NV spin-transition frequency, from megahertz to the gigahertz regime. This method can be applied to enable highly sensitive detection of magnetic ions such as Gd 3+ , the most common contrast agent used in magnetic resonance 67 . NV centres are allowing studies with these contrast agents down to the scale of individual cells, such as the detection and imaging of the plasma membrane of a HeLa cell labelled with Gd 3+ ions, with a spatial resolution of 400 nm (ref. 68 ). The resolution of NV T1 relaxometry can be further improved with a NV scanning probe set-up, as demonstrated by a spatial resolution of 10 nm for intracellular ferritin in Hep G2 cells 69 .

Biomagnetic sensing with nanodiamonds

Bringing very small biological samples (such as organelles within cells) close to the NV centres located in a macroscopic diamond chip can be challenging. Nanodiamonds containing NV centres are being investigated as an alternative approach for such applications. Nanodiamonds can be inserted into the interior of cells, tissue and other biological samples. Functionalization of the nanodiamond surface can also enable targeting to proteins or other biological targets of interest. As the NV axis is randomly oriented for nanodiamonds, it is difficult to perform sensitive NV magnetometry using coherent techniques such as optically detected magnetic resonance (ODMR). However, NV T1 relaxometry can still be used, thus allowing the detection of metalloproteins 70 , Gd 3+ spin-labelled lipid bilayers 71 and the rotational Brownian motion of spin-labelled molecules 72 .

A further application of T1 relaxometry with NV centres in nanodiamonds is the nanoscale detection of free radicals in biological samples. Formation of free radicals is linked to cardiovascular diseases and neurological disorder 73 . Free radicals can also play a vital role for the immune system 74 . Their sensitive detection with subcellular spatial resolution can therefore have far-reaching consequences in understanding biological processes. T1 relaxometry with NV centres in nanodiamonds makes such detection possible and has recently been used to study free radicals in single mitochondria 75 and in human dentritic cells 76 . In these experiments, the challenge is to carefully analyse the effect of free radicals on the T1 of the NV and rule out other influences. Another promising nanodiamond application is in vivo thermometry, which is discussed below.

Challenges and outlook

A key challenge for NV-based magnetic sensing and imaging of cells and tissues is to improve the sensitivity, which can lead to faster measurements and enable real-time mapping of neuronal activity and real-time functional imaging of biological samples, for example. Here we discuss some key opportunities for improved sensitivity 9 : improved readout techniques, which includes increasing the readout fidelity and minimizing the NV spin-state initialization and readout times; improved sample quality, which includes increasing the number of sensor spins per unit diamond sensing volume and extending the dephasing time; and improved measurement protocols, such as double quantum magnetometry 77 .

Techniques to improve readout fidelity include spin-to-charge conversion 78 , repetitive readout using nuclear spins coupled to the NV as quantum memories 79 , and enhanced photon collection through various forms of diamond fabrication, tailored lenses or light guides 80 . Although these techniques have been highly successful for single NV measurements, more work is required for their adaptation to large-scale diamond chips with NV ensembles.

On the material side, high-density NV ensembles have typically been grown with high-pressure, high-temperature methods. More recently, high-quality chemical vapour deposition (CVD) samples have been prepared, including growth of thin nitrogen layers on relatively nitrogen-free substrates. To maximize NV creation in such layers, vacancy creation via electron irradiation is typically performed, resulting in NV ensembles with densities up to 4 ppm (ref. 81 ). Unfortunately, the CVD growth process for high NV densities typically introduces additional paramagnetic defects and strain, affecting the coherence time of the sensor. Methods to mitigate these effects are being developed 82 , 83 . For NV centres within a few tens of nanometres of the diamond surface, surface-related charge instabilities and noise further degrade NV properties. Approaches to address this problem are actively being explored, including careful surface cleaning and termination 84 , and delta doping of NVs, in which NVs are created in a thin surface layer and an additional diamond layer is then overgrown 85 . Another challenge in biomedical applications is reproducibility of results. To meet this challenge, it will be important to develop recipes to clean the diamond surface and maintain the coherence properties of the shallow NV centres in multiple rounds of experiments.

Nano- and microscale NMR with NV centres

NMR is a spectroscopic tool widely used in chemistry, biology and medicine for the structural determination of organic and biological molecules 86 . The technique usually relies on the detection of thermally polarized nuclear spins; to do so, large magnetic fields of the order of several tesla need to be applied 87 , 88 . A major limitation of traditional NMR is its low sensitivity, typically requiring millimetre-scale samples.

Extending NMR spectroscopy to microscale and nanoscale samples would enable exciting applications. It would, for example, allow chemical analysis of mass-limited samples that are expensive or difficult to synthesize. Furthermore, NMR spectroscopy of a single-cell volume could enable detailed studies of cell structure and function, with applications in metabolomics and disease diagnosis 89 , 90 . Bringing NMR down to the nanometre scale would also make single-protein detection possible, opening up the possibility of determining the structure of functional membrane proteins under near-physiological conditions and studying their dynamics 91 . Membrane proteins are the targets of more than half of FDA-approved drugs 92 , and the real-time study of protein–molecule binding would aid drug discovery.

NV-based NMR

The advent of NV-based magnetometry has enabled NMR spectroscopy of nanoscale and microscale samples under ambient conditions 6 , 93 (Fig.  5a ). Here, the sample is placed near the NV centres in diamond, with distances in the range of nanometres to micrometres depending on the specific application 6 , 94 (Fig.  5a ). At the nanoscale, NV-based NMR benefits from the large statistical polarization of the sample spins, while on the microscale, thermal polarization dominates 95 , often necessitating further enhancements via high magnetic fields 96 and hyperpolarization methods 97 , 98 . One feature of NV centres is their large magnetic field sensing bandwidth, ranging from d.c. to gigahertz 7 . Detection of multiple nuclear spin species 99 , 100 and even electron spins 101 is therefore possible with the same experimental set-up, without the need of changing the radiofrequency equipment as is the case for traditional NMR and electron paramagnetic resonance spectroscopy.

figure 5

a , Single-NV and NV-ensemble NMR set-ups. b , c , Pulse sequences used for NMR detection with NV centres: XY8-k (XY8 is a sequence of microwave pulses with X and Y phase shifts and is repeated k times, part b ) and coherently averaged synchronized readout (CASR, part c ). d , NMR spectrum detected by NV ensembles showing resolved chemical shift. e , Inset: image of a grating etched on a fluorine-enriched microsphere on an atomic force microscope tip. Main image: line scan of the NMR spectrum detected by a single NV centre as the sphere is moved over the NV centre. Parts a , b adapted with permission from ref. 100 , Springer Nature Ltd. Parts c , d adapted with permission from ref. 6 ,  Springer Nature Ltd. Part e adapted with permission from ref. 115 ,  Springer Nature Ltd.

Figures of merit

For NV-based NMR, the key figures of merit are the spatial resolution, spectral resolution and sensitivity of the spectrometer. The spatial resolution, or sensing volume, is of the order of the (depth) 3 of the NV centres, typically ranging from (4 nm)³ to (10 µm)³, and can be chosen based on the specific application. For NV-ensemble measurements, the spatial resolution is further limited by the laser spot size. The sensitivity, conversely, follows similar considerations to those discussed in the previous section on NV-based magnetic sensing. At the nanoscale, single-proton spin detection in 1-s integration has been demonstrated 94 ; whereas at the microscale, the detection of ~10 14 thermally polarized proton spins (~10 picolitre) has been demonstrated with 1-s integration 6 . The sensitivity can be further improved via hyperpolarization, as discussed below.

To resolve molecule-specific resonances, such as chemical shifts and J -couplings, a high spectral resolution of around one part per million (of the order of hertz in absolute frequency units) is required 102 . This resolution has been realized using different techniques 5 , 6 . The achievable spectral resolution is limited by both the NV centre and the sample. The limitation from the NV centre depends on the applied sensing sequence: dynamical decoupling (Fig.  5b ) can achieve a spectral resolution of ~1 kHz, limited by the NV T2 time 93 . Correlation spectroscopy can further improve the resolution to ~100 Hz, limited by the NV T1 time 99 . Even further enhanced spectral resolution can be reached with memory-spin-enhanced sensing 5 , 103 , limited by the T1 of the NV nitrogen nuclear spin, which can be >260 s (ref. 103 ). Another approach is to coherently average a sensing step that is then synchronized to an external clock 6 , 104 , 105 (Fig.  5c ).

On the sample side, physical diffusion (liquids) or spin diffusion (solids) is often the limiting factor. Fast translational diffusion in liquids limits the spectral resolution to ~1 kHz for viscous liquids and makes liquids with low viscosity undetectable 100 . This problem can be addressed by confining samples into a nanoscale volume 106 , 107 . For solid-state samples, dipole–dipole broadening is the limiting factor 94 , and heteronuclear and homonuclear decoupling can help to improve the resolution 5 . Additionally, NV-based multidimensional NMR can help in reconstructing the chemical structure of a biomolecule. In a proof-of-principle experiment, 27 13 C spins were localized in a diamond lattice relative to a single NV centre 108 . NV-based NMR has also been applied to samples external to the diamond, as demonstrated by the detection of a single protein with a spectral resolution of 1 kHz (ref. 94 ).

Hyperpolarization

Spin polarization beyond thermal equilibrium, typically achieved by transferring polarization from more readily polarizable electronic spins to the target nuclear spins, can enhance the NMR signal and thus improve detection sensitivity. Dynamic nuclear polarization, based on the Overhauser mechanism 97 , and parahydrogen-based signal amplification by reversible exchange (SABRE) 98 were used to hyperpolarize proton spins to 0.5%, leading to a signal enhancement of NV-based NMR of about 2 × 10 5 and the detection of target molecules at concentrations as low as 1 millimolar 98 . The NV spins can also serve as a source of hyperpolarization, because they can be well polarized via optical pumping (Fig.  2b ). Through this technique, surrounding 13 C nuclear spins were polarized to ~720 times the thermal value at 7 T (refs. 109 , 110 , 111 ). Unfortunately, no external spin hyperpolarization has yet been demonstrated. This is due to low diamond surface-to-volume ratios 111 , decreased spin coherence times of near-surface NVs 112 , 113 and short nuclear spin T1 times close to the diamond surface 84 , 114 . Laboratories worldwide are working to address these challenges, by better control of the diamond surface and by achieving high densities of shallow NVs with improved coherence properties, for example 81 , 112 , 113 .

Nanoscale and microscale magnetic resonance imaging

The full potential of NV-based NMR unfolds when imaging biological samples, as it can reveal changes in chemical composition at the nanoscale to microscale (Fig.  5d ). At the microscale, magnetic resonance imaging (MRI) can be realized by a wide-field set-up with an ensemble of NV centres 100 , and scanning probe systems can be used for MRI with higher spatial resolution of the order of ~10 nm (ref. 115 ) (Fig.  5e ).

Owing to the high sensitivity on the nanoscale of NV centres, NVs are also considered a promising tool for studying surface chemistry. Functionalization of the diamond surface is of great importance for these applications, because it immobilizes molecules close to NV centres and enables surface NMR detection with NV centres 116 , 117 , 118 .

Future developments

It is well established that NV-based sensors can perform NMR spectroscopy of nanoscale and microscale samples and, under certain conditions, detect chemical shifts and J -couplings. Despite this progress, several major challenges remain for NV-based NMR. Incorporation into microfluidics is necessary for high-throughput NMR screening of certain samples, such as those that are mass-limited; higher sensitivities are required for structure determination of individual molecules; deterministic single (bio)molecule placement near a single NV centre would be desirable, possibly via scanning probe techniques 115 or surface treatment 116 , 117 , 118 ; and finally, increased spectral resolution by reducing sample diffusion 106 , 107 and designing new pulse sequences 83 will be highly beneficial.

With these further developments, NV-based NMR will expand capabilities beyond conventional techniques and open many avenues in chemistry as well as molecular and cell biology. Nanoscale NV-based NMR, aided by multidimensional spectroscopy and spin-labelling techniques, will enable the structural determination of complex molecules, such as transmembrane proteins in near-physiological conditions. Furthermore, wide-field NV-based MRI with its subcellular spatial resolution could be applied for single-cell metabolomics studies. Another application is to correlate NV-based NMR with optical microscopy of fluorophore labels, which can be useful for single-molecule studies. Ultimately, the goal would be to make these techniques accessible to non-physicists. Towards this goal, miniaturization of the tool is important. With recent developments 119 , 120 and further integration, chip-scale NV spectrometers may become a reality soon.

NV thermometry

Nv-based quantum thermometry.

Whereas the preceding sections focused on applications to magnetic field sensing, quantum sensors can also be sensitive to a range of other environmental influences 10 , 27 , 28 , 31 , 32 , 121 , 122 , 123 , 124 , 125 , providing rich sensing modalities relevant to the life sciences. In this section, we discuss one biological application of quantum sensors beyond magnetic field sensing: in vivo nanoscale thermometry with NVs in nanodiamonds. This modality enables local probing of a wide range of temperature-related biological phenomena in cells and small organisms, including the effects of external heat gradients and internal heat generation, providing tools for the control of cell cycles and organism development.

Like magnetic field sensing, NV-based quantum thermometry relies on temperature-dependent changes in microwave transition frequencies (Fig.  6a ) that originate from thermal expansion of diamond. The vibronic interactions between the NV spin and the host lattice result in a temperature-dependent zero-field splitting 124 , with a slope of approximately –74 kHz K −1 close to room temperature 31 , 121 , 122 , 123 , 124 . To optimize sensitivity while minimizing susceptibility to other effects, a four-point measurement scheme is typically used (Fig.  6b ). The temperature can also be measured via purely optical means through changes in the emission spectrum and intensity 28 , 125 , thus providing multimodal verification of results.

figure 6

a , NV energy-level diagram with spin quantum number m s  = 0,±1 and temperature-dependent zero-field splitting, D ( T ), which is typically used for thermometry. b , Four-point measurement scheme for noise-robust determination of temperature using NVs. c , Heat gradients between two cells AB and P1 at the early embryo stage, generated by localized heating using an infrared (IR) laser. Parts b,c adapted with permission from ref. 137 , PNAS.

Nanodiamond quantum sensors are well suited for high-spatial-resolution temperature sensing in cells and small organisms. Compared with conventional temperature probes, nanodiamond quantum sensors are nanoscale, stable and biocompatible 126 , 127 , 128 , 129 . They also provide a complementary tool to luminescent nanoscale thermometry performed with fluorescent nanoparticles or proteins 130 , which suffer from calibration issues, bleaching or susceptibility to frequency-dependent optical transmission 131 . Quantum sensing instead uses coherence between microwave transitions, reducing the sensitivity to optical transmission and other environmental factors.

NV centres can be created in nanodiamonds 10 , 31 , 70 , 71 , 72 , 127 , 128 , 129 , often in the form of NV ensembles to further increase sensitivity. The size of such nanodiamonds is typically around 50–100 nm, although smaller ones are available with inferior optical and spin properties 132 . With suitable surface treatment, these nanodiamonds can be delivered into individual cells. For some cell types, such as HeLa cells, natural uptake is sufficient, whereas for others, such as egg cells, injection techniques may be preferred 128 , 129 . Although suitably treated nanodiamonds have mostly been found to have no or low cytotoxicity, some studies suggest they can remain in organs for long periods 133 , motivating further long-term studies of their effects 128 , 134 . The NV temperature sensitivity is ~5 mK Hz −1/2 in isotopically purified, ultrapure bulk diamond 123 . The sensitivity in the nanodiamond form is poorer, however, because of strain effects and surface contamination. In a typical biological setting, the temperature sensitivity of NV nanodiamonds is ~1 K Hz −1/2 (refs. 31 , 135 , 136 , 137 ), comparable to other techniques 130 .

Applications of nanoscale thermometry

Sensitive nanoscale thermometry opens many possibilities in life science applications, especially in combination with localized exogenous heating induced by infrared laser illumination (Fig.  6c ). Laser heating has been used to explore the direct biochemical effects of elevated temperature (such as accelerated cell growth or protein denaturation) 31 , 135 , 138 , 139 , the expression of heat-shock protein promoters 140 , 141 , 142 , and thermal effects on cell and organism development. In an early proof-of-principle experiment that combines infrared heating and nanodiamond sensors, the threshold heating temperature that induces HeLa cell death was investigated 31 . More recently, local temperature manipulation and monitoring was used to control and invert the cell development cycle during embryogenesis in Caenorhabditis elegans 137 . Nanodiamonds have also been explored as a tool for in vivo temperature calibration for thermotherapeutic treatments 138 , 140 . Other possible applications of NV-based thermometry include nanoscale measurements of heat conductivity 143 , and endogenous heat generation 135 , 144 , 145 , 146 .

Although current techniques have yielded impressive demonstrations and shed light on the role of temperature on biological processes, considerable challenges remain. First, to measure absolute temperature changes accurately, it is necessary to perform precise in vivo calibration of quantum sensors in the presence of internal strain, stray magnetic fields, spatial movement in cells, and microwave and optical heating. Second, although techniques for incorporating nanodiamonds into living cells are fairly mature, more work is required on surface functionalization and nanodiamond synthesis to target specific organelles at the subcellular level 147 . Third, despite the fact that the temperature sensitivity of nanodiamond sensors is competitive with other technologies, further improvements are desired. These improvements include using hybrid nanodiamond–MNP schemes 148 , material improvements, spin echo techniques for T2-limited NV coherence measurements 31 , 131 , 132 (instead of the current T2*-limited measurements) and advanced readout methods 9 .

The field of quantum sensors has developed tremendously in the past decade, moving from early proof-of-principle experiments into real-world applications in biomedical sciences. Indeed, these developments have already spurred the creation of several start-up companies making use of the technologies discussed in the case studies above. Examples (not exhaustive) include: QuSpin, CercaMagnetics and FieldLine Inc., focusing on commercializing OPM-MEG technology; ODMR Technologies, focusing on NV-based magnetic resonance spectroscopy for chemical trace analysis; Quantum Diamond Technologies Inc. (QDTI), focusing on wide-field NV magnetic imaging of disease biomarkers; and NVision Imaging Technologies, focusing on NV-based hyperpolarization of nuclear spins for molecular analysis and medical imaging.

Although there are promising opportunities, many challenges remain, probably calling for collaborations between multiple academic domains and industry. On the one hand, as discussed in the case studies for NV-based optical magnetic imaging and NMR spectroscopy, the sensitivities of current quantum sensors will probably need to be further improved through a combination of new sensing protocols and material developments. On the other hand, further integration and miniaturization of such technologies, to enable scalability and ease of operation under realistic conditions, will be crucial for broad acceptance and commercial success. With these improvements, we expect quantum sensors to become key tools for characterization and diagnostics of biomedical systems.

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Acknowledgements

This work was supported by the Moore Foundation. N.A. acknowledges support from the Alexander von Humboldt Foundation.

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Nabeel Aslam, Hengyun Zhou, Elana K. Urbach, Mikhail D. Lukin & Hongkun Park

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

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Nabeel Aslam

Quantum Technology Center, University of Maryland, College Park, MD, USA

Matthew J. Turner & Ronald L. Walsworth

Department of Electrical and Computer Engineering, University of Maryland, College Park, MD, USA

Department of Physics, University of Maryland, College Park, MD, USA

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Aslam, N., Zhou, H., Urbach, E.K. et al. Quantum sensors for biomedical applications. Nat Rev Phys 5 , 157–169 (2023). https://doi.org/10.1038/s42254-023-00558-3

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