The Opinion Pages | OP-ED CONTRIBUTOR
‘Moonshot’ Medicine Will Let Us Down
By MICHAEL J. JOYNERJAN. 29, 2015
ROCHESTER, Minn. — PRESIDENT OBAMA’S new budget is expected to include hundreds of millions of dollars for so-called precision medicine. The initiative, which he introduced last week in his State of the Union address, has bipartisan support and is a bright spot in the otherwise tight funding environment for medical research. Unfortunately, precision medicine is unlikely to make most of us healthier.
The basic idea behind it is that we each have genetic variants that put us at increased or decreased risk of getting various diseases, or that make us more or less responsive to specific treatments. If we can read someone’s genetic code, then we should be able to provide him or her with more effective therapeutic and preventive strategies.
But for most common diseases, hundreds of genetic risk variants with small effects have been identified, and it is hard to develop a clear picture of who is really at risk for what. This was actually one of the major and unexpected findings of the Human Genome Project. In the 1990s and early 2000s, it was thought that a few genetic variants would be found to account for a lot of disease risk. But for widespread diseases like diabetes, heart disease and most cancers, no clear genetic story has emerged for a vast majority of cases.
Age, sex, body weight and a few simple blood tests are much better predictors of Type 2 diabetes, for example, than a genetic score based on how many snippets of “risky” DNA you have. And the advice for those at risk to exercise more and eat more healthfully remains the same.
When higher-risk genetic variants are found, their predictive power is frequently dependent on environment, culture and behavior. The main genetic variant associated with obesity, for instance, is associated with obesity only in people born after the early 1940s — most likely because of the low-physical-activity, high-calorie world that emerged after World War II.
A second unexpected finding of the Human Genome Project was the problem of “missing heritability.” While the statistics suggest that there is a genetic explanation for common conditions and diseases running in families or populations, it turns out that the information on genetic variants doesn’t explain that increased risk.
Several high-profile attempts to use genetic variants to target patients with commonly used drug therapies have also failed in clinical trials. Perhaps the most notable example is the anticoagulant warfarin, which is used by millions of patients to prevent blood clots and strokes. Researchers have found that genetic information on how patients metabolize drugs does not improve on the standard way of adjusting the dose up or down, based on factors like age, weight and blood test results.
For relatively rare diseases like cystic fibrosis, exciting new drugs have been developed using genetic information, but they have not been able to fix defective genes via gene therapy, as originally hoped. There have also been positive reports about precision therapies for specific genetic defects in cancer, but it’s difficult to design clinical trials to test this strategy in a large number of patients. Many tumors are also notorious for their ability to mutate and ultimately circumvent the best therapies.
The push toward precision medicine could also lead to unintended consequences based on how humans respond to perceptions of risk. There is evidence that if people believe they are less at risk for a given disease, they feel excessively protected and their behavior gets worse, putting them at increased risk. Likewise, those who feel they are at greater risk, even if the increased risk is small, might become fatalistic, making their behavior worse as well. Then there are the worriers, who might embark on a course of excessive tests and biopsies “just in case.” In a medical system already marked by the overuse of diagnostic tests and procedures, this could lead to even more wasteful spending.
We have been down this road before. The idea behind the “war on cancer” was that a deep understanding of the basic biology of cancer would let us develop targeted therapies and cure the disease. Unfortunately, although we know far more today than we did 40-plus years ago, the statistics on cancer deaths have remained incredibly stubborn. The one bright spot has been tobacco control — again highlighting the dominant role of culture, environment and behavior versus biological destiny in what ails most of us.
Given the general omertà about researchers’ criticizing funding initiatives, you probably won’t hear too many objections from the research community about President Obama’s plan for precision medicine. But I am deeply skeptical. Like most “moonshot” medical research initiatives, precision medicine is likely to fall short of expectations. Medical problems and their underlying biology are not linear engineering exercises, and solving them is more than a matter of vision, money and will.
We would be better off directing more resources to understanding what it takes to solve messy problems about how humans behave as individuals and in groups. Ultimately, we almost certainly have more control over how much we exercise, eat, drink and smoke than we do over our genomes.
Michael J. Joyner is an anesthesiologist and physiologist at the Mayo Clinic.
SundayReview | CONTRIBUTING OP-ED WRITER
Redefining Mental Illness
JAN. 17, 2015
TWO months ago, the British Psychological Society released a remarkable document entitled “Understanding Psychosis and Schizophrenia.” Its authors say that hearing voices and feeling paranoid are common experiences, and are often a reaction to trauma, abuse or deprivation: “Calling them symptoms of mental illness, psychosis or schizophrenia is only one way of thinking about them, with advantages and disadvantages.”
The report says that there is no strict dividing line between psychosis and normal experience: “Some people find it useful to think of themselves as having an illness. Others prefer to think of their problems as, for example, an aspect of their personality which sometimes gets them into trouble but which they would not want to be without.”
The report adds that antipsychotic medications are sometimes helpful, but that “there is no evidence that it corrects an underlying biological abnormality.” It then warns about the risk of taking these drugs for years.
And the report says that it is “vital” that those who suffer with distressing symptoms be given an opportunity to “talk in detail about their experiences and to make sense of what has happened to them” — and points out that mental health services rarely make such opportunities available.
This is a radically different vision of severe mental illness from the one held by most Americans, and indeed many American psychiatrists. Americans think of schizophrenia as a brain disorder that can be treated only with medication. Yet there is plenty of scientific evidence for the report’s claims.
Moreover, the perspective is surprisingly consonant — in some ways — with the new approach by our own National Institute of Mental Health, which funds much of the research on mental illness in this country. For decades, American psychiatric science took diagnosis to be fundamental. These categories — depression, schizophrenia, post-traumatic stress disorder — were assumed to represent biologically distinct diseases, and the goal of the research was to figure out the biology of the disease.
That didn’t pan out. In 2013, the institute’s director, Thomas R. Insel,announced that psychiatric science had failed to find unique biological mechanisms associated with specific diagnoses. What genetic underpinnings or neural circuits they had identified were mostly common across diagnostic groups. Diagnoses were neither particularly useful nor accurate for understanding the brain, and would no longer be used to guide research.
And so the institute has begun one of the most interesting and radical experiments in scientific research in years. It jettisoned a decades-long tradition of diagnosis-driven research, in which a scientist became, for example, a schizophrenia researcher. Under a program called Research Domain Criteria, all research must begin from a matrix of neuroscientific structures (genes, cells, circuits) that cut across behavioral, cognitive and social domains (acute fear, loss, arousal). To use an example from the program’s website, psychiatric researchers will no longer study people with anxiety; they will study fear circuitry.
Our current diagnostic system — the main achievement of the biomedical revolution in psychiatry — drew a sharp , clear line between those who were sick and those who were well, and that line was determined by science. The system started with the behavior of persons, and sorted them into types. That approach sank deep roots into our culture, possibly because sorting ourselves into different kinds of people comes naturally to us.
The institute is rejecting this system because it does not lead to useful research. It is starting afresh, with a focus on how the brain and its trillions of synaptic connections work. The British Psychological Society rejects the centrality of diagnosis for seemingly quite different reasons — among them, because defining people by a devastating label may not help them.
Both approaches recognize that mental illnesses are complex individual responses — less like hypothyroidism, in which you fall ill because your body does not secrete enough thyroid hormone, and more like metabolic syndrome, in which a collection of unrelated risk factors (high blood pressure, body fat around the waist) increases your chance of heart disease.
The implications are that social experience plays a significant role in who becomes mentally ill, when they fall ill and how their illness unfolds. We should view illness as caused not only by brain deficits but also by abuse, deprivation and inequality, which alter the way brains behave. Illness thus requires social interventions, not just pharmacological ones.
ONE outcome of this rethinking could be that talk therapy will regain some of the importance it lost when the new diagnostic system was young. And we know how to do talk therapy. That doesn’t rule out medication: while there may be problems with the long-term use of antipsychotics, many people find them useful when their symptoms are severe.
The rethinking comes at a time of disconcerting awareness that mental health problems are far more pervasive than we might have imagined. The World Health Organization estimates that one in four people will have an episode of mental illness in their lifetime. Mental and behavioral problems are the biggest single cause of disability on the planet. But in low- and middle-income countries, about four of five of those disabled by the illnesses do not receive treatment for them.
When the United Nations sets its new Sustainable Development Goals this spring, it should include mental illness, along with diseases like AIDS and malaria, as scourges to be combated. There is much we still do not know about mental illness, and much we can do to improve its care. But we know enough to do something, and to accept that knowing more and doing more should be a fundamental commitment.
Correction: January 25, 2015
An opinion article about mental illness last Sunday incorrectly referred to a group that recently issued a report on schizophrenia. It is the British Psychological Society, not the British Psychological Association.
T. M. Luhrmann is a contributing opinion writer and a professor of anthropology at Stanford.