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P ERSPECTIVES gies that steer the system toward a state with 1960s, they are a solution looking for a 3. J. Javanainen, S. M.Yoo, Phys. Rev. Lett. 76, 161 (1996). an improved signal-to-noise ratio (5). The problem. Some of the first applications are 4. T. L. Gustavson et al., Class. Quantum Grav. 17, 2385 of Saba et al. (1) should inspire likely to be in interferometric measurement (2000). a new generation of work on the quantum devices. The advance reported by Saba et al. 5. JM Geremia, J. K. Stockton, H. Mabuchi, Science 304, 270 (2004). mechanics of phase and atom number (6, 7). (1) is an important step in this direction. 6. C. Orzel et al., Science 291, 2386 (2001). Since their discovery in 1995, gas-phase 7. M. Greiner et al., Nature 415, 39 (2002). Bose-Einstein condensates have offered References and Notes 8. Supported by NSF grant PHY-0354599 and NASA fascinating insights into basic physics, but 1. M. Saba et al., Science 307, 1945 (2005). grant NAG3-2880. in the words of a quip about lasers from the 2. M. R.Andrews et al., Science 275, 637 (1997). 10.1126/science.1110247

CELL So what does the future hold for model organism research? In the case of S. cere- Whither Model visiae, the eukaryotic model organism with the smallest number of , we contend that it will be “solved” within the next 20 to Organism Research? 30 years. Of course, not every facet of biology will be known: Precise biochemical Stanley Fields and Mark Johnston functions will not be available for every product, the level of every metabolite will lmost everything we know about the mechanisms that underlie the ; the not have been measured under all possible fundamental properties of living cellular components that synthesize, mod- environmental stresses, and the subtle effects Acells—how they grow and divide, ify, repair, and degrade nucleic acids and of mutations on folding, stability, or how they express their genetic information, ; the signaling pathways that allow modification will not be wholly predictable. and how they use and store energy—has cells to communicate; and the mechanisms But no basic molecular process in yeast will come from the study of model organisms. that lead to the selective expression of sub- remain obscure. This is a remarkable accom- These simple creatures traditionally include sets of genes. Remarkably, the operating plishment that should be celebrated. And if the bacterium coli and its principles of these cellular processes have we expect to essentially “solve” over the , bakers’ yeast been conserved throughout the of . next few decades a cell constructed from , the Second, problems of biology and 6000 genes, how much longer can it be elegans, the fruit human are becoming increasingly before we “solve” the fruit fly with only melanogaster, and the seductive. Given that the flow of informa- twice as many genes, or the roundworm with Mus musculus, each a representative of the tion and around individual cells only about three times as many genes? diversity of life. Our colleague Gerry Fink is established, at least in outline, many biol- The benefits that we will realize from has likened this handful of organisms to the ogists find more excitement in, for exam- these successes include a working blueprint Security Council of the United Nations ple, discovering how organ systems first of a cell, then of multicellular organ- because, among the world’s multitude of develop and function, how learning and isms, that will enable researchers to deci- organisms, they garner most of the attention memory operate, and how innate and adap- pher ever more complex biological of researchers and dictate the distribution of tive immunity coordinate their responses. processes such as development, the most of the biomedical research funds that We want to understand how people get old, , and neurobiology. are not targeted to specific . A few why they get sick, and what we can do about Because of the spectacular progress of other organisms—the fission yeast it. The intrinsic appeal of these topics is bol- model organism research, we can expect to pombe, the mustard stered by encouragement from the National reach a thorough understanding of the thaliana, the Institutes of Health and other funding agen- molecular basis of life. This Security Danio rerio, and the laevis— cies to conduct “translational research,” Council, unlike its political counterpart, is may qualify for seats on the council, but studies that directly address the prevention proving to be a resounding success. membership is limited. But has the very suc- or treatment of disease. Third, the tools and That said, are we playing a dirge to cess of experimental approaches using resources that made uncomplicated model model organism research or singing a paean model organisms made them (and the scien- organisms so attractive to begin with can be to its reinvention? We are singing, because tists who study them) endangered? Now applied increasingly well to much more we believe that the hegemony of model may be an opportune time to ask: What complex creatures including mice and organisms in biological research will per- more can model organisms tell us about fun- . Thus, we now have essentially sist. We see at least five reasons why. damental biological processes? complete mammalian sequences, 1) Over the coming few decades, model Three daunting issues confront biolo- an expanding resource of purified genes organisms will continue to provide insights gists who devote their careers to studying and proteins, DNA chips to measure gene into replication, transcription, translation, model organisms. First, some of the most expression, and vast numbers of DNA protein secretion, metabolism, and many crucial questions have been answered, at sequence polymorphisms to map traits such other aspects of , , least in part. Thus, we know a lot about the as susceptibility to disease. Perhaps most and , because they offer the keen- disquieting for the model organism est methods of analysis. In fact, the value of S. Fields is in the Howard Hughes Medical Institute, researcher is the recent acquisition by model organisms will only increase, because Departments of Genome Sciences and Medicine, mammalian biologists of a method that was the human geneticist who identifies a disease University of Washington, Seattle,WA 98195, USA. M. once the sole province of those working on gene implicated in a conserved cellular Johnston is in the Department of , Washington University Medical School, St. Louis, MO simpler creatures: facile elimination of process will turn to these models to provide 63110, USA. E-mail: [email protected], gene function. The new method of RNA deeper insights into the function of that gene. [email protected] interference has leveled this playing field. And that researcher will discover a rich

www.sciencemag.org SCIENCE VOL 307 25 MARCH 2005 1885 Published by AAAS P ERSPECTIVES encyclopedia of knowledge that can be ing optimal methods for prevention and which are so different from model organ- drawn upon for formulating incisive experi- treatment. Genetic diversity is the grist for isms, wreak havoc with fatal diseases like ments to illuminate the disease process. the mill of natural selection that produced , African sleeping sickness, and 2) Model organisms will increasingly be the remarkable diversity of life on Earth, and Chagas’ disease? How do strange bacteria used for the direct investigation of medical model organisms should continue to teach and viruses elude our immune systems and problems that seemingly have little to do us about the origin of the . stymie our best efforts at drug ? with them. For example, the misfolding or 5) Model organisms will remain the prov- How do genes and the environment interact aggregation of proteins implicated in the ing ground for developing new technologies, in behavioral diseases like or process of in disorders which typically spread quickly throughout autism? What is the basis of memory and like Alzheimer’s disease, Parkinson’s dis- the research community. For example, our consciousness? ease, and Huntington’s disease, can be reca- skills in isolating and manipulating genes The reductionist approach of biologists pitulated in yeast, , and . In addi- were won while studying bacteria and bacte- has enabled remarkable achievements by tion, other components discovered in these riophages. Many other technologies got their causing us to focus on just a few experimen- organisms may be important in the disease start or achieved their apogee in yeast, tally tractable organisms, but it also has process. Analysis of aging in simple models including two-hybrid analysis, high- tended to restrict our vision. There is much is turning up genes that play analogous throughput protein purification and localiza- to learn about the many organisms that pop- roles in more complex organisms. Model tion, genomewide epistasis analysis (syn- ulate our planet, most in ways we can’t yet organisms will provide further insights into thetic lethality), gene expression profiling, begin to fathom. How do creatures survive the cell cycle and , glucose metabo- protein arrays, and genomewide chromatin in extreme environments? How do some lism and , segregation immunoprecipitation (ChIP). Worms and manage to metabolize bizarre substrates? and mental retardation, protein glycosyla- flies have been the test beds for large-scale How do individuals organize themselves tion and lysosomal storage diseases, mech- RNA interference screens. We don’t see into incredibly complex communities? This anisms of drug action and resistance, and these developments abating. Indeed, the list of questions seems endless (as seemed much more. Studies of S. cerevisiae will more the fund of knowledge of simple organ- the list of genes in model organisms not so help us to unravel the workings of its patho- isms grows, the more useful they become for long ago). Providing adequate answers to genic cousins such as ; subsequent technological innovation. these and many other questions is certain to studies of D. melanogaster will reveal But will an organism like yeast be able to occupy us for a long time. And the knowl- secrets of the Anopheles mosquito. maintain its seat on the Security Council? edge and sophisticated analytical tools that 3) Model organisms will remain at the Not indefinitely. And just as yeast has led model organism research has laid at our feet forefront for the foreseeable future in the way in many areas of research, we bring the entire General Assembly of organ- efforts to sort out biological complexity and expect that its fate as an experimental isms within our reach, enabling us eventu- achieve a more quantitative understanding organism will foreshadow that of the rest of ally to answer a question that has framed our of life processes, which is needed to unravel the council. Does this mean that the end of enterprise from its beginning: What is life? the network of molecular interactions that biology is near? Hardly. We will still be a constitute an organism as complicated as a long way from a comparably deep-seated References and Notes 1. We are grateful to C. Berg, G. Fink, E. Grayhack, M. human. For example, it is with yeast that understanding of humans and our afflic- Olson, E. Phizicky, J.Thomas, and R.Waterston for their biologists first will elucidate how DNA tions. How do cells and organs regenerate thoughtful comments. binding proteins, DNA sequence elements, after damage? How do eukaryotic parasites, 10.1126/science.1108872 components of the transcriptional machin- ery, chromatin structure, and signaling pathways combine in the circuitry of gene regulation. The resulting comprehension of biological networks that will result will Signal Processing in Single Cells bestow upon biologists the predictive pow- ers and design capabilities long held by Farren J. Isaacs,William J. Blake, James J. Collins physicists and engineers. Such insights will require the application of multiple tech- onsider a high-tech version of the the Times Square environment. In this issue, nologies, the confluence of individual “telephone game” in which you and a Rosenfeld et al. on page 1962 (1) and investigator’s experiments and genomewide Cgroup of your friends attempt to Pedraza and van Oudenaarden on page 1965 data sets, and the intense collaboration of transmit a message via your cell phones. (2) investigate a living-cell version of this experimentalists and computational biolo- One person in the chain has a phone from game by exploring how signals are trans- gists. Learning how to carry off this ambi- the 1990s, which is very noisy. Another per- mitted through gene cascades in noisy cel- tious project is itself a lofty goal of model son is standing in the middle of Times lular environments. organism research. Square in New York City. It would not be Cell phones consist of multiple, interact- 4) Model organisms offer the best hope surprising if the message received by the ing components. Engineers characterize the for coming to grips with the breadth of person at the end of the chain, or cascade, performance of such devices by determin- genetic diversity and the depth of its conse- were corrupted as a result of noise intrinsic ing quantitatively the input-output relation- quences. Most of the variance among indi- to the old phone and the noise arising from ships, or transfer functions, of the respec- viduals of a species is due to small differ- tive components. Rosenfeld et al. present a ences in multiple genes, and it is with model F. J. Isaacs is at the Lipper Center for Computational new method for calculating the transfer organisms that we will first learn how to ana- Genetics and Department of Genetics, Harvard function for the expression of a single gene. lyze and understand complex quantitative Medical School, Boston, MA 02115, USA. W. J. Blake Specifically, they investigate the relation- and J. J. Collins are at the Center for BioDynamics and traits. Such an understanding will provide Department of Biomedical Engineering, Boston ship between the concentration of active the principles and procedures for predicting University, Boston, MA 02215, USA. E-mail: transcription factor (input) and the rate at

disease susceptibilities in humans and tailor- [email protected] which target protein is produced (output) in :

1886 25 MARCH 2005 VOL 307 SCIENCE www.sciencemag.org Published by AAAS