J O S E P H P. H E R E M A N S

More than 90% of the energy we use comes from thermal processes1, which produce the bulk of the

electricity generated by power plants, as well as powering aeroplanes and most cars. Heat engines have existed since the early eighteenth century, drove the Industrial Revolution and gave rise to the science of thermodynamics. Thermoelectricity was discovered about a cen-tury later2 and is based on the same thermody-namic principles that heat engines depend on, except for the fact that thermoelectric power generators use electrons, rather than steam or air, as the working fluid. A testament to the importance of these fields is the fact that pro-gress in the thermal sciences has been unre-lenting: this includes work by Zhao et al.3 on page 373 of this issue.

The second law of thermodynamics dictates that, to deliver work, heat engines must oper-ate between a source of heat at a hot tem-perature (Thot) and a heat sink at a cooler temperature (Tcold). The Carnot efficiency, ηmax = 1 - (Tcold/Thot), is the upper bound for the efficiency (η) of a heat engine, where η is the ratio between the amount of work an engine does and the amount of heat it uses. A thermoelectric generator works as follows.

A temperature gradient, ,T, across two thermo electric materials — a semiconductor in which most of the charge carriers are electrons (n-type semiconductor) and a semiconduc-tor that has mostly notional holes created by the absence of electrons (p-type) — creates an electric field, E, between the cold side and the hot side of each material (Fig. 1). The Seebeck coefficient, S, which is given by the ratio E/,T and is negative for the n-type material and posi-tive for the p-type, corresponds4 to the entropy of the electron divided by its charge. The two materials complete a cycle that converts the heat supplied at the hot side into electrical power. Assuming that S does not vary along the length of each thermoelectric material even though the temperature does, if this cycle were reversible it would have the Carnot efficiency.

Thermodynamically irreversible processes limit the efficiency of the cycle to a value much lower than that of the Carnot efficiency. Examples of such processes are heat conduc-tion through the crystal lattice of atoms that constitute the semiconductors and the Joule heating that arises inside the semiconductors when the voltage produced by the electric field is used to deliver a current to an external elec-trical load (Fig. 1). The fraction of the Carnot efficiency of a thermoelectric cycle is quanti-fied by the thermoelectric figure of merit ZT

oscillator stalls (Fig. 1c). As a result, the activity of the intracellular module follows that of the QS module. Once the proteins produced by the QS module are degraded to lower levels, sufficient ClpXP is available to degrade λ-repressor protein again, and the intra cellu lar oscillator returns to its normal, high-frequency oscillations.

Prindle and co-workers’ approach does not require complex engineering to synchro-nize the oscillators because the authors have tinkered with the cell’s own components. Moreover, whereas genetic devices are often designed to minimize the interactions between different components of the biocircuit, here these interactions have been strength-ened. This strategy is appealing because the researchers’ data suggest that exploration of the synergistic interactions between genetic devices and host cells will benefit circuit build-ing in synthetic biology.

Prindle and colleagues’ results provide an excellent argument for using the cell’s

natural machinery to integrate multiple syn-thetic components, because the authors have achieved fast, tunable and robust synchroniza-tion of two different modules. Complex deci-sion-making circuits might strongly benefit from the authors’ design. However, it is impor-tant to remember that scaling up the number of modules in a circuit remains a major issue within synthetic biology7.

If circuit complexity is to grow in size and diversity, further improvements will be needed. For example, different strategies will be required to synchronize other types of genetic device, such as logic gates. The current work indicates that it may be possible to isolate dif-ferent parts of a synchronized circuit in differ-ent cells, exploiting the cells as natural units of computation to perform basic logic functions such as AND or NOR. In this context, the use of different cell types communicating with one another to perform different functions might be a natural step forward8–10, expanding on the method designed by Prindle et al. to allow

generation of more complex, decision-making circuits. ■

Ricard Solé and Javier Macía are in the Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain. e-mails: ricard.sole@upf.edu; javier.macia@upf.edu

1. Purnick, P. E. & Weiss, R. Nature Rev. Mol. Cell. Biol. 10, 410–422 (2009).

2. Prindle, A. et al. Nature 508, 387–391 (2014). 3. Oklobdzija, V. G. et al. Digital System Clocking: High-

Performance and Low-Power Aspects (Wiley, 2003).4. Danino, T., Mondragón-Palomino, O., Tsimring, L. &

Hasty, J. Nature 463, 326–330 (2010). 5. Stricker, J. et al. Nature 456, 516–519 (2008).6. Cookson, N. A. et al. Mol. Syst. Biol. 7, 561 (2011).7. Kwok, R. Nature 463, 288–290 (2010).8. Tamsir, A., Tabor, J. J. & Voigt, C. A. Nature 469,

212–215 (2011).9. Regot, S. et al. Nature 469, 207–211 (2011).10. Solé, R. V. & Macía, J. Nat. Comput. 12, 485–497

(2013).

This article was published online on 9 April 2014.

T H E R M O E L E C T R I C I T Y

The ugly ducklingSingle crystals of tin selenide have been shown to display, along one crystallographic direction of their high-temperature state, the highest thermoelectric efficiency of any bulk material. See Letter p.373

Figure 1 | Working principle of a thermoelectric generator. a, A thermoelectric generator consists of two thermoelectric semiconductors (n-type and p-type) subjected to a temperature difference, Thot − Tcold, and electrically connected in series through conducting plates on the top and bottom. In the n-type semiconductor, most charge carriers are negatively charged electrons, whereas in the other one most of the carriers are positively charged holes. In a temperature gradient, electrons and holes tend to accumulate on the cold side. An electric field E develops between the cold side and the hot side of each material, which gives a voltage when integrated over the length of each. The voltages of the n- and p-type semiconductors add up and drive an electrical current through an electrical load, here an electrical resistor. The product of the voltage and the current is the electrical power output of the generator.

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of the system as a whole, which is the average of the zT of the n- and p-type semiconduc-tors, where zT = S2T/ρϰ, with ρ representing each semiconductor’s electrical resistivity, ϰ its thermal conductivity and T the absolute temperature of the device. The thermal con-ductivity has two components: electrons carry some heat (electronic conductivity, ϰe), but most of the heat is carried by phonons, vibra-tions of the atoms in the crystal lattice that also transport sound (lattice conductivity, ϰlat). The goal of thermoelectric research is to discover new materials with maximum zT, by maximiz-ing the ratio S2/ρ and minimizing ϰlat without increasing ρ.

The maximum achievable value of zT has doubled in the past 15 years5 from 1 to 2, thanks to the application of nanotechnology and quantum theory to this problem. Engi-neering the energy-band structure of the materials5 — for example, through the effect of quantum confinement or by enhancing interactions between the wavefunctions of impurities and of free electrons — is used to boost S2/ρ. Decreases in ϰlat can be achieved by phonon engineering5 of the semiconduc-tors — by, for instance, nanostructuring them, generating specific localized lattice vibrations (rattling phonon modes) in them, or selecting atoms that induce chemical bonds that vibrate highly anharmonically6. For decades before Zhao and colleagues’ study, which examined the thermoelectric efficiency of single crystals of tin selenide (SnSe), the record for zT was held by alloys created using several of these techniques in lead telluride7 (PbTe), a semi-conductor that has a simple rock-salt crystal structure and a long history in thermoelectric technology, infrared diode lasers and radiation detectors.

In comparison to PbTe, SnSe is the ugly duckling. Chemically and structurally akin to PbTe, SnSe is lighter, has stiffer bonds and a distorted lattice. This made it seem a poor choice for thermoelectrics; indeed, SnSe has a low zT at room temperature. It was a surprise to learn that Zhao and colleagues had inves-tigated SnSe at all, let alone to see it achieve the highest zT (2.6 along one crystallographic direction of its high-temperature phase) of any bulk material in an as-grown sample; that is, one without any addition of impurities or other optimization. SnSe has good prospects for practical use: it is not subject to the legis-lation that limits the use of Pb, contains only Earth-abundant elements (unlike Te), and can be prepared with good reproducibility3.

Finally, the physics of SnSe is fascinating. The authors attribute the material’s low ϰlat to the high anharmonicity of its chemical bonds. A solid with purely harmonic bonds would look like a three-dimensional array of balls and springs. If an atom is pulled from its equilibrium position during the passage of a phonon, the force that the atom is subjected to is proportional to its displacement, and the

proportionality constant of this relationship is called the spring constant. In an anharmonic solid, the spring constant does not remain constant with atom displacements, which has important consequences when two phonons run into each other. The presence of the first phonon then changes the value of the spring constant seen by the second phonon. The sec-ond phonon thus runs into a medium with modified elastic properties, which is more likely to reflect it. Anharmonicity results in enhanced phonon–phonon scattering, which reduces ϰlat without affecting the solid’s elec-tronic properties5,6. Therefore, this effect may well be behind the high zT of SnSe, an idea that will stimulate further experimental and theoretical work. ■

Joseph P. Heremans is in the Departments of Mechanical and Aerospace Engineering and of Physics, Ohio State University, Columbus, Ohio 43210, USA.e-mail: heremans.1@osu.edu

1. www.iea.org2. Seebeck, T. J. Magnetische Polarisation der

Metalle und Erze durch Temperatur-Differenz (Abhandlungen der Preussischen Akad. Wissenschaften) 265–373 (1822–23; reprinted W. Engelmann, 1895).

3. Zhao, L.-D. et al. Nature 508, 373–377 (2014).4. Callen, H. B. Thermodynamics: An Introduction to the

Physical Theories of Equilibrium Thermostatics and Irreversible Thermodynamics (Wiley, 1960).

5. Heremans, J. P., Dresselhaus, M. S., Bell, L. E. & Morelli, D. T. Nature Nanotechnol. 8, 471–473 (2013).

6. Nielsen, M. D., Ozolins, V. & Heremans, J. P. Energy Environ. Sci. 6, 570–578 (2013).

7. Biswas, K. et al. Nature 489, 414–418 (2012).

S U Z A N N E W O L F F & A N D R E W D I L L I N

Cellular organelles are simultaneously distinct from the rest of the cell and completely reliant on it for their

identity and function. A poignant example of this nebulous individualism comes from the mitochondrion, a subcellular entity that began long ago as an independent organ-ism but which, over millennia, has become increasingly dependent on the rest of the cell, and now serves as its energy-generating centre. Inter actions between the mitochon-drion and the cell provide this organelle with a direct connection to changes in the contents of its surroundings, allowing it to initiate defence mechanisms when things go awry. In this issue, Liu et al.1 (page 406) report the effect of cellular and microbial metabo-lites on the initiation of protective reactions in mitochondria.

When changes occur that are stressful to mitochondria (for example, changes in their ability to import the molecules required for normal function), they activate a protective program called the mitochondrial unfolded protein response2 (UPRmt). This defence mechanism is designed to maintain normal mitochondrial function, and its activation is typically symptomatic of an imbalance in the cell. A diverse set of stimuli can activate the UPRmt, including disruption of the proteins, import machineries and protease enzymes that

help the mitochondrion to function3. Initiation of this defence begins with transportation of the transcription factor ATFS-1 — consid-ered to be the major factor in mitochondrial protection against stress4 — to the nucleus, where it upregulates expression of other genes involved in the response. By contrast, under non-stressed conditions, ATFS-1 is imported into mitochondria, where it is readily degraded by proteases4.

Liu et al. report that when they induced the UPRmt in the nematode worm Caenorhabditis elegans, by genetically or pharmacologically inactivating genes involved in normal mito-chondrial function, the worms displayed an aversion to bacteria — their typical source of food. They hypothesized that UPRmt induc-tion might cause such a change in behaviour because the cell interprets the program’s activa-tion as symptomatic of a pathogenic attack or as a sign of poor nutrient availability (Fig. 1). If so, this could imply that variations in metabo-lite levels, which might be caused by the pres-ence of pathogens or a lack of nutrients, play an integral signalling part in the activation of mitochondrial stress responses. These hypoth-eses are supported by previous observations suggesting a variety of methods by which bacteria are linked to and influence metabo-lism5 and mitochondrial stress6 in C. elegans.

Next, Liu and colleagues set out to define the intracellular metabolic pathways that are required for UPRmt induction. Using

C E L L B I O L O G Y

The stressful influence of microbesAn investigation into cellular stress responses reveals how cell compartments called mitochondria use information about the surrounding metabolites and microorganisms to protect themselves from damage. See Letter p.406

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