emission and propagation of dislocations,depending on how the load is applied. Analytical3,4, computational5,6 and experi-mental7,8 studies have been carried out in an attempt to pin down the relationshipsbetween applied thermo-mechanical load-ing and the way in which a material will react. A combination of factors are usuallyinvolved: temperature8; motion or dynamicsof existing defects6,7; the specific elementsand alloys that make up the crystal5; the ori-entation of the crystal lattice with respect tothe load; the rate at which the load is applied;existing microstructural barriers such ascrystal-grain boundaries; and properties ofthe material that determine its resistance toductile and brittle deformation.

This last factor was well summarized byRice3, who compared the energetic ‘cost’ ofcreating new surfaces within the crystal (thesurface energy) with the energy barrier that must be overcome to allow atomicplanes to slip over one another (the unstablestacking fault energy). Rice used fracturemechanics to perform a straightforwardanalysis, and found that a critical ratio ofthese energies separates ductile from brittlebehaviour for a particular crystal-lattice typeand orientation.

Given the above list of factors, it is clearly difficult to predict whether a materialwill fail in a ductile or a brittle fashion. Materials scientists try to determine thecompeting mechanisms involved and toidentify properties in the material that influence nucleation and propagation. Pre-vailing theories of failure mechanics usequantities that are related to the load-bear-ing ability of a material, such as yield andfracture stresses, whereas newer methodsrely on evaluating the energetic barriersdescribed above. Complex systems willrequire a combination of these criteria toadequately describe any irreversible defor-mation process. Although it has yet to beused for this, the model devised by Li et al.1

has the potential to predict whether brittle orductile behaviour will occur.

It is in the area of predictive modellingthat the work of Li et al. will be immenselyuseful. The authors present a methodologyfor using their stability parameter in finite-element calculations — a simulation tech-nique that models materials as a continuum,but uses the same interatomic potentials as inatomistic simulations. This enables systemswith larger-than-atomic dimensions to besimulated, and can take into accountmicrostructural features such as grainboundaries and different phases of the mate-rial. There is also the exciting possibility ofrefining the approach to operate effectivelyat finite temperatures and high loading rates.Li et al. have achieved a significant steptowards understanding the defective worldof materials in which we live. ■

Jonathan A. Zimmerman is at Sandia National

Laboratories, PO Box 969, Livermore, California94551-0969, USA. e-mail: jzimmer@sandia.gov1. Li, J., Van Vliet, K. J., Zhu, T., Yip, S. & Suresh, S. Nature 418,

307–310 (2002). 2. Askeland, D. R. The Science and Engineering of Materials (PWS-

Kent, Boston, Massachusetts, 1994).

3. Rice, J. R. J. Mech. Phys. Solids 40, 239–271 (1992).4. Beltz, G. E., Lipkin, D. M. & Fischer, L. L. Phys. Rev. Lett. 82,

4468–4471 (1999).5. Farkas, D. MRS Bull. 25, 35–38 (2000).6. Abraham, F. F. J. Mech. Phys. Solids 49, 2095–2111 (2001).7. Wall, O. Eng. Fract. Mech. 69, 835–849 (2002).8. Smida, T. & Bosansky, J. Mater. Sci. Eng. A 323, 21–26

(2002).

news and views

286 NATURE | VOL 418 | 18 JULY 2002 | www.nature.com/nature

Within our cells are many membrane-bounded compartments, each ofwhich communicates with only a

subset of other such ‘organelles’ — generallywhen small vesicles bud off from one andmerge with another. The efficiency withwhich cells use their organelles to carry outcomplex tasks has led to the belief that move-ment through the system of organellesoccurs in strictly defined directions. So, theendoplasmic reticulum (ER) — in whichproteins destined for export from the cell aresynthesized and modified — communicatesprimarily with the Golgi apparatus. This inturn interacts with a limited set of otherorganelles and, eventually, with the plasmamembrane, defining an avenue of vesiculartraffic for protein export. In the reversedirection, extracellular molecules internal-ized by endocytosis first enter endosomesand later reach lysosomes, where they aredegraded (Fig. 1).

Although lateral communication be-tween the organelles for export and import iswell documented, their vectorial organiza-tion has been supported by the positions ofER and lysosomes at the ends of the twoavenues. But faith in these traditional routes,already shaken by studies of phagosome biogenesis1, is tested again by a report fromGagnon and colleagues2 in Cell, which showsthat proteins characteristic of the ER are present in phagosomes. This has impli-cations for our understanding of cellularorganization and of how microbes manipu-late that organization.

Phagosomes are membrane-boundedorganelles formed when one cell engulfsanother, or some inanimate particle, byenclosing it in surface membrane. Earlystudies indicated that new phagosomes weremade of plasma membrane3, and that thesubsequent merger of phagosomes withlysosomes created a phagolysosome — atoxic environment for ingested microbes. Bycurrent thinking, phagolysosomes form byprogressive interactions of phagosomes withendosomes and lysosomes4. Delivery tophagolysosomes is considered the end of the

road and a fate for ingested microbes toavoid, if possible.

So pathogens that live within host cellsenter by mechanisms that often resemblephagocytosis, but then take different routes.An early challenge to the conventional viewof organelle interactions came from studiesof Trypanosoma cruzi, which enters host cellsby stimulating the fusion of lysosomesdirectly with the plasma membrane1. Otherpathogens, such as Legionella pneumophilaand Brucella abortus, are ingested by phago-cytosis, inhibit the fusion of phagosomeswith lysosomes, and then inhabit an ER-likecompartment5.

And perhaps such seemingly extraordi-nary routes are not as uncommon as onemight think. Gagnon et al.2 have now foundthe ER acting out of order, fusing with theplasma membrane and apparently providingmembrane for phagocytosis. Using a pro-teomics approach the authors first showedthat phagosomes containing latex beads —purified from extracts of professionalphagocytic cells known as macrophages —displayed several ER marker proteins. Elec-tron microscopy then showed ER mem-branes in continuity with the plasma mem-brane near cell-bound particles. Moreover,early phagosomes contained patches of bothER and lysosomal membranes. Gagnon et al.also found that newly formed phagosomeswere enriched with ER proteins, and, asphagosomes aged inside macrophages, thelevels of ER markers diminished and thenumber of lysosomal markers increased.Strangely, the levels of ER markers in phago-somes increased again later, indicating thatphagosomes continued to fuse with ERmembranes long after phagocytosis.

Although further evidence will be neededbefore we can say that the ER is essential tophagocytosis, it is reasonable to concludethat the ER supplies membrane to somephagosomes. Phagocytosis has been shownto involve fusion of intracellular organelleswith the plasma membrane6; endosomeshave been considered the most likelyorganelles, but lysosomes and the ER can

Cell biology

The extraordinary phagosomeJoel A. Swanson

The finding that a cellular compartment called the endoplasmic reticulumcan merge with the cell’s outer membrane is surprising. It would not havebeen predicted from our knowledge of cell organization.

© 2002 Nature Publishing Group

provide membrane as well. It is not clear whythe delivery of ER to phagosomes was notdiscovered in earlier electron-microscopicstudies, especially given that Gagnon et al.found ER markers in several different classesof phagosome, including those that take up the microbes Leishmania donovani andSalmonella typhimurium. But perhaps ERrecruitment is not needed for all types ofphagocytosis in macrophages.

Whatever the reason, these results2 clearlysuggest new lines of organelle communica-tion, simplifying some previously complexmodels. For example, there are implicationsfor how proteins are processed by ‘antigen-presenting’ cells and displayed on the cellsurface for detection by the immune system.Molecules from intracellular pathogens aregenerally loaded onto so-called class I majorhistocompatibility complex proteins in theER. Sometimes proteins from outside cellscan also be loaded via this ER pathway, andsome circuitous routes have been proposedfor how those proteins reach the ER7. Theresults of Gagnon et al. suggest a more directroute. Moreover, if the ER also interacts withthe plasma membrane in the absence ofphagocytosis — a process that may be moredifficult to detect — it could provide a shortcut for some bacterial toxins to travel fromthe cell surface to the ER. Until now, thesetoxins had been thought to reach the ER bytravelling ‘backwards’ through the Golgiapparatus8.

The new findings also suggest that theexotic routes of some intracellular pathogensare not so odd after all. Many pathogensdefine their compartmental home evenbefore they separate from the plasma mem-brane, rather than remodelling a conven-tional phagosome after entry9. For example,Legionella pneumophila is thought to recruitER to phagosomes, apparently by hijacking a normal cellular pathway for organelledegradation called autophagy5. But if furtherstudies show that a variety of phagosomescontain ER proteins from the start, then the mechanism that creates the Legionellacompartment can be viewed as a variation on

normal phagocytosis. That said, there prob-ably isn’t a ‘normal’ route for a phagosome.Gagnon et al. find that the ER merges withphagosomes in macrophages but not in neu-trophils — another kind of professionalphagocyte. Apparently, even phagosomescontaining inert latex beads follow differentpatterns of maturation after phagocytosis.

Finally, the extraordinary variationamong phagosomes may also hint at greaterdiversity among other organelles. With theincreased sensitivity of proteomic methods,we may learn that organelle marker proteins

are not as specific as previously thought, and that the boundaries that distinguishorganelles are not as sharp. Vectorial move-ments through organelles might be con-trolled at the level of individual molecules or patches of membrane, rather than by constrained interactions between discreteorganelles. Phagosomes might then acquireunusual combinations of markers throughthe way in which the particles they con-tain affect marker dynamics. The resultingvariety in marker proteins could provide away for cells to sense the contents of theirphagosomes. ■

Joel A. Swanson is in the Department ofMicrobiology and Immunology, University ofMichigan Medical School, Ann Arbor, Michigan48109-0620, USA.e-mail: jswan@umich.edu

1. Andrews, N. W. Trends Cell Biol. 5, 133–137 (1995).

2. Gagnon, E. et al. Cell 110, 119–131 (2002).

3. Muller, W. A., Steinman, R. M. & Cohn, Z. A. J. Cell Biol. 86,

292–303 (1980).

4. Desjardins, M., Huber, L. A., Parton, R. G. & Griffiths, G.

J. Cell Biol. 124, 677–688 (1994).

5. Dorn, B. R., Dunn, W. A. & Progulske-Fox, A. Cell. Microbiol. 4,

1–10 (2002).

6. Bajno, L. et al. J. Cell Biol. 149, 697–705 (2000).

7. Watts, C. & Amigorena, S. Semin. Immunol. 13, 373–379

(2001).

8. Sandvig, K. & van Deurs, B. EMBO J. 19, 5943–5950 (2000).

9. Amer, A. O. & Swanson, M. S. Curr. Opin. Microbiol. 5, 56–61

(2002).

news and views

NATURE | VOL 418 | 18 JULY 2002 | www.nature.com/nature 287

Figure 1 Intracellular organelles that interactwith phagosomes — membrane-boundedcompartments for the uptake of certainextracellular substances. Organelles involved inprotein synthesis and secretion, including theendoplasmic reticulum (ER), Golgi apparatusand trans-Golgi network (TGN), have not beenthought to interact significantly withphagosomes. Rather, phagosome formation atthe plasma membrane leads to progressiveinteractions with endocytic compartments —early endosomes (EE), late endosomes (LE) andlysosomes (L) — ultimately forming aphagolysosome. But the paper by Gagnon et al.2

shows that ER markers are present inphagosomes at the earliest stages of theirformation (red arrow).

TGN

Golgi

ER

LE

L

EE

Phagolysosome

Plasmamembrane

More than sixty years ago a reportappeared demonstrating that rats feda diet containing 30–50% fewer calo-

ries live for four years instead of the normalthree1. ‘Calorie restriction’ (CR) has sincebeen shown to extend the lifespan of speciesranging from unicellular yeast, to worms andflies, and certain mammals2. As they describeon page 344 of this issue3, Lin et al. have dis-covered that CR increases lifespan in yeast byturning up the rate of respiration by a factorof three. This finding challenges the tradi-tional view that CR extends lifespan bydecreasing metabolism and the associatedproduction of damaging free-radical formsof oxygen. These free radicals are a by-product of the electron-transport chain bywhich mitochondria — subcellular orga-nelles — generate energy during respiration.

It is not yet known if CR in humansincreases lifespan, but experiments underway in primates suggest that it does4.Prompted by the continuing stream of press reports about the rodent experiments,

a variety of optimists, hucksters and fanaticshave started to promote CR and to practise itwith the aim of living longer themselves — orat least transferring wealth from the rest ofus. Considering how unpleasant it is to fol-low a low-calorie diet, if the molecular path-way downstream of CR can be identified,perhaps ‘CR mimetics’ can be developedwhich will produce the anti-ageing benefitsbut spare us the hunger.

The precise mechanism by which CRdelays ageing has not been established, but ithas been assumed that some global metabol-ic switch is involved, together with reducedfree-radical production. Calorie restrictionalso reduces blood glucose and insulin levels,suggesting that neuroendocrine signallingand reduced glycation of macromoleculesmay also be involved. Finally, CR may act as aminor stress, which ‘trains’ the animal todeal with free-radical and other damage tomacromolecules to delay ageing5.

In yeast, lifespan is defined by the numberof divisions a mother cell can undergo to

Longevity

Don’t hold your breath Siu Sylvia Lee and Gary Ruvkun

In some organisms a reduced-calorie diet increases lifespan. Conventionalthinking about the mechanism involved now comes under question fromthe results of experiments with yeast.

© 2002 Nature Publishing Group