news and views

392 NATURE | VOL 426 | 27 NOVEMBER 2003 | www.nature.com/nature

word ‘half-lives’ are intrinsic constants oflanguage, Swadesh anticipated by more thana decade the notion of the ‘molecular clock’that is central to sequence-based evolution-ary biology2.

In fact there are striking correspondencesbetween the objections to Swadesh’s methods and issues faced in phylogeneticreconstruction2. Why should we believe thatlanguages (or genomes) evolve at a constantrate over time, or that individual words andword classes (or proteins and protein fami-lies) have the same inherent rates as oneanother4? Do Swadesh lists (or core gene setscommon to many genomes5) fairly representoverall evolutionary processes? How can webe sure that similarities reflect commonancestry, rather than chance convergences6?Conversely,how do we reliably recognize dis-tant relatives whose spellings have drifted farapart (into what biologists call the ‘twilightzone’ of sequence similarity)? Why shouldwe even presume that the ‘tree of language’(or that of life) is a tree,as opposed to a sort ofnetwork, given that lexical borrowings andlanguage mixture (and horizontal transferbetween genomes7) are well-known occur-rences? Box 1 provides some examples.

Over the years, historical linguists andevolutionary biologists have separately tack-led such challenges with steadily increasingsophistication8, for instance supplantingSwadesh’s overall similarity measure (whichphylogeneticists would call a ‘distance’method) with cladistic techniques thataccount for each word (or gene, or sequenceresidue, or any other observable character)to model the actual process of evolution6.Gray and Atkinson3 apply the latest compu-tational tools — maximum-likelihood mod-els and bayesian inference techniques, whichoffer a good framework for dealing withissues such as variable rates — to a data set ofIndo-European languages developed andrefined by lexicostatisticians4.

The topology of the resulting tree oflanguages holds no surprises for linguists,but the work goes further to estimate absoluteages with statistical support. Calibrating andcross-validating various branchings againstknown historical events, Gray and Atkinsondevelop robust confidence intervals for the date of the root of the tree, whence theIndo-European languages arose. This rangeappears to be several millennia too early tosupport a prominent theory that the proto-language was disseminated by nomadic Kurgan horsemen from the steppes of Asia,beginning about 6,000 years ago. But thedates fit well with the notion that Indo-Euro-pean originated among nascent farmingcommunities in Anatolia, in modern-dayTurkey, some 2,000–4,000 years before that.

By breathing new life into glottochronol-ogy, this work will doubtless revive olddebates. But at the same time it should stim-ulate even more cross-fertilization of ideas

Cell biology

Thanks for the memoryJill C. Sible

In response to a transient hormonal cue, a developing egg commitsirreversibly to a mature state. Surprisingly, this irreversible switch iscomposed of intrinsically reversible components.

Few decisions in life are truly irrevoca-ble, even at the cellular level. Yet thereare times when it’s crucial not to turn

back — during the development of multi-cellular organisms, for instance, when cellsmust make an irreversible commitment to anew fate in response to a transient stimulus.This process, called differentiation, is wellknown, but it’s not really clear how a cell‘remembers’ its commitment long after thesignal, frequently a hormone, has disap-peared. On page 460 of this issue, Xiongand Ferrell1 show how brief exposure to thehormone progesterone triggers an irre-versible switch in cell fate in developing frogeggs. The memory is sustained by positivefeedback loops in the underlying controlsystem. When the positive feedback is per-turbed, the cell does the unthinkable and‘dedifferentiates’, reverting to characteristicsof the immature egg.

For more than 30 years, investigation ofthe maturation of frog eggs has been fertileground for discoveries about how cellsdivide and differentiate. In 1971, Masui andMarkert2 demonstrated that a bit of cyto-plasm taken from a mature frog egg andinjected into an immature egg would inducematuration, replacing the need for proges-terone. The authors named this mysteriousactivity MPF, for maturation-promotingfactor. MPF was purified in 1988, and wasshown to consist of two proteins — anenzyme called Cdc2, which attaches phos-phate groups to other proteins, and an unstable co-factor called a cyclin, which isrequired for Cdc2 activity3,4. A few years later, the activity of a second enzyme,MAPK,was shown to be required for egg matura-tion5.MAPK also phosphorylates proteins.

Subsequently, intensive biochemical andmolecular investigations by many laborato-ries have produced a detailed picture of thesignalling cascades that are elicited in animmature egg by progesterone. The picturehas become quite complicated, with more

than 30 different molecules involved. In fact,a recent comprehensive review of the litera-ture6 required a poster-sized insert to depictall of the known biochemical responses ofeggs to progesterone. In an attempt to sortthrough this web of molecular information,most scientists organize their thoughtsaround the two key enzymes — Cdc2 andMAPK — and the signalling events that activate each of them7.

Organizing the network in this way hashelped investigators to appreciate the exten-sive positive feedback that is inherent in themolecular control system underlying eggmaturation (see Fig. 1 on page 461). Positivefeedback occurs when a molecule that is activated by a signalling pathway activatessome earlier step in that pathway, thusstrengthening and perpetuating the signal.Cdc2 activates itself in many ways: by inducing the synthesis of cyclin,by phospho-rylating and turning off a Cdc2 inhibitor,and by phosphorylating and turning on aCdc2 activator. Likewise, MAPK triggers thesynthesis of Mos, a protein upstream in the

Figure 1 No turning back. When a hormonestimulates an egg cell to mature, the switch incell fate is irreversible even after the hormonalsignal is gone. Xiong and Ferrell1 show that thislong-term cellular memory is sustained bystrong positive feedback in the underlyingmolecular control system.

Hormonalsignal Positive

feedback

Immature egg Mature egg

among those studying the intertwined treesof life and language. ■

David B. Searls is in the Bioinformatics Division, Genetics Research, GlaxoSmithKlinePharmaceuticals, 709 Swedeland Road, PO Box 1539,King of Prussia, Pennsylvania 19406, USA.e-mail: David_B_Searls@gsk.com

1. Ventris, M. & Chadwick, J. J. Hellenic Stud. 73, 84–103 (1953).

2. Searls, D. B. Nature 420, 211–217 (2002).

3. Gray, R. D. & Atkinson, Q. D. Nature 426, 435–439 (2003).

4. Kruskal, J. B., Dyen, I. & Black, P. in Lexicostatistics in Genetic

Linguistics (ed. Dyen, A.) 30–55 (Mouton, The Hague, 1973).

5. Makarova, K. S. & Koonin, E. V. Genome Biol. 4, 115

(2003).

6. Ringe, D., Warnow, T. & Taylor, A. Trans. Philol. Soc. 100,

59–129 (2002).

7. Brown, J. R. Nature Rev. Genet. 4, 121–132 (2003).

8. Renfrew, C., McMahon, A. & Trask, L. (eds) Time Depth in

Historical Linguistics (McDonald Inst. Archaeol. Res.,

Cambridge, UK, 2000).

news and views

NATURE | VOL 426 | 27 NOVEMBER 2003 | www.nature.com/nature 393

MAPK activation cascade. Furthermore, theCdc2 and MAPK pathways activate eachother. Except for the synthesis of a few keyproteins such as Mos and cyclin, most of thesignalling and feedback events in this systemconsist of phosphorylation6.

Despite this wealth of molecular infor-mation about egg maturation, and theappreciation of positive feedback in the mol-ecular circuitry, until now no one couldexplain how eggs persist in the mature state— with high Cdc2 and MAPK activity —long after progesterone has been removed.Ferrell and Xiong previously carried out theoretical studies of the problem8, andfound that positive feedback such as thatseen in the Cdc2 and MAPK cascades couldcreate a biochemical ‘memory’. This pre-diction was certainly not intuitive, as thesefeedback events operate largely by phospho-rylation — known to be rapid and readilyreversible. Was it not more likely that a long-term response to a transient signal would bemaintained by an irreversible event, such asthe destruction of a key regulatory protein,maybe an inhibitor of Cdc2 or MAPK?

It appears not.Proof of Ferrell and Xiong’stheoretical prediction required careful exp-erimentation. In particular, the predictiondemands that inhibiting the positive feed-back will cause a mature egg to ‘de-mature’, atleast with respect to key biochemical events.The authors now have compelling evidenceto support this idea1. They find that three different treatments that block the positivefeedback between MAPK and Mos result intransient, rather than sustained, activation ofboth MAPK and Cdc2. So, positive feedbackis necessary to maintain the biochemicalmemory of a mature egg (Fig. 1). Xiong andFerrell also provide an additional, theoreticalexplanation for their data, with compu-tational simulations that show how an essentially reversible switch can be renderedirreversible depending on the strength of thepositive feedback in the system.

Beyond its particular contributionsregarding the maturation of eggs,the work ofXiong and Ferrell1 should have much broaderimpact owing to the approach they presentfor addressing questions of cellular function.As in work regarding the cellular switch thatcontrols entry into, and exit from, nucleardivision9,10, Xiong and Ferrell’s experimentswere driven by theoretical predictions aboutthe fundamental mechanisms that controlsuch switches.These predictions derive froma systems-level view, but require quantita-tive, reductionist-style experimentation totest their validity. The ability to think andwork on such a broad scale, from systemthrough to molecule, is the most impressiveaspect of Xiong and Ferrell’s work. Thenotion of pairing theoretical and computa-tional biology with experimental cell biologyshould catch on, and the positive feedbackinherent in this interdisciplinary brand of

Planetary science

Conveyed to the Kuiper beltRodney Gomes

The small icy bodies that make up the Kuiper belt are the most distantobjects known in the Solar System. A consistent picture is now emergingwhich suggests that these objects formed much closer to the Sun.

Since the first member of the Kuiperbelt was discovered1 in 1992, manyunexpected features of their orbits

and physical properties have been uncov-ered. One surprise was the very low totalmass observed in the belt — about one-tenthof the mass of the Earth, when it was predict-ed to be a hundred times larger than that. Toexplain the missing mass, it has been pro-posed that collisions between Kuiper-beltobjects over the lifetime of the Solar Systemhave gradually transformed most of theirmass into dust; bombarded by solar radia-tion,these dust grains are eventually expelledfrom the Solar System. But such theorieshave never been able to satisfactorily explainthe extent of the depletion of the original

Kuiper-belt mass. On page 419 of this issue,Levison and Morbidelli2 propose an alterna-tive. They show that some objects that nowexist in the Kuiper belt might have beenpushed there from original positions nearNeptune’s present orbit: the original Kuiper-belt region could, in fact, have been virtuallyempty, and only a small amount of mass wassubsequently deposited there.

According to current theory,the planets ofthe Solar System formed from a primordialdisk of gas and dust, as the dust accumulatedinto gradually larger objects. Of course, ingoing from dust to planets there must havebeen intermediate stages, such as a disk offledgling planets,or planetesimals,of roughlyasteroid size. In regions where the total mass

Figure 1 Expansion plan. The primordial, compact Solar System (left) was surrounded by a disk ofasteroid-size planetesimals, which extended roughly as far as Neptune’s present orbit. Thegravitational pull of this disk eventually induced a planetary migration, during which the orbits of allthe major planets (except Jupiter) expanded. As a consequence, most planetesimals experienced closeencounters with the planets and were ejected from the Solar System. A few remnants were pushed outinto stable orbits, forming the present-day Kuiper belt (right). Two distinct, yet complementary,mechanisms of gravitational interaction explain how these remnants became divided between high-inclination orbits3 and low-inclination orbits2, with respect to the plane of the Solar System.

Highinclination

Lowinclination

Neptune

Kuiper belt

Neptune

Disk

Neptune

Plane of theSolar System

Planetesimal disk

Primordial Solar System

Present Solar System

Expansion

Sun Sun

science is likely to drive many breakthroughsin our understanding of cellular controls. ■

Jill C. Sible is in the Biology Department, VirginiaPolytechnic Institute and State University, DerringHall, Blacksburg, Virginia 24061-0406, USA.e-mail: siblej@v.edu

1. Xiong, W. & Ferrell, J. E. Jr Nature 426, 460–465 (2003).

2. Masui, Y. & Markert, C. L. J. Exp. Zool. 177, 129–145

(1971).

3. Gautier, J., Norbury, C. H., Lohka, M., Nurse, P. & Maller, J. L.

Cell 54, 433–439 (1988).

4. Gautier, J. et al. Cell 60, 487–494 (1990).

5. Kosako, H., Gotoh, Y. & Nisheda, E. EMBO J. 13, 2131–2138

(1994).

6. Schmitt, A. & Nebreda, A. R. J. Cell Sci. 115, 2457–2459 (2002).

7. Abrieu, A., Doree, M. & Fisher, D. J. Cell Sci. 114, 257–267 (2001).

8. Ferrell, J. E. Jr & Xiong, W. Chaos 11, 227–236 (2001).

9. Pomerening, J. R., Sontag, E. D. & Ferrell, J. E. Jr Nature Cell

Biol. 5, 346–351 (2003).

10.Sha, W. et al. Proc. Natl Acad. Sci. USA 100, 975–980 (2003).