GENETICS, GENOMICS, AND MEDICINE | Kickoff

GENETICS, GENOMICS, AND MEDICINE

12 May

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.

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