Human Genome Project

Ines Rothe

Copyright 1999


Human curiosity is one of the most powerful engines that drive new knowledge, development, advancements and life improvements today. Some 100,000 or 200,000 years ago Homo sapiens emerged, and up to today humans are still searching for answers such as what we are and where we came from.

For all of the diversity of the world's more than five billion people, full of creativity and contradictions, every human mind and body is built and runs with fewer than 100,000 kinds of protein molecules. And for each of the proteins, a single corresponding gene is responsible to ensure an adequate and timely supply. Genes are often described as the biological blueprints or recipes for life and are found in the DNA, carrying the genetic information from one generation to the next. Many people are convinced that genes are special, that they contain a person's essence, which has enormous spiritual and commercial value. In the deepest sense, we are who we are because of our genes, and therefore it is essential to gain knowledge about the manifold mysteries of life, our genes, and our biological inheritance in full ultimate molecular detail. With advances in molecular genetics, it became possible to launch the Human Genome Project (HGP) - a sequencing project that determines the genetic makeup of an organism by reading off the sequence of the three billion DNA bases, which encode all of the information necessary for the life of the organism. Profits, curiosity and dreams of better methods to prevent and treat diseases are driving efforts to find and decode human genes. The sequence of our genome will ultimately allow us to discover the secrets of life's processes, the biochemical basis of our senses and our memory, our development and our aging, our similarities and individual differences. The genome project itself offers no promises of cancer cures or quick fixes for Alzheimer's disease, and no detailed understanding of genius or schizophrenia. But if we are ever to uncover the mysteries of carcinogenesis, if we are ever to know how biochemistry contributes to mental illness, if we ever hope to really understand the processes of growth and development, we must first have a detailed map of the genetic landscape. That's what the HGP promises and what makes this international effort so breathtaking.

Human Genome Background and History

The idea of the HGP was initiated in 1977, when simple and efficient methods for sequencing DNA were described. Before that time the possibility of sequencing the entire human genome was no more than extreme wishful thinking. In the 1980's it was becoming increasingly apparent to many scientists that an understanding of basic biology would be greatly enhanced if the detailed structure of DNA was understood. Over the last two decades, automated DNA sequencers have made the process of obtaining the base-by-base sequence of DNA easier. In 1984, for the first time a meeting was sponsored by the Department of Energy (DOE) to address the problem of detecting extremely low levels of very rare changes in DNA (mutations) in humans exposed to radiation and other environmental hazards. At that time, it was realized that the level of effort including the automation of DNA analysis techniques would be similar to the requirements for sequencing the human genome. Several other meetings followed until the first formal proposal appeared in 1986 published by Renato Dulbecco who focused on potential benefits to cancer research from the availability of the complete genomic sequence (Edwin McConkey 1993). The immediate public response was considerable skepticism about the possibility and economical feasibility of the HGP, the value of the results, its impact on the rest of biological research, goal definitions, funding, and potential risks of information abuse.

The HGP formally began in the fall of 1990 as a $3 billion, 15-year effort to find the estimated 80,000-100,000 human genes and determine the sequence of the 3-billion chemical bases that make up human DNA and underlies all life's diversity. Despite voices of concern in the scientific community, the U.S. National Human Genome Research Institute (NHGRI) started allocating funding for the creation of the HGP in 1988 and delegated $17.2 million to the National Institute of Health (NIH) and $10.7 million for DOE, based on the agency's interest and experience with genetic research related to radiation effects and its background in computer science (Edwin McConkey 1993). James D. Watson, Ph.D., the famous codiscoverer of the DNA double helix, was recruited to direct the NIH effort. Watson has been enthusiastic about the prospect of creating a complete catalogue of the three billion base pairs in the human genome - the straightforward concept of sequencing the entire human genome and mapping, all to be achieved within the lifetime of one scientist. In response to widespread concern about possible negative consequences of increased knowledge of the human genome, between 2 and 5% of the total budget have been set aside for a program on ethical, legal and social implications. An international Human Genome Organization (HUGO) was founded in April, 1988 by an independent group of scientists initially for the purpose of assisting with coordinating national efforts, facilitating exchange of research resources, encouraging public debate, and providing information on the implications of human genome research. HUGO now has primary responsibility for organizing workshops on individual human chromosomes. It will also coordinate projects on sequencing and mapping cDNAs.

The major goals defined in the HGP are: (1) construction of a high resolution genetic map of the human genome; (2) production of a variety of physical maps of all human chromosomes and the chromosomes of selected organisms; (3) determination of the complete sequence of human DNA and of the DNA of selected model organisms; (4) development of the capabilities for collecting, storing, distributing, and analyzing the data produced, and (5) creation of appropriate technologies necessary to achieve these objectives (Pearson and Söll 1991).

Rapid technological advances have accelerated and shifted the expected completion date to 2003. In 1998, new 5-year goals were published including identifying regions of the human genome that differ from person to person since it is believed that these DNA sequence variations play a major role on how individuals respond to diseases, and environmental insults such as bacteria, viruses, and toxins, and drugs. Additional goals of the new plan focus on comparing human DNA sequences with those from organisms such as the laboratory mouse and yeast, addressing the ethical, legal, and social issues surrounding genetic tools and data, developing the computational capability to collect, store, and analyze DNA data, and developing interdisciplinary training programs for future genomics scientists (Collins et al. 1998). One goal of sequencing the genome is to identify, in the proper order, the three billion base pairs that make up human DNA. The other goal of the HGP is to map the human genome and create landmarks throughout the genome that can be used as reference points or as unique sequences of DNA that locate genes in their vicinity. Landmarks are an ordered collection of overlapping cloned DNA segments that together span a given region of the genome and help develop physical maps. Such landmarks can be identified by the use of genetic tests. Once a physical map is constructed, each gene on a chromosome can be located in terms of its position relative to a marker. Physical maps in addition with linkage maps are helpful in identifying genes responsible for diseases and are also necessary for sequencing. However, only a tiny fraction of human DNA is known to code for protein or RNA, the rest (95% or more) either is nonfunctional or has some function that has not yet been identified. Such an effort would begin with cDNA localization of most or all of the 50,000 genes, followed by base-sequence (order of bases in a gene) determination of the entire genome. Analyses of base sequences are also being conducted, but these are concentrated on currently identifiable genes, such as those implicated in genetic diseases. Automation is making the task of sequencing less laborious and costly, and powerful computer programs manage and analyze the data. Based on experience gained from pilot projects, an international consortium predicts they will produce at least 90 percent of the human genome sequence in a "working draft" form already by the spring of 2000 ( The ultimate goal of the HGP is exploiting the knowledge gained from this project for a truly, profound molecular-level understanding of how we develop from embryo to adult, what makes us work and what causes things to go wrong.

The project also includes the genomic analysis of organisms other than the human. Comparative mapping studies are being carried out simultaneously in a number of other organisms, especially in the laboratory mouse (Mus musculus), the fruitfly (Drosophila melanogaster), a nematode worm (Caenorhabditis elegans), yeast (Saccharomyces cerevisiae), and Escherichia coli. Comparisons of DNA sequences and the chromosomal organization of related genes and clusters of genes from different organisms are powerful tools for identifying the elements essential for their functions. The information gained from the comparative mapping studies of other organisms will add greatly to human's understanding of evolutionary relationships due to the extensive homologies among different genomes and conservative nature of evolution, but they also significantly increase the scope and cost of the overall project (Clark 1999).

Project Controversies

The project has been controversial for many reasons. A great deal of variety remains in the approaches available to sequencing the human genome. It is not yet clear which will prove the most efficient and most cost effective way to read long stretches of DNA. Major questions and considerations included whether the sequence of the human genome should be done randomly, in the expectation that all the pieces would fit together eventually, or whether to sequence portions of the genome that are already known to be of biochemical interest and responsible for common genetic diseases. Should one chromosome being studied at a time and should any massive sequencing be done with present technology or delayed until more rapid, automated techniques will become available. Some scientist have argued that the conventional approach of first identifying an important gene, then cloning and studying it, is scientifically more interesting and more cost-effective over the long term. Supporters of the project argue that many important genes that might be very difficult to identify will be uncovered in the course of the investigation. Even apparently nonfunctional DNA ("junk DNA") may turn out to be important. There is considerable debate about whether wholesale sequencing is worth the billions of dollars it is likely to cost, especially since other projects will necessarily go unfunded to allow this initiative, and it will mean a huge redirection of talent from other genetic engineering projects. Keeping in mind that the human genome contains three billion gene pairs it was estimated in 1986 that one skilled person could sequence 100,000 base pairs per year at an average cost of $1/base pair (Edwin McConkey 1993). Many genes known to be responsible for genetic diseases are being studied, and many more already being uncovered appear to be associated with predispositions to diseases such as heart disease and cancer. In the long run, however, there seems little doubt that the human gene project, if fully carried out, will make possible many kinds of therapeutic intervention, and cast considerable light on chromosomal organization and evolution (Gottesman and Collins 1994).

Project Implications

Our knowledge about human genetics clearly expand at a great rate over the coming years. This fundamental understanding will permit control over many biological processes, and biological control will transform medicine, agriculture, animal husbandry, and pharmaceutical production. The project has already stimulated significant investment by large corporations and lead to the creation of new companies hoping to capitalize on the project's profound and inestimable implications. Great desire exists among biotechnology companies to acquire efficient technologies such as the genome-driven drug discovery. An understanding of human DNA certainly will be an important key in understanding a host of human diseases. Cancers, in particular, are now being understood as genetic diseases, since cancerous growths arise from either acquired or hereditary changes in cellular DNA. Once we know how altered DNA induces cancer development, effective tools can be developed to prevent or treat malignant growths. It is important that this knowledge will be used well, and not to stigmatize or discriminate, but to improve human health.

The HGP should illuminate fundamental functions of the body and become invaluable basis for genomic technology, however it will primarily open a fascinating area for exploration. A large portion of the value of the projects rests on the expansion of our basic understanding of biological life in general and the explicit promise of the relief of suffering from the more than 4,000 genetic hereditary diseases (i.e. Huntington disease and cystic fibrosis) either through prevention or cure (Gottesman and Collins 1994).

Understanding of the human genome will have an enormous impact on the ability to assess risk posed to individuals by exposure to toxic agents and scientists know that genetic differences make some people more susceptible and others more resistant to such agents. Far more research work will be needed to determine the genetic basis of variability. This knowledge addresses the DOE's goal to understand the effects of low level exposures to radiation and other energy-related agents, especially in terms of cancer risk.

The advantage of the Human Genome Project has been the recognition that it attracted extra funding to the work, raised the profile of the effort within the scientific communities, and provided elements of organization and cooperation that would not have occurred with individual scientists pursuing projects based on their personal interest.

Human Genome Mapping and Sequencing

Scientists have begun to complete mapping of the total informational content of the human genome, a major coordinated international effort and challenge with the United States taking the leading role so far. Mapping is the process of determining the position and spacing of genes, or other genetic landmarks, on the chromosomes relative to one another. There are basically two types of maps, genetic and physical, which differ in the methods used to construct them and in the metric that is used to measure the distance between genes. The introduction of DNA markers, such as restriction fragment length polymorphisms (RFLPs) to detect genetic variation among individuals. Such markers are relatively easy to find in large numbers and have been used to construct genetic maps. A complete map of the human genome was completed in 1994 with additional work still being necessary to identify more markers. Emphasis is now on sequencing the human genome.

The HGP's continued emphasis is on obtaining a complete and highly accurate reference sequence (1 error in 10,000 bases) that is largely continuous across each human chromosome. Scientists believe that knowing this sequence is critically important for understanding human biology and for applications in other fields.

Craig Venter is the president of Celera Genomics that is on its way of becoming one of the largest DNA sequencing center in the world. He claims that his team will finish the DNA sequence of the entire human genome in just 18 months, finishing it by the end of 2001 instead of 2005 and at a cost ten times less than the publicly funded project. Celera does not plan to make all its sequence data immediately available, although Venter has said scientists will have free access to parts of it. Celera plans to patent several hundred human genes and a large set of human single nucleotide polymorphisms for use in individually tailored medicine by pharmaceutical companies (Wade 1999).

Large-scale human DNA sequencing was not initiated until 1996, after preliminary mapping had been accomplished. Genetic DNA sequencing had been a tremendously labor intense process until now. What sets Venter's business apart is its scale and promised high speed sequencing robots that determine the precise order of nucleotide bases in DNA in a steady flow of data-signals representing the DNA bases A, C, G, and T. However, opponents of Venter's promises believe that such "whole-genome shotgun" would leave over 100,000 serious gaps in Venter's human genome project. This type of cloning ignores mapping the genome-defining molecular landmarks that will allow sequence data to be assembled correctly. Venter's technique breaks the genome in millions of overlapping fragments and determines part of the sequence of chemical units within each fragment. Computer programs then put these pieces together to recreate the sequence of the genome (Beardsley 1998). Some scientists believe that the whole genome shotgun cloning could degrade the quality of data, and that the publicly funded HGP would reduce standards in accuracy and completion to keep pace. Unlike Venter's process, the public consortium's approach is to break a chromosome down into large overlapping fragments which then will be studied to find out the region on the chromosome from which each fragment comes. This process is known as mapping. The number of mapped human genes is rapidly increasing. About one-fifth of all protein-coding genes in our genome, most of them associated with specific diseases or predispositions, were defined, usually by positional cloning (Velázquez and Bourges 1999). Even after the HGP is completed and all the genes are mapped and sequenced, it will take years of intense and careful work to understand the interaction of multiple genes in producing complex, polygenic conditions and traits.

Significant information about the content of the human genome and differential expression in various tissues has been derived from partial cDNA sequences, called expressed sequenced tags (ESTs). Analysis of EST sequences in the public domain now indicates that over 40,000 unique cDNAs have been sequenced, which represents a significant number of the estimated 50,000-100,000 human genes ( Until the human genome is completed, EST databases will be an important drug discovery tool to identify and clone disease genes and to study gene expression (Maddox 1995).

Many scientists felt that mapping and sequencing should be an international effort since there is only one human species and the results of analyzing human genome will be useful for all of us. In Germany, there is a widespread opposition to learning a lot about human genetics before regulations have been established to prevent misuse of the information (Koenig 1997). The Hitler Nazi regime in Germany between 1933 and 1945 killed millions of Jews, Gypsies, mental patients, and disabled people in concentration camps in the name of the pseudoscience eugenics. Any suggestion that eugenic improvements may be feasible, as a result of gained knowledge from the HGP, are alarming signs and create strong objections to the sequencing of human genome. That eugenics philosophy which lead to the horrors of National Socialism in Germany have made many people appropriately sensitive to the potential abuses of genetic science. Some people fear that once we have the tools to "play around" with our genes, we may be tempted to use them to design a "super" race of human beings. Beyond abuses, there are basic problems in the application of genetic knowledge in medicine and society related to the benefits and harms of testing and screening, issues of privacy and confidentiality issues of regulation, and issues of justice in access to the powerful new tools.

HGP and its Connection with Genetic Testing and Gene Therapy

The HGP will provide knowledge, which will offer a new era of molecular medicine characterized not by treating symptoms, but rather looking to the deepest causes of diseases. Rapid and more accurate diagnostic tests (genetic screening) will make possible earlier treatment for countless diseases. Even more promising, insight into genetic susceptibilities to disease and to environmental impacts coupled with preventive gene therapy will become possible and in some cases actually "fix" genetic errors before they can trigger the disease. A technique that uses short strands of genetic material, known as DNA probes, will be used to detect normal and abnormal genes for diagnostic and screening purposes, and gene therapy will be used to transfer genes into cells to repair, alter or enhance their function. The ability of exploiting such genetic technologies to diagnose, cure and alter the course of diseases results from the identification of all human genes and understanding of their specific functions.

A great deal of the work to date on the ethical, legal, and social implications of the HGP has focused on genetic testing. Patients who can afford the expenditure for genetic testing can simply buy the service they desire even if it is not covered by their public or private insurance plan. This would classify people and benefit only those people who can afford wealth-based access.

Genetic information can be complex and difficult to understand, leading people to misunderstand the results. Therefore genetic testing and its predictive power must be supported by careful counseling. Insurers may require applicants for insurance to be tested to determine their susceptibility to genetic disorders. Positive results can lead health insurers to refuse to insure the individual, to charge prohibitively high premiums. Positive test results also can prevent the individual from obtaining life insurance, or at least from being able to purchase a policy at an affordable price. Employers may show interests in genetic information similar to those to health insurers. Employers may refuse to hire people with genetic tendency to develop disease in order to avoid having to pay the cost of the future treatment.

For the same reason, a positive genetic test result may cause an employer to try to fire a current employee. Employers also may fear that an affected employee may create safety risks for customers or other employees, if the disorder is one that, like Huntingson's disease, can diminish coordination and judgement. Family members may seek another member's test results in order to learn if they themselves are at risk. This information can be beneficial to the family or can destroy family relationships. Young couples (prospective mates) may insist on genetic testing before they will agree to become married in the first place.

But one must not overlook the tremendous benefits that genetic testing potentially can provide. Even if the genetic disorder can not be treated, knowledge of one's risk can enable an individual to make important decisions in areas of family planning, reproduction, financial planning, and life-style choices.

My Personal View and Conclusion

Most people think that science is remote from work they do, lives they live, and the decisions that they make day by day. The HGP is probably one of the most profound research efforts in human history, which will certainly impact all of us because of the many implications for medicine and human health. The HGP is rich with promises, but also fraught with social implications. It is quite likely that the new knowledge from the HGP will be used in ways that don't always have to do with health. Our challenge is to reduce any negative impacts, which result from the misuse of genetic information. In my opinion, researchers, scientists, business and governmental people who are involved in the HGP must avoid any activity that could cause harm while they pursue professional and personal goals. On the other hand, individuals not directly participating in genetic research are responsible to educate themselves and seek information about potential risks and benefits of genetic research and about the interventions that it produces before they utilize new genetic technologies. Individuals with access to information about their genetic endowments will be able to predict their susceptibility to genetically related disorders in the future. Threats evolve around the major question of whether or not an individual has access to genetic technologies. One type of threat occurs when individuals are denied access to technologies that would benefit them. The likelihood of genetic technologies becoming available to some peoples but not to others, and that a major determinant of access will be wealth, raises profound social issues.

The regulation of access of technologies and information obtained from the HGP should be handled very carefully and is probably one of the most difficult tasks for the future. This is especially true since the project has international dimensions and opinions on this issue differ among participating countries. That leads into another question, whether countries that do not directly contribute to the success of the HGP should be treated differently in terms of access to information and technologies being generated from the HGP.

The HGP will accelerate the acquisition of probes for genes that determine an individual's susceptibility to heart disease, to certain types of cancer, to diabetes, and to some types of mental illness. We expect to learn the underlying causes of many genetic diseases, including sickle cell anemia, Tay-Sachs disease, Huntington disease, cystic fibrosis, and several forms of cancer. This will enable us to predict the likelihood of the disease occurrence in any individual. However, people should be aware of the fact that the HGP will not serve as a provider of the desired mystic crystal ball for prediction of human's fate, life expectancy or potential death causes. The HGP could rather be seen as a force for us to deal with more problems sooner than would otherwise eventually have occurred, but it is not the cause of creating ethical, legal, and social problems.

We are in the process of taking control of life, shaping our future, and receiving the power to predict and plan our lives in ways never before possible. We will produce new species, diagnose illness long before it happens, know human beings at the biochemical level, manipulate our reproductive processes, and change us. Too much confidence in our knowledge and gained power will hopefully not create the feeling in us of being able to alter the outcome of millions of years of evolution. We need to worry about whether genetic technology generated from the HGP will make us less accepting of people who are different. For example, if it is possible to predict and prevent the birth of a child with a gene-related disorder, how will we react to children who have that disorder?

As true for all science research: the manner in which we will use and apply new knowledge will determine its benefit or dramatic pitfalls. I do not question that the initiative should go forward and believe that a well-planned and well-executed project such as the HGP will yield great benefits for many areas. But I feel and fear, that as an "ordinary" individual I have little control over the way that genetic research will be used, for good or for bad.

Project applications will flow from the information it provides and turn genetic discoveries into drugs. Hopefully new useful medical approaches to fight diseases will arise from genetic research and break the limits of current conventional methods. Genetics will tell us a lot more about ourselves, our biochemical constitution, gene functions and their role in disease processes. Because of that, we will be able to target particular conditions more exactly and produce treatments that act more precisely on the specific disease and also on the specific individuals without side effects.

The complete human genome sequence will tell us something about gene function, but much work will remain until we know what every gene product does and how expressions of that gene is controlled. And lets not forget the fact that the sequenced human genome will only be a model and will not exactly reveal what is written in somebody's genome or in any other particular person's genome. This is because every human being is different. Each person's genome is unique contributing to a unique personality. The HGP is a good example of possible international collaboration. I like the fact that this fundamental research is not limited to the U.S. only but instead links scientists, researchers, computer experts and other people from all over the world in the effort to learn more about ourselves. Many countries are interested in participating in the project and all are interested in the outcomes. I hope that such beneficial global collaboration will also become apparent in determining fair regulations that concern the access and uses of the new information.


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