© 1999 Macmillan Magazines Ltd

structural support for this. The mis-sensemutations identified in CERP form a clusteraround the ATP-binding cassettes at residuesthat are conserved in ABC1 orthologuesfrom other species such as the mouse andthe nematode worm. A similar clustering ofmutations has been found in other geneticdisorders of ABC transporters. As we identi-fy different variants of CERP, we may finddifferent effects on function.

And what about regulation of CERP? Theintracellular concentration of cholesterol istightly controlled owing to its importance inmembrane metabolism, protein prenylationand the formation of steroid hormones.Expression of the genes that encode proteinsinvolved in cholesterol biosynthesis andtransport is regulated by proteins withsterol-responsive domains, which controlgene transcription and protein turnover11.Consistent with this, expression of CERPis upregulated by cholesterol. Yet levels ofHDL are not decreased by the statins, whichreduce intracellular levels of cholesterol. So,it is not clear whether CERP is regulated in a

similar way to other sterol-responsive genes.Nonetheless, its tight regulation and crucialrole in generating HDL make CERP anexcellent target for drugs. Small moleculesthat increase its activity — and, hence, levelsof HDL — will almost certainly be found.The next step, therefore, will be to establishwhether increased expression of CERP intransgenic mice protects against experimen-tal atherosclerosis. James Scott is at the Imperial College School ofMedicine and the MRC Clinical Sciences Centre,Hammersmith Hospital, Du Cane Road, LondonW12 0NN, UK.e-mail: j.scott@ic.ac.uk1. Fielding, C. J. & Fielding, P. E. J. Lipid Res. 36, 211–229 (1995).

2. Brooks-Wilson, A. et al. Nature Genet. 22, 336–345 (1999).

3. Bodzioch, M. et al. Nature Genet. 22, 347–351 (1999).

4. Rust, S. et al. Nature Genet. 22, 352–355 (1999).

5. Francis, G. A., Knopp, R. H. & Oram, J. F. J. Clin. Invest. 96,

78–87 (1995).

6. Luciani, M. F. et al. Genomics 21, 150–159 (1994).

7. Marcil, M. et al. Lancet (in the press).

8. Linton, K. J. & Higgins, C. F. Mol. Microbiol. 28, 5–13 (1998).

9. Rosenberg, M. F. et al. J. Biol. Chem. 272, 10685–10694 (1997).

10.Simons, K. & Ikonen, E. Nature 387, 569–572 (1997).

11.Korn, B. S. et al. J. Clin. Invest. 102, 2050–2060 (1998).

matter because we don’t see it directly, whichin turn assures that the nature of this matterremains elusive.

Fortunately, gravity also interacts directlywith light, in a phenomenon known as gravi-tational lensing. Imagine having many lightsources of identical intrinsic brightness(these are called standard candles) placed atrandom directions in the sky, at a fixed dis-tance from us. Now consider two extrememodels for the distribution of matter in theUniverse: either all matter is in microscopicform (such as elementary particles, perhapsclumped at the scale of galaxies, but nosmaller), or it is entirely macroscopic (suchas solar-mass black holes, clumped or not).Although the standard candles all emit thesame amount of light, the observed bright-nesses in each model will cover a range of val-ues, owing to the clumpiness of matter in theUniverse. In some instances the line-of-sightto a source might pass near or through aclump of matter (such as a black hole orgalaxy), with the gravitational effects of thematter causing the photons to converge,resulting in a brightened image. In othercases the line-of-sight may pass far from anymatter, so that the resulting image is dim.The precise distribution of the candles’observed brightness depends critically onthe macroscopic or microscopic structure ofthe intervening matter (Fig. 1), and it is thisskewed spread in brightness that Metcalf andSilk1 propose to measure.

To detect this gravitational lensing oneneeds standard candles (if you don’t knowhow bright an image is supposed to be, youcan’t tell whether it has changed in bright-ness). It is thought that we can tell the intrin-sic peak luminosity of a type Ia supernova towithin about 15%, making these objectsexcellent standard candles by astrophysicalstandards (Fig. 2). Metcalf and Silk ask howmany such supernovae would need to be

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NATURE | VOL 400 | 26 AUGUST 1999 | www.nature.com 819

Over 2,000 years ago, the Greeksthought they had it all worked out. Intheir cosmology, the entire Universe

was composed of four elements: earth, wind,fire and water. Now, despite several millen-nia of effort, modern cosmologists are signif-icantly worse off. We have no idea what thebulk of the Universe is composed of. We can-not even tell whether the majority of matterin the Universe is in some microscopic form(such as axions or other exotic particles) or insome macroscopic form (such as browndwarfs or primordial black holes). Our igno-rance of the mass of the basic building blocksof the Universe spans a good 50 orders ofmagnitude. In a paper in the AstrophysicalJournal last month, Metcalf and Silk1 pro-pose that, by observing the gravitationaleffects of matter on the light from distantsupernovae, it is possible to distinguishbetween microscopic and macroscopicforms of matter.

Although the idea of using supernovae asa cosmological probe of the matter distribu-tion in the Universe has been suggested previ-ously2–4, Metcalf and Silk are able to includerecent developments in our characterizationof type Ia supernovae along with a full analy-sis of the gravitational effect of different dis-tributions of matter on the observed super-novae brightness. In so doing they make aconcrete proposal for a fundamental test ofthe ‘dark matter’ which, if successful, wouldbe an important step forward in understand-ing the essential composition of the Universe.

There are strong reasons for believingthat directly observable matter is a smallfraction (less than one-tenth) of the totalmatter in the Universe5. The presence of darkmatter, which does not reveal itself throughthe emission or absorption of photons, isinferred from its gravitational effects onother (directly visible) objects. As data inastrophysics and cosmology rely almostexclusively on the observation of photons(X-ray, optical, radio and so on), this leads toa catch-22: we predict the existence of dark

Cosmology

Shedding light on dark matterDaniel E. Holz

1

Figure 1 The observed brightness of supernovaeat a redshift of one, corresponding to a time ofexplosion halfway back to the Big Bang. In aperfectly smooth, homogeneous and isotropicUniverse, all such ‘standard candles’ would havea brightness of one. In a lumpy Universe,gravitational lensing by the intervening matterresults in a probability distribution of observedbrightness. Metcalf and Silk1 have calculated twodistributions: one for matter in macroscopicform (such as solar-mass black holes), and theother for microscopic matter (such aselementary particles).

Figure 2 A type Ia supernova (SN1994D) imagedwith the Hubble Space Telescope. Supernovaebrighten over the course of a couple of weeks,reaching a maximum brightness comparable tothat of an entire galaxy, and then fade back toobscurity over several more weeks. The intrinsicpeak brightness of a type Ia supernova is thoughtto be known fairly accurately, making themuseful standard candles.

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seen to be able to detect a spread in theirobserved luminosities as a result of gravita-tional lensing by dark matter. They find thatwith 50 supernovae at a redshift, z, of one(which corresponds to a time of explosionhalfway back to the Big Bang), it would bepossible to distinguish between microscopicand macroscopic dark matter with greaterthan 90% confidence. What makes this resultparticularly interesting is that two teamshave been chasing supernovae6,7, andbetween them have already observed severalat z ö 1. This data set has been responsiblefor one of the most exciting recent results incosmology: that the expansion of the Uni-verse appears to be accelerating8. As thesegroups continue their observations, they willcertainly amass a large enough data set tomake the Metcalf and Silk proposal viable.

Just as with the ‘accelerating Universe’results, the greatest concern in the measure-ment of the gravitational-lensing effect is therobustness of the supernovae as standardcandles. This property is at present a purelyphenomenological observation. If it turnsout that supernovae at high redshifts have aqualitatively different spread in peak bright-ness from ones nearby — although there isno indication of this so far — the Metcalf andSilk proposal would be infeasible. Even with50 truly standard candles the lensing signalwill probably remain inconclusive, as it islikely that the dark matter is in some combi-nation of micro- and macroscopic matter,instead of the all-or-nothing models consid-ered by Metcalf and Silk.

There are two possible ways to improvethis method. By increasing the number ofobserved supernovae (to more than 100 atz ö 1) it would be possible to determine theprecise fraction of matter in different forms.Alternatively, by observing supernovae atgreater distances one probes more of theUniverse, thus obtaining a more pro-nounced lensing signal and allowing betterdiscrimination between possible models. Asthey increase the number of supernovaedetections, the observational teams are alsopushing to higher redshifts (with a recentsighting at z ö 1.2), and may be able to reachas high as z 4 1.6. Looking to the future, SaulPerlmutter and collaborators have proposeda satellite, SNAPSAT, which would dramati-cally increase both the statistics (up to 2,000supernovae per year) and redshift (up to z ö2) of observed supernovae. The lensing sig-nal in such a comprehensive data set wouldprovide a powerful probe of both the compo-sition and structure of the dark-matterdistribution.

Gravitational lensing is an ideal tool forstudying the dark-matter composition of theUniverse, as it uses the one property darkmatter is assured to have: gravity. In thecoming years supernovae may not only tellus how much of the matter in the Universeeludes our sight, but in what fundamental

form it is to be found. Perhaps we’ll even beable to whittle our ignorance down to a mereone or two orders of magnitude. Two thou-sand years later we are poised to regain thelevel of certainty of the ancient Greeks. Daniel E. Holz is at the Albert Einstein Institute(Max Planck Institute for Gravitational Physics), Am Mühlenberg 5, D-14476 Golm, Germany.e-mail: deholz@aei-potsdam.mpg.de

1. Metcalf, R. B. & Silk, J. Astrophys. J. 519, L1–L4

(1999).

2. Linder, E., Schneider, P. & Wagoner, R. Astrophys. J. 324,

786–793 (1988).

3. Rauch, K. Astrophys. J. 374, 83–90 (1991).

4. Holz, D. E. & Wald, R. M. Phys. Rev. D 58, 063501

(1998).

5. Turner, M. S. http://xxx.lanl.gov/abs/astro-ph/9901109

6. Riess, A. G. et al. Astron. J. 116, 1009–1038 (1998).

7. Perlmutter, S. et al. Astrophys. J. 517, 565–586 (1999).

8. Glanz, J. Science 282, 2156–2157 (1998).

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Guanine-nucleotide-binding (G) pro-teins are molecular switches thatregulate a variety of cellular process-

es, transducing the signals received at a cell’ssurface to elicit a proper biological responsefrom the proteins inside. They come in twoflavours — the heterotrimeric G proteinsand the small GTPases — and both canbe regulated in two ways. The first involvesthe guanine-nucleotide-exchange factors(GEFs), which induce formation of the GTP-bound (active) form of the G protein. Thesecond invokes the G proteins’ intrinsicGTPase activity, which, by hydrolysing GTPto GDP, induces an inactive conformation.This hydrolysing activity can be greatlyenhanced by GTPase-activating proteins(GAPs).

Mochizuki et al.1 (on page 891 of thisissue) and Jordan et al.2 (in the Journal of Bio-logical Chemistry) now describe an unex-pected mechanism by which heterotrimericG proteins can regulate a small GTPase called

Rap1. Heterotrimeric G proteins consist ofa, b and g subunits. In the inactive form,this trimeric complex is bound to a so-calledseven-pass membrane receptor (or serpen-tine receptor) on the cell surface. When thereceptor is stimulated, GDP is exchanged forGTP. The activated G protein then breaksfree from the receptor, and the Ga subunitdissociates from the Gbg heterodimer.The new studies show that a-subunits ofheterotrimeric G proteins directly associatewith a GAP for Rap1, resulting in modula-tion of Rap1 and the extracellular-signal-regulated kinase (ERK).

Rap1 has recently attracted considerableattention. It is the closest relative of Ras —the godfather of the small GTPases — and isusually activated after stimulation of cell-surface receptors. These receptors may belinked to Gs proteins (which activate anenzyme called adenylyl cyclase) or Gq pro-teins (which activate phospholipase C)3,resulting in production of the intracellular

Signal transduction

Rhapsody in G proteinsJohannes L. Bos and Fried J. T. Zwartkruis

Figure 1 Positive and negative regulation of Rap1 by various heterotrimeric guanine-nucleotide-binding (G) proteins. Receptors (R) that couple to Gq through phospholipase C, and to Gs throughadenylyl cyclase, generate the common second messengers cyclic AMP, diacylglycerol (DAG) andcalcium. These second messengers bind to, and activate, Rap1-specific guanine-nucleotide exchangefactors (GEFs). Mochizuki et al.1 now show that receptors which couple to Gi inhibit Rap1 throughdirect binding of a Rap1 GTPase-activating protein (GAP) called Rap1GAPII to the a-subunit of Gi

(Gai). Jordan et al.2 show that the inactive form of Gao binds to Rap1GAP, resulting in activation ofRap1. C3G and Spa1 are additional regulators of the Rap1 cycle. Active Rap1 may modulate activity ofthe extracellular-signal-regulated kinase (ERK), and additional targets are predicted.

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