‘Moonshot’ Medicine Will Let Us Down
By MICHAEL J. JOYNERJAN. 29, 2015
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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.
Redefining Mental Illness
JAN. 17, 2015
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CreditRoman Muradov
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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.
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