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Systems Biology and Its Relevance to Alcohol Research

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Systems Biology and Its Relevance to Alcohol Research Commentary: Systems Biology and Its Relevance to Alcohol Research Q. Max Guo, Ph.D., and Sam Zakhari, Ph.D. Systems biology, a new scientific discipline, aims to study the behavior of a biological organization or process in order to understand the function of a dynamic system. This commentary will put into perspective topics discussed in this issue of Alcohol Research & Health, provide insight into why alcohol-induced disorders exemplify the kinds of conditions for which a systems biological approach would be fruitful, and discuss the opportunities and challenges facing alcohol researchers. KEY WORDS: Alcohol-induced disorders; alcohol research; biomedical research; systems biology; biological systems; mathematical modeling; genomics; epigenomics; transcriptomics; metabolomics; proteomics ntil recently, most biologists’ emerging discipline that deals with, Alcohol Research & Health intend to efforts have been devoted to and takes advantage of, these enormous address. In this commentary, we will Ureducing complex biological amounts of data. Although scientists try to put the topics discussed in this systems to the properties of individual and engineers have applied the concept issue into perspective, provide views molecules. However, with the com­ of an integrated systemic approach for on the significance of systems biology pleted sequencing of the genomes of years, systems biology has only emerged as a new, distinct discipline to study 1 High-throughput genomics is the study of the structure humans, mice, rats, and many other and function of an organism’s complete genetic content, organisms, technological advances in complex biological systems in the past or genome, using technology that analyzes a large num­ the fields of high-throughput genomics1 several years. A database search using ber of genes at a time. See the glossary, p. 84, for descriptions of other technical terms used in this article. and functional genomics2 have gener­ the phrase “systems biology” in the ISI ated enormous amounts of information Web of Science has found only 3 pub­ 2 Functional genomics aims to discover, on a large scale, 3 the biological function of particular genes and to uncover on the properties of genes, RNAs, lications in 2001; in 2006, this number how sets of genes and their products work together in proteins, and metabolic products (i.e., had reached 575 (see figure 1). health and disease. An example includes gene expression metabolites) in an organism. The bil­ With the emergence of this power­ profiling. lions of data points generated by these ful new discipline, we are tempted to 3 RNA is mostly involved in the processes of translating high-throughput studies are far beyond ask the following questions: Is systems genetic information from DNA into proteins. Some non- coding RNAs also are directly involved in other biological the reach of reductionist approaches. biology suitable for alcohol research? processes in the cell. High-throughput technologies have What kinds of alcohol-related problems offered biologists tremendous opportu­ can we address using a systems biolo­ Q. MAX GUO, PH.D., is program direc­ nities but also have created considerable gy approach? What opportunities and tor and SAM ZAKHARI, PH.D., is director, challenges. How can we take advantage challenges are there in current and both at the Division of Metabolism and of this wealth of information to under­ future research? These are the kinds Health Effects, National Institute on stand its biological significance in health of questions that the articles in this Alcohol Abuse and Alcoholism, Bethesda, and disease? Systems biology is an special systems biology issue of Maryland. Vol. 31, No. 1, 2008 5 for alcohol research, and discuss ways and tissues simultaneously. mere collection of components. opportunities and challenges facing Because the approaches taken by theory- Rather, they are derived and shaped alcohol researchers. oriented systems biologists are very by millions of years of evolutionary abstract and require specific expertise selection for survival, fitness, and in computation and modeling, early reproduction. For example, the What Is Systems Biology? systems biologists in the field of alcohol mitotic spindle5 in a cell is not just research will most likely adopt the created from simple polymerization Systems biology is a new scientific pragmatic approach. of α- and β-tubulins.6 It involves the discipline that studies the behaviors interaction of the polymerized micro­ of complex biological organizations tubules with motor proteins and the or processes through the integration What Is a Biological communication with many other cel­ of diverse quantitative information System? lular signals to accurately segregate and mathematical modeling to gener­ the sister chromosomes. The emer­ ate a predictive hypothesis on the “Biological system” is a loosely defined gent properties during chromosome functions of the dynamic biological term. To understand what constitutes segregation cannot be achieved by system (Aderem 2005; Auffray et al. a biological system, it is helpful to the collective properties of tubulins, 2003; Hood et al. 2004; Kirschner revisit a visionary paper by Hartwell microtubules, motors, or chromo­ 2005; Liu 2005; O’Malley and Dupre and colleagues (1999) published before somes alone. The spindle can be con­ 2005; Weston and Hood 2004). systems biology became a household sidered a functional module, which Systems biology may have quite term for biologists. Although the communicates and interacts with and different meanings to different people. authors did not mention the phrase organizes many other molecules and In general, systems biologists can be “systems biology” in that paper, their structures. The amazing harmony of organized into two camps. In the first proposed concept of functional mod­ spindle behaviors during cell division camp, the “systems-theoretic biologists” ules provides the building blocks for is achieved through evolutionary think that the focus of systems biology defining a biological system. Hartwell is to elucidate system principles and and colleagues proposed that the func­ 4 An emergent property is the new characteristic gener­ properties of operation based on com­ tions of a cell are carried out by mod­ ated through the interaction of individual components. ponent interactions in the biological ules made of many different kinds of 5 The mitotic spindle is an assembly of microtubules, system (Bork and Serrano 2005; interacting molecules. They argued structural components in the cell, created during the O’Malley and Dupre 2005). To that these functional modules provide process of cell division known as mitosis. them, systems biology is very abstract a critical level of biological organiza­ 6 α- and β-tubulins are the proteins that make up micro­ and precise. The mere integration of tion. Functional modules are not a tubules. constituents in the system for under­ standing the emergent properties4 of component interactions is insufficient for these theory-oriented systems 600 biologists. However, the majority of today’s systems biologists, who can be 500 described as “pragmatic systems biol­ ogists,” are gathered in the other 400 camp (O’Malley and Dupre 2005). They use systems biology as a practi­ 300 cal but vague term, denoting the study of interconnected phenomena 200 as systems and the collective analysis of large amounts of diverse data by integration and modeling. Despite 100 Number of Publications Number of Publications these differences, the pragmatic and theoretic systems biologists share 0 some common ground. For example, 2000 2002 2004 2006 both agree that systems biology Year involves data integration and mathe­ matical modeling and that models Figure 1 Number of publications with “systems biology” as a key word in the generated through systems biology search of the ISI Web of Science. The data plotted are from 2000 to studies should be predictive. 2006. The Web address for the ISI Web of Science is: http://portal. Alcohol-induced disorders are very isiknowledge.com/portal.cgi complex, involving numerous path­ 6 Alcohol Research & Health Systems Biology and Alcohol Research selection, as evidenced by comparing phate [ATP] synthase) have 13 and generate a model of how Complex I the spindle formations during closed 16 subunits, respectively. Each of functions. Based on this model, we mitosis and open mitosis. During closed these complexes can be considered a should be able to hypothesize and pre­ mitosis in yeast, the spindle is formed functional module, consisting of vari­ dict how the function of the complex within the nuclear membrane, which ous interacting subunits. But each of would change if we perturb a specific does not break down during mitosis. these complexes also can be consid­ component in the system, say by However, in higher organisms, the ered a biological system if our goal is ethanol. For example, if the amount nuclear membrane breaks down dur­ to understand how each of the com­ of one nuclear-encoded subunit is ing mitosis and the spindle is formed plexes works. However, if our goal is rate limiting for assembly of the com­ without constrains of the nuclear to understand how ATP is generated plex, one may predict that the expres­ membrane (open mitosis). The func­ through oxidative phosphorylation,8 sion of this nuclear gene is tightly tion of the nuclear membrane for we would consider the entire electron regulated. Aberrant regulation of its spindle formation in yeast may have transport chain
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