If you are a judge or lawyer, you will need to know about the Human Genome Project because its scope is pervasive and its potential legal implications are vast. Information gleaned from the project is sure to be playing in a courtroom near you in the not-too-distant future. You have probably already seen cases involving forensic DNA evidence in paternity suits or criminal prosecutions. If so, you have merely witnessed the tip of the iceberg. Discrimination cases based on the dissemination of genetic testing information to official or private entities will be featured shortly. Motions for injunctive relief will be filed based on irreparable harm to general health, life, or the species posed by gene therapy and other biotechnology regimes. There will be judicial review of the administrative regulation of genetic testing methods and genetic counseling services. Soon we can even expect criminal jurisprudence of claims challenging the validity of individual responsibility based on free will considerations in light of the discovery of genetic traits that, it will be claimed, predispose certain individuals to violence or antisocial, thrill-seeking behavior.
Experts will present complex evidence for one party, and they will be met by experts from the other. Your limited awareness of the scientific "knowledge" gathered in the last two decades will probably handicap you. If so, you will be like many of your peers and community members. However, unlike many, you will not be able to throw up your arms, admit ignorance, and choose to walk away. It will be your job to present this type of evidence clearly, or to determine whether it should be allowed in the courtroom, or to make sure that jurors who are completely unversed in its implications are made as familiar as possible with genetic technology so that they can understand the cases before them and rule fairly and adequately.
To do so, you will need a working familiarity with the Human Genome Project and the issues of genetics as they will present themselves in the courtrooms of America.
SOME NECESSARY BACKGROUND
Long before there was a formal Human Genome Project (HGP), the Department of Energy (DOE) and its predecessor agencies had been interested in developing sensitive methods to detect changes to genetic materials induced by ionizing radiation and to understand the related health effects.[1] It has been known for some time that the genetic-information-containing DNA is the part of a cell that is the most sensitive to the effects of radiation and other pollutants, even in low doses.[2] As new technologies for understanding and working with DNA were developed in the 1980s, the idea arose to sequence the entire human genome systematically, and with this idea arose the HGP. It was recognized early on that once this project was completed, it would furnish a comprehensive reference source that others could build on without having to repeat the research from scratch.
Understanding the Basic Science. Perhaps we are outstripping ourselves. You are probably asking, Exactly what is the HGP? Simply put, the HGP is an attempt to map completely the entire spectrum of genetic materials that can be found in all human beings. It is a research effort initiated by the DOE and jointly managed by the DOE and the National Institutes of Health (NIH). A unifying fact of human genetics is that all humans have genomes --the complete set of our genetic instructions on the 23 pairs of chromosomes within each of us --that are 99.9 percent identical in sequence. The DNA molecules that carry these genetic instructions are linear, information-containing molecules made up of four simple bases or building blocks --adenine, cytosine, guanine and thymine --that pair up to form the well-known DNA double helix. Although each one of our cells contains about six billion base pairs of DNA, three billion from each parent, we think that our differences are determined by only about one base pair in each thousand. Thus, at this most fundamental level of molecular definition, what we share dwarfs what distinguishes us.
The HGP will determine the complete sequence of the DNA from a typical human cell and will provide information and resources to understand some of the critical differences that make us individuals and that often contribute to diseases. Such information and resources, and the resulting insights garnered therefrom, will contribute to many areas of biology and biotechnology beyond those that are strictly health related, but they will also open the way to new approaches to treating diseases.[3-5] The discovery in 1994 of two genes involved in the origins of breast cancer exemplified the promise of genomic research.[6, 7] This discovery was made by a large group of researchers with critical help from resources generated by the DOE.
The DOE's Participation. Given the magnitude of the task of mapping and sequencing the human genome, there was an early appreciation that the unique capabilities and resources of the DOE National Laboratories would be critically important. These labs could contribute specialized resources, such as sophisticated engineering and high-performance computing, and could facilitate the close collaboration of various scientists from many fields, including molecular biologists, engineers, physicists, chemists, and mathematicians. Other unique assets of the DOE labs were the synchrotron light sources and neutron sources that have facilitated the relatively new science of structural biology. Structural biology, together with computational biology, helps to define the three-dimensional structures of biomolecules and to complement the work on genomics and gene function in general.
With the Office of Management and Budget's approval, the DOE committed its first funds for human genome research in October 1986. After the NIH started its own genome effort the next year, a coordinated project was formally launched. In 1988, the DOE and the NIH signed a Memorandum of Understanding that committed the two agencies to work together by coordinating activities and leveraging their respective strengths as assets.[8] The official "clock" on the project was started on October 1, 1990. At the same time, a joint five-year plan for the project was agreed to, with the delineation of specific technical milestones in mapping and sequencing. Because of rapid progress in several technical areas, especially genome mapping, the joint plan was revised four years ago with the publication of a new and more ambitious five-year plan.[9]
Economic and Societal Implications. One goal of the HGP is to localize all of the estimated 80,000 genes on the human chromosomes and to determine the sequence of all three billion units of DNA that constitute one set of those chromosomes. This information will vastly accelerate studies that will characterize what those genes do and how disease can result from errors in their functioning. An important element of the HGP is to enable technologies that will allow biologists to uncover gene function more efficiently. This is important because while the HGP will describe the human genome in molecular detail, its longer term and more profound impact will be to reveal critical mechanisms of human biology and supply the medical context within which investigations on the molecular pathology of human diseases can most efficiently take place. This will lead to a future medicine in which prevention will be firmly rooted in mechanistic knowledge and potential interventions can be more targeted and effective.[10] We also believe that this will lead to more cost-effective medical care since prevention is almost always cheaper than treatment.
The promise of the HGP goes far beyond medicine to many other areas of science. In addition to its many implications for medicine and human health --which includes mutation detection, more accurate risk assessment, more precise disease diagnosis, more rapid characterization of genetic damage and repair processes, and the identification of precision pharmaceuticals based on intimate biological knowledge --this international project is creating technologies and resources that will be applied to the characterization of the genomes of other living organisms. This information will, in turn, provide us with important new practical applications in energy, environmental protection, agriculture, and industrial processes. The appeal of this targeted approach to biology can be seen in the recent establishment of genome projects for several microbes,[11] agricultural crops,[12] and animals.[13] We are already experiencing a dramatic technological revolution affecting many of America's most important enterprises, such as agriculture, chemicals, medicine, and energy production, leading to environmentally sustainable technologies. For example, new varieties of plants will be developed for renewable biomass-based energy production. Biological catalysts such as enzymes or catalytic antibodies will be designed to order for mining and processing, just as one designs the mechanical components of industrial systems. Bioprocessing will minimize pollution, while bioremediation will clean up wastes. The genetic information encoded in the genomes of many organisms will lead to designer drugs that will revolutionize medicine and create new materials for specific applications. We can reasonable expect that the biotechnology of the near future will accomplish society's objective of sustainable development.
Tremendous insights are emerging from genome studies in model systems, because fundamentally a cell is a cell is a cell. Over eons, evolution has conserved the biochemistry that worked well for the simplest organisms and has adapted this biochemistry to respond to changing environmental conditions. The genes that determine structure and function for similar single cell organisms are often similar, in sequence and products, to those that determine the structure and function of human cells.[14] By studying simple cells and simple organisms, we will better understand comparable structures and functions in human cells. For example, the work on comparative genomics at the Oak Ridge National Laboratory and elsewhere exploits the similarities of mouse and human genomes.[15-18]
THE ACHIEVEMENTS AND CHALLENGES OF THE HGP
Specific Medical Advances. Without meaning to be overly "scientific," we would like to highlight some recent achievements of the genome program. Understanding these achievements will allow greater appreciation of just what the project is and what its cumulative effect may be. In 1995, for example, the highest resolution physical maps for human chromosomes were completed by the Los Alamos National Laboratory and the Lawrence Livermore National Laboratory for chromosomes 16 and 19, respectively.[19, 20] The chromosome 19 map has already contributed to the characterization of the genetic defect underlying the disease of myotonic dystrophy and to the description of the unusual genetic mechanism of aberrant triplet repeats that is now known to contribute to the onset of at least nine diseases, including Huntington's disease.[21-24] Genes mapped to chromosome 16 include those involved in Batten's disease, polycystic kidney disease, Crohn's disease, forms of breast and prostate cancer, and Fanconi's anemia, as well as many others.[19] In addition, the DNA repair genes HHR23A, XRCC1, and ERCC2, as well as genes involved in olfactory receptors, Alzheimer's disease, and one form of migraine headache, have been discovered on chromosome 19.[20]
In a different context, but highly important, the Lawrence Berkeley National Laboratory has produced two megabases of human sequence, using directed sequencing, just in the last year or so. Lee Hood at the University of Washington in Seattle has sequenced nearly 700,000 consecutive base pairs of DNA from the human T cell receptor complex, as well as a comparable amount of mouse T cell receptor DNA.[25] These sequences have provided surprising insights into the evolution and function of certain white blood cells important for many immune responses to invading pathogens and are widely thought to be involved in both autoimmune diseases and protection against early tumor development.
Additional accomplishments include advances in technologies that are speeding up DNA sequencing, among them the development of novel "vectors" (critical for the manipulation of DNA in fragment sizes that can readily be characterized and studied), particularly Bacterial Artificial Chromosomes or BACs.[26] A DOE-funded BAC library contributed to the discovery of the Breast Cancer-1 gene by supplying the particular BAC containing the appropriate DNA fragment from chromosome 17.[6] Another library from a DOE-supported researcher at Roswell Park Memorial Institute was important for the identification of the BRCA2 gene on chromosome 13.[7]
The Importance of Gene Databases. A major challenge for the entire HGP, and one that the DOE continually emphasizes, is the development of informatics tools --e.g., data management and analysis --to deal with the expected avalanche of HGP data. Both the DOE and the NIH firmly plan to make all the HGP data available to the public in the shortest possible time after its acquisition and verification. Furthermore, the access to the HGP data must be extremely userfriendly, so that all biologists --indeed, all scientists-- can use the data in their research. The Genome Data Base (GDB) is one of the important databases supported by both the NIH and the DOE and is the worldwide repository for genome mapping data[27] that may be the model for future databases of the HGP. While the main GDB central facility is in Baltimore, an increasing number of interconnected "nodes" have been established at various international locations to facilitate access via the Internet by researchers around the world. This is part of the "federated information infrastructure" concept[28, 29] that allows users to link their computers to a global network of different related databases distributed around the world. Another example of a DOE-supported HGP database is the Genome Sequence Data Base (GSDB) based at the National Center for Genome Resources (NCGR) in Santa Fe.[30] The GSDB collects primarily genome sequence data and is connected with the GDB through the federated infrastructure. Our ambition is that these and other databases will work together to provide access to, and answers about, the human genome.
Why will these databases be so important in the future? Consider that three billion letters, if printed, would fill some 200 major city phone books, a cumbersome way to store data. Locating the few thousand letters of interest would require a major effort. Computers will play a critical role in enabling physicians, researchers, or anyone else to access and use the results of the HGP. In addition, we estimate that only about 5 percent of the genome sequence is actually used for the determination of expressed proteins, and that small portion is scattered across the genome. The sequence for any given gene may exist as a number of noncontiguous pieces that are only properly assembled at the time of transcription into messenger RNA immediately prior to translation into protein.[31] (Messenger RNA is the "working copy" of the genetic information contained in the DNA "master copy" stored in the chromosome.) A little understood mechanism called alternative splicing allows the same piece of DNA to generate different protein products under different circumstances, making the understanding of gene organization more complex from the standpoint of understanding the roles of genes in disease processes.[31]
>From the beginning, the DOE genome program has been a highly focused but constantly evolving program. Over the next several years, a much larger emphasis will be placed on high-throughput sequencing, determining millions of base pairs annually. The principal goal of the HGP remains the complete sequence of a generic human genome by 2005, and we expect to fulfill this goal. Our optimism stems from recent successes in sequencing the genomes of simpler organisms, coupled with improvements in sequencing reagents and instrumentation, as well as the development of more effective clone resources. The NIH has started six pilot projects for high-throughput sequencing, and the DOE is also committing an increased portion of its HGP budget to high-throughput DNA sequencing. Ultimately, the sequencing will be done by many laboratories and universities around the globe. Even as this effort begins, the DOE and the NIH, among others, are exploring how we need to prepare ourselves, both as scientists and science managers, for the challenges of the "next generation" of biology that will follow.
CONFRONTING THE ETHICAL, LEGAL AND SOCIAL ISSUES
James Watson, who won the Nobel Prize in Physiology in Medicine in 1962 for codiscovering the structure of DNA, made a seminal contribution to the HGP when he recognized that knowledge derived from genome studies has broader medical and societal implications. This led directly to the establishment of a program devoted to the ethical, legal, and social implications (ELSI) of genome research. One goal of the ELSI program is to address the implications of vastly increased genetic information and protocols on individuals and society. Another ELSI goal is to identify and develop appropriate policy options to confront and contain future ELSI problems. Because we know that "genetic information" has been misused previously in the United States and other countries, we must ensure that such mistakes are never repeated. Both the DOE and the NIH are optimistic that the ELSI program can contribute to the integration of HGP results in ways that are less disruptive, painful, or destructive than those in the past.
The list of ELSI issues is long and virtually all of them have legal ramifications. They include the fair use of genetic information; the impact on genetic counseling and medical practice; the effects on personal reproductive decisions; past uses and misuses of genetic information; privacy implications of personal genetic information in various settings, e.g., the work place, schools, or in the context of adoptions; issues of the commercialization and intellectual property protection of genome results, including DNA sequences; conceptual and philosophical implications; implications of personal genetic variation; and genetic literacy and the understanding of genetic information, particularly information related to complex conditions that involve multiple genes and genetic-environmental interactions. This last category, involving health issues like mental illness, heart disease, diabetes, or cancer, represents the most complex of ELSI issues because the underlying science is poorly understood.[32, 33] For example, informing a woman that she carries an allele at BRCA1 that is associated with a high lifetime risk of developing breast cancer is a serious issue, particularly if treatment options are difficult, painful, debilitating, or oftentimes less than successful. A recent study suggests that many women from high-risk families simply prefer not to know.[34] However, other individuals or entities may want to know about such conditions, including insurers and employers (who often are responsible for insuring their employees). Congress has started to debate and legislate these issues. The Health Insurance Portability and Accountability Act, sponsored by Senators Kennedy (D--Massachusetts) and Kassebaum (R--Kansas), passed by the 104th Congress in 1996 and signed into law by President Clinton, offers some limited protection from loss of health insurance due to genetic information. The extent of this protection is undoubtedly an issue that courts will have to adjudicate.
However, before we get completely engrossed in the complexity and uncertainty of these issues, we should carefully note a few of the ELSI program's successes. Developed by a DOE ELSI grantee, a model genetic privacy bill was introduced into the U.S. Senate in November 1995, and parts of it have been incorporated into the Genetic Confidentiality and Non-Discrimination Act introduced by Senator Pete Domenici (R--New Mexico) in June 1996. While the 104th Congress did not act on this legislation, a revised version has been introduced into the 105th Congress. Workshops on genetics have been presented to help judges better appreciate the relevance of genetic information in the courtroom, and publications like this special issue of The Judges' Journal have been prepared and disseminated. We have produced curricula for high schools that will affect approximately 2.5 million students of high school biology, many of whom may be studying biology and its societal implications for the last time in their lives.[35] Another DOE ELSI project is exploring the implications of patenting genome sequences on the transfer of genome information and technologies to the commercial sector, a subject of considerable controversy and one that will be hotly debated over the next several years as the products of genome research move into the marketplace.[36, 37]
Many of the ELSI issues that face us are not new to medicine, but they will become more prominent as the HGP progresses. Our challenge is to anticipate them whenever possible and to reduce their negative impact where practicable. The DOE ELSI program has maintained close contact and coordination with the ELSI program of the NIH's genome program, and the two agencies have jointly supported the DOE-NIH ELSI Working Group, which coordinates ELSI policy development between the two programs.
We see many ELSI challenges in the future. Informed consent for participants in genetic research will remain an important issue. Genetics involves shared familial information, and the diagnosis of one person has direct implications for his or her family members. It is extremely important that patients and research participants understand what information and future predictive insights about them may emerge from genetic studies, particularly when they involve genetic testing or screening for multigenic and predisposition diseases. For example, over six hundred mutations in the gene for the cystic fibrosis transmembrane regulator can lead to cystic fibrosis.[38, 39] Many experts think that only seven of these mutations are responsible for 85 percent of the cases of cystic fibrosis seen clinically, and it is these seven for which most people are tested. However, a negative test for cystic fibrosis disease-associated alleles does not necessarily mean that a person does not have a risk for cystic fibrosis. The gene for breast cancer susceptibility (BRCA1) is another case in point. Over 150 alleles in the gene have been discovered, [40] and one in particular is common in women of Ashkenazi Jewish background.[41] The BRCA1 region is very large, [7] and the number of alleles that actually predispose to breast cancer is not yet known. We also know very little about other influences that are necessary (along with one of these mutations) for breast cancer. What do you tell someone who tests positive for a disease-associated allele when you can only be vague about its clinical implications? What responsibilities do physicians and counselors have in the communication of risk information to patients when the risks themselves are poorly understood? What liability issues accompany genetic information? Can genetic information be "owned" and, if so, by whom and under what circumstances? These and other issues that arise from genetic information will challenge the courts and will be exacerbated as we get better at "reading" and interpreting the content of our genomes.
COURTS IN THE HGP CONTEXT
A major challenge in the judicial arena is to introduce the most current and rigorous scientific information related to genomics in a form that is most useful and understandable to judges and juries. Molecular genetics, like some other sciences, can be complicated and often confusing, even to those with scientific background and training. Because molecular genetics is also changing continuously, one can easily pit one scientific "expert" against another, with no clear mechanism to adjudicate between the two. Most scientists are uncomfortable with what they perceive to be the rigid demands of judicial proceedings and shy away from"beyond reasonable doubt" pronouncements. The all-too-frequent result is that the scientific perspective is represented by fringe elements of the scientific community that may distort the state of the science. Although such distortion is not unique to genetics, prominent and widely publicized examples have been witnessed during the last several years, and the future unfortunately holds the promise of many more.
The scientific community involved in genetics need to mobilize quickly to deal with this issue, and the ELSI element of the HGP could provide a useful organizing mechanism. One model for arriving at scientific consensus that could be explored is the one developed by climate scientists to advise governments on climate change from man-made emissions of greenhouse gases. Organized by the United Nations in 1988, the Intergovernmental Panel on Climate Change (IPCC) has brought together the international scientific community involved in global climate issues to assess periodically the state of the science of climate change prediction, the associated impacts, and the optimum approaches to dealing with mitigation and adaption to the predicted changes.[42] The IPCC has employed rigorous procedures of peer review and quality assurance and has accomplished the remarkable feat of arriving at consensus statements that have guided governments in their pursuit of policies that are addressing the threats of manmade climate change. It will be an interesting challenge to explore whether the IPCC model can be adapted for the use of genetic information in the judicial arena, especially since the 1993 Supreme Court decision in Daubert v. Merrell-Dow[43] places responsibility on individual trial judges to determine the relevance --and this the admissibility-- of scientific evidence.
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