For diseases that are caused by defective genes rather than microbes or degenerative processes associated with aging, the healer of the future might have to be a genetic engineer rather than an immunologist. On June 26, 2000, leaders of the Human Genome Project announced the completion of working drafts of the complete human genome and their imminent publication in the British journal Nature and the American journal Science. Francis Collins, director of the National Human Genome Research Institute, predicted that that genomics would revolutionize diagnostics, preventive medicine, and therapeutics within decades. Genomics would, in particular, allow physicians to predict the disease patterns and drug reactions of individual patients. With the completion of the Human Genome Project, scientists immediately began to use the partial maps to locate, isolate, and clone speciﬁc dis- ease genes. This information can be used to improve diagnostic meth- ods, help prevent disease, design speciﬁc agents to treat patients, and, in some cases, might lead to gene therapy that could correct defective genes. Genetic data on hereditary forms of cancer have allowed individuals with particular oncogenes to undergo pre-emptive surgical removal of organs such as the stomach, breast, ovary, uterus, colon, and thyroid gland. Another product of the Human Genome Project is the development of forensic genomics. Originally thought of as a way to establish databases for identifying criminals, forensic DNA analysis can also help identify human remains even after signiﬁcant tissue decomposition, by sequencing mitochondrial DNA from hair, teeth, and bones.
Critics of the Human Genome Project warned of potential ethi-
cal, social, and legal problems associated with the ability to determine genetic information. To deal with potential problems, the National
Center for Human Genome Research promoted studies of the ethical, legal, and social implications (ELSI) of the genome project. Advocates of patients’ rights demanded the passage of laws that would safeguard genetic privacy. Such laws would prevent employers from using genetic information in making employment decisions and would prevent healthcare organizations and medical insurance plans from using genetic information when making enrollment decisions. In 1995, the Equal Employment Opportunity Commission published guidelines that extended the protections speciﬁed by the Americans with Disabilities Act to cover discrimination based on genetic information related to illness, disease, or other conditions. Proof that protection against discrimination based on genetic information was necessary was demon- strated in a landmark case in 2001, in which the U.S. Equal Employ- ment Opportunity Commission (EEOC) went to court to stop a company from testing its employees for genetic defects. In this unprecedented legal battle over medical privacy in the workplace, the EEOC argued that basing employment decisions on the results of genetic tests violated the Americans With Disabilities Act. Concerns about the potential abuse of genetic data led many states to ban the use of genetic screening for making employment-related decisions. Because genetic information could lead to new forms of discrimi- nation, many scientists and ethicists have supported the Universal Declaration of the Human Genome and Human Rights, which states that: ‘‘No one shall be subjected to discrimination based on genetic characteristics that is intended to infringe or has the effect of infring- ing human rights, fundamental freedoms and human dignity.’’
The Human Genome Project stimulated the rapid development of new disciplines, as well as a new vocabulary. With the com- pletion of the ﬁrst major phase of the Human Genome Project, scientists could directly confront the task of analyzing tens of thousands of human genes and their relationship to the hundreds of thousands of human pro- teins. In keeping with the new vocabulary spawned by the Human Genome Project, scientists suggested organizing a complete inventory of human proteins, which would be known as the Human Proteome Project (HUPO). The term proteome, which was coined in 1995, refers to the ‘‘set of PROTEins encoded by the genOME.’’ Because proteins are involved in disease states, complete descriptions of proteins, could stimulate rational drug design, as well as the discovery of new disease markers and therapeutic targets.
In 1990, the year that the Human Genome Project began in ear- nest, after many debates about safety and ethical issues, William French Anderson (1936–) and colleagues at the U.S. National Institute of Health won approval from the Recombinant DNA Advisory Commit- tee (RAC) to conduct the ﬁrst human gene therapy trial in the United States. Researchers were attempting to use genetic engineering to
correct a life-threatening inherited disease. The patient in this experi- ment was a four-year-old girl born with severe combined immunodeﬁ- ciency disease (SCID), a rare genetic disease of the immune system. Patients with SCID have a defect in the gene for adenosine deaminase (ADA), an enzyme that is necessary for the production of white blood cells in the bone marrow. Unable to ﬁght infections, children with SCID usually die long before reaching adulthood. A retrovirus was used as a vector to introduce copies of the gene for ADA into stem cells taken from the patient’s bone marrow. Modiﬁed stem cells were then infused into the patient where they developed into white blood cells that produced ADA for several months.
Despite the optimism generated by Anderson’s ﬁrst case, genetic
therapy remained very controversial and many critics argued that, given the potential dangers of genetic manipulation and the use of viruses as vectors, human trials were premature. In 1999, the death of 17-year-old Jesse Gelsinger during a gene therapy trial led to new debates about the safety of gene therapy. Gelsinger died of multiple organ failure four days after treatment for ornithine transcarbamylase (OTC) deﬁciency. (The enzyme OTC is needed to remove ammonia from the blood.) A preparation of modiﬁed adenovirus, which was being used as a vector to deliver the gene for OTC, had been infused into Gelsinger’s main liver artery. In response to investigations of Gelsinger’s death, the Food and Drug Administration stopped several gene therapy studies using adenovirus vectors. All gene therapy fell under intense scrutiny and had to comply with stricter standards. Nevertheless, in 2002, after reports of adverse affects among patients in otherwise promising gene therapy tests for hemophilia B and X-linked SCID, the Food and Drug Administration suspended about 30 gene therapy trials. Subsequent clinical trials were subjected to a higher level of regulatory oversight and stricter requirements that made clinical trials for all forms of gene therapy much more costly and difﬁcult.