Vol 435|16 June 2005

NEWS & VIEWS

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LOW-TEMPERATURE PHYSICS

Tunnelling into the chillJukka Pekola

The trend towards ever smaller electronic instruments had left refrigerators out in the cold. Now a practical, compact device uses quantum mechanical tunnelling to cool close to absolute zero.

The French physicist Jean Peltier discovered in1834 that when an electrical current is passedthrough a solid-state circuit, heat is in somecases removed. Yet one obvious application, asolid-state micro-refrigerator capable of cool-ing to cryogenic millikelvin temperatures, hasremained science fiction. Writing in AppliedPhysics Letters, Clark et al.1 report significantprogress in constructing such a device.

Several sophisticated astronomical and ana-lytical instruments rely on thin-film sensorsthat must be cooled to temperatures of 0.1 K or lower. One example is the satellite-based,ultrasensitive radiation detectors that arebeing used in the search for anisotropy — tinytemperature fluctuations — in the cosmicmicrowave background thought to be leftoverradiation from the Big Bang. Advances inmicrofabrication mean that such sensors canbe very small and light — an obvious advan-tage in space-borne astronomical instruments.So the required combination of small bulk and low-temperature operation highlights theneed for miniaturized refrigerators. In 1994,Nahum et al.2 demonstrated the so-called NISrefrigeration effect using a metallic thin-filmdevice, and since then progress has been rapid.Clark et al.1 now supply a first practical devicebased on this effect.

The principle of NIS refrigeration is simple(Fig. 1): a normal metal (N) is separated by aninsulating (I) barrier from a superconductor(S). Electrons can pass across the insulating barrier only by quantum tunnelling — a consequence of the uncertainty in quantummechanics that means there is a finite proba-bility of finding a particle on the other side of abarrier, even if, in terms of classical physics, itdoes not possess enough energy to surmountthat barrier. Cooling occurs as a consequenceof the different electron configurations in theN and S regions: in the normal metal, electronsoccupy states with an almost constant densityover the whole range of relevant energies,whereas in the superconductor there is a gap inwhich no electron energy states exist. Elec-trons in the normal metal at energies corre-sponding to the gap in the superconductor areforbidden from tunnelling through the insu-lating barrier.

In the absence of an external voltage, the Nand S regions are in thermodynamic equilib-rium, with their zero energy points (‘chemicalpotentials’) aligned — in the middle of theenergy gap in S (Fig. 1). Applying a voltage Vacross the barrier shifts the chemical potentialof N relative to that of S. At low temperatureand voltage, the relative shift of the zero levelsis not sufficient to allow electric current to

flow between N and S, as the energy of theoccupied states in N still corresponds either toforbidden states in the gap, or to occupiedstates below the energy gap in S — thus quantum tunnelling remains forbidden. But at higher voltages, as the energy shift in Napproaches �, half of the energy gap in S, current suddenly starts to flow owing to thevertical matching of the most energetic occu-pied states in N and the empty, but allowed,states above the energy gap in S. As only themost energetic electrons are free to tunnel, theelectron gas left behind has a lower averageenergy than existed before tunnelling — thus,the electron system in N cools down.

Cooling of a micrometre-scale, thin-filmcopper bar from 300 millikelvin down to 100mK using a double-junction NIS device wasdemonstrated in 1996, and temperaturesbelow 50 mK were reached last year3,4. How-ever, the cooling power in these experimentswas low — typically of the order of one pico-watt (10�12 W) — insufficient to cool astro-nomical detectors, where the backgroundradiation typically exceeds this level. The cool-ing power has since been increased by almosttwo orders of magnitude by scaling up thephysical dimensions of the refrigerator5,6.

In most applications, however, chilling theelectrons alone is not enough: heat must alsobe removed from the platform that houses thedetector (or sample) to be cooled. One way to do this is to thermally isolate a dielectricplatform (typically, a thin membrane of siliconnitride) by micromachining techniques, andto suck the heat from it to the cooled electronsin the NIS refrigerator. This approach has pre-viously been used7 to reduce the temperatureof such an insulating apparatus by a factor oftwo, from 200 to 100 mK.

New processes and different combinationsof materials have since enhanced the coolingpower of NIS refrigerators still further6. Clarket al.1 incorporate these techniques into a full refrigerator, and test its cooling power on a ‘macroscopic’ germanium resistance thermometer in the form of a 250-�m-sidedcube glued onto a silicon nitride membrane.Their device can reduce the temperature ofthis system significantly below that of its

eV

k BT

EnergyN SI

Figure 1 | The working principle of the NIS micro-refrigerator devised by Clark et al.1. In a normalmetal (N), energy states are filled with electronsat almost a constant density up to the chemicalpotential, which represents the top of theoccupied energies ‘smeared’ by an amount kBT,where kB is the Boltzmann constant and T is thetemperature in N. The electronic structure of asuperconductor (S) differs fundamentally fromthat of a normal metal in that it possesses anenergy gap of width 2� in which no electronenergy states are found. At very low temperatures,states in S are perfectly filled below the gap andempty above it. Applying a voltage V to the NISsystem causes the chemical potential (dottedline) of the metal to shift relative to that of thesuperconductor by an amount eV (e is the chargeon an electron). If V is sufficiently high, the mostenergetic filled states in N correspond to empty,but allowed states in S, enabling quantumtunnelling of electrons from N to S through theinsulating barrier (I) to take place. The energy ofthe electron system left behind in N is thereforereduced, resulting in cooling.

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surroundings — from 320 to 220 mK. Theauthors are thus the first to refrigerate a separate ‘bulky’, three-dimensional object,using an electronic method, down close toabsolute zero. And they believe that moreeffective heat removal from the hot side of therefrigerator and the use of numerous coolerelements in parallel will allow them to improveboth the attainable temperature reduction andthe surplus cooling power.

The work of Clark et al. is an exciting development towards a fully solid-state, cryogen-free micro-refrigerator, which couldeventually cover temperatures from the ambi-ent down to the millikelvin range. Such anachievement would have an enormous impactin overcoming the ‘cryophobia’ that at presentprevents the large-scale use of many devices

and sensors that can operate only at very lowtemperatures. ■

Jukka Pekola is in the Low TemperatureLaboratory, Helsinki University of Technology, PO Box 3500, Tietotie 3, Espoo 02150, Finland.e-mail: jukka.pekola@tkk.fi

1. Clark, A. M. et al. Appl. Phys. Lett. 86, 173508 (2005).2. Nahum, M., Eiles, T. M. & Martinis, J. M. Appl. Phys. Lett.

65, 3123–3125 (1994). 3. Leivo, M. M., Pekola, J. P. & Averin, D. V. Appl. Phys. Lett.

68, 1996–1998 (1996).4. Pekola, J. P. et al. Phys. Rev. Lett. 92, 056804 (2004).5. Luukanen, A. et al. in Proc. 9th Int. Workshop on Low

Temperature Detectors Vol. 605 (eds Porter, F. S.,McCammon, D., Galeazzi, M. & Stahle, C. K.) 375–378(AIP, Melville, NY, 2002).

6. Clark, A. M., Williams, A., Ruggiero, S. T., van den Berg, M. L. & Ullom, J. N. Appl. Phys. Lett. 84, 625–627 (2004).

7. Luukanen, A. J., Leivo, M. M., Suoknuuti, J. K., Manninen, A. J. & Pekola, J. P. J. Low Temp. Phys. 120, 281–290 (2000).

of the diversity among people. For example, ifenough mobile DNA insertions occur in thebrains of developing humans, then the out-come might be a change in their neuronal circuitry, for better or for worse.

One surprising find from this work is thatL1 elements are actually active in NPCs. Theseelements are considered by many researchersto be no more than genetic parasites. From anevolutionary standpoint, L1 elements shouldbe most successful if their expression isrestricted to germ cells (sperm and oocytes),or to stem cells early in development, becausemobility in these cell types will lead to anexpansion in the number of L1 elements. Conversely, de novo L1 insertions in other cell types (somatic cells) cannot be passed onto future generations, and, if detrimental tohost reproduction, would harm the chances ofL1 propagation.

In fact, previous studies of L1 expressionand mobility demonstrate L1 activity in germcells and in early developmental cells4–6, butnot in other cell types. There has been only oneprevious example of L1 mobility in a humansomatic cell: this insertion disrupts a gene thatcontributes to colon cancer7. Muotri et al. pro-vide the first evidence of L1 activity in normalcells cultured directly from an animal sample,and the first evidence of somatic L1 activitylate in development of a transgenic mouse.

The expression of L1s in NPCs appears to be inversely correlated with the expression ofSOX2, a gene that is poorly expressed in devel-oping NPCs but that has several vital functions

in adult neural cells. The authors furtherdemonstrate that L1 activation is related tochanges in histone proteins that are associatedwith gene expression in general. Histonesinteract directly with DNA, and their acetyla-tion and methylation pattern can determinewhether a region of DNA is ‘open’ and tran-scribed8. That histone modification might be ahost mechanism to control L1 activity is anintriguing possibility.

Also a surprise is the extent to which denovo L1 insertions affect NPC development.An analysis of mammalian genomes demon-strates that L1 elements insert more or lessrandomly, landing both within and outsidegenes9,10. The authors have not analysedenough de novo insertions from culturedNPCs to achieve statistical significance, butthere seems to be a striking preference forinsertions into or near genes. This particularlyapplies to genes that are neuronally expressed— in two cases (out of 17) insertions occur inthe same neuronally expressed gene. Evenmore interesting is the finding that NPC dif-ferentiation is affected by L1 insertions. Theresearchers convincingly demonstrate that onesuch insertion into the Psd-93 gene increasesthe expression of that gene, which in turninduces neural differentiation.

Why is there a discrepancy between the random insertion pattern of L1 elements pre-viously found in the genome, and the apparentnon-random insertion pattern observed incultured NPCs? One possibility is that ‘open’areas of DNA are more accessible for L1 inser-tion, and perhaps there are fewer ‘open’ areasin NPCs than in germ cells. Neuronallyexpressed genes are by definition ‘open’ inneuronal cells, and may be preferred sites fornew insertions. Future experiments shoulddetermine whether the non-random insertionpattern also occurs in vivo or is peculiar to cultured cells.

Muotri et al.2 hypothesize that mobile ele-ments could affect neuronal development anddiversity of brain function in humans, butthere are several questions to be answeredbefore this can be accepted. First, is the frequency of de novo insertions high enoughto affect neuronal function? Most NPCs arenot expected to contain de novo insertions,and many NPC insertions will have no effecton neuronal function (Box 1). Considering the predicted rarity of these events in vivo, the effects of mobile elements on neurons may be limited. That said, the authors did find several examples of these events in cultured cells.

Second, is the ability of L1 to move in NPCsa random quirk of nature? Or is this an evolu-tionarily maintained mechanism that createsindividual variation? At first glance, it wouldseem that this process cannot be evolutionar-ily maintained. Any insertions that occur inNPCs are not passed on in the germ line, soany changes that insertions make to an indi-vidual are eliminated with each generation.

GENETICS

LINEs in mindEric M. Ostertag and Haig H. Kazazian Jr

At least half the human genome consists of mobile elements, such as LINEs,some of which can jump around the genome. These elements have beencrucial in genome evolution, but they may also contribute to human diversity.

Barbara McClintock won the Nobel Prize inPhysiology or Medicine in 1983 for predictingthe existence of mobile elements, pieces ofDNA that move from one place in the genometo another. McClintock called them ‘control-ling elements’ and proposed that they couldaccount for developmental differences amongindividuals of a species — explaining, forexample, the differences in maize-kernelcolour that she observed1. Although her ideaswere not well received at the time, they haveproven to be remarkably prescient. On page903 of this issue, Muotri et al.2 provide evidence that mammalian mobile elements may have a role in creating “the uniqueness ofindividuals within a population”.

Mobile elements, also called jumping genes,exist in all living things, but the ‘long inter-spersed nucleotide element-1’ (LINE-1, or L1for short) is the only active human mobile ele-ment. This element encodes the machinery tomove itself and to mobilize other elements3.Muotri et al. demonstrate that a human L1 isactive in both cultured rat neural progenitorcells (NPCs) and the NPCs of a transgenicmouse. Remarkably, de novo L1 insertions incultured NPCs sometimes alter the expressionof neuronal genes, thereby affecting NPC differentiation (the process by which the cellsmature into specialized cells).

If L1 insertion occurs in the NPCs of devel-oping human neuronal cells, then some cellswill contain de novo insertions. The authorscautiously speculate that activity of mobile ele-ments might be responsible for creating some

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