TO KNOW OURSELVES ❖ THE U.S. DEPARTMENT OF ENERGY AND THE HUMAN GENOME PROJECT JULY 1996 TO KNOW OURSELVES ❖ THE U.S. DEPARTMENT OF ENERGY AND THE HUMAN GENOME PROJECT JULY 1996 Contents FOREWORD . 2 THE GENOME PROJECT—WHY THE DOE? . 4 A bold but logical step INTRODUCING THE HUMAN GENOME . 6 The recipe for life Some definitions . 6 A plan of action . 8 EXPLORING THE GENOMIC LANDSCAPE . 10 Mapping the terrain Two giant steps: Chromosomes 16 and 19 . 12 Getting down to details: Sequencing the genome . 16 Shotguns and transposons . 20 How good is good enough? . 26 Sidebar: Tools of the Trade . 17 Sidebar: The Mighty Mouse . 24 BEYOND BIOLOGY . 27 Instrumentation and informatics Smaller is better—And other developments . 27 Dealing with the data . 30 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS . 32 An essential dimension of genome research Foreword T THE END OF THE ROAD in Little has been rapid, and it is now generally agreed Cottonwood Canyon, near Salt that this international project will produce Lake City, Alta is a place of the complete sequence of the human genome near-mythic renown among by the year 2005. A skiers. In time it may well And what is more important, the value assume similar status among molecular of the project also appears beyond doubt. geneticists. In December 1984, a conference Genome research is revolutionizing biology there, co-sponsored by the U.S. Department and biotechnology, and providing a vital of Energy, pondered a single question: Does thrust to the increasingly broad scope of the modern DNA research offer a way of detect- biological sciences. The impact that will be ing tiny genetic mutations—and, in particu- felt in medicine and health care alone, once lar, of observing any increase in the mutation we identify all human genes, is inestimable. rate among the survivors of the Hiroshima The project has already stimulated signifi- and Nagasaki bombings and their descen- cant investment by large corporations and dants? In short the answer was, Not yet. prompted the creation of new companies hop- But in an atmosphere of rare intellectual fer- ing to capitalize on its profound implications. tility, the seeds were sown for a project that But the DOE’s early, catalytic decision would make such detection possible in the deserves further comment. The organizers of future—the Human Genome Project. the DOE’s genome initiative recognized that In the months that followed, much the information the project would generate— deliberation and debate ensued. But in 1986, both technological and genetic—would con- the DOE took a bold and unilateral step by tribute not only to a new understanding of announcing its Human Genome Initiative, human biology, but also to a host of practical convinced that its mission would be well applications in the biotechnology industry served by a comprehensive picture of the and in the arenas of agriculture and environ- human genome. The immediate response mental protection. A 1987 report by a DOE was considerable skepticism—skepticism advisory committee provided some examples. about the scientific community’s technologi- The committee foresaw that the project could cal wherewithal for sequencing the genome ultimately lead to the efficient production of at a reasonable cost and about the value of biomass for fuel, to improvements in the the result, even if it could be obtained eco- resistence of plants to environmental stress, nomically. and to the practical use of genetically engi- Things have changed. Today, a decade neered microbes to neutralize toxic wastes. later, a worldwide effort is under way to The Department thus saw far more to the develop and apply the technologies needed to genome project than a promised tool for completely map and sequence the human assessing mutation rates. For example, genome, as well as the genomes of several understanding the human genome will have model organisms. Technological progress an enormous impact on our ability to assess, 2 Foreword individual by individual, the risk posed by components found in highly radioactive environmental exposures to toxic agents. We waste, thus simplifying the task of further know that genetic differences make some of cleanup. Another approach might be to us more susceptible, and others more resis- introduce metal-binding proteins onto the tant, to such agents. Far more work must be microbe’s surface that would scavenge highly done before we understand the genetic basis radioactive isotopes out of solution. of such variability, but this knowledge will Biotechnology, fueled in part by directly address the DOE’s long-term mis- insights reaped from the genome project, will sion to understand the effects of low-level also play a significant role in improving exposures to radiation and other energy- the use of fossil-based resources. Increased related agents—especially the effects of energy demands, projected over the next 50 such exposure on cancer risk. And the years, require strategies to circumvent the genome project is a long stride toward such many problems associated with today’s knowledge. dominant energy systems. Biotechnology The Human Genome Project has other promises to help address these needs by implications for the DOE as well. In 1994, upgrading the fuel value of our current ener- taking advantage of new capabilities devel- gy resources and by providing new means for oped by the genome project, the DOE for- the bioconversion of raw materials to refined mulated the Microbial Genome Initiative to products—not to mention offering the sequence the genomes of bacteria of likely possibility of entirely new biomass-based interest in the areas of energy production and energy sources. use, environmental remediation and waste We have thus seen only the dawn of a reduction, and industrial processing. As a biological revolution. The practical and eco- result of this initiative, we already have com- nomic applications of biology are destined for plete sequences for two microbes that live dramatic growth. Health-related biotechnol- under extreme conditions of temperature and ogy is already a multibillion-dollar success pressure. Structural studies are under way to story—and is still far from reaching its poten- learn what is unique about the proteins of tial. Other applications of biotechnology are these organisms—the aim being ultimately to likely to beget similar successes in the coming engineer these microbes and their enzymes decades. Among these applications are sev- for such practical purposes as waste control eral of great importance to the DOE. We can and environmental cleanup. (DOE-funded look to improvements in waste control and an genetic engineering of a thermostable DNA exciting era of environmental bioremedia- polymerase has already produced an enzyme tion; we will see new approaches to improv- that has captured a large share of the several- ing energy efficiency; and we can even hope hundred-million-dollar DNA polymerase for dramatic strides toward meeting the fuel market.) demands of the future. The insights, the And other little-studied microbes hint technologies, and the infrastructure that are at even more intriguing possibilities. For already emerging from the genome project, instance, Deinococcus radiodurans is a species together with advances in fields such as com- that prospers even when exposed to huge putational and structural biology, are among doses of ionizing radiation. This microbe has our most important tools in addressing these an amazing ability to repair radiation- national needs. induced damage to its DNA. Its genome is currently being sequenced with DOE sup- port, with the hope of understanding and ultimately taking practical advantage of its unusual capabilities. For example, it might Aristides A. N. Patrinos be possible to insert foreign DNA into this Director, Human Genome Project microbe that allows it to digest toxic organic U.S. Department of Energy 3 The Genome Project– Why the DOE? A BOLD BUT LOGICAL STEP HE BIOSCIENCES RESEARCH com- much to learn about how low doses munity is now embarked on a produce their insidious effects. When present program whose boldness, even merely in low but significant amounts, toxic audacity, has prompted compar- agents such as radiation or mutagenic chemi- Tisons with such visionary efforts cals work their mischief in the most subtle as the Apollo space program and the ways, altering only slightly the genetic Manhattan project. That life scientists instructions in our cells. The consequences should conceive such an ambitious project is can be heritable mutations too slight to pro- not remarkable; what is surprising—at least duce discernible effects in a generation or two at first blush—is that the project should trace but, in their persistence and irreversi- its roots to the Department of Energy. bility, deeply troublesome nonetheless. For close to a half-century, the DOE Until recently, science offered little and its governmental predecessors have been hope for detecting at first hand these charged with pursuing a deeper understand- tiny changes to the DNA that encodes our ing of the potential health genetic program. Needed was a tool that risks posed by energy use could detect a change in one “word” of In 1986 and by energy-production the program, among perhaps a hundred technologies—with special million. Then, in 1984, at a meeting convened the DOE interest focused on the jointly by the DOE and the International was the first effects of radiation on Commission for Protection Against Environ- federal agency humans. Indeed, it is fair to mental Mutagens and Carcinogens, the ques- say that most of what we tion was first seriously asked: Can we, should to announce know today about radiologi- we, sequence the human genome? That is, an initiative cal health hazards stems can we develop the technology to obtain a from studies supported by word-by-word copy of the entire genetic to pursue a these government agencies.