19 October 2005

Fourth Annual Medical Student Research Symposium
Pharmacogenomics:
Scientific and Ethical Issues
for a Brave New World

Paul A. Insel, M.D., Departments of Pharmacology and Medicine,
University of California, San Diego, La Jolla CA

In this keynote address for the annual Medical Student Research Symposium, researcher Paul Insel discusses the burgeoning field of pharmacogenomics, how developments in this area will change medicine, and how new research applications will raise social and ethical questions.

The Human Genome Project (HGP) provided new insights on human life’s genetic blueprint, but sequenced DNA of a limited number of subjects, ignoring substantial inter-individual genetic variation, most commonly single nucleotide polymorphisms and base changes in DNA either “silent” or producing changes in encoded amino acids and proteins.

The genome project revealed G-protein-coupled receptors (GPCR), found on cell surface membranes, are the largest family of receptors mediating signaling from the outside to the inside of cells. As regulators of external (sensory) and internal (hormone, neurotransmitter) environments, GPCR modulate cell, tissue and organismal function. Much is now understood about GPCR actions and how information transfer from outside to inside cells is accomplished. Indeed, drugs activating or blocking GPCR represent the largest group of pharmacological agents currently in clinical use.

Components involved in GPCR actions show substantial genetic variation in humans, including single nucleotide polymorphisms and other changes occurring in gene-coding sequences and at sites influencing gene and protein expression. Genetic variants in the GPCR pathway can alter, among other things, aspects of biochemistry, physiology, and pharmacological responses to drugs acting on GPCR. Such results point to the prospect of “personalized medicine,” whereby disease identification and treatment will be determined in large part by individuals’ particular genetics – from genetic abnormalities in disease/drug targets to genetically derived differences in drug absorption, distribution, metabolism and action. This field is known as pharmacogenomics.

Individuals in different ethnic subpopulations differ in their frequency of genetic variation of GPCR and other genes. Those of African ancestry, who are genetically “older,” tend to have more frequent genetic variation, suggesting genetic change (“drift”) occurs secondary to exposure to environmental and infectious agents altering genes, minimizing those agents’ impact on health and survival, thus conferring “selective advantage.” Recent work by Dr. Insel and colleagues suggests differences in frequency of expression of genetic variants between men and women, implying an impact of sex hormones, or other factors. Given these ethnic- and, perhaps, gender- specific differences in frequency of genetic variation, Dr. Insel proposes that the biomedical community and society overall are on the threshold of a major revision in the way people, their physiology and disease susceptibility are classified for purposes of health maintenance, disease detection and prognosis. If we are to embark on truly personalized medicine, Dr. Insel believes we will need to use genetic markers to (re)classify human beings in terms of “normal” physiology, response to drugs and environmental stimuli, and individual propensity for disease and its progression.

Some interesting questions follow: Will genetic markers replace medical history as a way of determining family identity and ancestral relationships and, if so, might use of this approach have unintended societal consequences? Will genetic identity prove a useful predictor of inter-individual differences in disease susceptibility and prognosis and in drug response? In an era of personalized medicine, how can we ensure individuals’ “genetic passports” and the information they contain will be used to aid in understanding and improving human health, and not misused?

Suggested resources:

1. National network and website for pharmacogenomics: www.pharmgkb.org
2. Mayeux R. Mapping the New Frontier: Complex Genetic Disorders
[new series – R. Mayeux, ed].  J Clin Invest 115: 1404-1457, 2005.
3. Crawford DC, N ickerson DA. Definition and Clinical Importance of Haplotypes.  Annu Rev Med  56: 303-320, 2005.
4. Kirstein SL, Insel PA. Autonomic Nervous System Pharmacogenomics: a Progress Report.  Pharmacol Rev 56: 31-52, 2004.
5. Tate SK , Goldstein DB. Will Tomorrow’s Medicines Work for Everyone?  Nat Genet 36: S34-42, 2004.

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Paul A. Insel, M.D., attended George Washington University for two years, then went to medical school at the University of Michigan, where  he received his M.D. in 1968. After internship and residency in internal medicine on the Harvard Medical Service at Boston City Hospital, he  entered the U.S. Public Health Service at the NIH and also worked as an attending physician at Baltimore City Hospitals’ Endocrine Unit and at Johns Hopkins University. In 1974, h e began research training in pharmacology in the Department of Medicine and Cardiovascular Research Institute at the University of California, San Francisco. In 19 78, he moved to the University of California, San Diego, to  help develop the medical school's fledgling Division of Pharmacology. In his faculty career at UCSD, he has trained 37 post-docs and 14 visiting scientists, plus graduate, undergraduate and medical students. A professor of medicine and pharmacology at UCSD since 1987, he has directed the Medical Scientist Training Program, in which students earn both the M.D. and Ph.D. degrees, since 1989. Dr. Insel was the founding president of the National Organization of M.D.-Ph.D. Training Directors. In addition, he has served as chair of Step 1 of the USMLE national licensing examination for U.S. physicians. He is currently editor of the leading pharmacology journal, Molecular Pharmacology, and associate editor of The American Journal of Physiology – Cell Physiology.

Co-presented with the Office of the Associate Dean for Research