Gene Chips and Arrays Revealed: A Primer on Their Power and Their Uses Stanley J. Watson and Huda Akil This article provides an overview and general explanation of the rapidly developing area of gene chips and expres- sion array technology. These are methods targeted at allowing the simultaneous study of thousands of genes or messenger RNAs under various physiological and patho- logical states. Their technical basis grows from the Hu- man Genome Project. Both methods place DNA strands on glass computer chips (or microscope slides). Expression arrays start with complementary DNA (cDNA) clones derived from the EST data base, whereas Gene Chips synthesize oligonucleotides directly on the chip itself. Both are analyzed using image analysis systems, are capable of reading values from two different individuals at any one site, and can yield quantitative data for thousands of genes or mRNAs per slide. These methods promise to revolution- ize molecular biology, cell biology, neuroscience and psychiatry. It is likely that this technology will radically open up our ability to study the actions and structure of the multiple genes involved in the complex genetics of brain disorders. Biol Psychiatry 1999;45:533–543 © 1999 Society of Biological Psychiatry Key Words: Expression arrays, genes, mRNA, brain Why Do We Need Gene Arrays or Gene Chips? B etween the mid-1970s and the early 1980s, the world of biology, including neurobiology, embarked on a major conceptual revolution, as critical ideas and tools of molecular biology were radically altered. Over the next 10 to 15 years, the fields of genetics and molecular and cellular biology matured both theoretically and techni- cally. A major offshoot of this revolution is the Human Genome Project, which focuses on the description and sequencing of the human genome, along with that of a few other selected species. As a result of these two forces— rapidly advancing molecular biology and genetics, and the torrent of information from the Human Genome Project, biomedical research finds itself at a critically exciting time. Once all the genes are known and their chromosomal locations assigned, and once we have a sense of their allelic variations (see Burmeister’s paper in this issue), the nature of the questions we ask will change. We will no longer need to decode the DNA sequences. Rather, we need to move to a better understanding of structure, function, and regulation of the resultant proteins. The first stage of basic information will have been laid out. The hard work of asking the right questions and attempting to understand the functioning of these genes in the context of health and disease will have just begun. This increase in fundamental knowledge is accompa- nied by a dawning realization that in order to understand many genetic disorders, it is critical for us to understand not only the actions of single genes, but the interactions between multiple genes. Nowhere is this truer than in the brain, and no set of diseases as a group exemplify this necessity better than the psychiatric disorders. Much of modern cellular and developmental biology studies how genes modulate each other and are modulated by internal and external environmental triggers (ranging from light and sound, to ions, transmitters, hormones, growth factors, and nutrients) to control developmental and cellular processes. Neurobiology concerns itself not only with all these signaling mechanisms, but also with the functions of cellular networks, which represent an addi- tional level of complexity and plasticity in the interplay among the action of various genes. Since all brain func- tions are dependent on the interactions of countless genes, it is not surprising that brain-related disorders will reflect disruptions in multiple genes. Of course, there are many cases where a defect in a single, critical gene along the cascade of events is sufficient to cause a clear-cut illness (e.g., Huntington’s disease). However, many psychiatric illnesses, when considered closely, appear to represent problems in “regulation” or “fine tuning” of complex functions, such as emotional tone or cognitive processing. For example, no one believes that a patient suffering from a mood disorder is congenitally incapable of generating or experiencing normal affective responses such as sadness or joy. The illness likely reflects a difficulty in dampening the responses or terminating them when no longer appro- From the Mental Health Research Institute, and Department of Psychiatry, University of Michigan, Ann Arbor, Michigan. Address reprint requests to Stanley J. Watson, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720. Received August 21, 1998; revised October 19, 1998; accepted October 21, 1998. © 1999 Society of Biological Psychiatry 0006-3223/99/$19.00 PII S0006-3223(98)00339-4