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E very once in a while, cos- mologists are dragged, kicking and screaming, into a universe much more unset- tling than they had any reason to expect. In the 1500s and 1600s, Copernicus, Kepler, and Newton showed that Earth is just one of many planets orbiting one of many stars, destroying the com- fortable Medieval notion of a closed and tiny cosmos. In the 1920s, Edwin Hubble showed that our universe is constantly expanding and evolving, a find- ing that eventually shattered the idea that the universe is unchang- ing and eternal. And in the past few decades, cosmologists have discovered that the ordinary mat- ter that makes up stars and galax- ies and people is less than 5% of everything there is. Grappling with this new understanding of the cosmos, scientists face one overriding question: What is the universe made of? This question arises from years of pro- gressively stranger observations. In the 1960s, astronomers discovered that galaxies spun around too fast for the collective pull of the stars’ gravity to keep them from flying apart. Something unseen appears to be keeping the stars from flinging themselves away from the center: unilluminated matter that exerts extra gravitational force. This is dark matter. Over the years, scientists have spotted some of this dark matter in space; they have seen ghostly clouds of gas with x-ray tele- scopes, watched the twinkle of distant stars as invisible 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 to accounting for how the universe is structured. When astronomers look up in the heavens with powerful telescopes, they see a lumpy cosmos. Galaxies don’t dot the skies uni- formly; they cluster together in thin tendrils and filaments that twine among vast voids. Just as there isn’t enough visible matter to keep galaxies spinning at the right speed, there isn’t enough ordinary matter to account for this lumpiness. Cosmologists now conclude that 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 by comparison to another mystery: dark energy. In the late 1990s, scientists examining distant supernovae discovered that the universe is expanding 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, gas cloud properties—all converge on a consis- tent, but bizarre, picture of the cosmos. Ordi- nary matter and exotic, unknown particles together 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 three increasingly difficult sets of questions. What is ordinary dark matter made of, and where does 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, a dark-matter trap buried deep underground or a high-energy atom smasher will discover a new type of particle within the next decade. And finally, what is dark energy? This question, which wouldn’t even have been asked a decade ago, seems to transcend known physics more than any other phenomenon yet observed. Ever-better measurements of super- novae and cosmic background radiation as well as planned observations of gravitational lensing will yield information about dark energy’s “equation of state”—essentially a measure of how squishy the substance is. But at the moment, the nature of dark energy is arguably the murkiest question in physics— and the one that, when answered, may shed the most light. –CHARLES SEIFE CR ED IT :H IG H -Z S U P ER N O V A S EA R C H T EA M /H S T /N A S A 1 JULY 2005 VOL 309 SCIENCE www.sciencemag.org78 In the dark. Dark matter holds galaxies together; supernovae measurements point to a mysterious dark energy. What Is the Universe Made Of S p e c ia l S e c ti o n F rom the nature of the cosmos to the nature of societies, the following 100 questions span the sciences. Some are pieces of questions discussed above; others are big questions in their own right. Some will drive scientific inquiry for the next century; others may soon be answered. Many will undoubtedly spawn 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 theorists and cosmologists are trying to figure out whether our universe is part of a bigger “multiverse.” But others suspect that this hard-to-test idea may be a question for philosophers. What drove cosmic inflation? In the first moments after the big bang, the universe blew up at an incredible rate. But what did the blowing? Measurements of the cosmic microwave background and other astrophysical obser- vations are narrowing the possibilities. Published by AAAS F or centuries, debating the nature of consciousness was the exclusive purview of philosophers. But if the recent 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 finally shifted from a philosophical question to a scientific one that can be solved by doing experiments? The answer, as with any related to this topic, depends on whom you ask. But scientific 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 been hugely influenced by René Descartes, the French philosopher who in the mid–17th century declared that body and mind are made of different stuff entirely. It must be so, Descartes con- cluded, because the body exists in both t ime and space , whereas the mind has no spatial dimension. Recent scientif- ically oriented acc- ounts of conscious- ness generally reject Descartes’s solution; most prefer to treat body and mind as different aspects of the same thing. In this view, conscious- ness emerges from the properties and organization of neu- rons in the brain. But how? And how can scientists, with their devotion to objective observation and meas- urement, gain access to the inherently private and subjective realm of consciousness? Some insights have come from examin- ing neurological patients whose injuries have altered their consciousness. Damage to certain evolutionarily ancient structures in the brainstem robs people of conscious- ness entirely, leaving them in a coma or a persistent vegetative state. Although these regions may be a master switch for con- sciousness, they are unlikely to be its sole source. Different aspects of consciousness are probably generated in different brain regions. Damage to visual areas of the cere- bral cortex, for example, can produce strange deficits limited to visual awareness. One extensively studied patient, known as D.F., is unable to identify shapes or deter- mine the orientation of a thin slot in a vertical disk. 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 she seems 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 researchers hope that scanning the brains of subjects engaged in such tasks wil l reveal c lues about the neural activity required for conscious awareness. Work with monkeys also may elucidate some aspects of consciousness, particularly visual awareness. One experimental approach 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 version they 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 an explanation 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 the most enigmatic aspect of the conscious human mind: the sense of self. Yet the exper- imental work has begun, and if the results don’t provide a blinding insight into how consciousness arises from tangles of neu- rons, they should at least refine the next round of questions. Ultimately, scientists would like to understand not just the biological basis of consciousness but also why it exists. What selection pressure led to its development, and how many of our fellow creatures share it? Some researchers suspect that con- sciousness is not unique to humans, but of course much depends on how the term is defined. Biological markers for conscious- ness might help settle the matter and shed light on how consciousness develops early in life. Such markers could also inform medical decisions about loved ones who are in an unresponsive state. Until fairly recently, tackling the subject of consciousness was a dubious career move for any scientist without tenure (and perhaps a Nobel Prize already in the bag). Fortunately, more young researchers are now joining the fray. The unanswered questions should keep them—and the printing presses—busy for many years to come. –GREGMILLER What Is the Biological Basis of Consciousness 79 C R E D IT :L E S T E R L E FK O W IT Z /C O R B IS S p e c ia l S e c ti o n 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 stars and galaxies form? The broad brush strokes are visible, but the fine details aren’t. Data from satellites and ground- based telescopes may soon help pinpoint, among other particulars, when the first genera- tion of stars burned off the hydrogen “fog” that filled the universe. Where do ultra- high-energy cosmic rays come from? Above a certain energy, cosmic rays don’t travel very far before being destroyed. So why are cosmic-ray hunters spotting such rays with no obvious source within our galaxy? What powers quasars? The mightiest energy fountains in the universe probably get their power from matter plunging into whirling supermassive black holes. But the details of what drives their jets remain anybody’s guess. What is the nature of black holes? Relativistic mass crammed into a quantum-sized object? It’s a recipe for disaster—and scientists are still trying to figure out the ingredients. JPL/NASA E. J. SCHREIER, STSCI/NASA Published by AAAS C R E D IT :J U P IT E R I M A G E S 1 JULY 2005 VOL 309 SCIENCE www.sciencemag.org80 S p e c ia l S e c ti o n W hen leading biologists were unraveling 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 make up our DNA. Few bets came close. The con- ventional wisdom a decade or so ago was that we need about 100,000 genes to carry out the myriad cellular processes that keep us functioning. But it turns out that we have only about 25,000 genes—about the same number as a tiny flowering plant called Arabidopsis and barely more than the worm Caenorhabditis elegans. That big surprise reinforced a growing realization among geneticists: Our genomes and those of other mammals are far more flexible and complicated than they once seemed. The old notion of one gene/one pro- tein has gone by the board: It is now clear that many 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 the central challenges facing biologists. In the past few years, it has become clear that a phenomenon called alternative splicing is one reason human genomes can produce such complexity with so few genes. Human genes contain both coding DNA—exons— and noncoding DNA. In some genes, different combinations of exons can become active at different times, and each combination yields a different protein. Alternative splicing was long considered a rare hiccup during tran- scription, but researchers have concluded that it may occur in half—some say close to all— of our genes. That finding goes a long way toward 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 mechanisms that determine which genes or suites of genes are turned on or off at particular times and places. Researchers are discovering that each gene needs a supporting cast of hundreds to get its job done. They include proteins that shut down or activate a gene, for example by adding acetyl or methyl groups to the DNA. Other proteins, called transcription factors, interact with the genes more directly: They bind to landing sites situated near the gene under their control. As with alternative splicing, activation of different combinations of landing sites makes possible exquisite control of gene expression, but researchers have yet to figure out exactly how all these regulatory elements really work or how they f it in with alternative splicing. In the past decade or so, re- searchers have also come to appreci- ate the key roles played by chromatin proteins and RNA in regulating gene expression. Chromatin proteins are essentially the packaging for DNA, holding chromosomes in well-def ined spirals. By slightly changing shape, chro- matin may expose different genes to the transcription machinery. Genes also dance to the tune of RNA. Small RNA molecules, many less than 30 bases, now share the limelight with other gene regulators. Many researchers who once focused on messenger RNA and other rela- tively large RNA molecules have in the past 5 years turned their attention to these smaller cousins, including microRNA and small nuclear RNA. Surprisingly, RNAs in these various guises shut down and otherwise alter gene expression. They also are key to cell differentiation in developing organ- isms, but the mechanisms are not fully understood. Researchers have made enormous strides in pinpointing these various mechanisms. By matching up genomes from organisms on different branches on the evolution- ary tree, genomicists are locating regulatory regions and gaining insights into how mechanisms such as alternative splicing evolved. These studies, in turn, should shed light on how these regions work. Experiments in mice, such as the addition or deletion of regulatory regions and manipulating RNA, and computer models should also help. But the cen- tral question is likely to remain unsolved for a long time: How do all these features meld together to make us whole? –ELIZABETH PENNISI 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 Humans Have So Few Genes W H A T D O N ’ T W E K N O W ? Why is there more matter than antimatter? To a particle physicist, matter and anti- matter are almost the same. Some subtle difference must explain why matter is common and antimatter rare. Does the proton decay? In a theory of every- thing, quarks (which make up protons) should somehow be convertible to leptons (such as electrons)— so catching a proton decaying into some- thing else might reveal new laws of particle physics. What is the nature of gravity? It clashes with quantum theory. It doesn’t fit in the Standard Model. Nobody has spotted the particle that is responsible for it. Newton’s apple contained a whole can of worms. Why is time different from other dimensions? It took millennia for scien- tists to realize that time is a dimension, like the three spatial dimensions, and that time and space are inextrica- bly linked. The equations make sense, but they don’t satisfy those who ask why we perceive a “now” or why time seems to flow the way it does. JUPITER IMAGES JUPITER IMAGES Published by AAAS www.sciencemag.org SCIENCE VOL 309 1 JULY 2005 81 C R ED IT S (T O P TO B O T TO M ): JU PI T ER IM A G ES ;A FF Y M ET R IX S p e c ia l S e c ti o nF orty years ago, doc- tors learned why some patients who received the anesthetic succinyl- choline awoke normally but remained tempo- 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 gene variant. Roughly 1 in 3500 people carry two deleterious copies, putting them at high risk of this distressing side effect. The solution to the succinylcholine mys- tery was among the first links drawn between genetic variation and an individual’s response to drugs. Since then, a small but growing number of differences in drug metabolism have been linked to genetics, helping explain why 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 coming down with a variety of diseases. Gene vari- ants have been linked to elevated risks for dis- orders from Alzheimer’s disease to breast cancer, 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 which genetic tests will determine disease risks and guide prevention strategies and therapies. But digging up the DNA responsible—if in fact DNA is responsible—and converting that knowledge into gene tests that doctors can use remains a formidable challenge. Many conditions, including various can- cers, heart attacks, lupus, and depression, likely arise when a particular mix of genes collides with something in the environment, such as nicotine or a fatty diet. These multigene interactions are subtler and knot- tier than the single gene drivers of diseases such as hemophilia and cystic fibrosis; spotting them calls for statistical inspiration and rigorous experiments repeated again and again to guard against intro- ducing unproven gene tests into the clinic. And determining treatment strategies will be no less complex: Last summer, for example, a team of sci- entists linked 124 different genes to resistance to four leukemia drugs. But identifying gene networks like these is only the beginning. One of the toughest tasks is replicating these studies—an especially difficult proposition in diseases that are not overwh