Scientific, Ethical Questions Temper Pharmacogenetics

The field of pharmacogenetics, the study of inherited differences that influence a person's response to drugs, rivals bioinformatics in claims about how it will revolutionize pharmaceutical research. To be sure, pharmacogenetics and its allied discipline, pharmacogenomics (the use of tools such as microarrays and proteomics to study drug response) has opened a wealth of research questions and job opportunities. But scientists are still working to untangle the ethical and research complications that delay the development of new medications. The area has "a lot of sizzle," says John Mellors, a professor of medicine at the University of Pittsburgh and director of its HIV-AIDS program. "[Pharmacogenetics] is a buzzword, but it's an inordinately complex biological problem." Behind the hype of the new study area lies hope, and plenty of money for researchers. The growth in pharmacogenetics departments at biotech and pharmaceutical firms and in public financing through the National Institutes of Health Pharmacogenetics Research Network means new jobs and new opportunities to influence the course of biomedicine. Nevertheless, the complexity of drug development relates to the difficult study of responses to treatment, which involves differences in effectiveness, resistance, side effects, and drug metabolism. Single genes do not determine most of the effects of medications and not all responses have inherited roots. What's more, amassing databases of human genetic profiles creates enormous ethical and privacy problems. The genetic revolution in pharmaceuticals may be on the horizon, but science remains in the murky predawn. "It has a lot of potential, but so did nuclear energy," says Mellors. "It's a great area, but to think we'll be able to tell a person's individual response to an aspirin tablet or a new drug in the next few years, forget it. [The advances] will be incremental." Fulfillment and Limitations Despite some of these caveats, many researchers predict that scientists will develop drugs that better fit a person's genetic make-up, and they urge others to take on the risks of the research, because the benefits may eventually outweigh the complications. "I'm sure there will be a few early successes," says David Altshuler, an assistant professor of genetics at Harvard Medical School and director of medical and population genetics at the Whitehead Center for Genome Research in Cambridge, Mass. "But the true impact won't be until we can look over the whole genome and for those cases in which genes will be the answer." Altshuler sees three hurdles preventing the rapid development of custom medications. Some drug responses are caused by environmental factors such as age or diet, and teasing out this nature-versus-nurture difference may prove difficult. Also, no research group has yet pioneered technology to perform genomewide searches to look at every SNP--genetic markers called single nucleotide polymorphisms--that may be involved in a certain drug response. Finally, to obtain robust, reproducible results in pharmacogenetic association studies--comparing the frequency of SNPs in drug responders to that of drug nonresponders--scientists need to include thousands in their trials. However, most drug trials don't attract that many people. Altshuler, whose research centers on SNPs and predisposition to diabetes, also consults with biotech and pharmaceutical firms on pharmacogenetics research, and such relationships between academia and commerce are expected to flourish as the research evolves. Courtesy of St. Jude Children's Research Hospital William Evans (left); Mary Relling (right) After almost two decades of research, one example of an early pharmacogenetic success story comes from the labs of William Evans, chairman of the department of pharmaceutical sciences at St. Jude Children's Research Hospital in Memphis, and Mary Relling, an associate member in the same department. Their work, which began in the mid-1980s, focuses on pediatric leukemia and the interaction of genetics and drug dosing. One in 300 children are born with no activity for the enzyme thiopurine methyltransferase, which is important for metabolizing a drug called methotrexate. Ten percent are born without full activity for the enzyme. These children develop more severe toxicity in their bone marrow, which precludes physicians not only from giving leukemia drugs but also from administering other chemotherapy. "The kind of dosage needed in these rare patients is 5 percent of the standard dose, something you would never do empirically," says Evans. Relling and Evans discovered the mutations that cause toxicity, and with commercial tests for the mutations now available at reference labs in Europe and the United States, physicians can now easily determine which children with leukemia must take adjusted dosages. Understanding how certain disease organisms such as HIV become resistant to drugs is another application of pharmacogenetics. Nonetheless, understanding disease strains and resistance still helps physicians choose the best treatment.1 "I don't know where the field is going as far as cancer or drug metabolism, but in terms of resistance testing, it's probably the most advanced of any subfield," Evans says. (See also, "Personal Prescribing," page 10.) Along with Victor DeGruttola from the Harvard School of Public Health, Mellors is trying to improve the methods investigators use to predict the phenotype of the virus from the genotype of two small viral genes. Specifically, the researchers want to understand the genes' susceptibility to different AIDS drugs. Tibotec-Virco Group NV of Mechelen, Belgium, recently developed the database of HIV genotypes and has commercialized and automated the process for pinpointing a patient's viral phenotype. Ethical Issues Keeping individualized, detailed genetic data private is one of the most talked-about concerns that is part and parcel with the promise of tailor-made drugs. Privacy protection also carries implications for pharmacogenetics clinical trials. "The sticky issues involved are not only for individuals in terms of insurability, but also in terms of groups because a central aspect of pharmacogenetics is that there's huge interethnic variability in the frequency of mutations involved in the enzymes associated with handling medications," says Relling. "So there's a lot of sensitivity to avoid stigmatizing certain ethnic groups either positively or negatively." Relling sits on the ethics board of the Pharmacogenetics Research Network, a group of scientists funded by six NIH institutes, including the National Institute of General Medical Sciences (NIGMS). Rochelle Long, chief of the pharmacological and physiological sciences branch at NIGMS, says careful thought must go into developing pharmacogenetic tests to allay concerns regarding stigmatization and bring knowledge to those who need it. "We are very aware that any research into people's genetic backgrounds has the potential to be stigmatizing and so those of us in the field want to be proactive and consider people's concerns and perceptions." To this end, the Pharmacogenetics Research Network has put together a population advisory group to recommend how to ethically study the genomics of different racial or ethnic groups. According to Mellors, privacy issues are moot in HIV resistance tests, because the virus genotypes databases include no personal identifiers so genotypes can't be traced back to any individual. An Economic Argument Along with government activities, the private sector is also gearing up to do more pharmacogenetics research. Many big pharmaceutical companies and smaller genomics firms are sinking resources into new pharmacogenomics departments. "My experience is that just about every big pharma [company] has a group now that's called pharmacogenomics or genetics," says Evans. Still, he adds, "When pharmacogenetics came along, [drug companies] couldn't figure out if it was friend or foe. They see it as an avenue of potential drug discovery, but in view of marketing and prescribing, they're still trying to sort it out." Many scientists claim that pharmacogenetics has the potential to revolutionize the way that drugs are prescribed. In the future, writing a prescription for hypertension, for example, may be based on a patient's genetic ability to metabolize and absorb certain drugs better than others may do so. The real economic benefit of pharmacogenetics, according to Altshuler, won't be from selling diagnostic tests or from tailoring treatments, but from using genetics to help understand which people might benefit from a specific drug. Most drugs fail during clinical trials because of inadequate efficacy or toxic side effects, and the money spent on these failures adds to the costs of the products that finally make it to the pharmacy shelf. Medications found toxic to some patients and helpful to others during clinical trials could be resurrected using genetics to identify patients who can benefit from them. Armed with this knowledge, physicians could then administer the drug only to those known to benefit. Genetic knowledge can also enable clinicians to adjust dosages, as Evans and Relling have demonstrated with the tailoring of pediatric leukemia patients' medication. While researchers and others may be quick to boast about the potential profit in genetically tailored treatments, many also reflect on the accompanying responsibility. "There should be investment" in pharmacogenetics, Altshuler says, "but the public should know that the promise won't happen right away. We shouldn't promise more than we can deliver." Karen Young Kreeger (kykreeger@aol.com) is a contributing editor for The Scientist. 1.N.S. Halim, "An early pharmacogenomics application," The Scientist, 14[17]:20, Sept. 4, 2000. Opportunities in Pharmacogenetics Researchers caution against overhyping the public promise of pharmacogenetics, but they are quick to add that career opportunities continue to flourish in the field for basic and applied investigators.1 Many small genomics companies as well as large pharmaceutical firms are assembling departments in pharmacogenomics or pharmacogenetics. "Careerwise, it's a great time to be coming in," says William Evans, chairman of the department of pharmaceutical sciences at St. Jude Children's Research Hospital in Memphis. The optimal training background couples molecular biology with experience in clinical trial design. A few years ago, the federal government also started pumping money into pharmacogenetics. Rochelle Long, program director and chief of the pharmacological and physiological sciences branch at the National Institute of General Medical Sciences (NIGMS), works with the Pharmacogenetics Research Network (www.nigms.nih.gov/pharmacogenetics), a group of scientists funded by six National Institutes of Health groups, including NIGMS. The agency has granted nine awards totaling $12.8 million so far, with one ethics study given to a lawyer. Long expects that another four or five grants will be awarded this summer. Although the field of pharmacogenetics is immensely complex, Long points out that "there are lots of exciting research opportunities for those who want to think about pathways outside of the basic single-gene box, with plenty of room for collaborations across disciplines." --Karen Young Kreeger 1.J. Kling, "Opportunities abound in pharmacogenomics," The Scientist, 13[10]:16 May 10, 1999.

Scientific, Ethical Questions Temper Pharmacogenetics

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