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Human Genome Project
Human Genome Project J Marshall, University of Toronto, Toronto, ON, Canada ª 2012 Elsevier Inc. All rights reserved.
Glossary Deoxyribonucleic Acid (DNA) DNA is the chemical name for the molecule that carries genetic instructions in all living things. The DNA molecule consists of two strands that wind around one another to form a shape known as a double helix. Gene The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.
Introduction The international effort that came to be referred to as the Human Genome Project (HGP) has been portrayed as a battle between naysayers and cowboys, commercial and public interests, even good and evil. The project has inspired titles such as The Book of Life and The Code of Codes, and, when the project was completed, the U.S. National Institutes of Health (NIH) and National Human Genome Research Institute (NHGRI) in a news release compared the HGP to the moon landing. The project’s goals were straightforward: to map and sequence the human genome, which consists of all genes, other sequences encoded in DNA, and the genomes of several other model organisms (i.e., organisms that have charac teristics advantageous to genetics studies). The task was at first painstaking, but with the development of advanced sequencing technologies emphasizing speed, the mapping and sequencing effort finished ahead of its predicted 15-year schedule. This large-scale genetic research also gave rise to a panoply of ethical issues related to the use of human genetic information.
History Participants In 1986, the U.S. Department of Energy (DOE) began funding studies into the mapping and sequencing of genes to determine the effects of radiation on the human genome, and at approximately the same time there was an interest in genetics studies at the NIH. By 1988, the U.S. Congress had approved funding for the U.S. HGP to be coordinated by the DOE and the NIH’s newly established
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Genetic variation Most of any one person’s DNA, about 99.5%, is exactly the same as any unrelated person’s DNA. Differences in the sequence of DNA among individuals are called genetic variation. Genomics The study of the entire genome of an organism. Polymorphism A variation in the sequence of DNA among individuals.
National Center for Human Genome Research (later named the NHGRI) under the direction of James Watson, the codiscoverer of the structure of DNA. In the United Kingdom, the Medical Research Council approved an application to fund the British Human Genome Mapping Project, which began in 1989. Soon, other coun tries, such as Japan, France, Germany, and China, began funding their own national human genome programs (followed later by Italy, Russia, Australia, Canada, and others) so that the mapping of human genetic inheritance was undertaken throughout the world. In the 1990s, these national projects progressively converged and became the joint international effort known at the HGP. Controversy At the time of the establishment of the HGP, those who wanted to lead the endeavor expressed much enthusiasm, and many others saw the project as an exciting scientific frontier. However, the HGP did not smoothly come into existence. Controversy in the research community cen tered on its high cost, questions about feasibility and utility, and its ‘assembly-line’ methods. The HGP was a costly undertaking because it was funded as a ‘big science’ project – that is, a large-scale effort requiring the involvement of many research labora tories (originally 20 centers in six countries) and the development of elaborate technologies (to improve the speed and accuracy of DNA sequencing). The final bill was estimated to be approximately $3 billion. Some researchers feared that other biological research, espe cially innovative research from small laboratories, would be left unfunded and ignored. Critics did not think the sequencing technologies in use had been tested and
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developed sufficiently for such an intense undertaking, not to mention the fact that none of the key investigators had ever sequenced DNA at such a scale. Other commentators did not believe the resulting sequenced genome would be useful in any real sense in deciphering the biological roles of genes. There were complaints from researchers at the time, questioning the need to sequence the entire human genome. Most of the human DNA sequences did not code for genes and were therefore considered to be ‘junk.’ Researchers questioned the time and money put into sequencing genetic informa tion that was considered superfluous. Many researchers believed that HGP industrial assembly-line methods would be considered too tedious to attract the best qualified candidates. Some leaders in genetic research were concerned that innovative inves tigators would prefer to work in more experimental or theoretical fields of biology. Private versus Public A separate concern involved the activities of a private company called Celera Genomics, headed by former NIH genetics researcher Craig Venter. Venter and colleagues developed a new method to sequence DNA called ‘whole genome shotgun sequencing’ that he claimed would give his company an advantage over the publicly funded pro ject, which was at that time behind its set schedule, and allow Celera to publish the human genome sequence first. The method used by the HGP members involved ran domly cutting the genome into large sections and ordering them into a ‘physical map.’ These sections were then sequenced and assembled individually. Venter’s method omitted the mapping step, cut the entire genome into tiny fragments, and then sequenced and assembled them using computer algorithms. The elimina tion of time-consuming steps made Venter’s technique faster and less expensive. This development, it is uni formly agreed, added a competitive element to the completion of the human genome. Although Venter had left the NIH over his opposition to that organization’s filing patents on genes, he quickly harnessed a method of ‘licensing access’ to the rapid output of his new sequen cing approach.
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conservation are thought to exist between species, the model organisms’ sequences could be used for compara tive purposes. The secondary goals of the HGP included the improvement of technology used in sequencing and map ping; the creation of databases to store the amassed genetic information for future use; the development of mathematical and computational tools to analyze genetic information; and the identification of the major ethical, legal, and social issues (ELSI) related to the HGP. Planners also encouraged the creation of affiliations with industry primarily in the arena of technology develop ment, catalyzing the most aggressive partnerships between government-funded laboratories and biotechnol ogy start-up companies since the U.S. Bayh–Dole Act authorized such partnerships in 1981. The time line to complete the HGP was 15 years, but the sequencing finished ahead of schedule due to the development of new automated machines by the com pany that had partnered with Venter that increased the speed and concurrently lowered the costs. In 2001, the draft sequence of the human genome was published by NHGRI and the International Human Genome Sequencing Consortium (IHGSC) consisting of the offi cially recognized countries that took part in the international effort, led by U.K. researchers, along with Craig Venter and colleagues. Subsequently, IHGSC car ried out a ‘finishing phase’ to convert the draft sequence to an approximately 99% accurate, high-quality sequence of the human genome, published in Nature in 2004. The HGP has been portrayed as a success story because its goals were met under budget and earlier than planned. Commercial ventures were also more prepared than had been predicted to develop genetic tests and DNA-based drugs based on HGP information. At the time of the publication of the draft and the completed sequences, the long-term goals for the HGP were announced. These new goals were to categorize human genetic variation; to determine the genetic con tribution to disease and disease susceptibility; to investigate how genes are regulated and their functions; and to provide more opportunities for diagnosis, treat ment, prevention, and prediction at the individual level. Findings
Goals The main goal of the HGP was to identify all the genes in the human genome and in specific model organisms. The sequencing of model organisms such as mouse (Mus mus culans), fruit fly (Drosophila melanogaster), and nematode (Caenorhabditis elegans) was considered important to the human effort because it provided a less expensive way to test sequencing and mapping technologies. Also, because evolutionarily important areas of genome
The findings of the HGP have perhaps humbled its pioneers, who saw a revolution based on the genome sequence alone. The forecasts underestimated the chal lenges of using technology to tame biological complexity. However, the findings have also opened up new avenues for research in attempts to realize the promise of human genetics. The most recent version of the human genome sequence contains approximately 3 billion base pairs;
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however, there are still some gaps remaining to be sequenced. Although early estimates were as high as 100 000, it is currently believed that the human genome contains 20 000–25 000 genes. The actual number of genes contained in the human genome remains unknown due to lack of established criteria to identify them by form and function. The number of genes, when published, seemed disar mingly few compared to those for the sea urchin (�23 000) and the nematode (�19 000). However, rather than having hundreds of thousands of genes, it is now believed that human developmental complexity comes from various arrangements of DNA regions allowing for multiple functions. Also, many genes are expressed in multiple tissues at different times during the life span, which indicates that most genes do not have single effects but, rather, many (i.e., they are ‘pleiotropic’). In addition, the DNA sequences not coding for genes that were pre viously dismissed as junk DNA have been revealed to house intricate regulatory and processing regions.
Related Projects The HGP has spawned numerous big science, governmentfunded, international projects and has set a trend for biolo gical research initiatives. Human Genome Diversity Project The Human Genome Diversity Project (HGDP) was first proposed in 1991 as a complement to the HGP. Rather than sequencing alone, this project aimed to analyze interpopulation genetic variability. The main goal of the HGDP was to collect cell lines from indigenous, isolated populations of anthropological interest from throughout the world and to store these samples indefinitely in a public archive for future research use. Genetic categor ization of these ‘original’ populations was thought to provide insight into the history and geography of human populations as well as to provide information useful to future biomedical research. Controversy about the HGDP arose soon after its inception and was, on the whole, based on fears that HGDP results would feed ‘scientific racism’ and contri bute to the exploitation of indigenous people through the potential commercialization of their DNA. In 1995, due to the seeming intractable problems associated with the pro ject, the National Research Council of the National Academy of Sciences established an ethics committee to investigate the HGDP. In 1997, the committee deter mined that the project was worth pursuing, but particular attention had to be paid to informed consent, privacy and confidentiality, and community participation. The HGDP went ahead on a smaller scale than was originally
planned. The Human Genome Diversity Panel currently consists of 1064 samples from 54 widely distributed popu lations, typed with large numbers of markers. International HapMap Project Single nucleotide polymorphisms (SNPs) are identified as common, single base variations that occur in human DNA at a frequency of approximately 1 in every 1200 bases. These polymorphisms may be directly associated with disease risk or are markers for disease risk. Human sequence information has revealed millions of SNPs. The International HapMap Project (a collaboration of scientists and public and private funding agencies from Japan, the United Kingdom, Canada, China, Nigeria, and the United States) was established in 2002 to determine common patterns of DNA sequence variation in the human genome by characterizing SNPs, their frequen cies, and their patterns of inheritance. By 2005, ‘phase 1’ of the project had identified and characterized 1.3 million SNPs for 269 samples from four populations. These sam ples included 90 individuals from Nigeria, 90 individuals from Utah, 45 individuals from Beijing, and 44 individuals from Tokyo. The second phase was completed in 2007, cataloging 3.1 million SNPs in a larger number of samples. The aims of the HapMap are to permit researchers to chart sets of closely linked SNPs that are inherited in blocks, called ‘haplotypes.’ Because these SNPs, along with other important DNA regions, are inherited together in a block/haplotype, only a few SNPs are needed to study the entire genome. With such a map, certain types of genetic studies may be carried out at a reduced cost and with greater efficiency. By breaking the human genome into blocks, haplotypes have been linked to Crohn’s dis ease, type II diabetes, and other disorders. Similar to the HGDP, the HapMap project sampled different populations in order to study genetic variation and diversity in humans. To avoid the problems that arose during the planning of the HGDP, the HapMap project held public consultations and used a vocabulary of inclu sion during development. Questions arose regarding the expense of the project and the utility of the HapMap to the representatives from poor countries, where infectious rather than genetic diseases are of greater health conse quence. Some scientists also questioned the presumptions of the HapMap regarding inheritance patterns and its usefulness in understanding the genetic architecture of common diseases. 1000 Genomes The 1000 Genomes Project is another large-scale, technology-heavy, multi-million-dollar project aimed at elucidating human genetic variation. This project,
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with a nod to the HapMap, aims to create a catalog of common human genetic variants (with a frequency of 1% or higher) for approximately 1000 individuals sampled from broad geographic regions (Europe, Asia, and Africa) as a resource for studies into the genetic contribution to disease. It is hoped that the 1000 Genomes Project will provide genetic markers for com mon diseases (e.g., diabetes and heart disease) in greater detail and variety. The genomic catalog will be housed in a searchable database. The project will be carried out in three U.S. sequencing centers funded by NHGRI, the Wellcome Trust Sanger Institute in the United Kingdom, and Beijing Genomics Institute in Shenzhen, China. This project aims to make the sequencing of entire genomes for profiling easier and to lower the costs of sequencing. This aim is intended to encourage the devel opment of genomics for eventual clinical purposes. Critics have protested that 1000 Genomes is simply another project to compile genetic information with little ability to analyze the accumulating genomic data. Complaints have been made that the genomes will not be sequenced in great depth (there will be gaps) and therefore the results will not be as definitive as claimed.
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ELSI program was also meant to act as a model for other large-scale, public projects in the United States and internationally. The program has influenced policy in areas such as disability rights, privacy and anti discrimination legislation, and protections for research participants in genetics studies. However, some scholars have criticized the ELSI program as merely a means to deflect social and political criticisms. ELSI issues have evolved since the outset of the HGP, for example, from a focus on autonomy and genetic discrimination to concern about commercializa tion of genetic information and testing and the effects of genetic profiling in health care. The ethical issues exam ined here explore concerns regarding the current direction of much of the biological sciences toward a ‘big science’ HGP model and the direction of medicine toward a ‘personalized’ approach. Other ethical issues considered here deal with how genetic sequence infor mation is potentially used and interpreted in research and medicine – for instance, issues concerning genetic discrimination and stigmatization, the patenting of genetic information, and the commercialization of genetic tests. ‘Big Science’ and Genetics
ENCODE The ENCODE (which stands for ‘ENCyclopedia Of DNA Elements’) Project is organized in much the same way as the other large-scale, HGP-related research pro jects mentioned previously. It is largely funded by the NHGRI and began in 2003. The project involves hun dreds of scientists from 10 countries and aims to identify all of the functional sequences in the human genome and catalog them in a database for future studies. The project also aims to develop high-throughput methods to identify functional sequences. These refer to DNA sequences that are thought to regulate gene function among other unknown properties. The ENCODE pilot project has revealed that tran scription (one of the biological steps in the creation of a protein from DNA code) is much more complicated than previously thought. Essentially, researchers are still inter preting the results, but so far the findings add complexity to an already complicated genetics picture.
Ethical Issues With the establishment of the HGP, it was announced that the project would include a component to identify and address ELSI associated with the endeavor. There was a recognition among the leaders of the project and the governments at the time that the findings of the HGP could be of a potentially sensitive nature. The
Large-scale, expensive, government-funded scientific research, otherwise known as big science, had previously been the domain of physics. The HGP introduced big science to the study of biology. These large-scale projects are advantageous because they consist of numerous inter national teams of researchers and technicians using state of-the-art technology working toward explicit goals that are met quickly. The justification of the large investment in the HGP by its leaders and promoters was the dual promises of great benefits to humankind and the scientific and medical frontiers to be gained. At the outset of plan ning discussions about the HGP, it was agreed that if a ‘genomic revolution’ was going to occur, the effort would require the generation of massive amounts of sequencing information and the development of automated technol ogy and computational analysis tools. The original leaders of the HGP promoted a hypothesis-free or data-driven approach to the research funded under the auspices of the HGP. This meant that genetic sequence information would initially be gathered without concern for questions about the biological func tion or proof of principle. Rather, the data would be stored to be analyzed later. In this way, the future of the HGP relied on the development of technologies to ana lyze the vast amounts of genetic information gathered and even to help generate hypotheses. Indeed, highthroughput genotyping and other sophisticated labora tory methods have become increasingly available due to technological innovations. The issue now is how to use
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this technology to gain understanding toward practical applications. Due to the reliance on specific costly high-throughput technology, many small laboratories cannot afford this type of research or may find it necessary to partner with industry. The private sector, therefore, is increasingly needed for many types of large-scale genetics research studies, if large-scale sequencing or genotyping is necessary to their line of inquiry. Also, the places in which large-scale genetics studies are carried out are increasingly larger, factory-style laboratories. Although large-scale projects can produce deliverables quickly and efficiently, some critics have questioned the lack of attention to theoretical understandings of genetics. Personalized Medicine The promises of a uniquely personalized medicine flour ished as soon as sequencing of the human genome neared completion. The goal of personalized medicine is sup ported and financed internationally and is considered the next step in the application of HGP knowledge in the clinic. This type of medicine refers to a field of health care that is based on individuals’ unique genomic makeup (their genomic profile), their clinical background, as well as environmental influences. Although relatively simple genetic diseases continue to confound simple treatments, reports continue regarding the imminent use of personalized medicine for common, complex diseases based on genomics. Ethical issues concerning the use of genomic profiles for individualized medicine deal with problems in trans lating the complexities of genomics to the clinic, the potential for the exaggeration of inequalities, and questions concerning the preparedness of healthcare institutions and workforce for increased use of genomic information in the clinic. Genetic complexity
The two main specialties of personalized medicine consist of genomic profiling and prevention strategies. By defini tion, genetics is the study of single genes and their effects, but genomics has advanced the level of interrogation by an order of magnitude. Genomic profiling aims to study global genomic variation and to determine the functions and interactions of all genes in the genome, including the regulation of genes. It is hoped that information gleaned from genomic profiles can be harnessed to help predict individual susceptibility to disease and, based on suscept ibility, provide tools for prevention against predicted future illnesses; to provide early detection of disease; and to target medicines more efficaciously. The complex interaction of genes, their regulation, and influential environmental factors is not well under stood. Some observers believe our lack of understanding
of how genomic profiles contribute to the understanding of disease gives little meaning to the concept of suscept ibility and little reliability to effect on risk. Susceptibility relates to the potential for disease development in indivi duals based on probabilities. Probabilities are considered vague and difficult for most people (expert and layperson alike) to comprehend. Uncertainties regarding suscept ibility, when to act on risk information, and how to counsel individuals on susceptibility and risk are just a few of the issues that arise from attempts to use complex genetic information to provide individualized medicine. However, through the findings of the HGP and related projects, researchers in biology are increasingly addres sing genetic complexity. Many commentators have written about the promises of personalized medicine and recognized the challenges to understanding and are find ing ways to produce useful knowledge within those restraints. Recognizing a personal genetics that is not deterministic and simple but based on susceptibility and probabilities could provide individuals a wider scope within which to maneuver, creating a new way of looking at human genetic systems. Potential inequalities
Understanding health and disease at the individual mole cular level in combination with environmental factors may provide a key to disease prevention – that is, the application of various medical interventions before dis ease starts or at its earliest stages. The preventive actions would vary from person to person and may involve taking vitamins, avoiding environmental exposures, changing diet, or making other lifestyle alterations. Other interven tions could involve tailored drug therapies improving drug efficacy and preventing side effects. The general idea of genomic profiles in this context is that persona lized alterations of the environment can translate genomic-based knowledge into improvements in health for most patients. This model focuses attention primarily on individual risk and responsibility. Control over one’s own health is expected to arise simply by knowing one’s genetics and subsequently manipulating defective biological mechan isms and negative environmental influences. Some have complained that personalized, preventive medicine assumes that all individuals have access to immediate medical care and that all individuals have the ability to change their lifestyles or avoid the risks thought to be associated with genetics. Some authors have suggested that focusing on personal responsibility for illness can lead to a tendency to blame individuals for their own poor health outcomes. The idea that we can predict and prevent, rather than merely react to, the things that make us sick or die has a powerful appeal. This approach, inspired by the promise of genetic information, can bring with it hope to be able to
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control one’s future and create new opportunities for improving one’s life. If applied strategically to the greater public and not only to those who can afford expensive treatment or drug therapies, some believe that there is a possibility to build public health strategies around educa tion and to alter physical, psychological, and social risk environments where warranted. Personalized healthcare preparation
Premature introduction of genomic profiling to the clinic could lead to misinterpretation of genetic information, unnecessary genetic testing, and overzealous diagnosis and treatment that paradoxically could increase risk. In general, it is believed that family doctors have not been sufficiently trained in medical genomics in order to suc cessfully include genomics in their practice and provide effective counseling. Duty of care may require doctors to provide genomic testing and make diagnoses despite this lack of understanding. Patients consenting to genomic tests associated with personalized medicine would be required to understand matters that are more numerous and complex than ever encountered. Regulation of genomic medicine and increased resources for genetic counseling are considered necessary for successful intro duction of personalized medicine strategies to the clinic. Genetic Discrimination and Stigmatization Genetic discrimination refers to the possible general application of institutional and other discriminatory prac tices based on an individual’s or group’s genetic background. Genetic stigmatization is a similar term and refers to the labeling or stereotyping of an individual or group in a negative way based on their genetic back ground. The potential effects of genetic discrimination and stigmatization on race and culture and disability are discussed next. Race and culture
Genetics has been used to promote the eugenic beliefs that the management of heredity would improve the physical, mental, and behavioral traits of humankind. Also, race and class distinctions were thought to be due to biological differences. Currently, HGP researchers speak of attempts to make connections between DNA sequences and things such as health, disease, behavior, and human evolutionary history. These associations are found by examining differences in human genetic varia tion often between groups. Studying genetic differences has raised alarms of a potential ‘new eugenics.’ Scholars are still divided on the question of whether racial cate gorization is a legitimate way to organize genetic variation for the study of human disease and evolution or whether these genetic distinctions are artificial and carry the potential to be used as a new tool to discriminate
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against groups with perceived differential genetic and health risks. Some of the projects related to the HGP have used racial categories to study genetic differences (HGDP and HapMap). Controversy has arisen with regard to these projects based on the intersection of race, culture, and genetics. For example, the HGDP focused on populations labeled ‘isolated’ and ‘of anthropological interest.’ This caused concern from some indigenous rights groups regarding potential racist interpretations of the research and potential nefarious use of the collected data. Past abuses have made populations sensitive to the use of their biological samples through commercial exploitation and minimal benefit to the populations studied. In addi tion, indigenous rights groups have had concerns about the use of genetics to describe their heritage. Some have worried that tribal membership claims could be disputed due to genetic explanations that are often considered more valid than cultural associations. However, many scientists and other scholars have brought attention to the fact that just as simplistic ideas about genetics in general are being rethought, simplistic genetic explanations of race and culture are also being disproven. It is believed that the study of human genetic differences has demonstrated that there is no scientific basis for racism. In addition, some scholars believe that genomics creates new categorizations that are different from the eugenics of the past and offer new possibilities for defining humankind. Still others see the intersection of genetics and race and culture as a way to bring more minorities into science and improve medical care for specific communities. Disability
Genetics and disability were also a special concern of eugenicists, legislatures, and courts that viewed ‘feeble mindedness’ as an inherited defect that drained public resources and threatened humanity. Prenatal genetic screening and preimplantation genetic diagnosis, as well as genetic testing for disease, raise ethical issues regarding potential discrimination and stigmatization based on dis ability. Prenatal genetic screening is used at the population level during pregnancy to detect genetic and chromosomal disorders. Preimplantation genetic diagno sis is a procedure used in conjunction with in vitro fertilization to screen for specific genetic or chromosomal abnormalities before transferring fertilized eggs. Some of the justifications for the use of prenatal screening and preimplantation diagnosis for disability are that screening may help lower medical costs and reduce the burden of life with a disability. To some, these justifications seem disturbingly similar to the language of eugenics. Eric Parens noted that the choice to terminate a pregnancy based on disability is a decision that certain traits are undesirable, and Lawrence Gostin has written about the
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potential for insurance and employment discrimination based on genetic testing of people with genetic disorders and disabilities and their families. On the other hand, information gained from prenatal screening could lead to the early diagnosis and treatment of genetic disorders, which could highly benefit these children. Glenn McGee observed that genetic diagnosis provides choices to potential parents and could provide hope and possibility for their children. In addition, com plexities revealed by research on the genetic contribution to human disorders and disability have not found absolute distinctions between who is sick and healthy, normal and abnormal. Nikolas Rose argued that genetics can create new configurations around activist groups that identify through disease histories or risk identities. These com munities could use activist involvement to become more powerful, not less.
Commercialization The methods of the HGP have brought with them pro found changes in the way research is commercialized in the biological sciences. Many patents asserting rights over DNA sequences have been granted to researchers across the public and private sector and internationally. Commercialization has occurred on many fronts, such as genetic testing, screening, technology development, and drug development.
Gene patenting
The HGP was built on the idea that the genetic informa tion generated would be kept in public databases (technically) for anyone to use; however, there was always an intension to encourage the commercial aspects of the project. Patenting of genetically modified organisms was first permitted in the 1980s. These patented organisms were considered ‘man-made’ because they did not occur in nature and required human intervention. Patenting opportunities subsequently opened up for genes, SNPs, cell lines, and mice. The patenting of living things was originally considered illegitimate but is now generally widely accepted. Patents allow researchers, institutions, and companies to capitalize on inventions and are presumed to eliminate the need to withhold data from competitors. However, concerns have been raised that patenting impedes the sharing of data and the ability of other researchers to confirm published results. This secrecy could be due, for example, to the protection of competitive commercial or academic applications or due to increasing reliance on industry funding. Patents have also been known to result in restricted medical access to important genetic tests due to prohibitive costs.
Direct-to-consumer genetic testing
Genetic tests are currently being offered to consumers online. Predictive genomic profiling to produce persona lized lifestyle advice, whole genome scans to estimate genetic risk for common diseases, and genetic ancestry testing are all available from various international companies. Information about health and genealogy can have a powerful impact on an individual’s life. The companies that market these tests may provide recommendations based on test results; however, a lack of bona fide genetic counseling services could lead to the potential misinter pretation of results, a false sense of security, and even affect decisions about parenthood. The general lack of regulation and standardization of direct-to-consumer genetic testing has been criticized internationally. Some commentators have complained that it is difficult to eval uate companies’ claims based on proprietary databases, but that this evaluation needs to be carried out. Some suggest that genetic tests are no different from other traditional tests offered in the clinic because they are not always required to demonstrate utility on a test by-test basis. Some view choice as an important aspect of commercialized genetic testing such that if an individual wants to buy a test, which may be considered just like any other test, for personal reasons and consents, he or she should have every opportunity to make that purchase. However, it may be difficult to know exactly what one is consenting to, and some direct-to-consumer tests may be misrepresented through claims on a website. For these reasons, many believe more protections should be enforced to safeguard consumers.
Conclusion The HGP has ushered in a new model for biological research and a new direction for medical practice. There is little doubt that our understanding of the human gen ome has increased since the first days of the project, and the findings have been surprising and have challenged previously held beliefs about the genome and about humans. The practical application of genetic information in medicine is still on weak ground, and the genetic contribution to human disease is still not very well under stood. However, there is a market for genetic tests that provide information about ‘disease susceptibility’ despite the fact that susceptibility is a vague concept on which any meaning could be placed. There are also fears of a genetics based on exploitation, discriminatory practices, and commodification. Although the mapping and sequen cing tasks carried out for the HGP were relatively straightforward endeavors, the HGP has generated greater questions about human identity and complexity, nature, and society.
Human Genome Project See also: Eugenics; Genetic Exceptionalism; Genetic Screening; Genetics and Behavior; Genomic Databases, Ethical Issues in; Pharmacogenetics; Race and Genomics.
Further Reading Buchanan AV, Sholtis S, Richtsmeier J, and Weiss KM (2009) What are genes ‘for’ or where are traits ‘from’? What is the question? BioEssays 31: 198–208. Cavalli-Sforza LL, Menozzi P, and Piazza A (1994) The History and Geography of Human Genes. Princeton, NJ: Princeton University Press. Collins FS, Morgan M, and Patrinos A (2003) The Human Genome Project: Lessons from large-scale biology. Science 300(5617): 286–290. Cook-Deegan R (1994) The Gene Wars: Science, Politics, and the Human Genome. New York: Norton. Galas DJ and McCormack SJ (2003) An historical perspective on genomic technologies. Current Issues in Molecular Biology 5: 123–128. Gannett L (2010) The Human Genome Project, The Stanford Encyclopedia of Philosophy (Summer 2010 Edition). Gostin L (1991) Genetic discrimination: The use of genetically based diagnostic and prognostic tests by employers and insurers. American Journal of Law and Medicine 17(1–2): 109–144. International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409: 860–921. International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431: 931–945. Janssens ACJW, Gwinn M, Bradley LA, et al. (2008) A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions. American Journal of Human Genetics 82: 593–599. Kay LE (2000) Who Wrote the Book of Life? A History of the Genetic Code. Stanford, CA: Stanford University Press. Kevles DJ and Hood L (eds.) (1992) The Code of Codes: Scientific and Social Issues in the Human Genome Project. Cambridge, MA: Harvard University Press. McGee G (1997) The Perfect Baby: A Pragmatic Approach to Genetics. New York: Rowman & Littlefield. Parens E and Asch A (1999) The disability rights critique of prenatal genetic testing reflections and recommendations. The Hastings Center Report 29: S1–S22. Reardon J (2005) Race to the Finish: Identity and Governance in an Age of Genomics. Princeton, NJ: Princeton University Press. Rose N (2006) The Politics of Life Itself: Biomedicine, Power, and Subjectivity in the Twenty-First Century. Princeton, NJ: Princeton University Press. Sulston J and Ferry G (2002) The Common Thread: A Story of Science, Politics, Ethics, and the Human Genome. New York: Bantam. Venter JC, Adams MD, Myers EW, et al. (2001) The sequence of the human genome. Science 291: 1304–1351. Willard HF and Ginsburg GS (eds.) (2009) Genomic and Personalized Medicine (2 vols). London: Elsevier.
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Relevant Websites http://1000genomes.org – ‘1000 Genomes, A Deep Catalog of Human Genetic Variation.’ http://www.science.org.au/nova/006/006key.htm – Australian Government’s National Innovation Awareness Strategy, ‘The Human Genome Project.’ http://english.big.cas.cn/http – Beijing Institute of Genomics. http://bioethics.net – Bioethics.net. http://www.genomecanada.ca – Genome Canada. http://www.hapmap.org – International HapMap Project. http://www.genome.gov/10001772 – National Human Genome Research Institute, ‘All about the Human Genome Project.’ http://www.genome.gov/10005107 – National Human Genome Research Institute, ‘ENCODE Project.’ http://www.genome.gov/11006929 – National Human Genome Research Institute, ‘International Consortium Completes Human Genome Project.’ http://hsblogs.stanford.edu/morrison/human-genome-diversity project – Stanford University, Morrison Institute for Population and Resource Studies, ‘Human Genome Diversity Project.’ http://www.ornl.gov/sci/techresources/Human_Genome/ research/elsi.shtml – U.S. Department of Energy, ‘Human Genome Project Information.’ http://genome.wellcome.ac.uk/node30075.html – Wellcome Trust, ‘The Human Genome.’ http://www.sanger.ac.uk/Info/Press/2004/041020.shtml – Wellcome Trust Sanger Institute, ‘The Finished Human Genome.’ http://www.yourgenome.org – Wellcome Trust Sanger Institute, YourGenome.org.
Biographical Sketch Jennifer Marshall has an MSc in human genetics and an MSc in experimental medicine (specialization in Bioethics) from McGill University. She has been a research associate at the Health Law Institute at Dalhousie University and previously worked on projects at McGill University, Universite´ de Montre´al, and Health Canada regarding ethical aspects of the Human Genome Project, genomics in health care, large-scale genetic and human biological material banking, and community consultation strategies. She is currently a PhD student at the University of Toronto, Department of Health Policy, Management, and Evaluation.
Glossary Deoxyribonucleic Acid (DNA) DNA is the chemical name for the molecule that carries genetic instructions in all living things. The DNA molecule consists of two strands that wind around one another to form a shape known as a double helix. Gene The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.
Introduction The international effort that came to be referred to as the Human Genome Project (HGP) has been portrayed as a battle between naysayers and cowboys, commercial and public interests, even good and evil. The project has inspired titles such as The Book of Life and The Code of Codes, and, when the project was completed, the U.S. National Institutes of Health (NIH) and National Human Genome Research Institute (NHGRI) in a news release compared the HGP to the moon landing. The project’s goals were straightforward: to map and sequence the human genome, which consists of all genes, other sequences encoded in DNA, and the genomes of several other model organisms (i.e., organisms that have charac teristics advantageous to genetics studies). The task was at first painstaking, but with the development of advanced sequencing technologies emphasizing speed, the mapping and sequencing effort finished ahead of its predicted 15-year schedule. This large-scale genetic research also gave rise to a panoply of ethical issues related to the use of human genetic information.
History Participants In 1986, the U.S. Department of Energy (DOE) began funding studies into the mapping and sequencing of genes to determine the effects of radiation on the human genome, and at approximately the same time there was an interest in genetics studies at the NIH. By 1988, the U.S. Congress had approved funding for the U.S. HGP to be coordinated by the DOE and the NIH’s newly established
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Genetic variation Most of any one person’s DNA, about 99.5%, is exactly the same as any unrelated person’s DNA. Differences in the sequence of DNA among individuals are called genetic variation. Genomics The study of the entire genome of an organism. Polymorphism A variation in the sequence of DNA among individuals.
National Center for Human Genome Research (later named the NHGRI) under the direction of James Watson, the codiscoverer of the structure of DNA. In the United Kingdom, the Medical Research Council approved an application to fund the British Human Genome Mapping Project, which began in 1989. Soon, other coun tries, such as Japan, France, Germany, and China, began funding their own national human genome programs (followed later by Italy, Russia, Australia, Canada, and others) so that the mapping of human genetic inheritance was undertaken throughout the world. In the 1990s, these national projects progressively converged and became the joint international effort known at the HGP. Controversy At the time of the establishment of the HGP, those who wanted to lead the endeavor expressed much enthusiasm, and many others saw the project as an exciting scientific frontier. However, the HGP did not smoothly come into existence. Controversy in the research community cen tered on its high cost, questions about feasibility and utility, and its ‘assembly-line’ methods. The HGP was a costly undertaking because it was funded as a ‘big science’ project – that is, a large-scale effort requiring the involvement of many research labora tories (originally 20 centers in six countries) and the development of elaborate technologies (to improve the speed and accuracy of DNA sequencing). The final bill was estimated to be approximately $3 billion. Some researchers feared that other biological research, espe cially innovative research from small laboratories, would be left unfunded and ignored. Critics did not think the sequencing technologies in use had been tested and
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developed sufficiently for such an intense undertaking, not to mention the fact that none of the key investigators had ever sequenced DNA at such a scale. Other commentators did not believe the resulting sequenced genome would be useful in any real sense in deciphering the biological roles of genes. There were complaints from researchers at the time, questioning the need to sequence the entire human genome. Most of the human DNA sequences did not code for genes and were therefore considered to be ‘junk.’ Researchers questioned the time and money put into sequencing genetic informa tion that was considered superfluous. Many researchers believed that HGP industrial assembly-line methods would be considered too tedious to attract the best qualified candidates. Some leaders in genetic research were concerned that innovative inves tigators would prefer to work in more experimental or theoretical fields of biology. Private versus Public A separate concern involved the activities of a private company called Celera Genomics, headed by former NIH genetics researcher Craig Venter. Venter and colleagues developed a new method to sequence DNA called ‘whole genome shotgun sequencing’ that he claimed would give his company an advantage over the publicly funded pro ject, which was at that time behind its set schedule, and allow Celera to publish the human genome sequence first. The method used by the HGP members involved ran domly cutting the genome into large sections and ordering them into a ‘physical map.’ These sections were then sequenced and assembled individually. Venter’s method omitted the mapping step, cut the entire genome into tiny fragments, and then sequenced and assembled them using computer algorithms. The elimina tion of time-consuming steps made Venter’s technique faster and less expensive. This development, it is uni formly agreed, added a competitive element to the completion of the human genome. Although Venter had left the NIH over his opposition to that organization’s filing patents on genes, he quickly harnessed a method of ‘licensing access’ to the rapid output of his new sequen cing approach.
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conservation are thought to exist between species, the model organisms’ sequences could be used for compara tive purposes. The secondary goals of the HGP included the improvement of technology used in sequencing and map ping; the creation of databases to store the amassed genetic information for future use; the development of mathematical and computational tools to analyze genetic information; and the identification of the major ethical, legal, and social issues (ELSI) related to the HGP. Planners also encouraged the creation of affiliations with industry primarily in the arena of technology develop ment, catalyzing the most aggressive partnerships between government-funded laboratories and biotechnol ogy start-up companies since the U.S. Bayh–Dole Act authorized such partnerships in 1981. The time line to complete the HGP was 15 years, but the sequencing finished ahead of schedule due to the development of new automated machines by the com pany that had partnered with Venter that increased the speed and concurrently lowered the costs. In 2001, the draft sequence of the human genome was published by NHGRI and the International Human Genome Sequencing Consortium (IHGSC) consisting of the offi cially recognized countries that took part in the international effort, led by U.K. researchers, along with Craig Venter and colleagues. Subsequently, IHGSC car ried out a ‘finishing phase’ to convert the draft sequence to an approximately 99% accurate, high-quality sequence of the human genome, published in Nature in 2004. The HGP has been portrayed as a success story because its goals were met under budget and earlier than planned. Commercial ventures were also more prepared than had been predicted to develop genetic tests and DNA-based drugs based on HGP information. At the time of the publication of the draft and the completed sequences, the long-term goals for the HGP were announced. These new goals were to categorize human genetic variation; to determine the genetic con tribution to disease and disease susceptibility; to investigate how genes are regulated and their functions; and to provide more opportunities for diagnosis, treat ment, prevention, and prediction at the individual level. Findings
Goals The main goal of the HGP was to identify all the genes in the human genome and in specific model organisms. The sequencing of model organisms such as mouse (Mus mus culans), fruit fly (Drosophila melanogaster), and nematode (Caenorhabditis elegans) was considered important to the human effort because it provided a less expensive way to test sequencing and mapping technologies. Also, because evolutionarily important areas of genome
The findings of the HGP have perhaps humbled its pioneers, who saw a revolution based on the genome sequence alone. The forecasts underestimated the chal lenges of using technology to tame biological complexity. However, the findings have also opened up new avenues for research in attempts to realize the promise of human genetics. The most recent version of the human genome sequence contains approximately 3 billion base pairs;
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however, there are still some gaps remaining to be sequenced. Although early estimates were as high as 100 000, it is currently believed that the human genome contains 20 000–25 000 genes. The actual number of genes contained in the human genome remains unknown due to lack of established criteria to identify them by form and function. The number of genes, when published, seemed disar mingly few compared to those for the sea urchin (�23 000) and the nematode (�19 000). However, rather than having hundreds of thousands of genes, it is now believed that human developmental complexity comes from various arrangements of DNA regions allowing for multiple functions. Also, many genes are expressed in multiple tissues at different times during the life span, which indicates that most genes do not have single effects but, rather, many (i.e., they are ‘pleiotropic’). In addition, the DNA sequences not coding for genes that were pre viously dismissed as junk DNA have been revealed to house intricate regulatory and processing regions.
Related Projects The HGP has spawned numerous big science, governmentfunded, international projects and has set a trend for biolo gical research initiatives. Human Genome Diversity Project The Human Genome Diversity Project (HGDP) was first proposed in 1991 as a complement to the HGP. Rather than sequencing alone, this project aimed to analyze interpopulation genetic variability. The main goal of the HGDP was to collect cell lines from indigenous, isolated populations of anthropological interest from throughout the world and to store these samples indefinitely in a public archive for future research use. Genetic categor ization of these ‘original’ populations was thought to provide insight into the history and geography of human populations as well as to provide information useful to future biomedical research. Controversy about the HGDP arose soon after its inception and was, on the whole, based on fears that HGDP results would feed ‘scientific racism’ and contri bute to the exploitation of indigenous people through the potential commercialization of their DNA. In 1995, due to the seeming intractable problems associated with the pro ject, the National Research Council of the National Academy of Sciences established an ethics committee to investigate the HGDP. In 1997, the committee deter mined that the project was worth pursuing, but particular attention had to be paid to informed consent, privacy and confidentiality, and community participation. The HGDP went ahead on a smaller scale than was originally
planned. The Human Genome Diversity Panel currently consists of 1064 samples from 54 widely distributed popu lations, typed with large numbers of markers. International HapMap Project Single nucleotide polymorphisms (SNPs) are identified as common, single base variations that occur in human DNA at a frequency of approximately 1 in every 1200 bases. These polymorphisms may be directly associated with disease risk or are markers for disease risk. Human sequence information has revealed millions of SNPs. The International HapMap Project (a collaboration of scientists and public and private funding agencies from Japan, the United Kingdom, Canada, China, Nigeria, and the United States) was established in 2002 to determine common patterns of DNA sequence variation in the human genome by characterizing SNPs, their frequen cies, and their patterns of inheritance. By 2005, ‘phase 1’ of the project had identified and characterized 1.3 million SNPs for 269 samples from four populations. These sam ples included 90 individuals from Nigeria, 90 individuals from Utah, 45 individuals from Beijing, and 44 individuals from Tokyo. The second phase was completed in 2007, cataloging 3.1 million SNPs in a larger number of samples. The aims of the HapMap are to permit researchers to chart sets of closely linked SNPs that are inherited in blocks, called ‘haplotypes.’ Because these SNPs, along with other important DNA regions, are inherited together in a block/haplotype, only a few SNPs are needed to study the entire genome. With such a map, certain types of genetic studies may be carried out at a reduced cost and with greater efficiency. By breaking the human genome into blocks, haplotypes have been linked to Crohn’s dis ease, type II diabetes, and other disorders. Similar to the HGDP, the HapMap project sampled different populations in order to study genetic variation and diversity in humans. To avoid the problems that arose during the planning of the HGDP, the HapMap project held public consultations and used a vocabulary of inclu sion during development. Questions arose regarding the expense of the project and the utility of the HapMap to the representatives from poor countries, where infectious rather than genetic diseases are of greater health conse quence. Some scientists also questioned the presumptions of the HapMap regarding inheritance patterns and its usefulness in understanding the genetic architecture of common diseases. 1000 Genomes The 1000 Genomes Project is another large-scale, technology-heavy, multi-million-dollar project aimed at elucidating human genetic variation. This project,
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with a nod to the HapMap, aims to create a catalog of common human genetic variants (with a frequency of 1% or higher) for approximately 1000 individuals sampled from broad geographic regions (Europe, Asia, and Africa) as a resource for studies into the genetic contribution to disease. It is hoped that the 1000 Genomes Project will provide genetic markers for com mon diseases (e.g., diabetes and heart disease) in greater detail and variety. The genomic catalog will be housed in a searchable database. The project will be carried out in three U.S. sequencing centers funded by NHGRI, the Wellcome Trust Sanger Institute in the United Kingdom, and Beijing Genomics Institute in Shenzhen, China. This project aims to make the sequencing of entire genomes for profiling easier and to lower the costs of sequencing. This aim is intended to encourage the devel opment of genomics for eventual clinical purposes. Critics have protested that 1000 Genomes is simply another project to compile genetic information with little ability to analyze the accumulating genomic data. Complaints have been made that the genomes will not be sequenced in great depth (there will be gaps) and therefore the results will not be as definitive as claimed.
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ELSI program was also meant to act as a model for other large-scale, public projects in the United States and internationally. The program has influenced policy in areas such as disability rights, privacy and anti discrimination legislation, and protections for research participants in genetics studies. However, some scholars have criticized the ELSI program as merely a means to deflect social and political criticisms. ELSI issues have evolved since the outset of the HGP, for example, from a focus on autonomy and genetic discrimination to concern about commercializa tion of genetic information and testing and the effects of genetic profiling in health care. The ethical issues exam ined here explore concerns regarding the current direction of much of the biological sciences toward a ‘big science’ HGP model and the direction of medicine toward a ‘personalized’ approach. Other ethical issues considered here deal with how genetic sequence infor mation is potentially used and interpreted in research and medicine – for instance, issues concerning genetic discrimination and stigmatization, the patenting of genetic information, and the commercialization of genetic tests. ‘Big Science’ and Genetics
ENCODE The ENCODE (which stands for ‘ENCyclopedia Of DNA Elements’) Project is organized in much the same way as the other large-scale, HGP-related research pro jects mentioned previously. It is largely funded by the NHGRI and began in 2003. The project involves hun dreds of scientists from 10 countries and aims to identify all of the functional sequences in the human genome and catalog them in a database for future studies. The project also aims to develop high-throughput methods to identify functional sequences. These refer to DNA sequences that are thought to regulate gene function among other unknown properties. The ENCODE pilot project has revealed that tran scription (one of the biological steps in the creation of a protein from DNA code) is much more complicated than previously thought. Essentially, researchers are still inter preting the results, but so far the findings add complexity to an already complicated genetics picture.
Ethical Issues With the establishment of the HGP, it was announced that the project would include a component to identify and address ELSI associated with the endeavor. There was a recognition among the leaders of the project and the governments at the time that the findings of the HGP could be of a potentially sensitive nature. The
Large-scale, expensive, government-funded scientific research, otherwise known as big science, had previously been the domain of physics. The HGP introduced big science to the study of biology. These large-scale projects are advantageous because they consist of numerous inter national teams of researchers and technicians using state of-the-art technology working toward explicit goals that are met quickly. The justification of the large investment in the HGP by its leaders and promoters was the dual promises of great benefits to humankind and the scientific and medical frontiers to be gained. At the outset of plan ning discussions about the HGP, it was agreed that if a ‘genomic revolution’ was going to occur, the effort would require the generation of massive amounts of sequencing information and the development of automated technol ogy and computational analysis tools. The original leaders of the HGP promoted a hypothesis-free or data-driven approach to the research funded under the auspices of the HGP. This meant that genetic sequence information would initially be gathered without concern for questions about the biological func tion or proof of principle. Rather, the data would be stored to be analyzed later. In this way, the future of the HGP relied on the development of technologies to ana lyze the vast amounts of genetic information gathered and even to help generate hypotheses. Indeed, highthroughput genotyping and other sophisticated labora tory methods have become increasingly available due to technological innovations. The issue now is how to use
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this technology to gain understanding toward practical applications. Due to the reliance on specific costly high-throughput technology, many small laboratories cannot afford this type of research or may find it necessary to partner with industry. The private sector, therefore, is increasingly needed for many types of large-scale genetics research studies, if large-scale sequencing or genotyping is necessary to their line of inquiry. Also, the places in which large-scale genetics studies are carried out are increasingly larger, factory-style laboratories. Although large-scale projects can produce deliverables quickly and efficiently, some critics have questioned the lack of attention to theoretical understandings of genetics. Personalized Medicine The promises of a uniquely personalized medicine flour ished as soon as sequencing of the human genome neared completion. The goal of personalized medicine is sup ported and financed internationally and is considered the next step in the application of HGP knowledge in the clinic. This type of medicine refers to a field of health care that is based on individuals’ unique genomic makeup (their genomic profile), their clinical background, as well as environmental influences. Although relatively simple genetic diseases continue to confound simple treatments, reports continue regarding the imminent use of personalized medicine for common, complex diseases based on genomics. Ethical issues concerning the use of genomic profiles for individualized medicine deal with problems in trans lating the complexities of genomics to the clinic, the potential for the exaggeration of inequalities, and questions concerning the preparedness of healthcare institutions and workforce for increased use of genomic information in the clinic. Genetic complexity
The two main specialties of personalized medicine consist of genomic profiling and prevention strategies. By defini tion, genetics is the study of single genes and their effects, but genomics has advanced the level of interrogation by an order of magnitude. Genomic profiling aims to study global genomic variation and to determine the functions and interactions of all genes in the genome, including the regulation of genes. It is hoped that information gleaned from genomic profiles can be harnessed to help predict individual susceptibility to disease and, based on suscept ibility, provide tools for prevention against predicted future illnesses; to provide early detection of disease; and to target medicines more efficaciously. The complex interaction of genes, their regulation, and influential environmental factors is not well under stood. Some observers believe our lack of understanding
of how genomic profiles contribute to the understanding of disease gives little meaning to the concept of suscept ibility and little reliability to effect on risk. Susceptibility relates to the potential for disease development in indivi duals based on probabilities. Probabilities are considered vague and difficult for most people (expert and layperson alike) to comprehend. Uncertainties regarding suscept ibility, when to act on risk information, and how to counsel individuals on susceptibility and risk are just a few of the issues that arise from attempts to use complex genetic information to provide individualized medicine. However, through the findings of the HGP and related projects, researchers in biology are increasingly addres sing genetic complexity. Many commentators have written about the promises of personalized medicine and recognized the challenges to understanding and are find ing ways to produce useful knowledge within those restraints. Recognizing a personal genetics that is not deterministic and simple but based on susceptibility and probabilities could provide individuals a wider scope within which to maneuver, creating a new way of looking at human genetic systems. Potential inequalities
Understanding health and disease at the individual mole cular level in combination with environmental factors may provide a key to disease prevention – that is, the application of various medical interventions before dis ease starts or at its earliest stages. The preventive actions would vary from person to person and may involve taking vitamins, avoiding environmental exposures, changing diet, or making other lifestyle alterations. Other interven tions could involve tailored drug therapies improving drug efficacy and preventing side effects. The general idea of genomic profiles in this context is that persona lized alterations of the environment can translate genomic-based knowledge into improvements in health for most patients. This model focuses attention primarily on individual risk and responsibility. Control over one’s own health is expected to arise simply by knowing one’s genetics and subsequently manipulating defective biological mechan isms and negative environmental influences. Some have complained that personalized, preventive medicine assumes that all individuals have access to immediate medical care and that all individuals have the ability to change their lifestyles or avoid the risks thought to be associated with genetics. Some authors have suggested that focusing on personal responsibility for illness can lead to a tendency to blame individuals for their own poor health outcomes. The idea that we can predict and prevent, rather than merely react to, the things that make us sick or die has a powerful appeal. This approach, inspired by the promise of genetic information, can bring with it hope to be able to
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control one’s future and create new opportunities for improving one’s life. If applied strategically to the greater public and not only to those who can afford expensive treatment or drug therapies, some believe that there is a possibility to build public health strategies around educa tion and to alter physical, psychological, and social risk environments where warranted. Personalized healthcare preparation
Premature introduction of genomic profiling to the clinic could lead to misinterpretation of genetic information, unnecessary genetic testing, and overzealous diagnosis and treatment that paradoxically could increase risk. In general, it is believed that family doctors have not been sufficiently trained in medical genomics in order to suc cessfully include genomics in their practice and provide effective counseling. Duty of care may require doctors to provide genomic testing and make diagnoses despite this lack of understanding. Patients consenting to genomic tests associated with personalized medicine would be required to understand matters that are more numerous and complex than ever encountered. Regulation of genomic medicine and increased resources for genetic counseling are considered necessary for successful intro duction of personalized medicine strategies to the clinic. Genetic Discrimination and Stigmatization Genetic discrimination refers to the possible general application of institutional and other discriminatory prac tices based on an individual’s or group’s genetic background. Genetic stigmatization is a similar term and refers to the labeling or stereotyping of an individual or group in a negative way based on their genetic back ground. The potential effects of genetic discrimination and stigmatization on race and culture and disability are discussed next. Race and culture
Genetics has been used to promote the eugenic beliefs that the management of heredity would improve the physical, mental, and behavioral traits of humankind. Also, race and class distinctions were thought to be due to biological differences. Currently, HGP researchers speak of attempts to make connections between DNA sequences and things such as health, disease, behavior, and human evolutionary history. These associations are found by examining differences in human genetic varia tion often between groups. Studying genetic differences has raised alarms of a potential ‘new eugenics.’ Scholars are still divided on the question of whether racial cate gorization is a legitimate way to organize genetic variation for the study of human disease and evolution or whether these genetic distinctions are artificial and carry the potential to be used as a new tool to discriminate
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against groups with perceived differential genetic and health risks. Some of the projects related to the HGP have used racial categories to study genetic differences (HGDP and HapMap). Controversy has arisen with regard to these projects based on the intersection of race, culture, and genetics. For example, the HGDP focused on populations labeled ‘isolated’ and ‘of anthropological interest.’ This caused concern from some indigenous rights groups regarding potential racist interpretations of the research and potential nefarious use of the collected data. Past abuses have made populations sensitive to the use of their biological samples through commercial exploitation and minimal benefit to the populations studied. In addi tion, indigenous rights groups have had concerns about the use of genetics to describe their heritage. Some have worried that tribal membership claims could be disputed due to genetic explanations that are often considered more valid than cultural associations. However, many scientists and other scholars have brought attention to the fact that just as simplistic ideas about genetics in general are being rethought, simplistic genetic explanations of race and culture are also being disproven. It is believed that the study of human genetic differences has demonstrated that there is no scientific basis for racism. In addition, some scholars believe that genomics creates new categorizations that are different from the eugenics of the past and offer new possibilities for defining humankind. Still others see the intersection of genetics and race and culture as a way to bring more minorities into science and improve medical care for specific communities. Disability
Genetics and disability were also a special concern of eugenicists, legislatures, and courts that viewed ‘feeble mindedness’ as an inherited defect that drained public resources and threatened humanity. Prenatal genetic screening and preimplantation genetic diagnosis, as well as genetic testing for disease, raise ethical issues regarding potential discrimination and stigmatization based on dis ability. Prenatal genetic screening is used at the population level during pregnancy to detect genetic and chromosomal disorders. Preimplantation genetic diagno sis is a procedure used in conjunction with in vitro fertilization to screen for specific genetic or chromosomal abnormalities before transferring fertilized eggs. Some of the justifications for the use of prenatal screening and preimplantation diagnosis for disability are that screening may help lower medical costs and reduce the burden of life with a disability. To some, these justifications seem disturbingly similar to the language of eugenics. Eric Parens noted that the choice to terminate a pregnancy based on disability is a decision that certain traits are undesirable, and Lawrence Gostin has written about the
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potential for insurance and employment discrimination based on genetic testing of people with genetic disorders and disabilities and their families. On the other hand, information gained from prenatal screening could lead to the early diagnosis and treatment of genetic disorders, which could highly benefit these children. Glenn McGee observed that genetic diagnosis provides choices to potential parents and could provide hope and possibility for their children. In addition, com plexities revealed by research on the genetic contribution to human disorders and disability have not found absolute distinctions between who is sick and healthy, normal and abnormal. Nikolas Rose argued that genetics can create new configurations around activist groups that identify through disease histories or risk identities. These com munities could use activist involvement to become more powerful, not less.
Commercialization The methods of the HGP have brought with them pro found changes in the way research is commercialized in the biological sciences. Many patents asserting rights over DNA sequences have been granted to researchers across the public and private sector and internationally. Commercialization has occurred on many fronts, such as genetic testing, screening, technology development, and drug development.
Gene patenting
The HGP was built on the idea that the genetic informa tion generated would be kept in public databases (technically) for anyone to use; however, there was always an intension to encourage the commercial aspects of the project. Patenting of genetically modified organisms was first permitted in the 1980s. These patented organisms were considered ‘man-made’ because they did not occur in nature and required human intervention. Patenting opportunities subsequently opened up for genes, SNPs, cell lines, and mice. The patenting of living things was originally considered illegitimate but is now generally widely accepted. Patents allow researchers, institutions, and companies to capitalize on inventions and are presumed to eliminate the need to withhold data from competitors. However, concerns have been raised that patenting impedes the sharing of data and the ability of other researchers to confirm published results. This secrecy could be due, for example, to the protection of competitive commercial or academic applications or due to increasing reliance on industry funding. Patents have also been known to result in restricted medical access to important genetic tests due to prohibitive costs.
Direct-to-consumer genetic testing
Genetic tests are currently being offered to consumers online. Predictive genomic profiling to produce persona lized lifestyle advice, whole genome scans to estimate genetic risk for common diseases, and genetic ancestry testing are all available from various international companies. Information about health and genealogy can have a powerful impact on an individual’s life. The companies that market these tests may provide recommendations based on test results; however, a lack of bona fide genetic counseling services could lead to the potential misinter pretation of results, a false sense of security, and even affect decisions about parenthood. The general lack of regulation and standardization of direct-to-consumer genetic testing has been criticized internationally. Some commentators have complained that it is difficult to eval uate companies’ claims based on proprietary databases, but that this evaluation needs to be carried out. Some suggest that genetic tests are no different from other traditional tests offered in the clinic because they are not always required to demonstrate utility on a test by-test basis. Some view choice as an important aspect of commercialized genetic testing such that if an individual wants to buy a test, which may be considered just like any other test, for personal reasons and consents, he or she should have every opportunity to make that purchase. However, it may be difficult to know exactly what one is consenting to, and some direct-to-consumer tests may be misrepresented through claims on a website. For these reasons, many believe more protections should be enforced to safeguard consumers.
Conclusion The HGP has ushered in a new model for biological research and a new direction for medical practice. There is little doubt that our understanding of the human gen ome has increased since the first days of the project, and the findings have been surprising and have challenged previously held beliefs about the genome and about humans. The practical application of genetic information in medicine is still on weak ground, and the genetic contribution to human disease is still not very well under stood. However, there is a market for genetic tests that provide information about ‘disease susceptibility’ despite the fact that susceptibility is a vague concept on which any meaning could be placed. There are also fears of a genetics based on exploitation, discriminatory practices, and commodification. Although the mapping and sequen cing tasks carried out for the HGP were relatively straightforward endeavors, the HGP has generated greater questions about human identity and complexity, nature, and society.
Human Genome Project See also: Eugenics; Genetic Exceptionalism; Genetic Screening; Genetics and Behavior; Genomic Databases, Ethical Issues in; Pharmacogenetics; Race and Genomics.
Further Reading Buchanan AV, Sholtis S, Richtsmeier J, and Weiss KM (2009) What are genes ‘for’ or where are traits ‘from’? What is the question? BioEssays 31: 198–208. Cavalli-Sforza LL, Menozzi P, and Piazza A (1994) The History and Geography of Human Genes. Princeton, NJ: Princeton University Press. Collins FS, Morgan M, and Patrinos A (2003) The Human Genome Project: Lessons from large-scale biology. Science 300(5617): 286–290. Cook-Deegan R (1994) The Gene Wars: Science, Politics, and the Human Genome. New York: Norton. Galas DJ and McCormack SJ (2003) An historical perspective on genomic technologies. Current Issues in Molecular Biology 5: 123–128. Gannett L (2010) The Human Genome Project, The Stanford Encyclopedia of Philosophy (Summer 2010 Edition). Gostin L (1991) Genetic discrimination: The use of genetically based diagnostic and prognostic tests by employers and insurers. American Journal of Law and Medicine 17(1–2): 109–144. International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409: 860–921. International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431: 931–945. Janssens ACJW, Gwinn M, Bradley LA, et al. (2008) A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions. American Journal of Human Genetics 82: 593–599. Kay LE (2000) Who Wrote the Book of Life? A History of the Genetic Code. Stanford, CA: Stanford University Press. Kevles DJ and Hood L (eds.) (1992) The Code of Codes: Scientific and Social Issues in the Human Genome Project. Cambridge, MA: Harvard University Press. McGee G (1997) The Perfect Baby: A Pragmatic Approach to Genetics. New York: Rowman & Littlefield. Parens E and Asch A (1999) The disability rights critique of prenatal genetic testing reflections and recommendations. The Hastings Center Report 29: S1–S22. Reardon J (2005) Race to the Finish: Identity and Governance in an Age of Genomics. Princeton, NJ: Princeton University Press. Rose N (2006) The Politics of Life Itself: Biomedicine, Power, and Subjectivity in the Twenty-First Century. Princeton, NJ: Princeton University Press. Sulston J and Ferry G (2002) The Common Thread: A Story of Science, Politics, Ethics, and the Human Genome. New York: Bantam. Venter JC, Adams MD, Myers EW, et al. (2001) The sequence of the human genome. Science 291: 1304–1351. Willard HF and Ginsburg GS (eds.) (2009) Genomic and Personalized Medicine (2 vols). London: Elsevier.
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Relevant Websites http://1000genomes.org – ‘1000 Genomes, A Deep Catalog of Human Genetic Variation.’ http://www.science.org.au/nova/006/006key.htm – Australian Government’s National Innovation Awareness Strategy, ‘The Human Genome Project.’ http://english.big.cas.cn/http – Beijing Institute of Genomics. http://bioethics.net – Bioethics.net. http://www.genomecanada.ca – Genome Canada. http://www.hapmap.org – International HapMap Project. http://www.genome.gov/10001772 – National Human Genome Research Institute, ‘All about the Human Genome Project.’ http://www.genome.gov/10005107 – National Human Genome Research Institute, ‘ENCODE Project.’ http://www.genome.gov/11006929 – National Human Genome Research Institute, ‘International Consortium Completes Human Genome Project.’ http://hsblogs.stanford.edu/morrison/human-genome-diversity project – Stanford University, Morrison Institute for Population and Resource Studies, ‘Human Genome Diversity Project.’ http://www.ornl.gov/sci/techresources/Human_Genome/ research/elsi.shtml – U.S. Department of Energy, ‘Human Genome Project Information.’ http://genome.wellcome.ac.uk/node30075.html – Wellcome Trust, ‘The Human Genome.’ http://www.sanger.ac.uk/Info/Press/2004/041020.shtml – Wellcome Trust Sanger Institute, ‘The Finished Human Genome.’ http://www.yourgenome.org – Wellcome Trust Sanger Institute, YourGenome.org.
Biographical Sketch Jennifer Marshall has an MSc in human genetics and an MSc in experimental medicine (specialization in Bioethics) from McGill University. She has been a research associate at the Health Law Institute at Dalhousie University and previously worked on projects at McGill University, Universite´ de Montre´al, and Health Canada regarding ethical aspects of the Human Genome Project, genomics in health care, large-scale genetic and human biological material banking, and community consultation strategies. She is currently a PhD student at the University of Toronto, Department of Health Policy, Management, and Evaluation.