science special - great questions

8/17/2019 Science Special - Great Questions

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Every once in a while, cos-

mologists are dragged,kicking and screaming,into a universe much more unset-tling than they had any reason toexpect. In the 1500s and 1600s,Copernicus, Kepler, and Newtonshowed that Earth is just one of many planets orbiting one of many stars, destroying the com-fortable Medieval notion of aclosed and tiny cosmos. In the1920s, Edwin Hub ble showed that our universe is constantlyexpanding and evolving, a find-

ing that eventually shattered theidea that the universe is unchang-ing and eternal. And in the pastfew decades, cosmologists havediscovered that the ordinary mat-ter that makes up stars and galax-ies and people is less than 5% of everything there is. Grapplingwith this new understanding of the cosmos, scientists face one overridingquestion: What is the universe made of?

This question arises from years of pro-gressively stranger observations. In the1960s, astronomers discovered that galaxies

spun around too fast for the collective pull of the stars’ gravity to keep them from flyingapart. Something unseen appears to bekeeping the stars from flinging themselvesaway from the center: unilluminated matter that exerts extra gravitational force. This isdark matter.

Over the years, scientists have spotted some of this dark matter in space; they haveseen ghostly clouds of gas with x-ray tele-scopes, watched the twinkle of distant stars asinvisible clumps of matter pass in front of them, and measured the distortion of space

and time caused by invisible mass in galaxies.And thanks to observations of the abun-dances of elements in primordial gas clouds,

physicists have concluded that only 10% of ordinary matter is visible to telescopes.

But even multiplying all the visible “ordi-nary” matter by 10 doesn’t come close toaccounting for how the universe is structured.When astronomers look up in the heavenswith powerful telescopes, they see a lumpycosmos. Galaxies don’t dot the skies uni-formly; they cluster together in thin tendrilsand filaments that twine among vast voids.Just as there isn’t enough visible matter tokeep galaxies spinning at the right speed, thereisn’t enough ordinary matter to account for this lumpiness. Cosmologists now concludethat the gravitational forces exerted by another

form of dark matter, made of an as-yet-undiscovered type of particle, must be

sculpting these vast cosmic structures.They estimate that this exotic dark matter

makes up about 25% of the stuff in the uni-verse—five times as much as ordinary matter.

But even this mysterious entity pales bycomparison to another mystery: dark energy.In the late 1990s, scientists examining distant

supernovae discovered that the universe isexpanding faster and faster, instead of slow-ing down as the laws of physics would imply.Is there some sort of antigravity force blow-ing the universe up?

All signs point to yes. Independent meas-urements of a variety of phenomena—cosmic

background radiation, element abundances,galaxy clustering, gravitational lensing, gascloud properties—all converge on a consis-tent, but bizarre, picture of the cosmos. Ordi-nary matter and exotic, unknown particlestogether make up only about 30% of the stuff in the universe; the rest is this mysterious anti-

gravity force known as dark energy.This means that figuring out what the uni-verse is made of will require answers to threeincreasingly difficult sets of questions. Whatis ordinary dark matter made of, and wheredoes it reside? Astrophysical observations,such as those that measure the bending of light

by massive objects in space, are already yield-ing the answer. What is exotic dark matter?Scientists have some ideas, and with luck, adark-matter trap buried deep underground or ahigh-energy atom smasher will discover a newtype of particle within the next decade. And finally, what is dark energy? This question,

which wouldn’t even have been asked adecade ago, seems to trans cend known physics more than any other phenomenon yetobserved. Ever-better measurements of super-novae and cosmic background radiation aswell as planned observations of gravitationallensing will yield information about dark energy’s “equation of state”—essentially ameasure of how squishy the substance is. Butat the moment, the nature of dark energy isarguably the murkiest question in physics— and the one that, when answered, may shed the most light. –C HARLES S EI

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In the dark. Dark matter holds galaxies together; supernovaemeasurements point to a mysterious dark energy.

What Is theUniverse Made Of

From the nature of the cosmos to the nature of societies, thefollowing 100 questions span the sciences. Some are piecesof questions discussed above; others are big questions in

their own right. Some will drive scientific inquiry for the nextcentury; others may soon be answered. Many will undoubtedlyspawn new questions.

So Much More to Know … >>

W H A T D O N ’ T W E K N O W ?

Is ours the only universe?A number of quantum theoristsand cosmologists are trying tofigure out whether our universeis part of a bigger “multiverse.”But others suspect that thishard-to-test idea may be a questionfor philosophers.

What drove cosmicinflation?In the first momentsafter the big bang, theuniverse blew up atan incredible rate. Butwhat did the blowing?Measurements of thecosmic microwavebackground and otherastrophysical obser-vations are narrowingthe possibilities.

Published by AAAS


2/25

For centuries, debating the nature of consciousness was the exclusive

purview of philosophers. But if therecent torrent of books on the topic

is any indication, a shift has taken place:Scientists are getting into the game.

Has the nature of consciousness finallyshifted from a philosophical question to ascientific one that can be solved by doing

experiments? The answer, as with any related to this topic, depends on whom you ask. Butscientific interest in this slippery, age-old question seems to be gathering momentum.So far, however, although theories abound,hard data are sparse.

The discourse on consciousness has beenhugely influenced by René Descartes, theFrench philosopher who in the mid–17thcentury declared that body and mind aremade of d i fferentstuff entirely. It must

be so, Descartes con-cluded, because the

body exis ts in botht ime and space ,whereas the mind hasno spatial dimension.

Recent scientif-ically oriented acc-ounts of conscious-ness generally rejectDescartes’s solution;most prefer to treat

bod y and min d asdifferent aspects of the same thing. Inthis view, conscious-

ness emerges fromthe properties and organization of neu-rons in the brain. Buthow? And how can scientists, with their devotion to objective observation and meas-urement, gain access to the inherently privateand subjective realm of consciousness?

Some insights have come from examin-ing neurological patients whose injurieshave altered their consciousness. Damageto certain evolutionarily ancient structuresin the brainstem robs people of conscious-

ness entirely, leaving them in a coma or a persistent vegetative state. Although theseregions may be a master switch for con-sciousness, they are unlikely to be its solesource. Different aspects of consciousnessare probably generated in different brainregions. Damage to visual areas of the cere-

br al co r te x, fo r ex amp le , ca n pr odu cestrange deficits limited to visual awareness.

One extensively studied patient, known asD.F., is unable to identify shapes or deter-mine the orientation of a thin slot in a verticaldisk. Yet when asked to pick up a card and slide it through the slot, she does so easily.At some level, D.F. must know the orienta-tion of the slot to be able to do this, but sheseems not to know she knows.

Cleverly designed experiments can pro-duce similar dissociations of unconscious

and conscious knowl-edge in people with-out neurological dam-age. And researchershope that scanningthe brains of subjectsengaged in such taskswi l l reveal c luesabou t t he neu ra l

activity required for conscious awareness.Work with monkeysalso may elucidate

some aspects of consciousness, particularlyvisual awareness. One experimentalapproach is to present a monkey with an opti-cal illusion that creates a “bistable percept,”looking like one thing one moment and another the next. (The orientation-flipping

Necker cube is a well-known example.) Mon-keys can be trained to indicate which versionthey perceive. At the same time, researchers

hunt for neurons that track the monkey’s per-ception, in hopes that these neurons will lead them to the neural systems involved in con-scious visual awareness and ultimately to anexplanation of how a particular pattern of

photons hitting the retina produces the expe-rience of seeing, say, a rose.

Experiments under way at present gener-ally address only pieces of the consciousness

puzzle, and very few directly address themost enigmatic aspect of the conscioushuman mind: the sense of self. Yet the exper-imental work has begun, and if the resultsdon’t provide a blinding insight into howconsciousness arises from tangles of neu-rons, they should at least refine the nextround of questions.

Ultimately, scientistswould like to understand

not just the biological basis of consciousness but also why it exists. Whatselection pressure led to its development,and how many of our fellow creatures shareit? Some researchers suspect that con-sciousness is not unique to humans, but of course much depends on how the term isdefined. Biological markers for conscious-ness might help settle the matter and shed

light on how consciousness develops earlyin life. Such markers could also informmedical decisions about loved ones who arein an unresponsive state.

Until fairly recently, tackling the subjectof consciousness was a dubious career movefor any scientist without tenure (and perhapsa Nobel Prize already in the bag). Fortunately,more young researchers are now joining thefray. The unanswered questions should keepthem—and the printing presses—busy for many years to come.

–G REG M ILL

What Is the BiologicalBasis of Consciousness

C R E D I T : L

E S T E R L E F K O W I T Z / C O R B I S

continued

www.sciencemag.org SCIENCE VOL 309 1 JULY 2005

W H A T D O N ’ T W E K N O W

When and how did the first starsand galaxies form?The broad brush strokes are visible, but the finedetails aren’t. Data from satellites and ground-based telescopes maysoon help pinpoint,among other particulars,when the first genera-tion of stars burned offthe hydrogen “fog” thatfilled the universe.

Where do ultra-high-energy cosmicrays come from?Above a certainenergy, cosmicrays don’t travelvery far before beingdestroyed. So whyare cosmic-rayhunters spottingsuch rays with noobvious source withinour galaxy?

What powersquasars?The mightiestenergy fountainsin the universeprobably get theirpower from matterplunging into whirlingsupermassive blackholes. But the detailsof what drivestheir jets remainanybody’s guess.

What is the nature ofblack holes?

Relativistic mass crammedinto a quantum-sized object?

It’s a recipe for disaster—and scientists are stilltrying to figure out the ingredients.

JPL/NASA

E.J. SCHREIER,STSCI/NASA

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When leading biologists wereunraveling the sequence of the

human genome in the late 1990s,they ran a pool on the number of genes con-tained in the 3 billion base pairs that makeup our DNA. Few bets came close. The con-ventional wisdom a decade or so ago wasthat we need about 100,000 genes to carryout the myriad cellular processes that keepus functioning. But it turns out that we haveonly about 25,000 genes—about the samenumber as a tiny flowering plant called

Arabidopsis and barely more than the wormCaenorhabditis elegans .

That big surprise reinforced a growingrealization among geneticists: Our genomes

and those of other mammals are far moreflexible and complicated than they onceseemed. The old notion of one gene/one pro-tein has gone by the board: It is now clear thatmany genes can make more than one protein.Regulatory proteins, RNA, noncoding bits of DNA, even chemical and structural alter-ations of the genome itself control how,where, and when genes are expressed. Figur-ing out how all these elements work together to choreograph gene expression is one of thecentral challenges facing biologists.

In the past few years, it has become clear that a phenomenon called alternative splicingis one reason human genomes can producesuch complexity with so few genes. Humangenes contain both coding DNA—exons— and noncoding DNA. In some genes, differentcombinations of exons can become active atdifferent times, and each combination yields adifferent protein. Alternative splicing waslong considered a rare hiccup during tran-scription, but researchers have concluded thatit may occur in half—some say close to all— of our genes. That finding goes a long waytoward explaining how so few genes can

produce hundreds of thousands of different

proteins. But how the transcription machin-ery decides which parts of a gene to read at

any particular time is still largely a mystery.The same could be said for the mechanismsthat determine which genes or suites of genesare turned on or off at particular times and

places. Researchers are discovering that eachgene needs a supporting cast of hundreds to getits job done. They include proteins that shutdown or activate a gene, for example by addingacetyl or methyl groups to the DNA. Other

proteins, called transcription factors, interactwith the genes more directly: They bind tolanding sites situated near the gene under their control. As with alternative splicing, activationof different combinations of landing sites

makes possible exquisite controlof gene expression, butresearchers have yet tofigure out exactly howall these regulatoryelements really work or how they fit inwith alternativesplicing.

In the past decade or so, re-searchers have also come to appreci-

ate the key roles played by chromatin pr ot ei ns an d RNA in regu la ti ng ge ne

expression. Chromatin proteins areessentially the packaging for DNA,

holding chromosomes in well-defined spirals. By slightly changing shape, chro-

matin may expose different genes to thetranscription machinery.Genes also dance to the tune of RNA.

Small RNA molecules, many less than30 bases, now share the limelight with other gene regulators. Many researchers who oncefocused on messenger RNA and other rela-tively large RNA molecules have in the past5 years turned their attention to these smaller cousins, including microRNA and smallnuclear RNA. Surprisingly, RNAs in thesevarious guises shut down and otherwisealter gene expression. They also are keyto cell differentiation in developing organ-

isms, but the mechanisms are notfully understood.Researchers have made

enormous strides in pinpointingthese various mechanisms.By matching up genomesfrom organisms on different branches on the evolution-ary tree, genomicists arelocating regulatory regionsand gaining insights into

how mechanisms such asalternative splicing evolved.

These studies, in turn, should

shed light on how these regionswork. Experiments in mice, such asthe addition or deletion of regulatoryregions and manipulating RNA,

and computer models should also help. But the cen-tral question is likelyto remain unsolvedfor a long time: Howdo all these featuresmeld together to makeus whole?

–E LIZABETH P ENNI

0 10,000 20,000 30,000 40,000 50,000

D. melanogaster

C. elegans

Homo sapiens

Arabidopsis thaliana

Oryza sativa

Fugu rupides

Approximate number of genes

Why Do HumansHave So Few Genes


Why is theremore matter thanantimatter?To a particle physicist,matter and anti-matter are almostthe same. Somesubtle differencemust explain whymatter is commonand antimatter rare.

Does the protondecay?In a theory of every-thing, quarks (whichmake up protons)should somehow beconvertible to leptons(such as electrons)—so catching a protondecaying into some-thing else mightreveal new laws ofparticle physics.

What is thenature of gravity?It clashes withquantum theory.It doesn’t fit in theStandard Model.Nobody has spottedthe particle that is responsible for it. Newton’sapple contained a whole can of worms.

Why is time differentfrom other dimensions?It took millennia for scientists to realize that time isdimension, like the threespatial dimensions, and thtime and space are inextrbly linked. The equationsmake sense, but they donsatisfy those who ask whywe perceive a “now” or wtime seems to flow the wit does.

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C R E D I T S

( T O P T O

B O T T O M

) : J U P I T E R I M A G E S ; A

F F Y M E T R I X

Forty years ago, doc-tors learned whysome patientswho received

the anesthetic succinyl-choline awoke normally

bu t re ma in ed te mp o-rarily paralyzed and

unable to breathe:They shared an inher-ited quirk that slowed their metabolism of the drug. Later, scien-tists traced sluggish succinyl-choline metabolism to a particular genevariant. Roughly 1 in 3500 people carry twodeleterious copies, putting them at high risk of this distressing side effect.

The solution to the succinylcholine mys-tery was among the f irst links drawn betweengenetic variation and an individual’s responseto drugs. Since then, a small but growing

number of differences in drug metabolismhave been linked to genetics, helping explainwhy some patients benefit from a particular drug, some gain nothing, and others suffer toxic side effects.

The same sort of variation, it is now clear, plays a key role in individual risks of comingdown with a variety of diseases. Gene vari-ants have been linked to elevated risks for dis-orders from Alzheimer’s disease to breastcancer, and they may help explain why, for example, some smokers develop lung cancer whereas many others don’t.

These developments have led to hopes—

and some hype—that we are on the verge of an era of personalized medicine, one in whichgenetic tests will determine disease risks and guide prevention strategies and therapies. Butdigging up the DNA responsible—if in factDNA is responsible—and converting thatknowledge into gene tests that doctors canuse remains a formidable challenge.

Many conditions, including various can-cers, heart attacks, lupus, and depression,likely arise when a particular mix of genescollides with something in the environment,such as nicotine or a

fatty diet. These multigeneinteractions are subtler and knot-

tier than the single gene drivers of diseases such as hemophilia and cystic

fibrosis; spotting them callsfor statistical inspiration

and rigorous experimentsrepeated again and again

to guard against intro-ducing unproven genetests into the clinic. And

determining treatmentstrategies will be no lesscomplex: Last summer,for example, a team of sci-entists linked 124 differentgenes to resistance to four leukemia drugs.

But identifying gene networks like these isonly the beginning. One of the toughest tasksis replicating these studies—an especial lydiff icult proposition in diseases that are notoverwhelmingly heritable, such as asthma, or ones that affect fairly small patient cohorts,such as certain childhood cancers. Many clin-

ical trials do not routinely collect DNA fromvolunteers, making it sometimes difficult for scientists to correlate disease or drug responsewith genes. Gene microarrays, which measureexpression of dozens of genes at once, can befickle and supply inconsistent results. Genestudies can also be prohibitively costly.

Nonetheless, genetic dissection of somediseases—such as cancer, asthma, and heartdisease—is galloping ahead. Progress in other areas, such as psychiatric disorders, is slower.Severely depressed or schizophrenic patientscould benefit enormously from tests that

reveal which drug and dose will help them themost, but unlike asthma, drug response can bedifficult to quantify biologically, making gene-drug relations tougher to pin down.

As DNA sequence becomes more avail-able and technologies improve, the genetic

patterns that govern health will likely comeinto sharper relief. Genetic tools still under

construction, such as a haplotype map thatwill be used to discern genetic variation behind common diseases , could further accelerate the search for disease genes.

The next step will be designing DNA teststo guide clinical decision-making—and usingthem. If history is any guide, integrating suchtests into standard practice will take time. Inemergencies—a heart attack, an acute cancer,or an asthma attack—such tests will

be valuable only if they rapidly deliver results.Ultimately, comprehensive personal-

ized medicine will come only if pharma-ceutical companies want it to—and it willtake enormous investments in research and development. Many companies worry thattesting for genetic differences will nar row

their market and squelch their profits.Still, researchers continue to identify newopportunities. In May, the Icelandic companydeCODE Genetics reported that an experi-mental asthma drug that pharmaceutical giantBayer had abandoned appeared to decrease therisk of heart attack in more than 170 patientswho carried particular gene variants. The drugtargets the protein produced by one of thosegenes. The finding is likely to be just a fore-taste of the many surprises in store, as the

braids binding DNA, drugs, and disease areslowly unwound. –JENNIFER COUZI

continued

To What Extent Are

Genetic Variation andPersonal Health Linked


Are there smallerbuilding blocksthan quarks?Atoms were“uncuttable.” Thenscientists discoveredprotons, neutrons, andother subatomic parti-cles—which were, inturn, shown to be madeup of quarks and glu-ons. Is there somethingmore fundamental still?

Are neutrinos theirown antiparticles?Nobody knows thisbasic fact aboutneutrinos, although anumber of under-ground experimentsare under way.Answering this ques-tion may be a crucialstep to understandingthe origin of matter inthe universe.

Is there a unified theoryexplaining all correlatedelectron systems?High-temperature superconductorsand materials with giant andcolossal magnetoresistance are allgoverned by the collective ratherthan individual behavior of electrons.There is currently no commonframework for understanding them.

What is the most powerful laserresearchers can build?Theorists say an intense enoughlaser field would rip pho-tons into electron-positron pairs,dousing thebeam. But no oneknows whetherit’s possible toreach that point.

CERN

SANDIA NATIONAL LABORATORY

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5/25

A t its best, physics eliminates complex-ity by revealing underlying simplicity.Maxwell’s equations, for example,describe all the confusing and diverse phenomena of classicalelectricity and magnetism bymeans of four simple rules. Theseequations are beautiful; they havean eerie symmetry, mirroring oneanother in an intricate dance of symbols. The four together feel aselegant, as whole, and as completeto a physicist as a Shakespeareansonnet does to a poet.

The Standard Model of particle physics is an unfinished poem.Most of the pieces are there, and even unfinished, it is arguably themost brilliant opus in the literatureof physics. With great precision, itdescribes all known matter—allthe subatomic particles such asquarks and leptons—as well as theforces by which those particlesinteract with one another. Theseforces are electromagnetism,which describes how charged objects feel each other’s influence:

the weak force, which explainshow particles can change their identities, and the strong force,which describes how quarks stick together to form protons and other composite particles. But as lovelyas the Standard Model’s descrip-tion is, it is in pieces, and some of those pieces—those that describegravity—are missing. It is a fewshards of beauty that hint at some-thing greater, like a few lines of Sappho on a fragment of papyrus.

The beauty of the Standard Model is in its symmetry; mathematiciansdescribe its symmetries with objects known

as Lie groups. And a mereglimpse at the Standard Model’sLie group betrays its fragmented nature: SU(3) × SU(2) × U(1).Each of those pieces representsone type of symmetry, but thesymmetry of the whole is bro-ken. Each of the forces behavesin a slightly different way, soeach is described with a slightlydifferent symmetry.

But those differences might be superf icial. Electromagnet-ism and the weak force appear very dissimilar, but in the 1960s

physicists showed that a t h ightemperatures, the two forces“unify.” It becomes apparent thatelectromagnetism and the weak force are really the same thing,

just as it becomes obvious thatice and liquid water are the samesubstance if you warm them uptogether. This connection led

physicists to hope that the strong

force could also be unified withthe other two forces, yieldingone large theory described by asingle symmetry such as SU(5).

A unified theory should haveobservable consequences. For example, if the strong force trulyis the same as the electroweak force, then protons might not be

truly stable; once in a long while, theyshould decay spontaneously. Despite

many searches, nobody has spotted a proton decay, nor has anyone sighted any

part ic les p redicted by s ome symmetry-enhancing modifications to the Standard Model, such as supersymmetry. Worse yet,even such a unified theory can’t be com-

plete—as long as it ignores gravity.Gravity is a troublesome force. The theorythat describes it, general relativity, assumesthat space and time are smooth and continu-ous, whereas the underlying quantum physicsthat governs subatomic particles and forces isinherently discontinuous and jumpy. Gravityclashes with quantum theory so badly thatnobody has come up with a convincing wayto build a single theory that includes all the

particles, the strong and electroweak forces,and gravity all in one big bundle. But physi-cists do have some leads. Perhaps the most

promising is superstring theory.

Superstring theory has a large following because it provides a way to unify ever y-thing into one large theory with a singlesymmetry—SO(32) for one branch of superstring theory, for example—but itrequires a universe with 10 or 11 dimen-sions, scads of undetected particles, and a lotof intellectual baggage that might never beverifiable. It may be that there are dozensof unif ied theories, only one of which is cor-rect, but scientists may never have the meansto determine which. Or it may be that thestruggle to unify all the forces and particlesis a fool’s quest.

In the meantime, physicists will continueto look for proton decays, as well as searchfor supersymmetric particles in underground traps and in the Large Hadron Collider (LHC) in Geneva, Switzerland, when itcomes online in 2007. Scientists believe thatLHC will also reveal the existence of theHiggs boson, a particle intimately related tofundamental symmetries in the model of

particle physics. And physicists hope that oneday, they will be able to f inish the unfinished

poem and frame its fearful symmetry.–C HARLES S E

Can the Laws ofPhysics Be Unified

Fundamental forces. A theory thatties all four forces together is stilllacking.


Is it possible tocreate magneticsemiconductorsthat work at roomtemperature?Such devices havebeen demonstratedat low temperaturesbut not yet in arange warm enoughfor spintronicsapplications.

What is the pairing mechanismbehind high-temperaturesuperconductivity?Electrons in superconductors surftogether in pairs. After 2 decades ofintense study, no one knows whatholds them together in the complex,high-temperature materials.

Can we develop ageneral theory ofthe dynamics ofturbulent flows andthe motion of gran-ular materials?So far, such “nonequi-librium systems” defythe tool kit of statisti-cal mechanics, andthe failure leaves agaping hole inphysics.

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Can researchers make a perfectoptical lens?They’ve done it with microwavesbut never with visible light.

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C R E D I T : G

E T T Y I M A G E S

When Jeanne Calment died in anursing home in southernFrance in 1997, she was 122years old, the longest-living

human ever documented. But Calment’suncommon status will fade in subsequentdecades if the predictions of some biolo-gists and demographers come true.

Life-span extension in speciesfrom yeast to mice and extrapola-tion from life expectancy trends inhumans have convinced a swath of scientists that humans will routinelycoast beyond 100 or 110 years of age.(Today, 1 in 10,000 people in industrial-ized countries hold centenarian status.)Others say human life span may be far more limited. The elasticity found inother species might not apply to us. Further-more, testing life-extension treatments inhumans may be nearly impossible for practicaland ethical reasons.

Just 2 or 3 decades ago, research on agingwas a backwater. But when molecular biolo-gists began hunting for ways to prolong life,they found that life span was remarkably

pliable. Reducing the activity of an insulinlikereceptor more than doubles the life span of worms to a startling—for them—6 weeks. Putcertain strains of mice on near-starvation butnutrient-rich diets, and they live 50% longer than normal.

Some of these effects may not occur in other species. A worm’s ability to enter a “dauer”state, which resembles hibernation, may be

critical, for example. And shorter-lived speciessuch as worms and fruit flies, whose aging has

been delayed the most, may be more susceptibleto life-span manipulation. But successfulapproaches are converging on a few key areas:calorie restriction; reducing levels of insulinlikegrowth factor 1 (IGF-1), a protein; and prevent-

ing oxidative damage to the body’s tissues.

All three might be interconnected, but so far that hasn’t been confirmed (although calorie-restricted animals have low levels of IGF-1).

Can these strategies help humans live

longer? And how do we determine whether they will? Unlike drugs for cancer or heartdisease, the benefits of antiaging treatmentsare fuzzier, making studies difficult to set upand to interpret. Safety is uncertain; calorierestriction reduces fertility in animals, and labflies bred to live long can’t compete with their wild counterparts. Furthermore, garneringresults—particularly from younger volun-teers, who may be likeliest to benefit becausethey’ve aged the least—will take so long that

by the time results are in, those who began thestudy will be dead.

That hasn’t stopped scientists, some of whom have founded companies, fromsearching for treatments to slow aging. Oneintriguing question is whether calorierestriction works in h umans. It’s beingtested in primates, and the National Instituteon Aging in Bethesda, Maryland, is fundingshort-term studies in people. Volunteers in

those trials have been on a stringent dietfor up to 1 year while researchers monitor their metabolism and other factors thatcould hint at how they’re aging.

Insights could also come from geneticstudies of centen arians, who may haveinherited long life from their parents. Manyscientists believe that average human life spanhas an inherent upper limit, although theydon’t agree on whether it’s 85 or 100 or 150.

One abiding question in the antiagingworld is what the goal of all this work ought to

be. Overwhelmingly, scientists favor treat-ments that will slow aging and stave off age-

related diseases rather than simply extendinglife at its most decrepit. But even so, slowingaging could have profound social effects,upsetting actuarial tables and retirement plans.

Then there’s the issue of fairness: If anti-aging therapies become available, who willreceive them? How much will they cost?Individuals may find they can stretch their life spans. But that may be tougher toachieve for whole populations, althoughmany demographers believe that the averagelife span will continue to climb as it has con-sistently for decades. If that happens, muchof the increase may come from less dramaticstrategies, such as heart disease and cancer

prevention, that could also make the end of along life more bearable. –J ENNIFER COUZI

How Much Can HumanLife Span Be Extended

continued


Is superfluiditypossible in a solid?If so, how?Despite hints in solidhelium, nobody issure whether a crys-talline material canflow without resist-ance. If new types ofexperiments showthat such outlandishbehavior is possible,theorists would haveto explain how.

Are there stablehigh-atomic-numberelements?A superheavy elementwith 184 neutronsand 114 protonsshould be relativelystable, if physicistscan create it.

What is thestructure ofwater?Researchers continueto tussle over how manybonds each H 2 O moleculemakes with its nearest neighbors.

What is the natureof the glassy state?Molecules in a glassare arranged muchlike those in liquidsbut are more tightlypacked. Where andwhy does liquid endand glass begin?

Are there limits to rationchemical synthesis?The larger synthetic molecules get, the harder it is tcontrol their shapes and menough copies of them touseful. Chemists will neenew tools to keep their crations growing.

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Unlike automobiles, humans get along

pretty well for most of their lives withtheir original parts. But organs dosometimes fail, and we can’t go to themechanic for an engine rebuild or a new water

pump—at least not yet. Medicine has battled back many of the acute threats, such as infec-tion, that curtailed human life in past centuries.

Now, chron ic i llnesses and det erioratingorgans pose the biggest drain on human healthin industrialized nations, and they will only increase inimportance as the populationages. Regenerative medi-cine—rebuilding organs and

tissues—could conceivably bethe 21st century equivalent of antibiotics in the 20th. Beforethat can happen, researchersmust understand the signalsthat control regeneration.

Researchers have puzzled for centuries over how body

parts replenish themselves. Inthe mid-1700s, for instance,Swiss researcher AbrahamTrembley noted that whenchopped into pieces, hydra—tubelike crea-tures with tentacles that live in fresh water—

could grow back into complete, new organ-isms. Other scientists of the era examined thesalamander’s ability to replace a severed tail.And a century later, Thomas Hunt Morganscrutinized planaria, flatworms that canregenerate even when whittled into 279 bits.But he decided that regeneration was anintractable problem and forsook planaria infavor of fruit flies.

Mainstream biology has followed in Mor-gan’s wake, focusing on animals suitable for studying genetic and embryonic development.But some researchers have pressed on with

studies of regeneration superstars, and they’ve

devised innovative strategies to tackle thegenetics of these organisms. These efforts and investigations of new regeneration models— such as zebrafish and special mouse lines— are beginning to reveal the forces that guideregeneration and those that prevent it.

Animals exploit three principal strategiesto regenerate organs. First, working organcells that normally don’t divide can multiply

and grow to replenish lost tissue, as occurs ininjured salamander hearts. Second, special-

ized cells can undo their training—a processknown as dedifferentiation—and assume amore pliable form that can replicate and later respecialize to reconstruct a missing part.Salamanders and newts take this approach toheal and rebuild a severed limb, as dozebrafish to mend clipped fins. Finally, poolsof stem cells can step in to perform required renovations. Planaria tap into this resourcewhen reconstructing themselves.

Humans already plug into these mecha-nisms to some degree. For instance, after surgi-cal removal of part of a liver, healing signals

tell remaining liver cells to resumegrowth and division to expand the organ

back to its original size. Researchers havefound that when properly enticed, some typesof specialized human cells can revert to a morenascent state (see p. 85). And stem cells helpreplenish our blood, skin, and bones. So whydo our hearts fill with scar tissue, our lenses

cloud, and our brain cells perish?Animals such as salamanders and planariaregenerate tissues by rekindling genetic mech-anisms that guide the patterning of body struc-tures during embryonic development. Weemploy similar pathways to shape our parts asembryos, but over the course of evolution,humans may have lost the ability to tap into itas adults, perhaps because the cell divisionrequired for regeneration elevated the likeli-hood of cancer. And we may have evolved thecapacity to heal wounds rapidly to repel infec-tion, even though speeding the pace meansmore scarring. Regeneration pros such as

salamanders heal wounds methodically and produce pristine tissue. Avoiding fibrotic tissuecould mean the difference between regenerat-ing and not: Mouse nerves grow vigorously if experimentally severed in a way that preventsscarring, but if a scar forms, nerves wither.

Unraveling the mysteries of regenerationwill depend on understanding what separatesour wound-healing process from that of ani-mals that are able to regenerate. The differencemight be subtle: Researchers have identified one strain of mice that seals up ear holes inweeks, whereas typical strains never do. A rel-atively modest number of genetic differences

seems to underlie the effect. Perhaps altering ahandful of genes would be enough to turn usinto superhealers, too. But if scientists succeed in initiating the process in humans, new ques-tions will emerge. What keeps regeneratingcells from running amok? And what ensuresthat regenerated parts are the right size and shape, and in the right place and orientation? If researchers can solve these riddles—and it’s a

big “if ”—people might be able to order upreplacement parts for themselves, not just their ’67 Mustangs. –R.J OHN DAVENPORR. John Davenport is an editor of Science ’s SAGE

What ControlsOrgan Regeneration

Self-repair. Newts reprogram their cells to reconstruct a severed limb.


What is the ulti-mate efficiency ofphotovoltaic cells?Conventional solarcells top out at con-verting 32% of theenergy in sunlight toelectricity. Canresearchers breakthrough the barrier?

Will fusion alwaysbe the energysource of thefuture?It’s been 35 years awayfor about 50 years, andunless the internationalcommunity gets itsact together, it’ll be35 years away formany decades to come.

What drives thesolar magneticcycle?Scientists believediffering rates ofrotation from placeto place on the sununderlie its 22-yearsunspot cycle. Theyjust can’t make itwork in their simula-tions. Either a detailis askew, or it’s backto the drawing board.

How do planets form?How bits of dust and ice

and gobs of gas cametogether to form the

planets without thesun devouringthem all is stillunclear. Planetarsystems aroundother stars should

provide clues. S O L A R E L E C T R I C P O W E R A S S O C I A T I O N

JPL/NASA

Published by AAAS



Like Medieval alchemists whosearched for an elixir that could turn base metals into gold, biol-ogy’s modern alchemists have

learned how to use oocytes to turn normalskin cells into valuable stem cells, and evenwhole animals. Scientists, with practice,have now been able to make nuclear transfer

nearly routine to produce cattle, cats, mice,sheep, goats, pigs, and—as a Korean teamannounced in May—even human embryonicstem (ES) cells. They hope to go still further and turn the stem cells into treatments for

previously untreatable diseases. But like themedieval alchemists, today’s cloning and stem cell biologists are working largely with

processes they don’t fully understand: Whatactually happens inside the oocyte to repro-gram the nucleus is still a mystery, and scien-tists have a lot to learn before they can directa cell’s differentiation as smoothly as nature’s

program of development does every time a

fertilized egg gives rise to the multiple celltypes that make up a live baby.Scientists have been investigating the

reprogramming powers of the oocyte for half a century. In 1957, developmental biologistsfirst discovered that theycould insert the nucleus of adult frog cells into frog eggsand create dozens of geneti-cally identical tadpoles. But in50 years, the oocyte has yet togive up its secrets.

The answers lie deep incell biology. Somehow, scien-

tists know, the genes that con-trol development—generallyturned off in adult cells—getturned back on again by theoocyte, enabling the cell totake on the youthful potentialof a newly fertilized egg. Sci-entists understand relativelylittle about these on-and-off switches in normal cells, how-ever, let alone the unusualreversal that takes place dur-ing nuclear transfer.

As cells differentiate, their DNA becomesmore tightly packed, and genes that are nolonger needed—or those which should not beexpressed—are blocked. The DNA wrapstightly around proteins called histones, and genes are then tagged with methyl groups that

prevent the proteinmaking machinery in thecell from reaching them. Several studies have

shown that enzymes that remove thosemethyl groups are crucial for nuclear transfer to work. But they are far from the only thingsthat are needed.

If scientists could uncover the oocyte’ssecrets, it might be possible to replicate itstricks without using oocytes themselves, aresource that is fairly difficult to obtain and theuse of which raises numerous ethical ques-tions. If scientists could come up with a cell-free bath that turned the clock back on already-

differentiated cells,the implications could

be enormous. Labscould rejuvenate cellsfrom patients and per-haps then grow theminto new tissue thatcould repair parts

worn out by old ageor disease.But scientists are

far from sure if suchcell-free alchemy is

poss ible . Th e egg’svery structure, itsscaffolding of pro-teins that guide thechromosomes duringcell division, mayalso play a key role inturning on the neces-

sary genes. If so, developing an elixir of pro-teins that can turn back a cell’s clock mayremain elusive.

To really make use of the oocyte’s power,scientists still need to learn how to direct thedevelopment of the rejuvenated stem cellsand guide them into forming specific tis-sues. Stem cells, especially those from

embryos, spontaneously form dozens of cell types, but controlling that developmentto produce a single type of cell has proved more difficult. Although some teams havemanaged to produce nearly pure colonies of certain kinds of neural cells from ES cells,no one has managed to concoct a recipe thatwill direct the cells to become, say, a pure

population of dopamine-producingneurons that could replace thosemissing in Parkinson’s disease.

Scientists are just beginning to under-stand how cues interact to guide a celltoward its final destiny. Decades of work in developmental biology have provided a s tar t : Biologis ts have used mutantfrogs, f l ies, mice, chicks, and fish toidentify some of the main genes that con-t ro l a developing ce l l ’s decis ion to

become a bone cell or a muscle cell . Butobserving what goes wrong when a geneis miss ing i s eas ier than learning toorchestrate differentiation in a culturedish. Understanding how the roughly25,000 human genes work together toform tissues—and tweaking the rightones to guide an immature cell’s develop-ment—will keep researchers occupied for decades. If they succeed, however, theresult will be worth far more than i tsweight in gold.

–G RETCHEN V OGE

How Can a Skin CellBecome a Nerve Cell

continued

Cellular alchemist. A human oocyte. C R E D I T : D

O N W

. F A W C E T T / V I S U A L S U N L I M I T E D


What causes reversals inEarth’s magnetic field?Computer models and laboratoryexperiments are generating newdata on how Earth’s magneticpoles might flip-flop. The trick willbe matching simulations to enoughaspects of the magnetic fieldbeyond the inaccessible core tobuild a convincing case.

What causesice ages?Something about theway the planet tilts,wobbles, and careensaround the sun pre-sumably brings on iceages every 100,000years or so, but reamsof climate recordshaven’t explainedexactly how.

Are there earthquake precursors thatcan lead to useful predictions?Prospects for findingsigns of an imminentquake have been waningsince the 1970s. Under-standing faults willprogress, but routineprediction would requirean as-yet-unimaginedbreakthrough.

Is there—or was there—lifeelsewhere in the solar system?The search for life—past or pres-ent—on other planetary bodiesnow drives NASA’s planetary explo-ration program, which focuses onMars, where water abounded whenlife might have first arisen.

USGS

Published by AAAS



I t takes a certain amount of flexibility for a plant to survive and reproduce . It canstretch its roots toward water and itsleaves toward sunlight, but it has few optionsfor escaping predators or findingmates. To compensate, many

plants have evolved repair mecha-nisms and reproductive strategiesthat allow them to produce off-spring even without the meetingof sperm and egg. Some canreproduce from outgrowths of

stems, roots, and bulbs, but othersare even more radical, able to cre-ate new embryos from singlesomatic cells. Most citrus trees,for example, can form embryosfrom the tissues surrounding theunfertilized gametes—a feat noanimal can manage. The house-

plant Bryophy llum can sproutembryos from the edges of itsleaves, a bit like Athena springingfrom Zeus’s head.

Nearly 50 years ago, scientists learned that they could coax carrot cells to undergo

such embryogenesis in the lab. Since then, people have used so-called somatic embryo-genesis to propagate dozens of species,including coffee, magnolias, mangos, and roses. A Canadian company has planted entire forests of fir trees that started life intissue culture. But like researchers who cloneanimals (see p. 85), plant scientists under-stand little about what actually controls the

process. The search for answers might shed light on how cells’fates become fixed duringdevelopment, and how plants manage toretain such flexibility.

Scientists aren’t even sure which cells arecapable of embryogenesis. Although earlier work assumed that all plant cells were equallylabile, recent evidence suggests that only a sub-

set of cells can transform into embryos. Butwhat those cells look like before their transfor-

mation is a mystery. Researchers have video-taped cultures in which embryos develop butfound no visual pattern that hints at which cellsare about to sprout, and staining for certain pat-terns of gene expression has been inconclusive.

Researchers do have a few clues about themolecules that might be involved. In the lab,the herbicide 2,4-dichlorophenoxyacetic acid (sold as weed killer and called 2,4-D) can

prompt cells in culture to elongate, build anew cell wall, and start dividing to formembryos. The herbicide is a synthetic analogof the plant hormones called auxins, which

control everything from the plant’s response to light and grav-ity to the ripening of fruit. Auxins

might also be important in naturalsomatic embryogenesis: Embryos that

sprout on top of veins near the leaf edgeare exposed to relatively high levels of auxins. Recent work has also shown that

over- or underexpression of certain genesin Arabidopsis plants can prompt embryo-genesis in otherwise normal-looking leaf cells.

Sorting out sex-free embryogenesis mighthelp scientists understand the cellular switches that plants use to stay flexible while

still keeping growth under control. Develop-mental biologists are keen to learn how those

mechanisms compare in plants and animals.Indeed, some of the processes that controlsomatic embryogenesis may be similar tothose that occur during animal cloning or limb regeneration (see p. 84).

On a practical level, scientists would liketo be able to use lab-propagation techniqueson crop plants such as maize that stillrequire normal pollination. That would speed up both breeding of new varieties and the production of hybrid seedlings—a flex-ibility that farmers and consumers could

both appreciate. –G RETCHEN V OGE

How Does a SingleSomatic Cell BecomeA Whole Plant


What is the originof homochirality innature?Most biomoleculescan be synthesized inmirror-image shapes.Yet in organisms,amino acids arealways left-handed,and sugars arealways right-handed.The origins of thispreference remain amystery.

Can we predict howproteins will fold?Out of a near infini-tude of possible waysto fold, a proteinpicks one in just tensof microseconds.The same task takes30 years of computertime.

How many proteinsare there inhumans?It has been hardenough countinggenes. Proteins canbe spliced in differentways and decoratedwith numerous func-tional groups, all ofwhich makes count-ing their numbersimpossible for now.

How do proteins find theirpartners?Protein-protein interactions are atthe heart of life. To understand howpartners come together in preciseorientations in seconds,researchers need to know moreabout the cell’s biochemistry andstructural organization.

PROTEIN DATA BANK

Power of one. Orange tree embryos can sprout from a single somatic cell.

Published by AAAS



C R E D I T : R

O G E R R E S S M E Y E R / C O R B I S

The plate tectonics revolution wentonly so deep. True, it made wonderfulsense of most of the planet’s geology.But that’s something like understand-

ing the face of Big Ben; there must be a lotmore inside to understand about how and whyit all works. In the case of Earth, there’s another 6300 kilometers of rock and iron beneath the

tectonic plates whose churnings constitute theinner workings of a planetary heat engine.Tectonic plates jostling about the surface arelike the hands sweeping across the clock face:informative in many ways but largely mute asto what drives them.

Earth scientists inherited a rather simple picture of Ear th’s interior from their pre–plate tec tonics col leagues.Earth was like an onion. Seismicwaves passing through the deepEarth suggested that beneath the

broken skin of plates lies a 2800-kilometer layer of rocky mantle over-

lying 3470 kilometers of molten and— at the center—solid iron. The mantle wasfurther subdivided at a depth of 670 kilo-meters into upper and lower layers, witha hint of a layer a couple of hundred kilo-meters thick at the bottom of the lower mantle.

In the postrevolution era, the onion modelcontinued to loom large. The dominant pictureof Earth’s inner workings divided the planetat the 670-kilometer depth, forming with thecore a three-layer machine. Above the 670, themantle churned slowly like a very shallow potof boiling water, delivering heat and rock atmid-ocean ridges to make new crust and coolthe interior and accepting cold sinking slabs of old plate at deep-sea trenches. A plume of hotrock might rise from just above the 670 to forma volcanic hot spot like Hawaii. But no hot rock rose up through the 670 barrier, and no cold rock sank down through it. Alternatively,argued a smaller contingent, the mantlechurned from bottom to top like a deep stock-

pot, with plumes rising all the way from thecore-mantle boundary.

Forty years of probing inner Earth with ever more sophisticated seismic imaging has

boosted the view of the engine’s complexity

without much calming the debate about how itworks. Imaging now clearly shows that the670 is no absolute barrier. Slabs penetrate the

boundary, although with difficulty. Layered-earth advocates have duly dropped their impen-etrable boundary to 1000 kilometers or deeper.Or maybe there’s a f lexible, semipermeable

boundary somewhere that limits mixing to onlythe most insistent slabs or plumes.

Now seismic imaging is also outliningtwo great globs of mantle rock standing

beneath Africa and the Pacific like pistons.Researchers disagree whether they are hotter than average and rising under t heir own

buoyancy, denser and sinking, or merely pas-sively being carried upward by adjacent cur-rents. Thin lenses of partially melted rock dotthe mantle bottom, perhaps marking the bot-tom of plumes, or perhaps not. Geochemistsreading the entrails of elements and isotopesin mantle-derived rocks find signs of fivelong-lived “reservoirs” that must have resis-ted mixing in the mantle for billions of years.But they haven’t a clue where in the depths of

the mantle those reservoirs might be hiding.How can we disassemble the increasingly

complex planetary machine and find whatmakes it tick? With more of the same, plus alarge dose of patience. After all, plate tectonicswas more than a half-century in the making,and those revolutionaries had to look littledeeper than the sea floor.

Seismic imaging will continue to improveas better seismometers are spread more evenlyabout the globe. Seismic data are already

distinguishing between temperature and compositional effects, painting an even morecomplex picture of mantle structure. Mineral

physicists working in the lab will tease outmore properties of rock under deep mantleconditions to inform interpretation of theseismic data, although still handicapped bythe uncertain details of mantle composition.And modelers will more faithfully simulate thewhole machine, drawing on seismics, mineral

physics, and subtle geophysical observationssuch as gravity variations. Another 40 yearsshould do it. –R ICHARD A. K ER

How Does Earth’s

Interior Work

continued

A long way to go. Grasping theworkings of plate tectonics willrequire deeper probing.

How many forms of celldeath are there?In the 1970s, apoptosiswas finally recognized asdistinct from necrosis.Some biologists nowargue that the cell deathstory is even more com-plicated. Identifying newways cells die could leadto better treatments forcancer and degenerativediseases.

What keeps intracellular trafficrunning smoothly?Membranes inside cells transportkey nutrients around, and through,various cell compartments without

sticking to each other orlosing their way. Insightsinto how membranesstay on track could helpconquer diseases, suchas cystic fibrosis.

What enablescellular componentsto copy themselvesindependent ofDNA?Centrosomes, whichhelp pull apart pairedchromosomes, andother organelles repli-cate on their owntime, without DNA’sguidance. This inde-pendence still defiesexplanation.

What roles do differentforms of RNA play ingenome function?

RNA is turning out to play adizzying assortment of roles,

from potentially passing geneticinformation to offspring to muting

gene expression. Scientists are scram-bling to decipher this versatile molecule.

C. SLAYDEN/ SCIENCE

KATHARINE SUTLIFF/ SCIENCE

Published by AAAS



A lone, in all that space? Not likely.Just do the numbers: Several hun-dred billion stars in our galaxy, hun-dreds of billions of galaxies in the observ-able universe, and 150 planetsspied already in the immediateneighborhood of the sun. Thatshould make for plenty of warm,scummy little ponds where lifecould come together to begin

bi ll ions of year s o f evo lutiontoward technology-wieldingcreatures like ourselves. No, thereally big question is when, if

ever, we’ll have the technologi-cal wherewithal to reach out and touch such intelligence. With a

bi t of luck , it could be in thenext 25 years.

Workers in the searc h for extraterrestrial intelligence(SETI) would have needed more than a little luck in the first45 years of the modern hunt for like-minded colleagues outthere. Radio astronomer Frank Drake’slandmark Project Ozma was certainly atriumph of hope over daunting odds. In

1960, Drake pointed a 26-meter radio tele-scope dish in Green Bank, West Virginia, attwo stars for a few days each. Given thevacuum-tube technology of the time, hecould scan across 0.4 megahertz of themicrowave spectrum one channel at a time.

Almost 45 years later, the SETI Institutein Mountain View, California, completed its 10-year-long Project Phoenix. Oftenusing the 350-meter antenna at Arecibo,Puerto Rico, Phoenix researchers searched 710 star systems at 28 million channelssimultaneously across an 1800-megahertz

range. All in all, the Phoenix searchwas 100 trillion times more effectivethan Ozma was.

Besides stunning advances in search

power, the first 45 years of modern SETIhave also seen a diversification of searchstrategies. The Search for Extraterrestrial

Radio Emissions from Nearby Developed Intelligent Populations (SERENDIP) hasscanned billions of radio sources in theMilky Way by piggybacking receivers onantennas in use by observational astro-nomers, including Arecibo. And other groups are turning modest-sized opticaltelescopes to searching for nanosecond flashes from alien lasers.

Still, nothing has been heard. But then,Phoenix, for example, scanned just one or two nearby sunlike stars out of each 100 mil-lion stars out there. For such sparse sampling

to work, advanced, broadcasting civi-lizations would have to be abundant, or

searchers would have to get very lucky.To f ind the needle in a galaxy-size

haystack, SETI workers are counting on theconsistently exponential growth of computing

power to con tinue for another couple of decades. In northern California, the SETI

Institute has already begun constructing anarray composed of individual 6-meter anten-nas. Ever-cheaper computer power will even-tually tie 350 such antennas into “virtual

telescopes,” allowing scientists tosearch many targets at once. IfMoore’s law—that the cost of com-

putation halves every 18 months—holds for another 15 years or so,SETI workers plan to use thisantenna array approach to checkout not a few thousand but perhapsa few million or even tens of mil-lions of stars for alien signals. If

there were just 10,000 advancedcivilizations in the galaxy, theycould well strike pay dirt beforeScience turns 150.

The technology may well beavailable in coming decades, butSETI will also need money. That’sno easy task in a field with as higha “giggle factor” as SETI has. TheU.S. Congress forced NASA towash its hands of SETI in 1993

after some congressmen mocked the wholeidea of spending federal money to look for “little green men with misshapen heads,” as

one of them put it. Searching for anothertippy-top branch of the evolutionary tree stillisn’t part of the NASA vision. For more thana decade, private funding alone has drivenSETI. But the SETI Institute’s planned$35 million array is only a prototype of theSquare Kilometer Array that would putthose tens of millions of stars within reach of SETI workers. For that, mainstream radioastronomers will have to be onboard—orwe’ll be feeling alone in the universe a long

time indeed.–R ICHARD A. K E

Are We AloneIn the Universe

Listening for E.T. The SETI Institute is deploying an array of antennas andtying them into a giant “virtual telescope.”


What role dotelomeres and cen-tromeres play ingenome function?These chromosomefeatures will remainmysteries until newtechnologies cansequence them.

Why are some genomes reallybig and others quite compact?

The puffer fish genome is400 million bases; one

lungfish’s is 133 billionbases long. Repeti-

tive and duplicatedDNA don’t explainwhy this and othersize differencesexist.

What is all that“junk” doing in ourgenomes?DNA between genes isproving important forgenome function andthe evolution of newspecies. Comparativesequencing, microarraystudies, and lab workare helping genomicistsfind a multitude of geneticgems amid the junk.

How much will newtechnologies lowerthe cost ofsequencing?New tools and concep-tual breakthroughs aredriving the cost ofDNA sequencing downby orders of magni-tude. The reductionsare enabling researchfrom personalizedmedicine to evolution-ary biology to thrive.

NIST

GETTY IMAGES

Published by AAAS



For the past 50 years, scientists haveattacked the question of how life

began in a pincer movement. Someapproach it from the present, moving

backward in time from life today to its sim- pler ancestors. Others march forward fromthe formation of Earth 4.55 billion years ago,exploring how lifeless chemicals might have

become organized into living matter.Working backward, paleontologists havefound fossils of microbes dating back at least3.4 billion years. Chemical analysis of evenolder rocks suggests that photosyntheticorganisms were already well established onEarth by 3.7 billion years ago. Researcherssuspect that the organisms that left these tracesshared the same basic traits found in all lifetoday. All free-living organisms encodegenetic information in DNA and catalyzechemical reactions using proteins. BecauseDNA and proteins depend so intimately oneach other for their survival, it’s hard to imag-

ine one of them having evolved first. But it’s just as implausible for them to have emerged simultaneously out of a prebiotic soup.

Experiments now suggestthat earlier forms of lifecould have been based ona third kind of moleculefound in today’s organ-isms: RNA. Onceconsidered nothingmore than a cellular courier, RNA turnsout to be astonish-ingly versatile, notonly encoding geneticinformation but alsoacting like a protein.Some RNA moleculesswitch genes on and off, for example, whereas others bind to

proteins and other molecules. Laboratoryexperiments suggest that RNA could havereplicated itself and carried out the other func-tions required to keep a primitive cell alive.

Only after life passed through this “RNAworld,” many scientists now agree, did it takeon a more familiar cast. Proteins are thou-

sands of times more efficient as a catalystthan RNA is, and so once they emerged theywould have been favored by natural selec-tion. Likewise, genetic information can bereplicated from DNA with far fewer errorsthan it can from RNA.

Other scientists have focused their effortson figuring out how the lifeless chemistry of a

prebiotic Earth could have given rise to anRNA world. In 1953, working at the Univer-sity of Chicago, Stanley Miller and Harold Urey demonstrated that experiments could shed light on this question. They ran an elec-tric current through a mix of ammonia,methane, and other gases believed at the timeto have been present on early Earth. They

found that they could produce amino ac ids

and other important building blocks of life.

Today, many sci-entists argue that theearly atmosphere wasdominated by other

gases, such as carbondioxide. But experi-

ments in recent years haveshown that under these con-

ditions, many building blocksof life can be formed. In addition,

comets and meteorites may have delivered organic compounds from space.

Just where on Earth these building blockscame together as primitive life forms is a sub-

ject of debate. Starting in the 1980s, many sci-entists argued that life got its start in the scald-ing, mineral-rich waters streaming out of deep-

sea hydrothermal vents. Evidence for a hotstart included studies on the tree of life, whichsuggested that the most primitive species of microbes alive today thrive in hot water. But thehot-start hypothesis has cooled off a bit. Recentstudies suggest that heat-loving microbes arenot living fossils. Instead, they may havedescended from less hardy species and evolved

new defenses against heat. Some skeptics alsowonder how delicate RNA molecules could have survived in boiling water. No singlestrong hypothesis has taken the hot start’s

place, however, although suggestions includetidal pools or oceans covered by glaciers.

Research projects now under waymay shed more light on how life

began. Scientists are running experi-ments in which RNA-based cells may be ableto reproduce and evolve. NASA and theEuropean Space Agency have launched

probes that wil l v isit comets, narrowingdown the possible ingredients that mighthave been showered on early Earth.

Most exciting of all is the possibility of finding signs of life on Mars. Recent missionsto Mars have provided strong evidence thatshallow seas of liquid water once existed on theRed Planet—suggesting that Mars might oncehave been hospitable to life. Future Mars mis-sions will look for signs of life hiding in under-ground refuges, or fossils of extinct creatures.If life does turn up, the discovery could meanthat life arose independently on both planets— suggesting that it is common in the universe— or that it arose on one planet and spread to theother. Perhaps martian microbes were carried to Earth on a meteorite 4 billion years ago,infecting our sterile planet. –C ARL Z IMMECarl Zimmer is the author of Soul Made Flesh: TDiscovery of the Brain—and How it Changed the Wor

How and Where Did

Life on Earth Arise

continued

Cauldron of life? Deep-sea vents areone proposed site for life’s start.

C R E D I T : D

A V I D A

. H A R D Y / P H O T O

R E S E A R C H E R S I N C

.


How can genomechanges otherthan mutationsbe inherited?Researchers are find-ing ever more exam-ples of this process,called epigenetics,but they can’t explainwhat causes and pre-serves the changes.

How do organs andwhole organismsknow when to stopgrowing?A person’s right andleft legs almostalways end up thesame length, and thehearts of mice andelephants each fit theproper rib cage. Howgenes set limits oncell size and numbercontinues to mystify.

How is asymme-try determinedin the embryo?Whirling ciliahelp an embryotell its left from itsright, but scientistsare still looking for thefirst factors that give a rel-atively uniform ball of cells a head,tail, front, and back.

How do limbs, fins, andfaces develop and evolve?

The genes that determine thelength of a nose or the breadth of a

wing are subject to natural and sexualselection. Understanding how selectionworks could lead to new ideas about themechanics of evolution with respect todevelopment.

JUPITER IMAGESCENTER FOR FUNCTIONAL GENOMICS,

SUNY AT ALBANY

Published by AAAS



C ountless species of plants, animals,and microbes fill every crack and crevice on land and in the sea. Theymake the world go ’round, converting sun-light to energy that fuels the rest of life,cycling carbon and nitrogen between inor-ganic and organic forms, and modifying thelandscape.

In some places and some groups, hun-dreds of species exist, whereas in others,very few have evolved; the tropics, for example, are a complex paradise compared to higher latitudes. Biologists are striving tounderstan d why. The interplay between

environment and living organisms and between the organisms themselves play keyroles in encouraging or discouraging diver-sity, as do human disturbances, predator-

prey relationships, and other food web con-nections. But exactly how these and other forces work together to shape diversity islargely a mystery.

The challenge is daunting. Baseline dataare poor, for example: We don’t yet knowhow many plant and animal species thereare on Earth, and researchers can’t even

begin to predict the numbers and kinds of organisms that make up the microbialworld. Researchers probing the evolutionof, and limits to, diversity also lack a stan-dardized time scale because evolution takes

place over periods lasting from days to mil-lions of years. Moreover, there can bealmost as much variation within a speciesas between two closely related ones. Nor isit clear what genetic changes will result in anew species and what their true influenceon speciation is.

Understanding what shapes diversitywill require a major interdisciplinaryeffort, involving paleontological interpre-

tation, field studies, laboratory experi-mentation, genomic comparisons, and effective statist ical analyses. A fewexhaustive inventories, such as the United

Nat ions’ Mil lennium Project and anaround-the-world assessment of genes

from marine microbes, should improve baseline data, but they will

barely scratch the s urface. Modelsthat predict when one species will split

into two will help. And an emerging disci- pl in e ca ll ed evo- devo is pr ob in g howgenes involved in development con-

tribute to evolution. Together, these

efforts will go a long way toward clarify-ing the history of life.Paleontologists have already made

headway in tracking the expansion and contraction of the ranges of various organ-isms over the millennia. They are findingthat geographic distribution plays a keyrole in speciation. Future studies should continue to reveal large-scale patterns of distribution and perhaps shed more light onthe origins of mass extinctions and theeffects of these catastrophes on the evolu-tion of new species.

From field studies of plants and animals,

researchers have learned that habitat caninfluence morphology and behavior— par ticularly sexual selection—in ways thathasten or slow down speciation. Evolutionary

biologists have also discovered that specia-tion can stall out, for example, as separated

populations become reconnected, homoge-nizing genomes that would otherwisediverge. Molecular forces, such as low muta-tion rates or meiotic drive—in which certainalleles have an increased likelihood of being

passed from one generation to the next— influence the rate of speciation.

And in some cases, differences in diver-sity can vary within an ecosystem: Edges of ecosystems sometimes support fewer speciesthan the interior.

Evolutionary biologists are just begin-ning to sort out how all these factors areintertwined in different ways for differentgroups of organisms. The task is urgent:Figuring out what shapes diversity could

be important for understanding the natureof the wave of extinctions the world isexperiencing and for determining strate-

gies to mitigate it.–E LIZABETH P ENNIS

What DeterminesSpecies Diversity


What triggerspuberty?Nutrition—includingthat received inutero—seems to helpset this mysteriousbiological clock, butno one knows exactlywhat forces child-hood to end.

Are stem cells at theheart of all cancers?The most aggressive

cancer cells look alot like stem cells.If cancers arecaused by stemcells gone awry,

studies of a cell’s“stemness” may lead

to tools that couldcatch tumors soonerand destroy themmore effectively.

Is cancer susceptibleto immune control?Although our immuneresponses can suppresstumor growth, tumorcells can combat thoseresponses with counter-measures. This defensecan stymie researchers hoping to developimmune therapies against cancer.

Can cancers be controllerather than cured?Drugs that cut off a tumorfuel supplies—say, by stoping blood-vessel growthcan safely check or evenreverse tumor growth. Buhow long the drugs remaieffective is still unknown.

M.CLARKEET AL. , PNAS 100 (7),3983COPYRIGHT (2003) NAS,U.S.A.

L . H E U S E R A N D R

. A C K L A N D / U N I V E R S

I T Y

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Every generation of anthropologistssets out to explore what it is thatmakes us human. Famed paleo-anthropologist Louis Leakey thought

tools made the man, and so when he uncov-ered hominid bones near stone tools in Tan-zania in the 1960s, he labeled the putativetoolmaker Homo habilis , the earliest member

of the human genus. But then primatologistJane Goodall demonstrated that chimps alsouse tools of a sort, and today researchersdebate whether H. habilis truly belongs in

Homo . Later studies have honed in on traitssuch as bipedality, culture, language, humor,and, of course, a big brain as the unique

birthright of our species. Yet many of thesetraits can also be found, at least to somedegree, in other creatures: Chimps have rudi-

mentary culture, parrots speak, and some ratsseem to giggle when tickled.

What is beyond doubt is that humans,like every other species, have a uniquegenome shaped by our evolutionary history.

Now, for the first time, scientists can address

anthropology’s fundamental question at anew level: What are the genetic changes thatmake us human?

With the human genome in hand and pri-mate genome data beginning to pour in, weare entering an era in which it may become

possible to pinpoint the genetic changes thathelp separate us from our closest relatives. Arough draft of the chimp sequence has already

been released, and a more detailed version isexpected soon. The genome of the macaque isnearly complete, the orangutan is under way,and the marmoset was recently approved. All

these will help reveal the ancestral genotype atkey places on the primate tree.

The genetic differences revealed betweenhumans and chimps are likely to be profound,despite the oft-repeated statistic that onlyabout 1.2% of our DNA differs from that of chimps. A change in every 100th base could affect thousands of genes, and the percentage

difference becomes much larger if you countinsertions and deletions. Even if we documentall of the perhaps 40 million sequence differ-ences between humans and chimps, what dothey mean? Many are probably simply theconsequence of 6 million years of geneticdrift, with little effect on body or behavior,whereas other small changes—perhaps inregulatory, noncoding sequences—may havedramatic consequences.

Half of the differences might define achimp rather than a human. How can wesort them all out?

One way is to zero in on the genes thathave been favored by natural selection inhumans. Studies seeking subtle signs of

selection in the DNA of humans and other primates have identified dozens of genes, in particular those involved inhost-pathogen interactions, reproduction,sensory systems such as olfaction and taste,and more.

But not all of these genes helped set usapart from our ape cousins originally. Our genomes reveal that we have evolved inresponse to malaria, but malaria defense didn’tmake us human. So some researchers havestarted with clinical mutations that impair keytraits, then traced the genes’ evolution, an

approach that has identified a handful of tanta-lizing genes. For example, MCPH1 and ASPMcause microcephaly when mutated, FOXP2causes speech defects, and all three show signsof selection pressure during human, but notchimp, evolution. Thus they may have played roles in the evolution of humans’large brainsand speech.

But even with genes like these, it is oftendifficult to be completely sure of what they do.Knockout experiments, the classic way toreveal function, can’t be done in humans and apes for ethical reasons. Much of the work will therefore demand comparative analysesof the genomes and phenotypes of largenumbers of humans and apes. Already, someresearchers are pushing for a “great ape‘phenome’ project” to match the incomingtide of genomic data with more phenotypicinformation on apes. Other researchers arguethat clues to functioncan best be gleaned

by mining natura lhuman variabilit y,matching mutationsin living people to

subtle differences in biology and behavior.Both strategies face

logistical and ethical problems , bu t some progress seems likely.

A complete understanding of uniquelyhuman traits will, however, include more thanDNA. Scientists may eventually circle back to those long-debated traits of sophisticated language, culture, and technology, in whichnurture as well as nature plays a leading role.We’re in the age of the genome, but we canstill recognize that it takes much more thangenes to make the human.

–E LIZABETH C ULOTTA

What GeneticChanges Made UsUniquely Human

continued


Is inflammation amajor factor in allchronic diseases?It’s a driver of arthri-tis, but cancer andheart disease? Moreand more, the answerseems to be yes, andthe question remainswhy and how.

How do priondiseases work?Even if one acceptsthat prions are justmisfolded proteins,many mysteriesremain. How can theygo from the gut to thebrain, and how dothey kill cells oncethere, for example.

How much do vertebratesdepend on the innate immunesystem to fight infection?This system predates the verte-brate adaptive immune response.Its relative importance isunclear, but immunol-ogists are workingto find out.

Does immunologic memoryrequire chronic exposure toantigens?Yes, say a few prominentthinkers, but experiments withmice now challenge the theory.Putting the debate to restwould require proving thatsomething is not there, so thequestion likely will not go away

ART DAVIS/USDA

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www.sciencemag.org SCIENCE VOL 309 1 JULY 2005Published by AAAS



Why doesn’t a pregnant womanreject her fetus?Recent evidence suggests that the mother’simmune system doesn’t “realize”that the fetus is foreign eventhough it gets half itsgenes from the father.Yet just as NobelistPeter Medawar saidwhen he first raisedthis question in 1952,“the verdict has yet tobe returned.”

What synchronizesan organism’s cir-cadian clocks?Circadian clock geneshave popped up in alltypes of creatures andin many parts of thebody. Now the chal-lenge is figuring outhow all the gears fittogether and whatkeeps the clocks setto the same time.

How do migratingorganisms find their way?Birds, butterflies, andwhales make annualjourneys of thou-sands of kilometers.They rely on cuessuch as stars and magneticfields, but the details remain unclear.

Why do we sleep?A sound slumber mayrefresh muscles and organor keep animals safe fromdangers lurking in the darBut the real secret of sleepprobably resides in the brawhich is anything but stillwhile we’re snoring away

Packed into the kilogram or so of neural

wetware between the ears is every-thing we know: a compendium of use-ful and trivial facts about the world, the his-tory of our lives, plus every skill we’ve ever learned, from riding a bike to persuading aloved one to take out the trash. Memoriesmake each of us unique, and they give conti-nuity to our lives. Understanding how mem-ories are stored in the brain is an essentialstep toward understanding ourselves.

Neuroscientists have already made greatstrides, identifying key brain regions and

potential molecular mechanisms. Still, manyimportant questions remain

unanswered, and a chasm gapes be twee n th e mo le cu la r an d whole-brain research.

The birth of the modern era of memory research is often pegged to the publication, in 1957, of anaccount of the neurological

patient H.M. At age 27, H.M. had large chunks of the temporallobes of his brain surgicallyremoved in a last-ditch effort torelieve chronic epilepsy. The sur-gery worked, but it left H.M.unable to remember anything

that happened—or anyone hemet—after his surgery. The caseshowed that the medial temporallobes (MTL), which include thehippocampus, are crucial for making new memories. H.M.’scase also revealed, on closer examination, that memory is nota monolith: Given a tricky mirror drawing task, H.M.’s perfor m-ance improved steadily over 3 dayseven though he had no memory of his previ-ous practice. Remembering how is not the

same as remembering what, as far as the

brain is concerned.Thanks to experiments on animals and the advent of human brain imaging, scien-tists now have a working knowledge of thevarious kinds of memory as well as which

parts of the brain are involved in each. But persistent gaps remain. Although the MTLhas indeed proved critical for declarativememory—the recollection of facts and events—the region remains something of a

black box. How its various components inter-act during memory encoding and retrieval isunresolved. Moreover, the MTL is not the

final repository of

declarative memo-ries. Such memoriesare apparently filed to the cerebral cortexfor long-term stor-age, but how this hap-

pens, and how mem-ories are represented in the cortex, remainsunclear.

More than a cen-tury ago, the greatS p a n i s h n e u r o -anatomist Santiago

Ramón y Cajal pro- po se d th at ma ki ngm e m o r i e s m u s trequire neurons tostrengthen their con-nections with oneanother. Dogma atthe time held that nonew neurons a r e

bo r n in t he adu l t br ai n, so Ra mó n y

Cajal made the reasonable assumption thatthe key changes must occur between exist-

ing neurons. Un til recently,scientists had few clues about

how this might happen.Since the 1970s, however, work

on isolated chunks of nervous-systemtissue has identified a host of molecu-lar players in memory formation.

Many of the same molecules have been

implicated in both declarative and nonde-clarative memory and in species as varied assea slugs, fruit flies, and rodents, suggestingthat the molecular machinery for memoryhas been widely conserved. A key insightfrom this work has been that short-termmemory (lasting minutes) involves chemicalmodifications that strengthen existing con-nections, called synapses, between neurons,whereas long-term memory (lasting days or weeks) requires protein synthesis and proba-

bly the construction of new synapses.Tying this work to the whole-brain

research is a major challenge. A potential

bridge is a process called long-term potentia-tion (LTP), a type of synaptic strengtheningthat has been scrutinized in slices of rodenthippocampus and is widely considered alikely physiological basis for memory. Aconclusive demonstration that LTP reallydoes underlie memory formation in vivowould be a big breakthrough.

Meanwhile, more questions keep pop- ping up. Recent studies have found that pat-terns of neural activity seen when an animalis learning a new task are replayed later dur-ing sleep. Could this play a role in solidifyingmemories? Other work shows that our mem-

ories are not as trustworthy as we generallyassume. Why is memory so labile? A hintmay come from recent studies that revive thecontroversial notion that memories are

briefly vulnerable to manipulation each timethey’re recalled. Finally, the no-new-neuronsdogma went down in flames in the 1990s,with the demonstration that the hippocam-

pus, of all places, is a virtual neuron nurserythroughout life. The extent to which thesenewborn cells support learning and memoryremains to be seen.

–G REG M ILL

How Are MemoriesStored and Retrieved

Memorable diagram. SantiagoRamón y Cajal’s drawing of thehippocampus. He proposed thatmemories involve strengthenedneural connections.


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When Charles Darwin wasworking out his grand theoryon the origin of species, hewas perplexed by the fact that

animals from ants to people form socialgroups in which most individuals work for the common good. This seemed to r uncounter to his proposal that individual fitness

was key to surviving over the long term.By the time hewrote The Descent of

Ma n , however, hehad come up with afew explanations. Hesuggested that natu-ral selection could encourage altruistic

behavior among kinso as to improve thereproductive poten-tial of the “family.”He also introduced

the idea of reciproc-ity: that unrelated butfamiliar individualswould help eachother out if both werealtruistic. A centuryof work with dozensof social species has borne out his ideas tosome degree, but the details of how and whycooperation evolved remain to be worked out. The answers could help explain human

behaviors that seem to make little sense froma strict evolutionary perspective, such asrisking one’s life t

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