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In one of the University of Sheffield’s physics labs, a few hundred photosynthetic bacteria were nestled between two mirrors positioned less than a micrometer apart. Physicist David Coles and his colleagues were zapping the microbe-filled cavity with white light, which bounced around the cells in a way the team could tune by adjusting the distance between the mirrors. According to results published in 2017, this intricate setup caused photons of light to physically interact with the photosynthetic machinery in a handful of those cells, in a way the team could modify by tweaking the experimental setup.1

That the researchers could control a cell’s interaction with light like this was an achievement in itself. But a more surprising interpretation of the findings came the following year. When Coles and several collaborators reanalyzed the data, they found evidence that the nature of the interaction between the bacteria and the photons of light was much weirder than the original analysis had suggested. “It seemed an inescapable conclusion to us that indirectly what [we were] really witnessing was quantum entanglement,” says University of Oxford physicist Vlatko Vedral, a coauthor on both papers.

Quantum entanglement refers to the states of two or more particles being interdependent, regardless of the distance separating them. It’s one of many counterintuitive features of the subatomic landscape, in which particles such as electrons and photons behave as both particles and waves simultaneously, occupy multiple positions and states at once, and traverse apparently impermeable barriers. Processes at this scale are captured in the complex mathematical language of quantum mechanics, and frequently produce effects that appear to defy common sense. (See Glossary: Quantum Terminology infographic.) It was using this language that Vedral and colleagues had detected signatures of entanglement between photons and bacteria in data from the Sheffield experiment.

It’s almost ridiculous, counterintuitive, that quantum effects should persist inside cells. —Jim Al-Khalili, University of Surrey

Researchers have demonstrated entanglement many times in inanimate objects—in 2017, scientists reported they’d managed to maintain this interdependence between pairs of photons separated by 1,200 kilometers. But if Vedral and colleagues’ proposal that the phenomenon was taking place in bacteria is correct, the study could mark the first time entanglement has been observed inside a living organism, and add to a growing body of evidence that quantum effects are not as unusual in biology as once believed.2

That quantum phenomena might be observable in the messy world of living systems is historically a fringe idea. While quantum theories accurately describe the behavior of the individual particles making up all matter, scientists have long presumed that the mass action of billions of particles jostling around at ambient temperature drowns out any weird quantum effects and is better explained by the more familiar rules of classical mechanics formulated by Isaac Newton and others. Indeed, researchers studying quantum phenomena often isolate particles at temperatures approaching absolute zero—at which almost all particle motion grinds to a halt—just to quash the background noise.

“The warmer the environment is, the more busy and noisy it is, the quicker these quantum effects disappear,” says University of Surrey theoretical physicist Jim Al-Khalili, who coauthored a 2014 book called Life on the Edge that brought so-called quantum biology to a lay audience. “So it’s almost ridiculous, counterintuitive, that they should persist inside cells. And yet, if they do—and there’s a lot of evidence suggesting that in certain phenomena they do—then life must be doing something special.”

Al-Khalili and Vedral are part of an expanding group of scientists now arguing that effects of the quantum world may be central to explaining some of biology’s greatest puzzles—from the efficiency of enzyme catalysis to avian navigation to human consciousness—and could even be subject to natural selection.

“The whole field is trying to prove a point,” says Chiara Marletto, a University of Oxford physicist who collaborated with Coles and Vedral on the bacteria-entanglement paper. “That is to say, not only does quantum theory apply to these [biological systems], but it’s possible to test whether these [systems] are harnessing quantum physics to perform their functions.”

Enzyme Catalysis: A Tunnel Through the Barrier Traditional theories of enzyme catalysis hold that the proteins speed up reactions by lowering the activation energy. But some researchers argue that a quantum trick known as tunneling also plays a role, and that the structure of enzymes’ active sites might have evolved to take advantage of this phenomenon. PDF See full infographic: WEB © LUCY READING-IKKANDA A Many chemical reactions are prevented from happening spontaneously by an energy barrier, known as the activation energy. B Enzymes lower this barrier by stabilizing an intermediate, or “transition,” state that allows the reaction (such as the movement of a hydrogen atom within a molecule) to take place. C The intermediate state can be bypassed if particles within the molecule are transferred via quantum tunneling, where a particle essentially instantaneously traverses the barrier with a certain probability.

Quantum effects in biology’s fundamental reactions

By the mid-1980s, University of California, Berkeley, biochemist Judith Klinman was convinced that the traditional explanation of enzyme catalysis was incomplete. Contemporary theories held that enzymes interact with substrates on the basis of shape and classical mechanics, physically bringing together substrates at their active sites and stabilizing transition states of molecular structure to accelerate reaction rates up to a trillionfold or more. But Klinman had been getting odd results from in vitro experiments with an enzyme extracted from yeast.

In catalyzing the oxidation of benzyl alcohol to benzaldehyde, the alcohol dehydrogenase enzyme shifts a hydrogen atom from one position to another. Unexpectedly, when Klinman and her colleagues replaced specific hydrogen atoms in the substrate with the heavier isotopes deuterium and tritium, the reaction drastically slowed down. Although classical explanations of enzyme catalysis allowed for modest isotope effects, they couldn’t account for the large drop in rate Klinman observed. “What we saw were deviations from the existing theories,” she says.

Her team kept investigating, and, in 1989, published an explanation building on ideas already circulating among enzyme researchers: that catalysis involves a quantum trick called tunneling.3 Quantum tunneling is like kicking a football through a hill, explains Al-Khalili—where the football is an electron or another particle, and the hill is an energy barrier preventing a reaction from happening. “In the classical world you have to kick it hard enough to get it up the hill and down the other side,” he says. “In the quantum world, you don’t have to. It can go halfway up, disappear, and reappear on the other side.”

Klinman’s team posited in this and later papers that, during the catalysis of benzyl alcohol oxidation and many other reactions, hydrogen transfer takes place with assistance from tunneling. This helps explain why deuterium and tritium often hold reactions up—heavier particles are worse at tunneling, and can make tunneling harder for other particles in the same molecule. The effects observed by Klinman’s group have since been replicated by other labs for multiple enzymes and provide some of the strongest evidence for quantum effects in biological systems, Al-Khalili says. (See infographic.)

But while it’s now generally accepted that tunneling occurs in biological catalysis, researchers are divided on how much it matters—and whether it might be subject to natural selection. Chemist Richard Finke at Colorado State University, for example, showed that some reactions exhibit isotope effects to a similar degree whether or not an enzyme is present, suggesting that it’s unlikely that enzymes are particularly adapted to enhance tunneling effects in the reactions they catalyze.4 It’s also unclear how much tunneling speeds up reactions; some researchers argue that the effect generally contributes no more than a small boost to processes governed primarily by classical mechanics.

Photosynthesis: All Paths Traveled During the light-harvesting reaction of photosynthesis in plants and some microbes, a photon excites an electron in a chlorophyll molecule to create a structure called an exciton—an entity containing both the excited electron and the positively charged hole it leaves behind. This exciton is then transferred via other chlorophyll molecules until it reaches a protein complex called the reaction center. Traditional Model According to the traditional, or “incoherent,” model of this process, the exciton’s route to the reaction center is more or less random. Because energy can be lost during the transfer process, such a path can end up being wasteful. Quantum Model

By contrast, if the energy transfer process is “quantum coherent” such that the exciton travels like a wave, it can explore all possible paths simultaneously and only take the most efficient route. PDF See full infographic: WEB © LUCY READING-IKKANDA

Klinman says she thinks that tunneling in enzymes is far more fundamental. “Our view is that enzymes create very precise and compact active site structures” that promote tunneling, she says. During catalysis, for example, enzymes change conformation in a way that can bring hydrogen donor and acceptor sites close enough—within about 0.27 nanometers of each other—to facilitate tunneling, she notes.

Her group has pursued the idea by mutating enzymes’ active sites and observing how reaction rates and isotope effects change in vitro. Earlier this year, for example, the team created a version of soybean lipoxygenase that slightly mispositions its substrates in a way that should make hydrogen tunneling unfavorable. Compared with the wild type, the mutant enzyme’s catalytic power is four orders of magnitude lower, and it’s much more sensitive to the replacement of hydrogen with deuterium.5

Researchers are still quantifying tunneling’s role in catalysis, and Klinman emphasizes the importance of using multiple methods, including mutagenesis and computational modeling, to understand exactly how proteins speed up reactions. Experimental evolution of enzymes, in which researchers repeatedly select proteins to increase their catalytic power, could also offer insight into tunneling’s contribution—although at least one recent attempt to do this was inconclusive. Last year, a team that evolved an enzyme catalyzing a reaction involving hydrogen transfer reported that quantum tunneling was “not observed to significantly change” across the evolutionary process.6

The debate mirrors an ongoing conversation about the functional importance of quantum phenomena in another of Earth’s critical biological processes, photosynthesis. While Vedral and colleagues are investigating whether bacteria’s photosynthetic machinery becomes entangled with photons, other groups have been studying how another quantum effect could help maximize the efficiency of photosynthetic energy transfer.

During the light-harvesting reaction in plants and some microbes, photons excite electrons contained in chlorophyll molecules to create entities called excitons. These excitons are then transferred from chlorophyll molecule to chlorophyll molecule until they reach the reaction center—a cluster of proteins where their energy can be captured and stored.

Excitons can lose energy as they’re transferred, meaning that the more roundabout their routes are among the chlorophyll molecules, the less energy reaches the reaction center. Physicists suggested decades ago that this wastefulness could be averted if the transfer process was quantum coherent. That is, if excitons could travel like waves rather than particles, they could simultaneously try out all paths to the reaction center and take only the most efficient route. (See illustration.)

In 2007, a team led by chemists Graham Fleming of the University of California, Berkeley, and Robert Blankenship of Washington University in St. Louis claimed to have observed quantum coherence in complexes of chlorophyll molecules extracted from green sulfur bacteria, photosynthetic microbes often found in the deep ocean where light availability is low. The researchers used a technique that analyzes the energy absorbed and emitted by a sample, and detected a signal called quantum beating—oscillations they interpreted as evidence of coherence—in complexes cooled to 77 Kelvin. Over the next few years, they and other groups replicated the results at ambient temperatures,8 and extended the findings to chlorophyll complexes from marine algae9 and spinach.10

Whether these results reflect a meaningful quantum contribution to energy transfer in photosynthesis is up for debate. In 2017, for example, researchers in Germany took another look at green sulfur bacteria and reported that the coherence effect lasted less than 60 femtoseconds (0.00006 nanoseconds)—too brief to aid energy transfer to the reaction center.11 But last year, another group argued that there are multiple types of coherence in chlorophyll complexes, and some do appear to last long enough to be useful in photosynthesis.12 Other scientists point to hints that some bacteria can switch coherence effects on or off by producing different forms of a key light-harvesting protein.13 Such findings have reignited speculation that, like enzymes, photosynthetic machinery might have evolved to exploit quantum phenomena.

Coherence effects in photosynthesis are now a well-accepted phenomenon, says Blankenship. As is the case for tunneling in enzymes, “the most relevant discussion at this point is whether they really have an effect on [the] efficiency of the system or some other aspect of it that gives a real biological benefit. I think the jury’s still out.”

MAGNETORECEPTION: SPINNING SENSORS According to the radical-pair model of avian magnetoreception, cryptochrome, a protein found in the retinas of birds and other animals, may be the magnetosensor, detecting the direction of magnetic ?elds via changes to the spin states of some of its electrons. PDF See full infographic: WEB © LUCY READING-IKKANDA

Reactions within the cryptochrome protein generate a pair of molecules that each have a lone electron. These electrons, which can be entangled with each other, occupy one of two states: a “singlet” state, meaning the spinning direction of one is related to the spinning direction of the other such that the spins are antiparallel; or a “triplet” state, in which the two electrons tend to have spins that are close to parallel. The radical pair oscillates between these two states, and the probability of finding it in one state or the other is influenced by the direction of magnetic fields. If the singlet and triplet states of the radical pair are associated with different biochemical reactions, then the yields of products from those reactions can provide information about the direction of a magnetic field. If those products go on to influence neural signaling from the bird’s retina, then this mechanism could provide the basis for magnetoreception.





Quantum explanations for puzzles in animal biology

Every winter, European robins in the northern part of the continent migrate hundreds of kilometers south to the Mediterranean. It’s a navigational feat made possible by magnetoreception—specifically, the birds’ ability to detect the direction of the Earth’s magnetic field. But early attempts to explain this sixth sense, including the proposal that birds rely on internal magnetite crystals, failed to garner experimental support.

By the late 1990s, the problem had caught the eye of Thorsten Ritz, then a graduate student working on quantum effects in photosynthesis under the supervision of the late biophysicist Klaus Schulten at the University of Illinois at Urbana-Champaign. He became particularly interested in cryptochrome, a light-sensitive protein found in the retinas of birds for which there’s now “good evidence” of a role in magnetoreception, says Ritz, who has since moved to the University of California, Irvine. So in 2000, focusing on this protein and building on Schulten’s earlier theoretical work, Ritz, Schulten, and another Illinois colleague published what would come to be known as the radical-pair model to explain how magnetoreception might operate.14

The researchers proposed that reactions in the cryptochrome protein generate a pair of radicals—molecules that each have a lone electron. The behavior of those electrons, which can be quantumly entangled with each other, is sensitive to the alignment of weak magnetic fields such as the Earth’s. Changes in the alignment of this pair relative to the magnetic field could theoretically trigger downstream chemical reactions, allowing the information to be somehow transmitted to the brain. (See illustration.)

The hypothesis generated a handful of predictions that Ritz went on to test in collaboration with the biologists who first described magnetoreception in robins, Roswitha and Wolfgang Wiltschko. In a study published in 2004, for example, the team exposed robins to magnetic fields oscillating at frequencies and angles that the model predicted would disrupt the radical pair’s sensitivity to the Earth’s magnetic field—and effectively knocked out the birds’ ability to navigate.15

The idea has taken off since then, with growing theoretical support. And two 2018 studies of the molecular properties and expression patterns of one version of cryptochrome, Cry4, point to the protein as a likely candidate magnetoreceptor in zebra finches16 and European robins.17

More work is needed to determine whether or not avian magnetoreception really works this way, and to reveal if entanglement between the electrons of the radical pair is important. Scientists also don’t fully understand how cryptochrome could communicate magnetic field information to the brain, says Ritz. Meanwhile, his group is focused on mutagenesis experiments, which could help unravel cryptochrome’s magnetosensitivity. Last fall, University of Oxford chemist Peter Hore and biologist Henrik Mouritsen of the University of Oldenburg in Germany won European funding for QuantumBirds, a project with similar aims.

Now you’re not considered completely mad if you say you’re studying quantum mechanics in biology. It’s just considered a little bit wacky. — Johnjoe McFadden, University of Surrey

Magnetoreception isn’t the only puzzle in animal sensory biology that’s generated interest among quantum physicists; another scientifically mysterious sense that researchers hope to help crack is olfaction. The traditional theory—that odorant molecules fit into protein receptors on olfactory neurons to trigger smells—faces the challenge that some molecules with almost identical shapes have completely different odors, while others with different stereochemistry smell alike.

In the mid-1990s, University College London (UCL) biophysicist Luca Turin, now a respected perfume critic, proposed that olfactory receptors might be sensitive not just to shape, but to the frequencies of vibrating bonds in odorant molecules.18 He argued that when an odorant binds to a receptor, if its bonds are vibrating at a certain frequency they can facilitate the quantum tunneling of electrons within that receptor. This transfer of electrons, according to his model, triggers a signaling cascade in the olfactory neuron that ultimately sends an impulse to the brain.

Experimental evidence for the idea is still elusive, says Jenny Brookes, a UCL physicist who has formulated the problem mathematically to show that it’s theoretically feasible. “But that’s partly why it’s quite exciting.” In recent years, researchers have looked for isotope effects similar to the ones found in enzyme function. If tunneling plays a substantial role, odorant molecules containing heavier hydrogen isotopes should smell different from normal versions due to the lower vibration frequencies of their bonds.

The findings are mixed. In 2013, Turin’s group reported that humans can distinguish between odorants containing different isotopes.19 Two years later, other researchers failed to reproduce the results and called the theory “implausible.”20 But the idea didn’t go out of fashion. In 2016, another team reported that honey bees can differentiate odors with different isotopes,21 while a recent theoretical study presents a suite of new predictions to help test the model’s validity.22

Theoretical work is also driving interest in quantum biological explanations with far less experimental support. For example, some researchers have speculated that the coherence effects posited to play a role in photosynthesis could also contribute to such widespread biological phenomena as vision and cellular respiration. Others have suggested that proton tunneling could promote spontaneous mutations in DNA, although theoretical work by Al-Khalili and colleagues suggest this isn’t terribly likely, at least for the adenine-thymine base pairs they modeled.23

Perhaps the most extreme extension of quantum physics to the animal kingdom is the idea that weird quantum effects might play a role in the human brain. University of California, Santa Barbara, physicist Matthew Fisher has argued that neurons possess molecular machinery capable of behaving like a quantum computer, which instead of using bits of 0s or 1s operates with qubits, units of information that can have states of both 0 and 1 simultaneously.24

The brain’s qubits, Fisher proposed, are encoded in the states of phosphate ions inside Posner molecules, clusters of phosphate and calcium found in bone and possibly within certain cells’ mitochondria. Recent theoretical work by his team argues that the states of phosphate ions in different Posner molecules could be entangled with one another for hours or even days, and may therefore be able to perform rapid and complex computations.25 Fisher recently received funding to set up an international collaboration, called QuBrain, to look for these effects experimentally. Many neuroscientists have expressed skepticism that the project will turn up positive results.

GLOSSARY: QUANTUM TERMINOLOGY The world at the scale of spinning atoms and subatomic particles is governed by the probabilistic rules of quantum mechanics, which often produce effects that seem counterintuitive to organisms living in a world usually described perfectly well by more-standard physics. These effects have been harnessed for multiple technological applications, and the possible role of quantum phenomena in several biological systems is now being explored.

Entanglement: Two particles are said to be quantumly entangled if their states are interdependent, regardless of the distance separating them. In the classic example of entanglement two entangled electrons, when measured, will have opposite spins.



Important for: Quantum computing, quantum cryptography

Studied in: Photosynthesis, magnetoreception, human consciousness

Qubits: These units of information are the quantum equivalent of standard binary digits or bits. While a bit can have a state of 0 or 1, qubits can have multiple states simultaneously, and may be entangled with other qubits to perform parallel computations. Qubits can be encoded in the spin states of electrons and other subatomic particles.



Important for: Quantum computing

Studied in: Human consciousness

Tunneling: Particles at the quantum scale have wave-like properties, and their exact location at any moment is described by a probabilistic wave function. As a result, particles such as electrons can, with certain probabilities, traverse—or tunnel through—apparently impermeable energy barriers.



Important for: Thermonuclear fusion, scanning tunneling microscopy

Studied in: Enzyme catalysis, photosynthesis, olfaction, DNA mutation

Coherence: Because quantum objects can behave like waves, they can exhibit a property of waves called coherence when they are in a particular rhythm with one another. Quantum coherence underlies several effects observed by quantum physicists, including entanglement as well as interference patterns manifested as so-called quantum beating. Loss of coherence has traditionally been thought to happen very quickly in the molecular bustle of ambient- temperature environments.



Important for: Lasers, superconductors, quantum computing

Studied in: Photosynthesis, magnetoreception, vision, respiration PDF See full infographic: WEB

Putting quantum biology to work

Most ideas in quantum biology are still driven more by theory than by experimental support, but a number of researchers are now trying to close the gap. Vedral’s team plans to collect more data on bacterial entanglement later this year, and physicist Simon Gröblacher of Delft University of Technology in the Netherlands has proposed carrying out entanglement experiments with tardigrades. In 2017, Al-Khalili and his Life on the Edge coauthor, University of Surrey biologist Johnjoe McFadden, helped establish a doctoral training center for quantum biology to encourage interdisciplinary crosstalk and advance research efforts. Among the wider community of scientists and research funders, “now you’re not considered completely mad if you say you’re studying quantum mechanics in biology,” McFadden says. “It’s just considered a little bit wacky.”

Researchers who spoke to The Scientist also emphasize that, whether or not the theorized mechanisms garner experimental support, the speculation in quantum biology is itself valuable. “As we miniaturize our technology, we have a wealth of information in the biological world from which to draw inspiration,” says theoretical physicist and quantum computing researcher Adriana Marais, head of innovation at tech company SAP Africa. “This is a fantastic opportunity to investigate what life is, but also to learn lessons on how to engineer processes at this microscale in an optimal way.”

Real-world applications encompass technologies from more-efficient solar cells to new classes of biosensors. Last year, one group proposed a design for a “biomimetic nose,” based partly on the quantum theory of olfaction, to detect tiny concentrations of odorants.26 And Hore and others have highlighted the radical-pair mechanism that may underlie magnetoreception for use in devices to sense weak magnetic fields.

“We can use the information we gain to design systems on these principles,” says Ritz, “even if it turns out that that’s not how birds do it.”

References

Clarification (June 25): This story has been updated to clarify that, in quantum tunneling, there is a very brief lag time before a particle traversing a barrier appears on the other side. The Scientist regrets any confusion.