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damage is mediated by the transmission of certain signalling molecules such as adenosine triphosphate (ATP) from within the barrier into the culture medium (Fig. 1). Such transmission could occur through gap junctions — connections that allow the free flow of molecules and ions between adjacent cells in most mammals for the purposes of intercellular communication. Most cells that are directly exposed to nanoparticles experience oxidative damage that arises from free radicals generated from the reactive nanoparticle surface. The suggestion that external exposure can produce adverse effects owing to altered signalling mechanisms by means of gap junctions is different and deserves further scrutiny, because most mammalian cells communicate with each other by gap junctions and these interactions are critical for the development and normal function of multicellular organisms.

The findings have important implications for evaluating the safety of

particles in general, and for understanding the impact of nanoparticles on reproductive toxicology, which up until now has been largely ignored. So far, only limited information exists on whether engineered nanomaterials can cause adverse events in the developing embryo or fetus8–10. Given the speed at which applications and uses of nanomaterials are increasing, one of the main concerns is unintentional exposure from consumer products, from environmental sources or during manufacturing of materials containing nanoparticles. Furthermore, as more nanomaterials are being developed for medical applications, it is possible that treatments for common diseases (such as diabetes and infections) may one day contain nanoparticles, which could pose a risk to pregnant women receiving these treatments.

Our understanding of both the beneficial and harmful biological effects of nanoparticles remains incomplete. Indeed, the work by Case and co-workers

cautions that evaluation of the safety of nanoparticles should not rely only on whether they fail to cross protective barriers such as the placenta — direct and indirect effects should be treated with equal importance. Although their model is highly simplified and further studies are needed to confirm the findings, this is an important lesson. ❐

Päivi Myllynen is in the Department of Pharmacology and Toxicology, Institute of Biomedicine of the University of Oulu, PO Box 5000, FIN‑90014 Oulu, Finland. e‑mail: paivi.myllynen@oulu.fi

References1. Lewinski, N. et al. Small 4, 26–49 (2008).2. Singh, N. et al. Biomaterials 30, 3891–3914 (2009).3. Landsiedel, R. et al. Mutat. Res. 681, 241–258 (2009).4. Bhabra, G. et al. Nature Nanotech. 4, 876–883 (2009). 5. Hales, B. F. Curr. Opin. Genet. Dev. 15, 234–240 (2005). 6. Liu, F. et al. Am. J. Physiol. 273, C1596–1604 (1997).7. Saunders, M. Nanomed. Nanobiotechnol. 1, 671–684 (2009). 8. Tsuchiya, T. et al. FEBS Lett. 393, 139–145 (1981).9. Chan, W.-H. Acta Pharmacol. Sin. 28, 259–266 (2008).10. Park, M. V. D. Z. et al. Toxicol. Appl. Pharmacol. 240, 108–116 (2009).

The fact that quantum mechanics and the Heisenberg uncertainty principle place limits on our ability to make

measurements would, at first glance, seem to have little relevance to experiments in the solid state; the measurement precision achieved in such experiments is usually limited by more mundane concerns (for example, thermal fluctuations of voltages and currents). However, this seemingly innocuous expectation is now being challenged by a number of experiments in quantum nanoscience that are pushing the boundaries of measurement sensitivity ever closer towards ultimate quantum limits. Now on page 820 of this issue, researchers at JILA and the University of Colorado, both in Boulder, Colorado, report that they have used a resonant microwave circuit to continuously measure the position of a nanomechanical oscillator with a precision that is unprecedented for an electrical measurement1.

The origin of the quantum limit on continuous measurements of position is the phenomenon of ‘quantum back-action’,

the unavoidable disturbance caused by the very act of measurement. If we measure the position x of a mechanical resonator at time t, we will disturb its momentum by at least Δp. The uncertainty principle tells us that Δp is proportional to h/2π, where h is the Planck constant, and is inversely proportional to the intrinsic imprecision of our position measurement, which is the uncertainty stemming from noise in the output of our detector.

The goal of a continuous position measurement is to monitor x(t) over a period of time: the ‘kick’ delivered by the back action has an important role in these measurements because it leads to extra uncertainty in the position of the oscillator at later times. The total error in a position measurement at a given time will, therefore, include contributions from the back action at earlier times and from the intrinsic imprecision of the measurement. The smaller one makes the intrinsic imprecision, the larger becomes the contribution from back action.

Optimizing a continuous position measurement thus entails a trade-off between these two contributions. In the ideal case, both of these sources of uncertainty would make an equal contribution to the total error of the measurement. The uncertainty principle requires that this total measurement error cannot be smaller than the zero-point motion, which is the uncertainty in the position of the oscillator in its quantum ground state. This limit is known as the standard quantum limit for a continuous measurement of position (see ref. 2 for a detailed discussion). Reaching the standard quantum limit therefore involves reducing the measurement imprecision caused by noise in our detector to a value that corresponds to exactly half the ground-state position uncertainty: this is challenging because it means that the detector must be strongly coupled to the motion of the oscillator while having a very low level of intrinsic noise.

The oscillator in the Boulder experiment is a small aluminium wire that has a

MEASUREMENT

Facing Heisenberg at the nanoscaleBy measuring the motion of a nanomechanical oscillator with an extremely small error, researchers have passed a milestone on the road to measurements of position at the ultimate limit set by quantum mechanics.

Aashish Clerk

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resonance frequency of 1.04 MHz and the root mean square (RMS) amplitude of its zero-point motion is 2.7 × 10–14 m. John Teufel, Konrad Lehnert and colleagues use a resonant microwave circuit to measure the motion of this oscillator. The system behaves like a simple inductor–capacitor (LC) resonant circuit, with the motion of the beam modulating the capacitance, and hence the resonance frequency (Fig. 1). This modulation (and hence the motion responsible for it) is detected by monitoring the phase shift of a microwave tone reflected from the circuit. The measurement imprecision in this set-up is ultimately set by how well one can determine the phase shift of the reflected tone.

For optical signals it is possible to determine the phase shift in an ideal manner that is only limited by photon shot-noise. However, the situation is murkier in the microwave world because photomultipliers that operate at microwave frequencies are not readily available. Instead one must use a microwave-frequency voltage amplifier, but these devices are subject to yet another quantum limit: they must add a minimum amount of noise that corresponds to the energy of half a photon3. To make matters worse, the best commercially available amplifiers — cryogenic high-electron mobility transistors (HEMTs) — typically add 40–50 times this minimum amount of noise. Almost all previous experiments using electrical circuits as nanomechanical position detectors have been limited by this excess amplifier noise, resulting in measurement imprecisions that were much larger than the zero-point motion of the oscillator4–6.

The Boulder team’s key innovation is to circumvent this problem by implementing an improved version of an unusual type of microwave amplifier called a degenerate Josephson parametric amplifier. This device is essentially a second microwave circuit incorporating hundreds of superconducting tunnel junctions. The nonlinearity of the resulting system allows for a non-standard ‘phase-sensitive’ type of amplification where only one signal quadrature (for example, the cosine component of the signal) is amplified. For such an amplifier, there is no quantum limit: the amplification can in principle be completely noise free1.

The Josephson parametric amplifier used by the Boulder team does not attain this ideal level of performance, but the added noise is still an impressive factor of 40 times smaller than the best conventional HEMT amplifier. This low noise, combined with a strong coupling between the microwave circuit and the mechanical motion, results in

the imprecision of the overall measurement being extremely low: it can be as small as 40% of the uncertainty in the position of the oscillator in its quantum ground state. This implies that the Boulder experiment is in a regime where the imprecision due to noise in the detector’s output is less than half the value associated with the zero-point motion of the oscillator — thus fulfilling one of the two crucial requirements for actually reaching the standard quantum limit. The other requirement is to ensure that the size of the back action is no larger than the minimum value set by the uncertainty principle. Although this is expected to be true, it was not possible to verify in the current Boulder set-up because the expected

back action was obscured by the thermal fluctuations of the beam.

However, this problem could be overcome by harnessing the damping effect of the back action to cool the resonator to its ground state. Progress in this direction was recently demonstrated when Keith Schwab of the California Institute of Technology, and co-workers at Cornell University and the University of Maryland (with theoretical input from the present author), used a similar microwave system to cool a mechanical resonator to a state with only 3.8 thermal quanta7. Combining this cooling method with the measurement technique demonstrated by Teufel, Lehnert and colleagues should bring the standard quantum limit within the reach of experiments. This ideal sensitivity would in turn make possible a number of fascinating experiments that probe the quantum nature of the mechanical resonator; for example, one could continuously monitor the zero-point fluctuations of the resonator in time2.

It is worth pointing out that optomechanical systems, where an optical cavity is coupled to a mechanical resonator, are also able to reach the limit where the measurement imprecision is smaller than that at the standard quantum limit. However, these experiments typically involve beams with lower resonant frequencies and are difficult to cool cryogenically, which would make it difficult to reach the quantum ground state. Researchers at the Max Planck Institute for Quantum Optics and the Ecole Polytechnique Fédérale de Lausanne recently took an important step in overcoming these limitations by using a combination of cryogenic and back-action cooling to prepare an optomechanical system containing about 60 thermal quanta while achieving a measurement imprecision below the value needed for the standard quantum limit8.

On a broader level, the achievement of the Boulder team shows how innovative measurement and amplification strategies that evade the usual quantum limits can be successfully used in electronic systems to achieve unprecedented sensitivity. A crucial challenge for future work will be to exploit the possibilities presented by the ability to make truly quantum-limited measurements. One possibility would be to implement ideas for quantum control and feedback: these approaches could allow researchers to prepare and study highly non-classical mechanical states, and provide insights into the quantum dissipation of these states.

Another direction would be to use these strategies for ultrasensitive force

100 μm

10 μm

Figure 1 | Schematic showing the microwave resonant circuit used to measure the position of a nanomechanical resonator (the aluminium nanowire shown in the dashed circle) with an imprecision below that at the standard quantum limit. The microwave circuit is made from aluminium (grey) on a silicon substrate (blue). The system behaves like an LC circuit with a fixed inductance L and a capacitance C that is modulated by the motion of the resonator. The capacitor is formed by the aluminium nanowire and a piece of metal immediately to the right of the nanowire. Microwave systems have two advantages over optical systems in this type of experiment. The resonators can be smaller, which leads to larger zero-point motions (making it easier to detect quantum phenomena) and higher resonant frequencies (making it is easier to cool the system towards its ground state). They are also, in general, more compatible with cryogenic cooling, again making it easier to get close to the ground state, although cryogenic cooling of an optomechanical system has recently been demonstrated8.

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detection at the nanoscale: the Boulder group’s technique1 already allows a record force sensitivity over a relatively large bandwidth. Meanwhile, Schwab and co-workers9 have recently used a microwave approach to evade the effect of back action by driving the cavity coherently at two frequencies, but they were only able to achieve a measurement uncertainty of about 16 times the zero-point value because they used a commercial microwave voltage

amplifier. Combining their measurement scheme with the Josephson parametric amplifier used by the Boulder team would be extremely interesting, as true sub-quantum-limited measurements would then be possible. ❐

Aashish Clerk is in the Department of Physics, McGill University, Montreal, Quebec H3A 2T8, Canada. e‑mail: clerk@physics.mcgill.ca

References1. Teufel, J. D. et al. Nature Nanotech. 4, 820–823 (2009).2. Clerk, A. A., Devoret, M. H., Girvin, S. M., Marquardt, F. &

Schoelkopf, R. J. Preprint at <http://arxiv.org/abs/0810.4729> (2008).3. Caves, C. M. Phys. Rev. D 26, 1817–1839 (1982).4. Knobel, R. & Cleland, A. N. Nature 424, 291–293 (2003).5. Naik, A. et al. Nature 443, 193–196 (2006).6. Etaki, S. et al. Nature Phys. 4, 785–788 (2008).7. Rocheleau, T. et al. Preprint at

<http://arxiv.org/abs/0907.3313> (2009).8. Schliesser, A. et al. Nature Phys. 5, 509–514 (2009).9. Hertzberg, J. B. et al. Preprint at

<http://arxiv.org/abs/0906.0967> (2009).

One of the reasons that cancer is such a deadly disease is that tumour cells can spread from one organ

to another and spawn new tumours in a process known as metastasis. Renegade cancer cells that break away from primary tumours and enter the bloodstream are called circulating tumour cells, and identifying and destroying these cells is a highly challenging problem1. Researchers have tried to detect and isolate these circulating cells by running samples of blood through a microchip, but large volumes of blood are needed if only a few cells are present2. Various approaches to the in vivo detection of these cells have been proposed, but they involve observing small volumes of blood over a long period of time3,4.

On page 855 of this issue, Vladimir Zharov and colleagues5 of the University of Arkansas and Emory University in the US, and Saratov State University in Russia report the use of magnetic nanoparticles to trap rare circulating tumour cells in the bloodstream of mice under a magnet, followed by rapid detection using two-colour photoacoustic methods. The use of gold-plated carbon nanotubes as a second contrast agent allowed multiplex detection. With this approach, circulating tumour cells could be concentrated from a large volume of blood in the vessels of mice, allowing early diagnosis of cancer and, potentially, the prevention of metastasis.

Two types of nanoparticles were made to bind different receptors on cancer

cells (Fig. 1). Magnetic nanoparticles were targeted to the urokinase plasminogen activator receptors that are highly expressed on many types of cancer cells but are found at low levels in normal cells, whereas the gold-plated carbon nanotubes were targeted to folate receptors that are expressed in many cancer cells but are absent in normal blood cells6. Each nanoparticle species responds optimally to different wavelengths of light and so a two-wavelength system can uniquely identify circulating tumour cells that are labelled with both nanoparticles.

Mice with tumours at different stages of development were injected with a cocktail of both nanoparticles; after 20 min a magnet was attached to the mice, and circulating tumour cells that were targeted by the nanoparticles and captured under the magnet were monitored using a sensitive photoacoustic detection system. When the tissue surface is illuminated with nanosecond pulses of laser light, the subsurface light is absorbed by the nanoparticles. The light energy that is converted to heat induces a rapid thermoelastic expansion, resulting in ultrasound waves that are detected by the photoacoustic system.

By engineering the plasmon resonance of the nanoparticles to match the incident wavelength of light, very high optical absorption of the nanoparticles was achieved. Moreover, a very strong photoacoustic effect was produced using these nanoparticles because the laser-induced heating, which is thermally confined to a small volume, can cause the temperature rise around the nanoparticles to be very high. This means that the photoacoustic signature of

NANOMEDICINE

Detecting rare cancer cellsMagnetic nanoparticles and gold-plated carbon nanotubes allow rapid detection of circulating tumour cells in the blood vessels of mice using two-colour photoacoustic methods.

Roger J. Zemp

Ultrasound receiver

Laser

MagnetS

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Blood vessel

Photoacoustic signals

Magnetic trapping ofcirculating tumour cells

Circulating tumour cell

Targeted magneticnanoparticle

Targeted goldencarbon nanotube

Figure 1 | Capturing and detecting circulating tumour cells. Magnetic nanoparticles and gold-plated carbon nanotubes both target tumour cells. The combination of magnetic enrichment (courtesy of the magnet) and photoacoustic detection (the laser and ultrasound receiver) allows in vivo detection of circulating tumour cells.

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