Hessel Bouma III, ASA Fellow

Calvin College, Grand Rapids, MI
ASA Bioethics Commission chair

From: Perspectives on Science and Christian Faith 52 (September 2000): 152-155.

On June 26, 2000, the National Human Genome Research Institute¹ and Celera Genomics Corporation² announced the completion--or the beginning of the end--of the formal Human Genome Project (HGP). Officially begun in 1990, the project has a goal of mapping the 80,000-100,000 genes (estimates range from 50,000 to 140,000 genes) to the 24 human chromosomes (autosomes #1-22 and the X and Y sex chromosomes) and to sequence the 3 to 3.3 billion basepairs of DNA comprising the human genome. The HGP was projected to cost up to $3 billion and to take fifteen years to complete. It was begun with a common dream and faith--the dream that such knowledge would substantially benefit humankind; the faith that science would develop the necessary technology to make this project feasible and that humankind would use this knowledge wisely.

The HGP is the third massive science project undertaken by American scientists and society. In the 1940s, the Manhattan Project produced a test bomb and the two bombs dropped over Hiroshima and Nagasaki. From 1963 to the mid-1970s, the Apollo Project sought to place humans on the moon. Adjusted to current dollars, the Manhattan Project cost $22 billion, the Apollo Project cost $95 billion. Both these projects were undertaken with intense international competition. Both have had far-reaching consequences, socially as well as scientifically, unanticipated as well as anticipated, bad as well as good. From the outset of the HGP, supporters recognized there would be enormous implications to this project and designated 3-5% of the funding for explorations into the HGP's Ethical, Legal and Social Implications (ELSI).

Initially the HGP was undertaken jointly by the National Institutes of Health with its interest and expertise in addressing genetic conditions and the Department of Energy with its interest and expertise in monitoring radiation safety and managing large projects. Commendable efforts were made to work cooperatively between these agencies as well as with a consortium of scientists from other countries. As a public, federally funded project, it was largely understood that the results of this project would be in the public domain, openly available to all. More recently, however the HGP has been joined by several private companies with biomedical interests, most notably Celera Genomics Corporation. Competition can be healthy, and may result in faster completion of the project, possibly with increased, independent confirmation of the data. But competition can also be unhealthy, focusing on individual egos, excessive consumption of resources, and "winners" who take all. The media has taken to emphasizing the competition and often the unhealthy dimensions of it. In reality, there is significant complementary work and cooperation between the public and private endeavors. The most significant difference is not who gets the credit or which techniques are most productive, but the accuracy of the information and whether and how the information is made available for the betterment of humankind. Will it be made available immediately in the public domain, or held privately, at least for a time, to give those who produced the information the first opportunity to use it? Which approach will encourage further research and development in the most stewardly fashion?

To achieve the goal of mapping and sequencing the human genome, scientists have undertaken mapping and sequencing several model organisms. To date, the HGP has elucidated the genomes of the common bacterium, Escherichia coli (4,405 genes on a single chromosome consisting of ~4.6 million basepairs)³; the yeast Saccharomyces cerevisiae (~6,600 genes, 16 chromosomes, 12 million basepairs); the nematode worm, Caenorhabditis elegans (~18,000 genes, 6 chromosomes, 97 million basepairs); and the fruit fly, Drosophila melanogaster (~13,600 genes, 4 chromosomes, 180 million basepairs). Work is also progressing on the laboratory mouse, Mus musculus whose genome is nearly as complex as the human genome; current reports suggest the sequencing phase of its genome is one-third finished. These endeavors will assist in assembling more complex genomes, identifying functional genes, and initiating the exploration of gene function and regulation. Concurrently, the National Science Foundation is funding work on the plant, Arabidopsis thaliana. Other groups are working on the genomes of numerous microbes, animals such as cows and dogs, and plants such as corn and rice.

Unlike the Manhattan and Apollo Projects, the HGP will not have as clear and concise an end-point. First, the occurrence of highly repetitive sequences of structural DNA render sequencing some regions very difficult and of diminished interest. It may be some years before these regions are fully sequenced. Second, what standard of accuracy should be met in the sequencing data? The more errors we are willing to accept, the sooner we can declare the sequencing completed. Third, is the project complete when the sequencing is finished, when the pieces are all assembled, when all the putative genes in the sequences have been identified, or when the information is all made publicly available? As a case in point, sequencing the Drosophila genome was first publicly announced as complete last fall before the fragments were assembled. This spring, the genome was announced as complete and publicly released although there were nearly 1300 small gaps remaining as well as major sequence voids at the centromeres of the four chromosomes. (Notice, too, talk of completing the human genome refers only to mapping and sequencing the entire genome, not to the ethical, legal, and social implications of the HGP.) Like constructing a sizeable and complex building, at some point we simply declare the project finished despite it not being 100% complete and accurate, and move on to put the product to good use while wrapping up loose ends.

Sequencing the human genome represents one of the most significant milestones in our biomedical understanding of human beings. Knowing all the genes and their structure should facilitate studies leading to our understanding of how these genes function and are controlled, the roles they normally play, and the effects of mutations in these genes on human health. That understanding, in turn, may enable us to develop better treatments for persons with genetic conditions. When coupled with developments in the fields of assisted reproductive technologies, developmental biology, and genetic engineering, the prospect for genetic cures through gene therapy looms large. Given the enormous number of genetic conditions already identified in human (see the Online Mendelian Inheritance in Man database⁴ for the current, comprehensive listing), these are laudable goals for which completion of the HGP represents a very significant hurdle to be cleared, but just the beginning of the race. Nor should anyone anticipate that it is all downhill from here. 

In reality, knowing the structure and function of genes and mutated counterparts has opened doors first and foremost to diagnostic testing, then only gradually--and sometimes not at all--to better treatments. Throughout these gradual developments, scientists and clinicians--and sometimes families of affected persons--have envisioned gene therapy as the ultimate prize and portrayed it as imminent. Nearly fifty years ago, we first elucidated the molecular defect in sickle cell anemia. Only very gradually did we come to know how the various globin genes are expressed and find ways to manipulate their regulation. Diagnostic tests became available, and society hastily initiated mandatory genetic testing and engaged in considerable discrimination of persons who were carriers of or affected with sickle cell anemia. Gradually, medical treatments were developed such that life expectancy rose for persons with sickle cell anemia to reach an average today in the late 20s. Parents at risk of having a child with sickle cell anemia still have limited choices. They may choose not to have children. They might use preimplantation genetic diagnosis following in vitro fertilization⁵ or CVS or amniocentesis followed by pregnancy termination to avoid having such a child. Or parents might take the one-in-four risk of having a child with sickle cell anemia, then take the very risky step and pursue a bone marrow transplant for their affected child--a procedure which is risky itself and may lead to further complications from graft-versus-host disease.⁶ Perhaps the slow pace of progress in developing better treatments for this disease can be attributed to the fact that, until recently, scientists have been stymied by having to experiment exclusively on humans with sickle cell anemia. Now scientists have created transgenic mice as the first animal models for sickle cell anemia.⁷ Will animal experimentation lead to faster development of better treatments? In the meantime, there still is no cure for sickle cell anemia.

For decades, scientists, clinicians, and parents of children with serious genetic conditions have envisioned a time when we could replace affected genes with unaffected ones--gene therapy. In 1991, two young girls underwent the first gene therapy for ADA deficiency. Both girls have not just survived but thrived, though they have needed several courses of gene therapy intervention and remain on an alternative treatment as a safeguard. Since then, gene therapy has been attempted in several hundred research protocols, mostly involving cancer treatments. Most unfortunately, the recent deaths of two patients during the course of gene therapy experimentation has been a chilling warning call. In a myopic focus on achieving the goal of successful gene therapy, some researchers apparently have recruited research subjects with inadequate informed consent and many have neglected to report suspected instances of adverse reactions. At the same time, French researchers have revealed what appears to be the first successful somatic cell gene therapy in two infants to cure the otherwise lethal condition of X-linked severe combined immune deficiency.⁸

We've learned some valuable lessons over the past several decades. We are much more reticent to rush to mandatory genetic screening than before, and discrimination is appreciably less overt. But there are valuable lessons still to be learned. When is diagnostic testing for a genetic condition appropriate? How can we eliminate genetic discrimination in employment and insurance? Is it hype or hope to foresee better treatments or a cure for sickle cell anemia and other genetic conditions in the near future? In the absence of effective treatments and cures, how can we best care for persons with genetic conditions?

Among the most beneficial aspects of the HGP will be (1) aiding persons affected by significant genetic conditions to flourish, (2) enabling medicine to profile drug therapies specifically for patients based upon their genetic makeup, and (3) providing information for biotechnology to produce safer and perhaps more economical medicinal products. Too often, these goals are overshadowed in the popular media by science fiction accounts of designing people through enhancement genetic engineering or cloning. People seem enamored with the idea of altering physical attributes such as height, intelligence, and a longer life span (some even suggest immortality). There is a smattering of evidence from animals that some genetic alterations can affect these traits. Many others are drawn to finding the genetic basis for behaviors such as sexual orientation and practice, infidelity, and criminal behaviors, usually to justify diminished human responsibility and free will. The HGP may gradually shed some light on these complex issues, but we should be cautious about premature speculation. It is highly unlikely that these endeavors will become prominent outgrowths of the HGP in the foreseeable future.

As the formal HGP winds to an end, its many implications may very well be just beginning. First, as more and more genomes are sequenced, the molecular data will provide considerable evidence on the genetic similarities and dissimilarities between humans, other primates, and all living things. Will it clarify issues of evolutionary lineage and human origins? Second, the ethical, legal, social implications of the HGP will continue. Will it change how we view and value ourselves as persons? Can we maintain our individuality and privacy, avoid genetic discrimination, and value diversity? Will we care for persons for whom treatments and cures are still elusive? Can we work to assure the benefits of the HGP are accessible to everyone? These are exciting times to be a scientist and a Christian. The challenges and opportunities are immense. The end of the HGP is just the beginning.

©

¹ http://www.nhgri.nih.gov/index.html 

² http://www.celera.com 

³F. R. Blattner, et al., "The Complete Genome Sequence of Escherichia coli K-12," Science 277 (1997): 1453-74.

⁴ http://www3.omim.ncbi.nlm.nih.gov/omim/ 

⁵Xu Kangpu, et al., "First Unaffected Pregnancy Using preimplantation Genetic Diagnosis for Sickle Cell Anemia," Journal of the American Medical Association 281.18 (1999): 1701-6.

⁶Eric Kodish, et al., "Bone Marrow Transplantation for Sickle Cell Disease: A Study of Parents' Decisions," New England Journal of Medicine 325.19 (1991): 1349-53.

⁷C. Paszty, et al., "Transgenic Knockout Mice with Exclusively Human Sickle Hemoglobin and Sickle Cell Disease," Science 278 (1997): 876-8; and T. M. Ryan, et al., "Knockout-Transgenic Mouse Model of Sickle Cell Disease," Science 278 (1997): 873-6.

⁸M. Cavazzana-Calvo, et al., "Gene Therapy of Human Severe Combined Immunodeficiency (SCID)-X1 Disease," Science 288 (2000): 669-72.