Fall 10 // protomag.com

stat: an abbreviation for the Latin statim, an adverb that signals a need—for a surgical instrument, a medical supply or, as in this magazine, a short, compelling story—to be met without delay.

FOCUs //

A “TRUE SUPERBUG” is what researchers worry a drug-

resistant strain of Escherichia coli could become. The diarrhea-causing,

sometimes-fatal bacteria—here, supersized 500,000 times in a three-

foot-long glass sculpture created by artist Luke Jerram with the help

of virologists and glassblowers—is typically treated with antibiotics.

But research recently published in the journal Clinical Infectious

Diseases found that, among 1,600 U.S. patients afflicted by the bug in

2007, the ST131 strain caused as many as 69% of the infections that

were resistant to the main antibiotics used to treat E. coli.

08 intERviEw //Herbert Benson: The mind’s healing power

09 by thE nUMbERs //Exam room jitters

10 inFOgRaphiC //Paging through mental illness

11 MilEstOnE //Lord of the Fly Room

12 pOliCy watCh //Should genes be patented?

13 UpDatE //Simulators surge

13 DEFinED //Incidentalome

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The Mind’s Healing Power by lauren ware

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In the early 1970s, in the very laboratory at Harvard Medical School where physiologist Walter Cannon discovered the fight-or-flight response, a young cardiologist named Herbert Benson tested 36 devoted practitioners of meditation, monitoring changes in their oxygen consumption, heart rate, blood pressure and rate of breathing that exactly opposed those of the fight-or-flight response. His 1975 book describing the phenomenon, The Relaxation Response, rocketed to the top of the New York Times bestseller list, and Benson became famous as one of the first Western physicians to stress the importance of the mind in modern medicine.

Benson is the founder and director emeritus of the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital, where a recent study has shown that meditation, tai chi, yoga, exercise, prayer and a variety of similar practices can alter a person’s gene activity, changing the expression of genes related to stress and inflammation.

Q: Finding that behavior can alter gene expression is rather remarkable, isn’t it? What exactly did the study show?A: We compared 19 people who had regularly evoked the relaxation response for an average of nine years with 19 people who had never done so. In a scan of each subject’s 50,000 or so genes, we found that the activity of about 2,000 genes differed between the two groups. Among those in the relaxation response group, roughly 2,000 genes active in various stress-related physiological pathways, genes that trigger inflammation and genes that prompt cell death, had been deactivated. There is no evidence that the deactivations are permanent. We believe that daily practice of the relaxation response is necessary to sustain the changes.

Q: Judging by the title of your latest book, Relaxation Revolution: Enhancing Your Personal Health Through the Science and Genetics of Mind Body Healing, it seems you think those gene deacti-vations could profoundly affect a person’s health. A: More than 60% of visits to doctors are for stress-related complaints that are poorly treated, if at all, by pharmaceuticals and surgery. To the degree that d

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Fall 10 // protomag.com

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1897 year the italian physician scipione Riva-Rocci made the first known reference to patients experiencing heightened blood pressure after stepping into a clinical environment

1983 year the term “white-coat syndrome” was coined, when italian physician giuseppe Mancia and his colleagues reported in the journal Lancet that, on average, a patient’s heart rate and systolic and diastolic blood pressure rose significantly when a physician (hence the term “white coat”) entered the patient’s room

15–30 percentage of the general population estimated to experience white-coat hypertension (now used synonymously with white-coat syndrome) 140/90 Minimum office blood pressure reading on at least three occasions, in addition to daytime ambulatory blood pressure measurements below 135/85, required for a white-coat hypertension diagnosis

20 Estimated percentage of patients diagnosed with sustained hypertension (which requires treatment) who, in fact, may only have white-coat hypertension (which usually doesn’t require treatment), according to the journal Circulation

110,000 Estimated cost savings in dollars over six years for one clinic that monitored ambulatory blood pressure in 255 hypertensive patients 24 hours a day to distinguish sustained hypertension from white-coat hypertension, and treated only the sustained hypertensives, according to a 1995 study in the European Heart Journal

by thE nUMbERs //

exam room Jitters

A: People had long believed that the mind could interact with the body. Then scientists discovered that bacte-ria caused some diseases. They found, for instance, that penicillin could cure pneumonia. It didn’t matter whether you believed it could or not; it just did. With the emergence of these treat-ments, medicine came to believe that diseases could be cured and that the mind wasn’t important in this process. Q: How has this attitude affected your work during the past 40 years? A: I recognized that to truly win over mainstream medicine, I had to use cutting-edge scientific technology to study the mind body connection. When functional magnetic resonance imaging studies became available, we used them. Now that genomics-based studies are available, we use those. It’s much more difficult to establish the value of the mind body connec-tion using classic scientific methods, because of the complexity of the inter-actions between them and because the power of belief does play a big role in our responses to treatments. Tradition-ally, medical science has tried to ignore the power of belief by controlling for it—using a placebo.

Q: What’s the next step for the gene research? A: We’re repeating our study with people who have specific stress-related conditions—hypertension, irritable bowel syndrome and infertility—to see whether inducing the relaxation response alters the expression of genes related to these conditions. We expect results in a year or so.

any disease is caused or worsened by stress, practicing the relaxation response can improve the condition and symptoms.

Q: Your study also showed just how quickly the relaxation response affects one’s genes. A: That’s right. We taught the control group techniques to evoke the relax-ation response and had them practice the techniques for eight weeks. We then found changes in some of the same genes as those in the group that had practiced relaxation techniques for years. The changes were not as profound: Only about 1,500 genes, rather than 2,000 in the long-practic-ing group, showed changes in expression. But the longer you practice the relaxation response, the greater the effect, it seems.

Q: Do these findings vindicate a field of study that’s often derided as pseudoscience? A: We know from many years of previ-ous work that the mind has a profound therapeutic effect on the body, but it was wonderful to have the idea con-firmed with the most reductionistic criteria we could use: genomics. By reductionistic, I mean the prevailing approach to scientific research that assumes all our understanding about the world can be reduced to its par-ticular parts—in this case, to genes. Showing that the mind can affect the genes is an entirely different level of proof that people don’t expect.

Q: You have said that “It’s all in your head” wasn’t always pejorative. d

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130 pages

95 disorders 130 215 283567 886134

1952 1968 1987 1994 2000 2013

BRINGING PSYCHOLOGY TO THE MASSES

Two steps forward:• Introduction of a symptom list: An individual is diagnosed as having a particular mental disorder when a certain number of symptoms are present.

• Use of five axes—clinical disorders, personality disorders and mental retardation, general medical conditions, psychosocial and environmental problems, and highest level of functioning in the past year—to classify a patient’s entire psychological state

And several steps back:Certain normal behaviors and “lifestyle” conditions, such as social phobia, begin creeping in, as does a low threshold for diagnosis of mild major depression.

THE REVOLUTION, REVISED

Steps forward: More conditions are added, and criteria for existing ones are honed.

MORE PSYCHOSES AND NEUROSES

Steps forward: The term “reaction” is replaced by “disorder,” and the edition includes a markedly expanded glossary of basic categories as well as a new glossary of technical terms needed for differential diagnosis.

THE FREUDIAN MODEL

The first edition takes a psychodynamic approach, derived from Freud’s psychoanalytic theory, in which mental disorders are viewed as a person’s pathological reactions to certain biological, psychologi-cal and social factors (daily life, relationships, traumas). Neuroses and psychoses constitute the majority of conditions.

THE MORE RIGOROUS VERSION

Step forward: A stiffer standard of scientific evidence for changes and inclusions of disorders

Steps back: The DSM-IV may have inadvertently contributed to two psychological epidemics:

• The addition of Asperger’s syndrome resulted in a twentyfold increase in rates of autism, perhaps prompted by schools requiring a diagnosis from students to qualify for special education.

• Clarified diagnostic criteria for attention-deficit/hyper-activity disorder doubled rates of diagnosis.

Eleven years later, a study estimated that more than half the general population will fit criteria for a disorder in the DSM-IV by the age of thirty-two, fueling concerns that the manual was too broad.

THE PUBLISHING PLOY

No significant changes, just a bid to sell more books, critics say.

MAKING NORMAL ABNORMAL

Step forward: The severity of mental disorders will be measured in more complex, individualized ways.

188494

1980

283943 To be determined

To be determined

POSSIBLE STEPS BACKWARD

Medicalizing normality

• Possible additionof mixed anxiety depression, definedby commonplace symptoms we all experience in everyday life (three or four symptoms

of major depression plus two or more “anxious distress” symptoms: irrational worry, pre-occupation with unpleasant worries, having trouble relaxing, motor tension, fear that something awful may happen)

• Possible addition of minor neurocognitive disorder: small changes in cognitive function, typical of normal aging, especially in people older than age 50

• Possible addition of temper dysregulation disorder with dysphoria: normal temper tantrums, for which kids could be prescribed antipsychotics

• Possible addition of hypersexual disorder, which critics claim could allow “sufferers” to disavow personal responsibility

• Possible changes to major depressive disorder to include, for instance, bereavement, so that normal grief would become a mental disorder

Medicalizing criminality

• Possible addition of paraphilic coercive disorder: rape as a mental disorder (in the words of critics, an excuse)

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protomag.com // Fall 10

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inFOgRaphiC //

Paging Through Mental Illness by racHael Moeller gorMan // InfograPHIc by flyIng cHIllI

Since 1952 the Diagnostic and Statistical Manual of Mental Disorders has been the bible for psychologists and psychiatrists the world over. Sixteen years have passed since the last major revision, and an updated manual is long overdue, since the current version doesn’t reflect the copious research that has improved understanding of certain diseases. yet critics claim that not all changes will be for the good, arguing that the next revision of the DSM “will trivialize mental disorder and lead to a deluge of unneeded medication treatments.”

The DSM-5 task force and work groups are reviewing public comments on proposed changes. next, field trials will test the reliability of revisions. against this backdrop, here’s a look at how the DSM has evolved over the past 58 years; what changes may be in store for the DSM-5, due out in May 2013; and how the lines are being blurred between illness and life.

130 pages

95 disorders 130 215 283567 886134

1952 1968 1987 1994 2000 2013

BRINGING PSYCHOLOGY TO THE MASSES

Two steps forward:• Introduction of a symptom list: An individual is diagnosed as having a particular mental disorder when a certain number of symptoms are present.

• Use of five axes—clinical disorders, personality disorders and mental retardation, general medical conditions, psychosocial and environmental problems, and highest level of functioning in the past year—to classify a patient’s entire psychological state

And several steps back:Certain normal behaviors and “lifestyle” conditions, such as social phobia, begin creeping in, as does a low threshold for diagnosis of mild major depression.

THE REVOLUTION, REVISED

Steps forward: More conditions are added, and criteria for existing ones are honed.

MORE PSYCHOSES AND NEUROSES

Steps forward: The term “reaction” is replaced by “disorder,” and the edition includes a markedly expanded glossary of basic categories as well as a new glossary of technical terms needed for differential diagnosis.

THE FREUDIAN MODEL

The first edition takes a psychodynamic approach, derived from Freud’s psychoanalytic theory, in which mental disorders are viewed as a person’s pathological reactions to certain biological, psychologi-cal and social factors (daily life, relationships, traumas). Neuroses and psychoses constitute the majority of conditions.

THE MORE RIGOROUS VERSION

Step forward: A stiffer standard of scientific evidence for changes and inclusions of disorders

Steps back: The DSM-IV may have inadvertently contributed to two psychological epidemics:

• The addition of Asperger’s syndrome resulted in a twentyfold increase in rates of autism, perhaps prompted by schools requiring a diagnosis from students to qualify for special education.

• Clarified diagnostic criteria for attention-deficit/hyper-activity disorder doubled rates of diagnosis.

Eleven years later, a study estimated that more than half the general population will fit criteria for a disorder in the DSM-IV by the age of thirty-two, fueling concerns that the manual was too broad.

THE PUBLISHING PLOY

No significant changes, just a bid to sell more books, critics say.

MAKING NORMAL ABNORMAL

Step forward: The severity of mental disorders will be measured in more complex, individualized ways.

188494

1980

283943 To be determined

To be determined

POSSIBLE STEPS BACKWARD

Medicalizing normality

• Possible additionof mixed anxiety depression, definedby commonplace symptoms we all experience in everyday life (three or four symptoms

of major depression plus two or more “anxious distress” symptoms: irrational worry, pre-occupation with unpleasant worries, having trouble relaxing, motor tension, fear that something awful may happen)

• Possible addition of minor neurocognitive disorder: small changes in cognitive function, typical of normal aging, especially in people older than age 50

• Possible addition of temper dysregulation disorder with dysphoria: normal temper tantrums, for which kids could be prescribed antipsychotics

• Possible addition of hypersexual disorder, which critics claim could allow “sufferers” to disavow personal responsibility

• Possible changes to major depressive disorder to include, for instance, bereavement, so that normal grief would become a mental disorder

Medicalizing criminality

• Possible addition of paraphilic coercive disorder: rape as a mental disorder (in the words of critics, an excuse)

11

Fall 10 // protomag.com

by the spring of 1910, the pioneering geneticist Thomas Hunt Morgan was growing frustrated. years earlier, hoping to study mutations to forge an understanding of how species arise, he had stocked his columbia university laboratory with one-quart milk bottles filled with millions of fruit flies (collected from ripe bananas on the windowsill), then waited for a mutant to appear. one hundred years ago, after Morgan’s constant search for apparent mutations, a white-eyed fly appeared amid swarms of red-eyed Drosophila melanogaster.

This tiny creature catapulted biology toward the genomics revolution, firmly establishing the chromosomal theory of heredity. and from Morgan’s laboratory—dubbed the fly room—came a new model for structuring research laboratories.

Morgan was born in 1866, the year gregor Mendel published his famous work on the inheritance of certain traits in pea plants. Morgan, who was skeptical of Mendel’s work, thought the theory of factors (now called genes) carried on chromosomes was “an absurdity.” yet Morgan soon proved that very theory, showing not only the physical mechanism by which genes are inherited but also how they could explain Darwinian evolution. after crossbreeding the white-eyed fly, Morgan determined the mutation was a recessive, sex-linked trait, and that it was positioned near two other mutations that were usually inherited together—on a chromosome. He summarized what appeared to many as

“fantastic speculation” and “sensational conclusions” in 1915 in The Mechanism of Mendelian Heredity. for his work, in 1933 Morgan became the first american to receive the nobel Prize in Physiology or Medicine.

Morgan realized that his investigations left many questions unanswered. How do genes divide into exactly two equal parts during cell division, and how do they remain

stable most of the time and only occasionally introduce mutations? and why are they always in the same linear position? The answers to these questions would await the discovery of the structure of Dna in 1953.

Morgan also spearheaded the collaborative nature of american research laboratories. Previously a scientific leader lorded over his students in a strict hierarchy. In Morgan’s “democratic” fly room, merit counted more than seniority, and students interacted with lead investigators. “each carried on his own experiments, but each knew exactly what the others were doing, and each new result was discussed freely,” recalled one of his students. Thus Morgan may take some credit for the fast pace of discovery in american universities.

MilEstOnE //

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is one of the case’s 20 plaintiffs represented by the American Civil Liberties Union and the Public Patent Foundation. “DNA sequences are discovered, not invented,” she says. “Removing DNA from the body and cleaning it up a bit doesn’t make it novel.”

This misinterpretation of the law, contends ACLU attorney Chris Hansen, is suppressing scientific research. “Say that a disease is influenced by five or more genes, each owned by someone different,” he notes. “Inevitably that type of situa-tion will stifle clinical innovation.”

Moreover, he and the plaintiffs argue that Myriad’s monopoly on testing BRCA1 and BRCA2 ill serves patients faced with complex health decisions. If mutations are found, a patient is usually advised to undergo an elective mastectomy, even if no signs of the cancer are yet present. Many physicians would likely continue to use Myriad’s test even if its patents are invalidated, but the field would be open to competition, allowing for the development of other tests that could provide second opinions and force competitive pricing.

Myriad counters that gene patents fall well within the confines of patent law. “If we do not isolate the DNA, we can’t do our analysis,” says Richard Marsh, counsel for Myriad. “Patents benefit innovation. In exchange for getting a patent, you must disclose all the information about the invention to the public. And that allows people to make improvements and enlighten the general public.” As proof of both points, he cites the thousands of BRCA-related studies (conducted because Myriad either didn’t enforce the patent or granted scientists permission) that have been published in the years since Myriad claimed the patent. He also says that Myriad’s pricing is competitive with that of other genetic diagnostics and that second opinions are available to individuals through licensed providers who can check genetic sites of interest identified by the Myriad test.

Myriad, whose BRCA1 and BRCA2 patents begin to expire in 2014 and 2015, respectively, has filed an appeal, and argu-ments will be heard next year. “This is a landmark case along a road we’re just beginning to travel,” says Daniel Vorhaus, an attorney and editor of the Genomics Law Report. “And what’s great is that it has drawn a number of different voices into the conversation.”

pOliCy watCh //

Should genes be Patented? by kayT Sukel

If women with a family history of breast or ovarian cancer want to check for mutations of their BRCA1 and BRCA2 genes, which can help predict the likelihood of the diseases, they have exactly one option: undergo a blood test created by Myriad Genetics. That’s because Myriad holds a series of patents relating to both genes, protecting its intellectual property and restricting other laboratories from perform-ing the test. But in March, a federal judge ruled in favor of plaintiffs who argued that genes shouldn’t be patented—a decision that could affect the holders of thousands of gene patents issued since 1982.

According to the Patent Act, only a “new and useful process, machine, manufacture, or composition of matter” is worthy of a patent. After the U.S. Supreme Court ruled that a modified bacterium was patentable in 1980, the U.S. Patent and Trademark Office interpreted this rule broadly, allowing genes, removed and isolated from the body, to be patented.

That’s illogical, contends Mary Steele Williams, chief oper-ating officer of the Association for Molecular Pathology, which

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When medical simulators were featured in Proto’s inaugural issue five years ago (“All Too Human,” Fall 2005), they were still a sideshow in medical education. Even at elite medical schools, students might train just a few times a year on simulators—lifelike mannequins implanted with sensors that can raise or lower blood pressure and pulse, monitor breath-ing, even groan in pain or “die.”

Yet the story concluded with a confident prediction from Jeffrey B. Cooper, a senior biomedical engineer at Massachusetts General Hospital: “A generation ago people questioned whether computers would ever have a place in medicine. Now, they’re so common you don’t even think about them—you just realize the benefits. That’s where simulators are headed.”

His prediction is already coming to pass. There are about 1,000 simula-tion centers in the United States today, compared with perhaps 100 five years ago, says Mary Patterson, medical director of the Center for Simulation and Research at Cincinnati Children’s

Hospital Medical Center. “Now, it would be unusual for a student to get through medical school without expe-rience on simulators,” she says.

Moreover, the technology is be-coming more advanced. Computer graphics and mannequins are coming together in simulators that re-create such procedures as endoscopies, in which physicians thread their instru-ments into a bodily orifice, after which sensors detect the path of the instru-ments and create realistic images displayed on monitors. Eventually, some researchers predict, mannequins might themselves be phased out while virtual environments give trainees, clad in virtual-reality goggles and gloves, the look and feel of cutting into a patient.

Meanwhile, existing technologies are being used to train a much larger field of clinicians. Five years ago, simula-tion centers were concentrated in large medical schools and research hospitals. Today they are also found in nursing schools, regional hospitals and technical colleges that train physician’s assistants

and emergency medical technicians. Perhaps the most important

advance is the ability of simulation training to reduce medical errors. Several studies on simulation-based training have shown that central line catheter infections (a major health and cost issue for hospitals) occur less frequently in patients treated by clini-cians who had first practiced inserting catheters into mannequins.

“Five years ago, we all thought simula-tion was a good idea,” says Patterson. “We have evidence now that simulation really does make a difference.”

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Simulators Surge by cHarleS Slack

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incidentalome [in(t)-s -den-t l-om] n: a neologism that denotes incidental findings in genetic tests and, according to the term’s originator, “threatens to undermine the promise of molecular medicine.”

radiologists have long used the word incidentaloma to refer to masses or tumors they happen to see on scans while looking for something else. In a recent study at the Mayo clinic in rochester, Minn., for example, among 1,426 imaging exams, 567 revealed incidental findings. of those cases, only 35 (6.2%) led to additional imaging, biopsies or surgery, and only 6 cases demonstrated a direct benefit from the testing. by recommending that patients get checked out, radiologists often subject patients to unnecessary worry and the health care system to wasted money and resources; but if they don’t, they place that 6.2% of patients at risk.

Isaac kohane, who coined the term incidentalome and is co-director of the center of biomedical Informatics and Division of Health Sciences Technology at Harvard Medical School, charges that genomic testing has introduced the same problem but on an even larger scale. The incidentalome (the suffix “-ome” signifies the entire universe of these findings, much as it is used for such biological systems as genome and proteome) includes false positives, which are bound to happen in tests for single-gene diseases for which the patient has no history or symptoms. Doctors often order these tests “just in case” or as part of a much larger battery. It also includes insignifi-cant findings, as in the case of mail-order genome tests, which scan thousands of genes and pinpoint variants that heighten risks of certain diseases, but which often are no cause for concern.