by Jaron Terry, APR
P4 Medicine is rooted in our growing knowledge about the human genome and each individual's health risk and response to both knowledge and therapy. We are entering a time when we will have a greater understanding of our bodies and what makes them tick, say P4 Medicine advocates, but will we take ownership of this knowledge and steer clear of disease when we can?
P4 Medicine, described on page 12 as preventive, predictive, personalized and participatory, is based on emerging scientific knowledge across a host of factors – genetics and epigenetics; the four dimensions of health as they relate to resilience and wellness; and systems medicine – that all come together to create an orderly and precise, yet broad-based and holistic approach to health and disease.
DNA as Destiny?
In the 150 years since Charles Darwin's On the Origin of Species was published, it has been understood that it takes millions of years of natural selection for evolutionary changes to manifest in the phenotype (appearance) of humans. That is, one's genes remain relatively static over time and are responsible for each person's characteristics: redhead or blond, short or tall, prone to certain heritable diseases or destined for long life, etc.
In less than a dozen years since the completion of the Human Genome Project (HGP), which created a "map" of the more than 25,000 genes that make up the genome of humans, our understanding of genetic roots of heritable diseases has exploded.
Today, medical scientists estimate that about 10 percent of all cancer cases are hereditary. For example, the most common hereditary colorectal (and uterine) cancer syndrome identified since the completion of the HGP, is Lynch syndrome (LS), caused by an inherited mutation in one of four genes responsible for the repair of DNA. Studies by Albert de la Chapelle, MD, PhD, holder of the Leonard J. Immke Jr. and Charlotte L. Immke Chair in Cancer Research, and his colleagues at Ohio State's Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute have increased the world's understanding of Lynch syndrome and tests that can be used in at-risk families to identify it.
Heather Hampel, MS, CGC, a certified genetic counselor at Ohio State, likens heritable disease to people having a spelling mistake in their DNA. She explains that our DNA code includes the instructions for making proteins that our bodies need to develop and function properly. If there is a mistake – or misspelling – in one of the genes, it is unable to make certain proteins that are responsible for allowing it to do its job, such as DNA repair or tumor suppression.
Ohio State, which has one the largest teams of genetic counselors in the nation, was the first institution in the world to routinely perform genetic testing on all newly diagnosed colon cancers, finding that LS is responsible for approximately one in 35 cases of colon cancer.
"By providing genetic information to patients, their family members are armed with knowledge that allows them to make lifestyle changes and take other preventive measures or opt for additional screenings that may prevent the disease or allow it to be diagnosed at an early, curable stage," Hampel notes.
Good Choices Equal Good Health?
If the nature part of the equation is locked in our DNA, then the nurture aspect, according to the new science of epigenetics, is somewhat under personal control.
"Epigenetics puts an additional layer on top of DNA," says David Galas, PhD, former head of the U.S. Department of Energy's leadership of the Human Genome Project. The prefix "epi" is Latin for "above." Environmental, behavioral and other factors cause epigenetic "marks" on top of the cellular material that tell genes to turn off or on. Such marks are caused by biochemical modifications, the most understood form being a chemical mechanism called methylation.
"Methylation does not change or cause mutations to the DNA, but provides instruction for how the DNA is expressed. It is part of the regulatory pattern and is one of the major forms of epigenetic change," says Galas, who today is a scientist at the Institute for Systems Biology in Seattle, with which Ohio State has a strong working relationship.
Basically, epigenetics enables cells to respond quickly – in either a good or bad way – to environmental and behavioral changes. Such cellular responses – activation or inactivation of a tumor-suppressor gene, for example – may be influenced by people's life choices or those of their parents.
In 2008, the National Institutes of Health (NIH) earmarked $190 million for epigenetics research over the subsequent five years. It is hoped that gaining fundamental knowledge will greatly advance the practice of preventive medicine by adding another facet to predictive genomics and biomarkers (molecular, behavioral and environmental).
Leroy Hood, MD, PhD, who, along with The Ohio State University, co-founded the P4 Medicine Institute, played an important role in the Human Genome Project. He predicts that one day tools will be developed to analyze the genome in actual time and that individual genomic profiles will become a standard part of each person's medical record.
Dimensions of Wellness
Of the four Ps of P4 Medicine, "Participatory" calls on individuals to make better choices to promote wellness and avoid illness. Engaged consumers who take ownership of their health while working with medical providers to actively plan, manage and achieve health goals should understand the four dimensions of health as a measure for wellness:
- The Behavior dimension encompasses optimism, faith and spirituality, empathy and relationships, including family and social networks.
- Environment includes choices about diet and nutrition, sleep and biorhythms, geographic location, employment or workplace issues and culture.
- Genetic calls for gaining knowledge about family health history, undergoing pharmacogenomic and other types of genetic tests and full gene sequencing, to identify and understand DNA sequences, SNPs (Single Nucleotide Polymorphisms), and the ways epigenetics can influence health.
- The Physical dimension accounts for attributes such as the autonomic nervous system, biometrics, core strengths, balance and endurance, biomarkers and cognitive functioning.
The World Health Organization defines health as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." According to Marsh, health may simply be the opposite of aging, which brings a loss of resiliency in our body systems.
Patients who make good choices in all four dimensions of health will have the opportunity to experience a higher level of wellness and well-being.
For example, according to Ohio State High-Risk Family Heart Clinic genetic counselor Amy Sturm, MS, CGC, coronary artery disease (CAD), which affects one in two people in the United States and is the nation's leading cause of death for both men and women, is an extremely complex disease that is known to have a genetic component, as well as multiple environmental and behavioral factors.
"We know that epigenetics plays a role in CAD, because we can see differences between persons in the same family who smoke compared to those who do not," Sturm explains. "While two individuals may have the same genetic – or familial – risk to develop CAD, there are huge differences in how the disease affects persons depending on individual diet, how much exercise they get and, of course, if they smoke."
Ohio State's High-Risk Family Heart Clinic is one of the few clinics in the country where patients undergo multidisciplinary evaluations by both a cardiovascular genetic counselor and a cardiologist and have workups, including emerging risk-factor testing, and, in some cases, genetic testing and novel cardiac imaging. They are also counseled regarding their behavioral and environmental choices.
Ohio State is also a research collaborator in the Coriell Personalized Medicine Collaborative, a national study that is gathering genetic data from 1,800 patients who have been diagnosed with congestive heart failure or hypertension. This data will be collected along with electronic medical record data tracking each patient's care and outcomes. Results of the study will ultimately inform cardiologists and primary care physicians on the best ways to use personalized genetic-risk information to make clinical care decisions. Patient behavior is also being monitored throughout the study to determine the impact of environment and lifestyle choices on long-term health and recovery.
"The value of personalized medicine to patients will quickly reveal itself in this study," says Michael Christman, PhD, president and CEO of Coriell. He explains that one of the genetic variants being tested is a naturally occurring variation in patient response to a certain heart disease drug (Plavix) that renders it useless in 30 percent of all patients.
"Genetics directly affects the efficacy of this and other drugs – a simple blood test will inform a patient's cardiologist whether this drug will work or if an alternative should be prescribed," notes William Abraham, MD, FACP, FACC, director of Ohio State's Division of Cardiovascular Medicine and deputy director of the Dorothy M. Davis Heart and Lung Research Institute and holder of the Chair of Excellence in Cardiovascular Medicine.
The study will also determine if the impact of genetic counseling on patient behaviors makes a difference in disease outcome.
"We have families with huge pedigrees for genetic predisposition to CAD, but if individuals take a more positive approach to their life – making good behavioral and environmental choices – it can make a significant difference,"
A growing body of evidence is also showing that individuals who have a greater capacity for resilience – the ability to adapt and compromise, to make changes for their own and others' good – derive more health benefits than those who do not.
A Systematic Approach
"It is more difficult to reverse the disease process once it is well established than to prevent its development," says Ralph Snyderman, MD, chancellor emeritus and James B. Duke Professor of Medicine at Duke University, in explaining that the current approach to medical care begins with disease treatment as the focal point.
"As our understanding of disease progression broadens, it becomes clear that with better predictive tools, we will have the opportunity for a 180-degree flip in how medicine is practiced," adds Snyderman, who founded Proventys Inc., a healthcare technology company that develops risk assessment and clinical decision-support tools for personalized medicine.
He explains that, rather than trying to reverse damage, healthcare providers can use personalized health planning to anticipate an individual's disease risks and establish the means to prevent diseases from occurring. Snyderman envisions an approach to care that is focused on patients, their inherited disease risks, and the environmental factors that lead to disease prevention or progression. He envisions aligning the patient's personalized health plan with the various components of the healthcare system (hospitals, physicians, insurers, governmental agencies, etc.) to interact in a coordinated fashion to deliver effective personalized health care. By using a wide range of predictive tools and planning to mitigate disease risks, the practice of medicine, from a systems perspective, should be directed to enhancing health and well-being, limiting the damage of disease and preventing it in the first place.
For example, Timothy Hewett, PhD, FACSM, professor and director of research for OSU Sports Medicine, is studying the genetic aspects of anterior cruciate ligament (ACL) injuries with the hope of preventing many of them.
"Somewhere between 100,000 and 300,000 ACL ruptures occur in the United States every year, with women at five-times greater risk for this serious knee problem," says Hewett, whose research ranges from the molecular alteration of muscle and nerve interaction to injury prevention and athletic development.
In a first-of-its-kind study, Hewett and his associates are genotyping a family, beginning with twin 30-year-old sisters who have both experienced ACL injuries, as have multiple family members of prior generations.
"Although we're not sure at this point whether the benefit of the ACL Genetic Study will be in actually preventing the injury, counseling patients identified to be at genetic risk of injury, or in preventing the debilitating osteoarthritis that manifests one or two decades post-injury, we know that – as in the definitive Lynch syndrome studies – we have to start somewhere," Hewitt adds.
- P4 Medicine is based on growing scientific knowledge in the fields of human genetics and epigenetics, resilience, wellness and systems biology.
- Soon the technology will be available to analyze an individual's genome inexpensively in actual time. Genetic information will become a standard part of each person's medical record and lifetime health plan.show great promise in treating chronic disabilities ranging from movement disorders, epilepsy, stroke, headache and pain to psychiatric disorders.
- Detailed genetic information will allow individuals, under the advisement of their health professionals, to make lifestyle changes and take other preventive measures that prevent disease or allow it to be diagnosed at an early, curable stage.
- 2012 marks the fourth year of a five-year $190-million National Institutes of Health initiative in epigenetics research. It is designed to advance preventive medicine practices by identifying how molecular, behavioral and environmental factors influence genomics and interact with biomarkers.
From Left: William Abraham, MD; David Galas, PhD; Heather Hampel, MS; Timothy Hewett, PhD; Amy Sturm, MS