2012 Panel Discussion - Questions and Answers

Personal Genomics

Which do you think will be a greater challenge to incorporating personal genomics into medical practice, lack of genetics knowledge among patients or among doctors? What should be done to educate both these groups about genomics?

Although both these issues are frequently cited as obstacles to the incorporation of genomic data into mainstream medicine, I think the main challenges lie elsewhere. We simply do not have an adequate knowledge base about how an individual’s genome sequence relates to his or her susceptibility to disease and response to treatment. In specialty medicine—particularly involving some types of cancer and some Mendelian diseases—we have the needed knowledge. In these situations, patients and physicians educate themselves rather quickly and use the genomic data appropriately. I think we will see the same pattern as genomic data become more widely relevant to medical care. I just think this process will occur on a time scale of decades, not years.

We keep hearing about individualized medicine - What’s taking so long and will there ever be individualized medicine?

As the previous answer indicates, I think the hype about “individualized medicine” is out in front of the reality. Basic science is a major driver of medical progress, but the process is typically slow. The “Philadelphia chromosome,” a genomic aberration specific to chronic myelogenous leukemia (CML) was discovered in 1960. The molecular mechanism that accounts for the oncogenic effect of this aberration was discovered in the early 1980’s. Gleevac, a drug that counters this process was developed in the 1990’s. During the 2000’s clinical experience with gleevac—and other drugs that target the same process—began to produce long-term remissions of CML patients who would otherwise have died. This story involves a particularly favorable application of genomically personalized medicine. I am not suggesting that every advance of this type will take 50 years, but the time scale for translation of scientific insights into medicine is typically decades, not years.

What is the biggest obstacle standing in the way of clinical applications of genomics? How do we bring genomic applications to the clinical world?

As discussed above, I regard the biggest obstacle to clinical applications of genomics to be our lack of knowledge as to how an individual’s genome sequence influences his or her susceptibility to disease and response to treatment. I served last year, along with panelist Keith Yamamoto, on a National Research Council Committee that issued a report entitled “Toward Precision Medicine” (http://www.nap.edu/catalog.php?record_id=13284), which attempts to lay out a plan for acquiring the needed knowledge. However, the report warns that the process will be slow—revolutionary change in mainstream medicine will take generations. We should be more concerned about pursuing the goal in a rational way, than chasing the illusion of quick success.

For which diseases are you most optimistic for the prospects of genetic/genomic/proteomic-based diagnosis?

Two areas stand out, cancer and the diagnosis of congenital defects in newborn children. In cancer, there is a growing list of situations in which the genome sequence of the tumor is relevant to the choice of treatment. There are major challenges to expanding this list and increasing the patient benefit from genomically informed diagnoses: however, the path forward is clearer in cancer than in most diseases. In major part, this situation reflects the nature of cancer, a disease that is driven by mutations that occur in pre-cancerous and cancerous cells. Similarly, many congenital defects in newborns are due to new mutations, not present in the parents, or to rare combinations of mutations that are present—but not functionally consequential—in the parents. There are 4 million births in the United States each year. Perhaps 1% of these children have difficult-to-diagnose abnormalities. Early experience suggests that a significant fraction of these cases, albeit still a minority, can be diagnosed through genome sequencing. I should emphasize that it remains rare for this path to lead to improved treatments. However, families with affected children uniformly report that they want the most precise, achievable diagnosis, as quickly as possible. The “diagnostic Odyssey” on which many such families exhaust their financial and emotional resources is a sad, and often futile, overlay on the intrinsically stressful experience of adapting to life with developmentally abnormal child. This facet of pediatric medicine is likely to stimulate the sequencing of the genomes of tens of thousands of newborns each year in the near future. A major goal should be to enroll these children in long-term-follow-up programs along the lines suggested in the “Precision Medicine” report (see above). As already emphasized, the path toward major patient benefits from genomic medicine will be a long one, but we should make sure that we are actually on it.

Eventually there will be a "tipping point" where whole-genome sequencing becomes cheap enough that nearly everyone in the US will get sequenced. What do you think the likely social and research effects of this "tipping point" will be?

I agree with the “tipping-point” premise and can see positive and negative benefits. A positive benefit is that, if appropriate policies are adopted to capture the vast amount of information that will be gathered, we will all be able to contribute to, and benefit from, a collective-learning process that will ultimately lead to a healthier society. There are also risks. Premature, widespread adoption of genome sequencing, as a standard laboratory test, could lead to a substantial backlash against genomic medicine. Initially, few patients will benefit from the data. “Incidental findings” will be a major issue: everyone’s genome has plenty of idiosyncratic variants that are potentially alarming. We do not want the major legacy of genome sequencing to be the creation of a nation of the “worried well.” Finally, there is already an undesirable level of genetic determinism in popular discourse; widespread introduction of genome sequencing into mainstream medicine can only reinforce the tendency to blame everything on our genes. Many of medicine’s greatest successes—vaccination, for example—involve manipulations of environmental exposures that work well on most people despite all the variation in their genomes. Similarly, good nutrition and healthy lifestyles are mainstays of preventive medicine. Basic medical advice in these areas will continue to apply broadly to nearly everyone in the population.

For James Evans:
Will we be seeing clinical treatments or diagnosis based on genomics that will help to decrease healthcare costs in the new decade?

I cannot speak for Jim, but I doubt that genomics will decrease healthcare costs. Decreasing in cost—or, more realistically, a curtailment in the pace of increases—will have to come from adopting more sensible attitudes toward health, sickness, and death. Obviously such changes will come slowly. However, unsustainable trends cannot, by definition, go on: hence, change will come.

There are many reasons why genomics will not decrease healthcare costs. I address the most important of these in my answer to the previous question. As people live longer, health-care costs go up because of the medical complexity of caring for the very old. Some economic analyses even indicate that anti-smoking campaigns increase healthcare costs. Heavy smokers die relatively young, and the financial costs of their terminal illnesses are not particularly expensive, compared, for example, to those associated with Alzheimer’s, diabetes, and many other chronic diseases.

We should look to personalized medicine, and other medical advances, for longer, healthier, happier, and more fulfilling lives, not for a techno-fix of rising healthcare costs.

A question regarding Genetics & Clinical Medicine: Have services like “23 and me”, and online genetic testing service, had any impact on patient care – if not, do you expect they will?

These companies have little to offer the typical patient. I suspect that this industry will gradually displace some of the very expensive genetic testing and counseling that presently goes on within mainstream medicine. However, we are talking here about an activity that—important as it may be for some individuals and families—subsists on the periphery of mainstream medicine. The problem with direct-to-consumer-genetic testing (or, for that matter, any other model for providing such services) is that we do not know enough to interpret most of the results in actionable ways. Acquisition of that knowledge will be a long process. As knowledge expands, it is difficult to predict how testing and test interpretation will be made widely available. Direct-to-consumer marketing is just one possibility.

What is the future of phenotyping people and can we use social media?

In specialized areas, social media are already proving useful. The most promising examples involve rare, life-threatening diseases for which existing treatments are inadequate. Multiple myeloma, a form of bone-marrow cancer, is a good example. In these situations, groups of highly motivated patients—enough of whom are well educated to provide effective leadership—are taking increasing responsibility for their own care. Phenotyping (e.g., by monitoring measurable responses to particular drugs) is a key part of this activity. One can envision this model spreading to a longer list of more common diseases, particularly chronic diseases that require sustained medical attention over a period of decades.

I think social media will largely function as an adjunct to, rather than a means of bypassing, the health-care system. I expect to see health-care providers accelerate the current trend toward increased in-home monitoring of phenotypes (e.g., regular testing of blood pressure, blood sugar, lipid levels, activity levels, and so forth). As this practice expands, self-organized groups of patients will have more and more solid phenotypic data to share via social media. Researchers will undoubtedly tap into this resource.

With current technology, how do we link genome sequencing to gene therapy?

Unlike most other applications of genomics to medicine, gene therapy has the potential to make any genotyping result “actionable.” The problem is not in the linkage between genome sequencing and gene therapy, which is intrinsically tight, but in the immense challenges of developing safe and effective gene therapies for diseases that affect substantial numbers of people.

What should we do about partial genome testing? Example, current DNA tests for drug interactions and dosage.

I interpret this question to address the fate of specialized genetic tests, such as genotyping of the VKORC1 and CYP2C9 loci in order to improve initial dosing of the widely prescribed anti-clotting agent warfarin. Presumably such tests will give way at some point to whole-genome sequencing, the ultimate genetic test, since whole-genome analysis will become cheaper than targeted, single-gene or gene-panel tests. The key phrase here is “at some point.” One major issue is test reliability. At present, it is far easier to bring any specific genetic test up to FDA standards than to bring a whole-genome test, intended to guide immediate clinical action based on findings anywhere in the genome, to this level of reliability. Consequently, specialized tests and whole-genome sequencing are likely to co-exist for a long time. Improved technology will slowly tip the balance toward whole-genome sequencing. Also, more realistic standards for test reliability are likely to emerge, despite our litigiousness and inability to apply common-sense standards in medicine. There is a logical conflict between the view that testing is barely, or not at all, worthwhile (the current mainstream assessment of the warfarin test) and the requirement that, if testing is to be done, it must have 100.00% accuracy.

As the nascent paradigm of “P4 Medicine” (predictive, preventive, personalized, and participatory) emerges and matures, how will the role of, and the need for, physicians change? Will they perhaps go the way of scribes in the wake of the printing press?

No. There will be more disease in the future, not less, and the disease processes will pose ever-increasing medical complexities. These complexities will far outstrip whatever progress Apple makes in teaching Siri medicine, thereby leaving a huge role for human physicians. Success in medicine, of which we have had a lot and will see much more, increases the burden on the health-care system rather than decreasing. The reason is that with better medicine people live longer and die of more complicated causes. Pneumonia was once known as “the old man’s friend” since it killed so many of the elderly before they slid into multi-factorial sources of disability. Dealing with this paradox poses enormous social challenges. The solution cannot be to allow people to die early of preventable causes. However, it also cannot be to do everything medically possible until the last minutes of life. In between these options, we will need plenty of physicians to provide expert, humane, affordable care for our aging populations.