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small pore diameter (2 nm; ‘closed’ state).Other agents that affect closure of VDACinclude synthetic polyanions, cellular con-stituents such as NADH, and the so-calledVDAC modulator6. Shimizu et al. now addBcl-xL, Bax and Bak to this list.

The authors reconstituted VDAC in lipo-somes, and show that Bcl-xL stimulates clo-sure of the channel, whereas Bax and Bakfacilitate its opening. Moreover, they showthat Bax and Bak allow cytochrome c to passthrough VDAC. This is surprising, becausethe diameter of VDAC is normally too smallto allow cytochrome c to pass. Shimizu et al.propose that, after VDAC interacts with Baxand Bak, its conformation changes. Thisallows VDAC — possibly in combinationwith Bax or Bak — to form a megachannelthat is permeable to cytochrome c (Fig. 1a).The authors illustrated the requirement forVDAC using mitochondria purified fromVDAC-deficient yeast mutants. When theyadded human Bax to these mitochondria,there was no release of cytochrome c. But bycomplementing the mutant mitochondriawith human VDAC, they restored the abilityof Bax to induce an efflux of cytochrome c.

In fact, VDAC is not the only proteinrequired for the function of Bax in yeast —the ANT (ref. 7) and the F0F1-ATPase protonpump8 are also needed. Moreover, Baxcan interact with the ANT, and Bax doesnot cause death in ANT-deficient yeastmutants7. Shimizu et al. claim that the ANTis not needed for release of cytochrome cthrough VDAC. But perhaps, under somecircumstances, the ANT, through binding toBax, may facilitate opening of VDAC. Such apicture would fit with the PTP openingmodel (Fig. 1b).

Another function of VDAC, in concertwith the ANT, is ATP/ADP exchange — thatis, it allows ATP to move out of the mito-chondria and ADP to move in. In its closedconformation VDAC is impermeable toATP6, and, earlier this year, Vander Heiden etal.9 reported that an early event in apoptosis(before cytochrome c release) is a defectin mitochondrial ATP/ADP exchange. Soperhaps, during apoptosis, the ANT orVDAC (or both) fails to transport adeninenucleotides. In cells rescued by overexpres-sion of Bcl-xL, however, ADP/ATP exchangeis stimulated to sustain coupled respiration9.In light of Shimizu and colleagues’ resultswe can exclude the possibility that VDAC isresponsible for this increase. Instead, itseems that Bcl-xL closes VDAC, but that itmaintains ADP/ATP exchange through aVDAC-independent mechanism.

Members of the Bcl-2 family are multi-functional — control of cytochrome c releaseis only part of their activity. They are foundin other intracellular membranes, such asthe endoplasmic reticulum and nuclearmembranes, raising questions aboutwhether they might control transport of

molecules across other membranes. Theirmitochondrial activity may, however, beprevalent only in cells where the mitochon-dria are likely to be crucial to cell death. Thismay be the case in neurons, where, because oftheir mobility, mitochondria are ideal sen-sors of death signals that impinge on widelyspaced regions such as the cell body, neuritesand synapses. But wherever it may act, thearrival of VDAC into the apoptosis arenapinpoints this protein as a potential thera-peutic target for preventing mitochondrialdysfunction in acute pathologies associatedwith apoptosis.Jean-Claude Martinou is at the SeronoPharmaceutical Research Institute, 14 chemin des

Aulx, CH-1228 Plan-les-Ouates, Geneva,Switzerland.e-mail: jean-claude.martinou@serono.com1. Shimizu, S., Narita, M. & Tsujimoto, Y. Nature 399, 483–487

(1999).

2. Kroemer, G., Zamzami, N. & Susin, S. A. Immunol. Today 18,

44–51 (1997).

3. Green, D. R. & Reed, J. C. Science 281, 1309–1312

(1998).

4. Kelekar, A. & Thompson, C. B. Trends Cell Biol. 8, 324–330

(1998).

5. Mannella, C. A. J. Struct. Biol. 121, 207–218 (1998).

6. Colombini, M., Blachly-Dyson, E. & Forte, M. in Ion Channels

(ed. Narahashi, T.) 169–202 (Plenum, New York, 1996).

7. Marzo, I. et al. Science 281, 2027–2031 (1998).

8. Matsuyama, S., Xu, Q., Velours, J. & Reed, J. C. Mol. Cell. 1,

327–336 (1998).

9. Vander Heiden, M. G., Chandel, N. S., Schumacker, P. T.

& Thompson, C. B. Mol. Cell 3, 159–167 (1999).

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Natural archives of Earth’s past climatetake several forms — sea and lake sed-iments, tree rings, peat bogs and glaci-

er ice — all of which are used in reconstruct-ing climate history. But the records locked upin the large polar ice sheets are especiallyvaluable. Cores of this ice not only allowreconstruction of changes in local tempera-ture and precipitation, but also provideinformation about volcanic activity, stormi-ness, solar activity and atmospheric compo-sition.

Such records have already taken us back150,000 years, a period covering about twoglacial–interglacial cycles. Petit et al. (page429 of this issue1) now extend the mostimportant records to four climatic cycles —that is, to about 420,000 years BP (before pre-sent). This extension has been made possiblebecause, last year, ice-core drilling at Vostokstation in Antarctica reached a record depthof 3,623 m. Most notably, analysis of the coreallows investigation of whether transitionsfrom glacial epochs to interglacials, and backagain, always follow the same pattern orwhether a variety of mechanisms is involved.

Over the past few years, ice cores frompolar regions (Box 1) have delivered a varietyof unexpected results. It is because of ice-core data that we know that large variationsin climate were accompanied by naturallycaused changes in the atmospheric concen-trations of CO2 and CH4 — the most impor-tant greenhouse gases. Cores from Green-land provided the first evidence for fast anddrastic climate changes during the last glacialepoch, including the transition to the pre-sent interglacial (the Holocene, the past10,000 years) in the Northern Hemisphere.The records covering this transition, bothfrom Greenland and from Antarctica,inspired various proposals as to the mecha-nisms causing or amplifying the tempera-ture increase. With the extra data1, these

proposals can now be tested further.The four transitions from glacial to warm

epochs, covered by the new Vostok records,started at about 335,000 years, 245,000 years,135,000 years and 18,000 years BP. From thisone would infer a roughly 100,000-yearperiodicity, and time-series analyses of therecords indeed show a large, 100,000-yearcontribution to periodicity, along withanother at 41,000-year intervals. This sup-ports the idea that changes of the orbitalparameters of the Earth (eccentricity, obliq-uity and precession of axis) cause variationsin the intensity and distribution of solarradiation, which in turn trigger naturalclimate changes.

Of special interest is the interplaybetween greenhouse gases and climate. Allfour transitions from cold to warm climaticepochs have been accompanied by anincrease in atmospheric CO2 from about 180to 280–300 p.p.m.v. (parts per million byvolume; present concentration is 365p.p.m.v.), and in atmospheric CH4 from320–350 p.p.b.v. to 650–770 p.p.b.v. (partsper billion by volume; present concentration1,700 p.p.b.v.). Petit et al.1 report that, withinthe uncertainties in the record, the increasesin Antarctic temperature, CO2 and CH4 werein phase during all four transitions.

By contrast, based on measurements onthe same core, Fischer et al.2 have claimedthat for the last three terminations there wasa time lag of 500 to 1,000 years between thetemperature increase and the CO2 increase.The question of lags and leads in climatechange is obviously a highly important one.But identifying a 500–1,000-year time lag istaking the current data and state of knowl-edge to its limits. Uncertainties stem not onlyfrom the limited sampling frequency but alsofrom the problem of assigning dates tothe air-containing bubbles in the core3 (airbecomes enclosed in bubbles only at about

Climate change

Cornucopia of ice core resultsBernhard Stauffer

© 1999 Macmillan Magazines Ltd

100 m below the snow surface, and so air andice at the same level are of different ages).

Even if there does indeed turn out to bea time lag, CO2 can still be an importantamplifier for the temperature increase dur-ing the glacial–interglacial transition, whichitself lasts several thousand years. However,whether amplification by greenhouse gaseswas responsible for 50% of the temperatureincrease, as Petit et al. speculate, also remainsa hypothesis for the moment. Other amplifi-cation factors are relative humidity (watervapour is a greenhouse gas), surface albedo(changing ice cover and vegetation) andplanetary albedo (changing cloud cover).

The causes and mechanisms of CO2

increase at the beginning of the four transi-tions are also open to debate. From the Vos-tok results for the last two transitions,Broecker and Henderson4 concluded thatthe Southern Ocean is likely to be the mainagent in regulating atmospheric CO2. Simi-larities between CO2 concentration andAntarctic temperature for the previous twotransitions, as well as other parts of therecord, add further support to the idea thatthe Southern Ocean does indeed have a keyrole. But although there are plenty of ideasabout mechanisms linking events in theocean to those in the atmosphere (changes inCO2 solubility, phytoplankton productivity,iron fertilization and so on), there is no clearevidence to support any of them.

The Greenland ice cores revealed that fastand drastic temperature changes in theNorthern Hemisphere are almost synchro-nous with fluctuations in CH4 (ref. 5). Those

fluctuations are caused by variations in theextent and activity of sources (mainly wet-lands in the tropics and in northern meanlatitudes) which depend on temperature andprecipitation rates. Petit et al. speculate thatthe CH4 jumps in the first three transitionshad the same cause as the most recent one,where the evolution of Greenland tempera-

ture is known (the sharp temperatureincrease preceding the start of intense icemelting in the Northern Hemisphere). Ahighly simplified course of events for all fourtransitions would then be as follows: first,changing orbital parameters initiated theend of the glacial epoch; second, an increasein greenhouse gases then amplified the weakorbital signal; third, in the second half of thetransition, warming was further amplifiedby decreasing albedo caused by meltingof the large ice sheets in the NorthernHemisphere.

Analyses of polar ice cores have addedimmensely to our knowledge of the mecha-nisms that govern global climate change.Not least, the results of these analyses pro-vide tests for climate models intended topredict possible future responses to increas-ing concentrations of greenhouse gases. Theresults, however, are not easily come by —ice-core drillings in polar regions (Box 1) arelong and difficult projects, with many pit-falls. The paper by Petit et al.1 is furtherdemonstration that the perseverance of allthose involved in drilling projects — scien-tists, technicians and funding agencies —has ample rewards.Bernhard Stauffer is at the Physics Institute,Climate and Environmental Physics, University ofBern, Sidlerstrasse 5, CH-3012 Bern, Switzerland.e-mail: stauffer@climate.unibe.ch1. Petit, J. R. et al. Nature 399, 429–436 (1999).

2. Fischer, H., Wahlen, M., Smith, J., Mastroianni, D. & Deck, B.

Science 283, 1712–1714 (1999).

3. Schwander, J. et al. J. Geophys. Res. 102, 19483–19494 (1997).

4. Broecker, W. S. & Henderson, G. M. Paleoceanography 13,

352–364 (1998).

5. Chappellaz, J. et al. Nature 366, 443–445 (1993).

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NATURE | VOL 399 | 3 JUNE 1999 | www.nature.com 413

There are ice-drillingprojects in bothAntarctica andGreenland. Conditionsare harsh, and stuckdrills are an ever-presentproblem.

At Vostok, inAntarctica (pictured), theSoviets started deepdrilling in 1980. A depthof 2,202 m was reachedin 1985, when it becameimpossible to continue.A second hole had beenstarted in 1984, and itreached a final depth of2,546 m in 1990. In 1989,the project became aRussian–French–USendeavour, and thefollowing year a thirdhole was started; itreached 2,500 m depthin 1992 (age of the ice atthe bottom being about

200,000 years BP) andfinally 3,623 m in 1998.

In central Greenland,the European GRIP coredrilling reached bedrockin July 1992 at 3,028 mdepth; likewise the USGISP-2 drilling in July1993 (3,053 m depth).The undisturbed part ofboth cores covers the

past 105,000 years. Adeep drilling at North-GRIP will extend the agescale to cover at leastthe last interglacial(135,000 years).

Other projects inAntarctica are being runby various national andinternational groups. In1996 at Dome Fuji (EastAntarctica) the Japanesereached 2,503 m; inJanuary 1999, the USproject on the WestAntarctic ice sheet hitbedrock at 1,004 m. TheEuropean Project for IceCore Drilling inAntarctica (EPICA) is atwork at Dome Concordia(East Antarctica, presentdepth 786 m) and asecond drilling will startshortly in Dronning MaudLand. B.S.

Box 1: Ice cores south and north

Retroviruses

Closing the jointJohn M. Coffin and Naomi Rosenberg

We are starting to understand muchabout how retroviruses integratetheir DNA into host genomes. We

know, for example, how the viral integrasecarries out initial events in the process. Butretrovirologists have tended to ignore thesubsequent reactions, preferring to pass thebuck onto ‘cellular repair systems’. A reportby Daniel et al.1 in Science may now shedthe first ray of light on these systems. Theyhave found that a cellular damage-sensingsystem is implicated in completing retro-viral integration.

Retroviruses integrate their DNA intothat of the host as part of their replicationcycle2 — a feature that sets them apart fromall other agents that infect multicellularorganisms. A structure called the preinte-gration complex is formed from proteins ofthe incoming virus particle. Within thisstructure, viral DNA is produced from itsRNA genome by the action of reverse tran-

scriptase, leaving a double-stranded DNAmolecule with flush ends. Integrase, proba-bly acting with a cellular DNA-bindingprotein3, then associates with the ends ofthe newly made DNA, and carries out tworeactions at each end (Fig. 1, overleaf).

The first of these reactions is 3´ cleavage.Two bases are removed from the 3´ end ofeach strand, leaving a hydroxyl group. Inthe second (strand-transfer) reaction, theintegrase catalyses a direct attack by thathydroxyl group on the target cellular DNA.These two reactions occur 4–6 bases apart,so, although each strand of the viral DNA isjoined to its target, there is a 4–6-base gapas well as a two-base mismatch at each end.The reactions carried out by isolated pre-integration complexes stop at this point,indicating that cellular repair systemsare needed to finish the job. Clearly, if leftunrepaired, the gaps would cause seriousdamage — the checkpoint systems of the