Week 2: Genomics and P4 Medicine

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Week 2: Learning goals and objectives

In Week 2, you will be learning about the…

  • Key elements of “P4 medicine” and why it is considered to constitute a “Paradigm Shift” in healthcare.
  • Reason(s) why health care practitioners will need to be prepared to work in the Era of genomic medicine.
  • Ethical, policy and social issues inherent in P4 medicine, and emerging solutions.
  • “Systems Biology” and what it means for the responsible practice of personal and public health.
  • Argument(s) in support of a “Global Justice” framework for genomic science in the future.
  • Why a “realistic assessment” of the prospects for systems biology is “sorely needed.”

Your objectives are to…

  • Define P4 medicine and give examples of how it its various elements might/might not deliver better health to all than the present model of  U.S. health care.
  • Define what is meant by “Systems Biology” and why it is touted as being the only way to understand the roots of disease and provide solutions to global health problems.
  • List three (among many) ethical, policy, and social issues which must to be addressed before P4 medicine can deliver on its promises.
  • Offer arguments for and against a “Global Justice” model for the global application of genomics-based health care.

Thomas Kuhn, the author of “The Structure of Scientific Revolutions,” makes the point that most scientists are extremely conservative and reluctant to accept reformulations of the current dogmas that lead to paradigm changes; a failure of our educational system is that we do not teach most scientists how to think outside the box. Creating paradigm changes is exciting and often appreciated only in retrospect.

Leroy Hood, Director, Institute of Systems Biology

As we learned in Week 1, “The Genome Era” has great potential for improving the health of the public especially with regard to the spectrum of ethical and policy issues which are raised by its application in a number of different settings.

 

Leroy Hood receives Presidential Medal of Science

Leroy Hood receives Presidential Medal of Science

P4 medicine (“Predictive,” “Preventive,” “Personalized,” and “Participatory”) is a plan to radically improve the quality of human life via biotechnology. The term, “P4 medicine,” was coined by biologist Leroy Hood, one of the world’s leading scientists, a key player in the Human Genome Project, and the inventor of four pioneering instruments in molecular biology: the automated DNA sequencer and synthesizer, and the protein synthesizer and sequencer.

The premise of P4 Medicine is that, over the next 20 years, or so, medical practice will be revolutionized by biotechnology, to manage a person’s health, instead of manage a patient’s disease. Today’s medicine is reactive: we wait until someone is sick before administering treatment.

Medicine of the future will be predictive and preventive, examining the unique biology of an individual to assess their probability of developing various diseases and then designing appropriate treatments, even before the onset of a disease. Today’s medicine is myopic: we use only a few measurements to diagnose disease and are generally unable to make fine distinctions between individuals or between subtle variations of the same disease. Medicine of the future will use more sophisticated measurements, as well as more measurements overall, thereby yielding accurate health assessments for truly personalized treatments.

Prediction

SystemsBiologyThe technologies and tools of “Systems Biology” (a biology-based, holistic, inter-disciplinary study field that focuses on complex interactions in biological systems) will provide medical practitioners with two exciting sources of health-related diagnostic data: By examining an individual´s complete genetic makeup, a physician will be able to generate comprehensive predictions about the patient´s health prospects. And by examining protein markers which naturally occur in an individual´s blood, a physician will be able to accurately determine a person’s health status, including both the current effects of any abnormal genes and the current reactions to any environmental toxins or infectious pathogens.

Prevention

“Systems analyses” also provides insight into the dynamics of disease-perturbed networks of cells. A new “network-centric” rather than a “gene-centric” approach to choosing drug targets will employ multiple drugs to “re-engineer” a disease-perturbed network to make it behave in a more normal manner. This could make drugs more effective—not to mention far less expensive—because now there is a rationale for the choice of drug targets and their ultimate likelihood of preventing disease, in general.

Personalization

On average, each human differs from another by less than one percent of their genetic makeup. But these genetic differences give rise to our physical differences, including our potential predisposition to various diseases. So the ability to examine each individual’s unique genetic makeup and thereby customize our approaches to medical treatment is at the heart of this new era of predictive, preventive and personalized medicine.

The aim of this aspect of P4 medicine is to detect disease at an earlier stage, when it is easier and less expensive to treat effectively or, prevent altogether. Based on an individual’s genetic makeup, the probability of an individual contracting certain diseases can be determined, as well as reveal how an individual may respond to various treatments, thereby providing guidance for developing customized therapeutic drugs.

In his 2015 State of the Union address, President Obama unveiled the creation of the “Precision Medicine Initiative,” (PMI), a bold new research effort to revolutionize how we improve health and treat disease.  The potential for precision medicine to improve care and speed the development of new treatments has only just begun to be tapped. Translating initial successes to a larger scale will require a coordinated and sustained national effort—not to mention enhanced “genomic literacy” of caregivers and patients, alike. (See: Personalized Medicine Initiative)

As a result of this personalization, medicine of the future will become –

Participatory

The primary notion here is that educated and engaged patients can and will play a major role in advancing the concept of “personalized medicine.” Patients will actively participate in personal choices about illness and well–being. Participatory medicine will also require the development of powerful new approaches for securely handling enormous amounts of personal information and for educating both patients and their physicians in order to transform the way healthcare is delivered.  Indeed, the Lee Hood “vision” of the future is a world in which everyone knows the power of their own genome!

Achieving the goal(s) of P4 medicine will be technologically daunting, particularly considering that it is now known that the complexity of humans lay somewhere in the “deserts” between our 20,000, or so, disease-potential genes, earlier thought to be “junk DNA.”  The multi-year research effort to undertake this daunting assignment has been labeled “The ENCODE Project.”

Encode is a long-term project committed to unpack and interpret the “hard wiring of 98.5% of the human genome not involved in protein synthesis, the “Introns,” the “desert” which lies between the 1.5% (20-25,000 genes) of our genome with the capability of synthesizing the protein building blocks which make us human.

Genes, as it turns out, are surrounded by vast stretches of code, some of which control when, where and how genes turn on and off.  In part thanks to ENCODE, doctors today can assess the impact of small variations in a person’s genome on several diseases, and tailor their treatment accordingly.

In the years since ENCODE began its work in 2003 – and $185 million later – some sort of function has been assigned to approximately 80 percent of the human genome, including the identification of thousands of  “promoter” regions–the sites just upstream of genes where proteins bind to control gene expression–and hundreds of thousands of “enhancer” regions that regulate the expression of distant genes.

ENCODE has further identified thousands of points on the genome where a single-letter (single-molecule) difference in the code contributes to a genetic disease, with 90 percent of them falling outside of genes.

ENCODE continues to expand its reach into cross-species comparisons of genome regulation. A series of papers in 2014 provide data to support even further comparative analyses.

Together, the projects have now added more than 1,600 data sets, bringing the total number of available data sets to 3,300. (See: Expanding ENCODE)

These mechanisms for genetic fine-tuning may explain why humans are so complex, despite having fewer genes than grapes.

So, if anyone wants to get specific information about the molecular machinery underlying the genome, then ENCODE is the “go to” instructional manual.

Sorting out—and better understanding–the working elements of the human genome, in general, is likely to lead to significant social changes, with moral implications.

In addition, IT (information technologies involving the development, maintenance, and use of computer systems, software, and networks for the processing and distribution of data will have to be created to handle massive numbers of patients, each with huge repositories of data points on each of them, a quest reminiscent of the words of Lee Hood who remarked on the occasion of the official end of the Human Genome Project in 2003:

“I see a time 10 years in the future when every single patient will be surrounded by a virtual cloud of billions of data points, and we’ll have the software to be able to define uniquely the nature of health and the potential of disease for each individual.”

In such an environment, P4 medicine will transform the healthcare industry to be both effective and inexpensive, the lynchpins of any national healthcare system designed to improve global health care in the future.

Ethical and Policy Implications

The opportunities and challenges of P4 medicine, are numerous.  On the “opportunities” side there is the exploration a multi-billion dimensional data space leading to a deep understanding of disease mechanisms and hence effective and inexpensive new approaches to prediction, therapy, and prevention. The potential to correlate 100s of millions of patient genotypes and phenotypes and, in the process, transform predictive medicine (diagnostics) is also a key feature of P4 medicine.

The P4 principles can be described as follows:

  • Scientific innovation based upon systems biology and emerging technologies will yield insights and innovations that will enable industry disruption;
  • These technologic enablers will result in care that can be focused on health and wellness, the prediction and prevention of illness, and individualized care for consumers of the future; and
  • This disruption will provide a path to improved outcomes at lower costs via more effective diagnosis, more precise therapies, and reduced costs to bring therapies to market;

Even with these positives, however, there are many substantial challenges still to be addressed.

For starters, how to standardize (and secure) the massive amount of data which will be produced by a P4 medicine approach to disease.

At the present time, there is no universally accepted IT healthcare system adequate to store, analyze, transmit, protect, and integrate such data such as in biobanks for individual’s tissue and blood storage.

In principle, the ethical, legal, and social issues characteristic of virtually all of genomic science, inhabit the concept of P4 medicine.

Some notable examples on that list include:

  • Privacy and confidentiality of genetic information;
  • Fairness in the use of genetic information; psychological impact stigmatization, and discrimination due to an individual’s genetic makeup;
  • Issues surrounding the education (or lack of it) of physicians and other health-service providers, people identified with genetic conditions, and the general public, and the implementation of standards and quality-control measures;
  • Uncertainties associated with genetic testing performed when no treatment is available or when interpretation is unsure; and
  • the commercialization of products including property rights such as patents, copy-rights, and the accessibility of data and materials.

The current healthcare debate is centered on medicine of the past/present rather than medicine of the future.  Healthcare is a fundamental right of all citizens.  When viewed in the context of medicine of the present, current health care is ineffective, costly and, therefore, impossible to extend to all citizens.  Indeed, today’s healthcare debate is about rationing and who will be left out or poorly served.

The key is to understand medicine of the future (P4 medicine) aimed at realizing the transformation in health care it promises to bring, with effectiveness and reduced cost, to all.

As an important step forward on that journey, researchers have unveiled the most comprehensive atlas of genes underlying human metabolic pathways, paving the way for improved understanding and treatment of metabolic diseases such as diabetes, cardiovascular disease, and hypertension. (See: Metabolism Mapped)

In the view of Leroy Hood, and those engaged in a “systems” approach to medicine, the current debate on healthcare is centered on medicine of the past—and hence misses the enormous potential of medicine of the future (P4) for revolutionary change.

As Leroy Hood remarked: “Siloization…” – the act or process of placing identical data into a multitude of separate electronic places or electronic containers with many different medical systems – “with different IT for healthcare, no data standardization, no effective biobanks for sample storage and no agreement on ethical, policy, societal, and economic issues would be disaster.”

Resources and Discussion

Questions for Discussion

  • What are the technologies by which medicine of the future will manage an individual’s personal health instead of managing a patient’s disease?
  • Will our current health care system of balancing risks and benefits to patients fail if we have genomic data (of still imperfect quality) about how patients are likely to respond to different therapies?
  • How would “personalized” medicine be different from the current  (“Individualized”) ways in which patients are treated?
  • What are“SNPs” and what is their role in the study of human health?
  • What “bioethical issues” raised by the practice of “P4 medicine” may need to be developed into policy, and why?
  • What is the “ENCODE Project” and why are its goals important?
  • Which of the “Grand Challenges” described in the paper: “A Vision for the Future of Genomics Research” (see resource section above), do you find to be most challenging in the context of ethics and policy, and why?
  • How should health professionals be prepared for the Age of Genomics?