Part I--Genetic Fortune-Telling The Great Unraveling Mike Field ---------------------------- Staff Writer The recent discovery in a Hopkins lab of a gene that seems to inhibit antisocial behavior and extreme sexual aggressiveness in mice (see page 1) is not the first instance where scientists have claimed to isolate behavioral activity encoded in DNA. Previous studies have identified genes thought to contribute to obesity and homosexual behavior. Nor is this latest discovery likely to be the last, say experts. The possibility of a hereditary component in alcoholism, depression, memory retention and even musical ability has been hypothesized. As the 23 human chromosomes (see diagram) are painstakingly unraveled and mapped, gene by gene, it becomes increasingly likely that specific genetic mutations will be linked to any number of behavioral variations for good or ill. Do serial murderers share a common genetic aberration? Are painters or poets inspired by a strange twist in their DNA? No one can say for sure. What they can say, with a fair degree of certainty, is that the human genetic code has a profound--and, for now, only slightly understood--influence not only in how we look, but also how we act, think and view the world. The fault (or the virtue) is not, as the poet said, in the stars. It's in ourselves, coded in the spiraling structure of our deoxyribose nucleic acid, the ladderlike complex molecule that contains the complete and detailed recipe of who we are. Or, perhaps not. For while there are a small number of human diseases associated with the absence or mutation of one particular gene-- the so-called Mendelian diseases that can be traced in families using Mendel's laws of genetic inheritance--the bulk of disease, including most cancers, is the result of the actions of one or more genes in combination with any number of environmental factors. Behavioral patterns, say researchers, are probably similar, with a genetic component that predisposes an individual to certain responses to given stimuli within a specific environmental context. "When you talk about alcoholism, obesity, homosexuality or the like, you are talking about highly complex and variable patterns of behavior," said pediatrics professor Neil Holtzman, a School of Medicine geneticist with joint appointments in Epidemiology and Health Policy and Management at the School of Public Health. "I remain doubtful that we are ever going to find a single gene directly responsible for most of those who have these conditions." Holtzman is working on the second front of genetic research. He chairs the Task Force on Genetic Testing of the NIH-DOE Working Group on Ethical, Legal and Social Implications of Human Genome Research. The task force is charged with establishing criteria for safe and effective genetic testing and making recommendations for assuring the criteria are met. Since genes affect--at least potentially--lifestyle as well as life expectancy, the prospect of a simple blood test that could be used, say, to identify a predilection to violence has caused considerable concern, not only in the labs and classrooms of academia, but also across the nation's editorial pages and even through the halls of Congress. Who would administer such a test, and to what purpose? Do individuals--even, hypothetically, potential serial killers--enjoy an indisputable right to genetic privacy? Should someone genetically predisposed to breast cancer or Alzheimer's or depression be given the same job opportunities as someone genetically predisposed to live to an advanced age in perfect health? Should their health insurance cost more? Understanding DNA ----------------------------------------------------------------- Getting Down to the Basics Although genetics may be confusing to many, most of us display an implicit concept of heredity when we say, "She's got her mother's eyes and her father's nose." Understanding how genes work is really just an elaboration of this fundamental perception. Genes are the basic unit of human heredity. Best thought of as recipe files, each gene contains directions on how to create one specific protein, the building blocks from which the human body is composed. The human genome--that is, the sum total of all genetic material defining the characteristics of human beings--is thought to contain at least 100,000 genes, most of which have not yet been identified. Take almost any cell in your body--a bit of skin, or a drop of blood or a piece of hair--and within that cell's nucleus you will find every single gene needed to define who you are. These genes are contained in chromosomes. There are 23 pairs of chromosomes in each cell nucleus; they contain every gene needed to create and maintain life. Chromosomes vary in appearance, content and function and can be separated and identified with a high-power microscope. When scientists talk about "chromosome 9," they are referring to the same chromosome, with genes that serve the same purposes, in every human being. Each chromosome is composed of a tightly coiled strand of DNA combined with protein. DNA, or deoxyribose nucleic acid, looks remarkably like a long ladder, with two side rails and rungs between them, that has been twisted just like a piece of licorice. The DNA pictured above is in the process of replicating itself into two identical strands, the basic process in cell division. The side rails of DNA are composed of sugar and phosphate molecules in a regular pattern; they are connected by "rungs"-- called base pairs--consisting of either adenine and thymine (A-T) or cytosine and guanine (C-G), which are nitrogen-containing base molecules. If you imagine DNA as an incredibly long ladder, every so often--say from rung 100 all the way to rung 1,000--a section has a specific function: these are genes. A gene is a length of DNA containing a specific sequence of base pairs (or rungs); genes vary tremendously in length, and often contain thousands of base pairs (the entire human genome is estimated to contain 3 billion base pairs). Genes along the strand of DNA are often separated by sections whose functions aren't currently understood. The task of the Human Genome Project is to sequence--that is, to determine the order of the base pairs--each chromosome and thus every gene in the human body. Why? By mapping the normal sequence of each gene, mutations can be identified and, it is hoped, associated with specific diseases, physical characteristics or even behavioral patterns. Interestingly, the Human Genome Project is not directed to discovering the purpose or function of each gene, but only its location and base pair sequence; it will be up to other scientists in future research to determine the function of the 100,000 or so genes in the human body. ----------------------------------------------------------------- Like a genie in a bottle, the $3 billion project to identify and locate every human gene--known as the Human Genome Project-- offers the prospect of untold knowledge with far-reaching, perhaps unimaginable, consequences. Yet like the genie, there is a sense of lurking danger associated with unraveling nature's fundamental design code, the feeling that while knowledge may be power, it is a power we may not know how to wield in a way that will better most people's lives. So strong has been the sense of discomfort that the Human Genome Project has, from the start, carried money within its budget to provide for research into the moral and ethical issues associated with the research outcomes. Initially funded at 3 percent of the NIH's annual Human Genome Project budget, the commitment to ethical investigation was subsequently raised to 5 percent, partly because members of Congress became uneasy with some of the results research was suggesting. Part of that sense of unease lies within the cumulative nature of scientific discovery. In order to prevent or treat genetic diseases it is first necessary to identify the gene, in much the same way that the existence of microbes and bacteria had to be demonstrated before antibiotics could be developed. "There is a natural trajectory," said Holtzman, "where you develop the ability to test before you develop the ability to treat. This is the area where issues of genetic discrimination and other problems arise." Unfortunately, identifying the genetic basis for such late onset diseases as Alzheimer's or ALS--diseases that, currently, have no effective treatment--means that potentially thousands of Americans could be told they were going to come down with an untreatable ailment years or even decades before the disease begins to manifest itself. However, even this scenario fails to encompass the full complexity of the issues at stake. "If genetic testing becomes widespread there will be a certain number of false negative tests, where people are assured they are not at risk but will manifest the problem nonetheless," Holtzman said. "This is simply because it is unlikely we will ever be able to detect every possible genetic variant or possible problem. Only a handful of those affected with any of these problems will have a major gene that increases susceptibility, and for which a test can be devised." Yet the false negatives are, in all probability, the lesser problem when compared with the implications of how a false positive test can affect an individual's choices for the future. "One major problem that many people, including physicians, do not understand is that mutations do not necessarily lead to disease," Holtzman said. "Even if a mutation is detected, the person may simply never develop the illness [or the behavior patterns] associated with the gene. This leaves us with a very difficult question of what are we to do with these positive test results? They may be very helpful as a confirmation of a diagnosis, but many questions remain about their values in predicting risks in healthy people." How, then, should genetic testing be implemented, and how should we respond? ----------------------------------------------------------------- Next: As the number of genetic tests grows, so do the possibilities for discrimination, misdiagnosis and misinformation. Genetic counselors on the front lines in Part II of "Genetic Fortune-Telling." -----------------------------------------------------------------