A new optically addressable quantum bit (qubit) encoded in a fluorescent protein could be used as a sensor that can be directly produced inside living cells. The device opens up a new era for fluorescence microscopy to monitor biological processes, say the researchers at the University of Chicago Pritzker School of Molecular Engineering who designed the novel qubit.
Quantum technologies use qubits to store and process information. Unlike classical bits, which can exist in only two states, qubits can exist in a superposition of both these states. This means that computers employing these qubits can simultaneously process multiple streams of information, allowing them to solve problems that would take classical computers years to process.
Qubits can be manipulated and measured with high precision, and in quantum sensing applications they act as nanoscale probes whose quantum state can be initialized, coherently controlled and read out. This allows them to detect minute changes in their environment with exquisite sensitivity.
Optically addressable qubit sensors – that is, those that are read out using light pulses from a laser or other light source – are able to measure nanoscale magnetic fields, electric fields and temperature. Such devices are now routinely employed by researchers working in the physical sciences. However, their use in the life sciences is lagging behind, with most applications still at the proof-of-concept stage.
Difficult to position inside living cells
Many of today’s quantum sensors are based on nitrogen-vacancy (NV) centres, which are crystallographic defects in diamond. These centres occur when two neighbouring carbon atoms in diamond are replaced by a nitrogen atom and an empty lattice site and they act like tiny quantum magnets with different spins. When excited with laser pulses, the fluorescent signal that they emit can be used to monitor slight changes in the magnetic properties of a nearby sample of material. This is because the intensity of the emitted NV centre signal changes with the local magnetic field.
“The problem is that such sensors are difficult to position at well-defined sites inside living cells,” explains Peter Maurer, who co-led this new study together with David Awschalom. “And the fact that they are typically ten times larger than most proteins further restricts their applicability,” he adds.
“So, rather than taking a conventional quantum sensor and trying to camouflage it to enter a biological system, we therefore wanted to explore the idea of using a biological system itself and developing it into a qubit,” says Awschalom.
Fluorescent proteins, which are just 3 nm in diameter, could come into their own here as they can be genetically encoded, allowing cells to produce these sensors directly at the desired location with atomic precision. Indeed, fluorescent proteins have become the “gold standard” in cell biology thanks to this unique ability, says Maurer. And decades of biochemistry research has allowed researchers to generate a vast library of such fluorescent proteins that can be tagged to thousands of different types of biological targets.
“We recognized that these proteins possess optical and spin properties that are strikingly similar to those of qubits formed by crystallographic defects in diamond – namely that they have a metastable triplet state,” explain Awschalom and Maurer. “Building on this insight, we combined techniques from fluorescence microscopy with methods of quantum control to encode and manipulate protein-based qubits.”
In their work, which is detailed in Nature, the researchers used a near-infrared laser pulse to optically address a yellow fluorescent protein known as EYFP and read out its triplet spin state with up to 20% “spin contrast” – measured using optically detected magnetic resonance (ODMR) spectroscopy.
To test the technique, the team genetically modified the protein so that it was expressed in human embryonic kidney cells and Escherichia coli (E. coli) cells. The measured OMDR signals exhibited a contrast of up to 8%. While this performance is not as good as that of NV quantum sensors, the fluorescent proteins open the door to magnetic resonance measurements directly inside living cells – something that NV centres cannot do, says Maurer. “They could thus transform medical and biochemical studies by probing protein folding, monitoring redox states or detecting drug binding at the molecular scale,” he tells Physics World.
“A new dimension for fluorescence microscopy”
Beyond sensing, the unique quantum resonance “signatures” offer a new dimension for fluorescence microscopy, paving the way for highly multiplexed imaging far beyond today’s colour palette, Awschalom adds. Looking further ahead, using arrays of such protein qubits could even allow researchers to explore many-body quantum effects within biologically assembled structures.
Maurer, Awschalom and colleagues say they are now busy trying to improve the stability and sensitivity of their protein-based qubits through protein engineering via “directed evolution” – similar to the way that fluorescent proteins were optimized for microscopy.
“Another goal is to achieve single-molecule detection, enabling readout of the quantum state of individual protein qubits inside cells,” they reveal. “We also aim to expand the palette of available qubits by exploring new fluorescent proteins with improved spin properties and to develop sensing protocols capable of detecting nuclear magnetic resonance signals from nearby biomolecules, potentially revealing structural changes and biochemical modifications at the nanoscale.”
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