Fast-Changing Field of Medical Genetics Embraces Personalized Medicine

By Jeffrey Norris on October 21, 2008
The promise of personalized medicine based on your unique set of genes is real. But much of what you can find out today about your risky genes is not information that can easily be used to lower health risks or to choose the best treatments. Physicians, scientists and entrepreneurs talked about this fast-moving field of personalized medicine Wednesday at the UCSF Foundation Wellness Lecture Series event, “Medical Genetics: Are We Ready to Get Personal with Diagnosis and Treatments?” The speakers for the event included Robert Nussbaum, MD, chief of medical genetics at UCSF; Steven Kayser, PharmD, professor of clinical pharmacy at UCSF; biotech entrepreneur Anne Wojcicki, co-founder of 23andMe; and Bradley Aouizerat, PhD, associate professor of physiological nursing at UCSF. The speakers pointed to several new genetic tests that already are available from clinical laboratories. Still, it will be years before the bulk of the benefits of personalized medicine will be delivered, they said. Genes are like a set of instructions for shaping our bodies and keeping us up and running. The genetic code varies slightly from person to person, resulting not only in obvious differences in appearances, but also in much deeper differences in how our bodies function. Variations in genes affect health risks. Just as different machines of differing design are prone to their own peculiar malfunctions, our genes influence the nature of the diseases that take root within us. Genes influence susceptibility to both common and rare diseases. But most of them have effects that are less dramatic and less certain than the causative roles single genes famously play in certain diseases, such as Huntington’s disease. “It used to be thought that genetics was only about rare diseases,” Nussbaum said. “If you carried a ‘bad’ gene, you were going to get a bad disease. But that’s the case in only a few situations.” But making use of new information on genetic variants that act more subtly to elevate risks is proving difficult. “When you’re sitting in a doctor’s office, do you really want to know, ‘Is my chance for disease one and a half times greater than it is for everyone else in the waiting room?’ No, you want to know, ‘What’s going to happen to me?’ That’s not a relative risk; it’s an absolute risk. For the vast majority of genetic variants that have been studied up until now, the absolute risk is low, and the predictive value also is quite low,” Nussbaum said. In other words, if you have a gene known to elevate your risk of diabetes, you may or may not get diabetes, and if you don’t have the gene, you may or may not get diabetes. Researchers are now “teasing out the complexity,” Nussbaum said, in studies of diseases in which many genes appear to influence disease risk, but not very dramatically. Thanks to ongoing progress in mapping genes and their functions – building on the solid foundation of data established through the federally funded Human Genome Project – researchers also are discovering more about how genetic differences affect how people vary in their susceptibility to diseases. In the process, scientists are learning more about mechanisms of disease and potential treatment targets. While some scientists are acquiring countless megabytes of data – to help link genes and their variations on one hand, and to help link them to disease mechanisms and disease risk on the other – some researchers also are working to determine which information actually can be useful today in the clinic. Pharmacogenomics Genes can affect how we respond to drugs – both to existing drugs and to drugs yet to be developed. Good physicians use this information as they try to find the best treatments tailored to each individual. Speakers agreed that the first applications of personalized medicine will be in pharmacogenomics, in which knowledge of a patient’s genes is used in choosing medical treatment for that patient. In fact, some pharmacogenomics tests already are in use. Many genes now are known to affect how the body metabolizes certain drugs. More important for pharmacogenomics, variations in some of these genes are known to cause individuals to differ in their responses to treatment. “Adverse drug reactions can lead to as many as 100,000 deaths per year,” Kayser said. “Despite the fact that this figure is somewhat controversial and subject to debate, it is true that over the last 21 years, 28 drugs in the United States have been removed from the market due to some serious side effect.” The presence of different genes in different patients may influence the metabolism of up to 60 percent of the most common drugs associated with adverse drug reactions, according to Kayser. More effective drug choices and dosing can be achieved with what already is known, Kayser said. He noted that drug treatments for which individual testing could be done – or is already being done – include common drugs for pain treatment, statins for heart disease, selective serotonin reuptake inhibitors used to treat depression, the blood anticoagulant warfarin and 6-mercaptopurine, a drug used to treat childhood leukemia. In addition to helping individuals avoid bad reactions, research on genetic variations in disease and drug responses may lead to better targeting of existing drugs to patients who are most likely to benefit, and may also lead to the development of new drugs that help a subset of people with a particular disease, Kayser said. “The recognition of genetic variants in our makeup may not only help us predict the likelihood of an adverse event, but may also help us to identify populations of patients who will respond more effectively and safely to medication,” according to Kayser. Private Initiative Wojcicki described the goals of 23andMe, a company she co-founded. For a fee – recently lowered to $399 – individuals willing to provide DNA from saliva can receive an analysis of how their genetic fingerprints affect their risks for more than 90 diseases. The company also can offer individuals and families insight into their genetic ancestry. “It’s a fun, new way of looking at a family tree,” Wojcicki said. Individuals can access their own personal genetic data for reference at any time, and receive updates about disease risks. But Wojcicki believes that 23andMe also has an important role to play in speeding the discoveries needed to better understand, prevent and treat diseases. The genetic and other data collected from individuals who sign up for the service can be stripped of personal identifiers and offered to researchers. This is a significant and ever-growing source of useful data. The company also offers social networking through its website, which may make it easier for motivated individuals with particular diseases or genetically determined disease risks to band together to help drive more research and patient participation in research. “The research mission is really the long-term potential of 23andMe,” Wojcicki said. Who Will Interpret Genetic Information for Patients? Aouizerat pointed to educational issues associated with the phenomenon of increasing amounts of genetic information quickly becoming available to individuals outside of doctors’ offices. Traditionally, people have learned about disease risks associated with genetic variants or abnormalities from doctors or genetic counselors associated with medical practice. The genetic variations discussed with patients have traditionally been those that have already resulted in a serious disease affecting the patient or the patient’s family, or that have a high likelihood of doing so. But the increasing availability of information about genetic variations and risks complicates the picture for educating patients. “It’s safe to say genetic information has arrived, and it is in the public domain,” Aouizerat said. “The number of individuals actually trained to communicate about the implications of genetic information is relatively small right now, and is a bottleneck preventing optimal use of this information.” Aouizerat suggests that the frequent interactions of nurses with patients, especially those with chronic conditions, will enable well-trained nurses to explain genetic testing, test results, and associated disease and treatment risks. “I would argue that nurses will be the front line, at least in the foreseeable future, in interpreting the majority of genetic information that individuals obtain,” Aouizerat said. During his presentation, Aouizerat also described his recent, unpublished research on genetic factors that may influence susceptibility to fatigue among people with cancer and other conditions.