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Cell membranes are primarily heterogeneous liquids that exhibit a high degree of dynamic spatial

organization1,2, where membrane proteins are distributed into clusters and groups of clusters that dynamically restructure according to the conditions of the cell and its environment. Although the nature of the organization remains hotly debated3, several observations are indisputable. For example, under physiological conditions, unsaturated phospholipids in lipid–cholesterol membranes separate from cholesterol and saturated phospholipids4,5. Also, lipids in cell membranes are apparently poised near a miscibility critical point, as measurements of critical exponents in giant plasma-membrane vesicles derived directly from living cells revealed6. Now, Anand Subramanaian, Howard Stone and colleagues report in Nature Materials that the spatial arrangement of multiphase lipid membranes supported on networks of glycans — polysaccharides that reside adjacent to cellular membranes — falls in registry with patterns of glycan density7.

Using instability-driven pattern-formation processes to fabricate glycan surfaces, the authors generated macroscopic

patterns of glycan-rich and glycan-poor regions. Then they imaged with optical microscopy the macroscopic organization of coexisting single-phase domains (liquid ordered (Lo) with liquid disordered (Ld), or solid ordered (So) with Ld) in lipid bilayers supported on the patterned glycan substrates. They found that membranes resting on inhomogeneous glycan networks showed macroscopic lipid domains that were stable at room temperature (Fig. 1a,b), and that the characteristic length scales of the domains matched those of the supporting glycan network (Fig. 1c). From the analysis of the images they also concluded that the more ordered liquid (Lo) and solid (So) phases of the multiphase membranes exhibited greater affinity for the glycan-rich regions of the patterned substrate.

These observations illustrate a fundamental principle of the phase behaviour of lipid membranes: they are sensitive to environmental factors. Moreover, the findings of Subramaniam and co-authors are related to the fact that the membranes’ equilibrium states lie close to a miscibility critical point. This can be understood from a miscibility phase diagram (Fig. 2). At

the critical point and along the spinodal line, changes in composition are entirely unimpeded and the boundary energy (line tension) between coexisting phases vanishes. This means that as a lipid membrane approaches the critical point it becomes progressively more sensitive to external perturbations8,9. The mere existence of multiple phases and a nearby miscibility transition temperature guarantees that entropic components (which favour mixing) and energetic effects (which promote demixing) are nearly balanced. Therefore, even small perturbations can be expected to influence the membrane’s phase behaviour. This is what Subramaniam and colleagues have observed in their model experimental system.

The authors also found that homogeneous glycan networks are able to suppress macroscopic phase separation in the supported membranes (Fig. 1d,e). This observation is, however, not a direct corollary to the finding of templated phase organization on patterned glycan substrates. Actually, although in the absence of external forces the macroscopic shape of coexisting domains is governed by the minimization of boundary energy — and in flat bilayer membranes domains are round and grow by coalescence and Ostwald’s ripening — it takes only a weak perturbation to overcome the formation of round domains and drive the reorganization of existing phases, especially near a critical point. Such perturbation effects have been observed in supported membranes, for example by templating membrane curvature, but these did not affect the miscibility transition temperature10. As perturbations were relaxed, the coexisting domains exhibited a random configuration as they would in a free (unsupported) membrane — a stark contrast to the behaviour of membranes on glycan substrates.

Then, why does an intrinsically phase-separating membrane become homogeneous when there are no large-scale patterns on the glycan substrate? One possibility, of course, is that phase separation is present but at length scales below the limits of classical optical imaging.

CELL MEMBRANES

Glycans’ imprintsNetworks of glycans template multiphase lipid membranes, either by stabilizing large domains at the characteristic length scale of the network if inhomogeneous, or by suppressing macroscopic phase separation if homogeneous.

Jay T. Groves

Glycan Lipid: So/LdGlycan Lipid: Lo/Ld

Glycan Lipid: So/LdGlycan Lipid: Lo/Ld

Lo/LdSo/Ld

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L lipi

d (m

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d e

Figure 1 | The spatial organization of multiphase lipid membranes resting on glycan networks7. a,b, Inhomogeneous glycan networks imprint their structure on membranes showing coexistence between liquid-ordered (Lo) and liquid-disordered (Ld) (a), and solid-ordered (So) and Ld (b) domains. c, The characteristic length scale of the coexisting lipid domains (Llipid) matches that of the glycan network (Lnetwork). d,e, Multiphase membranes on homogeneous glycan networks do not exhibit macroscopic phase separation. Scale bars, 5 μm.

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In fact, this argument arises frequently with respect to why macroscopic phase separation is not directly visible in live cell membranes. If, on the other hand, the supported membrane is truly mixed, then one should conclude that the glycan substrate exerts a more extensive influence over the structure of the supported membrane and shifts the phase diagram of the system. A small shift could actually give rise to a large change in the macroscopic appearance of the membrane, especially in the vicinity of a critical point.

If the glycan substrate does indeed directly manipulate the thermodynamics of the lipid phase transitions, this has broad consequences for the interpretation of the role of lipids in live cell membranes. For one, the phase behaviour of free lipid membranes (for instance, as measured in giant unilamellar vesicles) may be a poor indicator of the phase behaviour of the composite system that is a cell membrane. In fact, glycan networks as well as other polymeric structures, such as the cortical actin cytoskeleton, are in intimate contact with cell membranes and could exert defining influence over the organization of the membranes’ phase

structures and transition temperatures. Extensive interactions among proteins are also known to occur in membranes, and

the resulting macromolecular structures may substantially alter the phase behaviour of the surrounding lipids. Overall, there is abundant evidence that the lipid composition of cell membranes is precisely regulated and essential for function. It may then well be that such a highly responsive medium is just what is required to allow membrane processes to work. ❐

Jay T. Groves is a Howard Hughes Medical Institute Investigator in the Department of Chemistry, University of California, Berkeley, California 94720, USA. e-mail: jtgroves@lbl.gov

References1. Singer, S. J. & Nicolson, G. L. Science 175, 720–731 (1972).2. Lingwood, D. & Simons, K. Science 327, 46–50 (2010).3. Leslie, M. Science 334, 1046–1047 (2011).4. Shimshick, E. J. & McConnell, H. M. Biochemistry

12, 2351–2360 (1973).5. Veatch, S. L. & Keller, S. L. Phys. Rev. Lett. 89, 268101 (2002).6. Veatch, S. L. et al. ACS Chem. Biol. 3, 287–293 (2008).7. Subramaniam, A. B., Guidotti, G., Manoharan, V. M. &

Stone, H. A. Nature Mater. 12, 128–133 (2013).8. Groves, J. T., Boxer, S. G. & McConnell, H. M.

Proc. Natl Acad. Sci. USA 95, 935–938 (1998).9. Groves, J. T., Boxer, S. G. & McConnell, H. M. J. Phys. Chem. B

104, 119–124 (2000).10. Parthasarathy, R., Yu, C-H. & Groves, J. T. Langmuir

22, 5095–5099 (2006).

The spin degree of freedom associated with electrons and nuclei is being intensively investigated as a key

element of future quantum technologies. A spin can be considered as a tiny bar magnet with two states, pointing either up or down (Fig. 1a). However, quantum mechanics also allows it to be in a superposition state in which it simultaneously points in both directions. By encoding the two states (up and down) as logic 0 and 1, the spin forms a ‘quantum bit’ (or qubit), the elementary building block for quantum information processing. Although both electronic and nuclear spins can be used as physical realizations of qubits, they each have their own pros and cons. Writing in Nature Materials, Morley and colleagues1 demonstrate a hybrid qubit system that avoids their respective disadvantages, by combining the electronic and nuclear spins of bismuth-doped silicon.

Generally speaking, quantum states are fragile and quantum information is easily lost in solid-state materials due to environmental noise. An ideal qubit should therefore be able to preserve the quantum information for long timescales. The state of a qubit can be illustrated as a vector (Fig. 1), and the effect of the environmental noise is to randomize its orientation, which implies leakage of the quantum information it stores (Fig. 1c). Owing to their small magnetic moments, nuclear spins are orders of magnitude less sensitive to noise compared with their electron counterparts (Fig. 1d). Consequently the quantum information can be preserved for timescales lasting up to minutes. In this regard, nuclear spins are considered as the most promising candidates for quantum memories.

Another desirable quality for a qubit is that it should also be possible to

manipulate and read out efficiently2. As for classical computers, quantum information processing requires logic gates, albeit quantum in nature. For example, flipping the spin states of a qubit (from up to down, and vice versa, Fig. 1a) corresponds to a quantum NOT gate. Spin states are usually manipulated by applying alternating magnetic fields, and whereas electron spins can be typically flipped in tens of nanoseconds, nuclear spins are thousands of times slower at performing the same operation (Fig. 1b). Again, this is a consequence of their small magnetic moments. Therefore the efficiency with which electronic qubits can be manipulated makes them the best choice for realizing a quantum processor.

Morley and colleagues1 show that electronic and nuclear spins of bismuth donors in silicon can be mixed to form hybrid qubits. As is the case for the

QUANTUM INFORMATION

Best of both worldsBoth electronic and nuclear spins have their pros and cons for quantum information processing. A silicon-based hybrid electronic–nuclear system can make the best of both properties.

Nan Zhao and Jörg Wrachtrup

Figure 2 | Schematic of a binary miscibility phase diagram of a lipid membrane. For temperatures below the critical point, a membrane with composition falling within the unstable region will spontaneously phase separate into coexisting phases with compositions corresponding to those marked by the binodal line at the same temperature. At the conditions corresponding to the spinodal line, the membrane is intrinsically unstable to perturbation. The membrane’s sensitivity to perturbations (grey lines denote contours of equal sensitivity) decreases the further the composition is from the unstable region.

Spinodal

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