Don’t Let Me Be Lonely, Doctor: On Epigenetics, Placebos, and “The Lost Art of Healing”

LILLIAN came to my office for a second opinion. Her first nephrologist had just done a kidney biopsy and handed her a diagnosis of fibrillary glomerulonephritis, an extremely rare form of kidney disease whose annual incidence is less than 50 cases per year. “My doctor said you were the only one who could help me,” she said, trying to muster a smile. I told her the truth: we knew very little about what causes fibrillary glomerulonephritis, and therefore we knew even less about what treatments might help. I suggested a course of the only therapy that had been shown, in case reports, to work for her disease, the monoclonal antibody rituximab, although the rationale for why this drug would work for this specific disease was at best speculative.

Six months later, her local nephrologist sent her back for another second opinion, specifically about whether she should try a second course of rituximab. Her lab results showed no response to the drug. “In fact,” I said, “if anything, your kidneys have gotten worse in the last six months.” Lillian started to tear up. When I offered her a box of tissues, her crying intensified. She soon fell into near hysterics. Her wailing was the only sound in the room. Two medical students were shadowing me that afternoon, and Lillian’s crying was clearly making them uncomfortable. I told her we would re-dose the rituximab. “I think a second round of therapy will help,” I said. “You will get better.” She stopped crying. “You really think so?” she asked. “Yes.” This was not an outright lie, because, if her kidneys failed, she’d get a transplant, in which case she would technically get better. When she left the office, the medical students asked me if I really thought she’d get better. “No,” I said, “but she needs to have some hope right now.” They laughed, but I was serious. And Lillian did get better.

¤

This year marks the 20th anniversary of Bernard Lown’s The Lost Art of Healing. Lown, now 94 years old, is a retired cardiologist best known for developing the direct current defibrillator used to resuscitate victims of cardiac arrests. He also accepted the Nobel Peace Prize in 1985 on behalf of International Physicians for the Prevention of Nuclear War, an organization he co-founded with a Russian cardiologist. Lown’s 1996 memoir, though, will also be one of his lasting legacies. The book is still distributed to first-year medical students around the world, part pleasure-reading gift and part instruction manual for the career they’ve chosen.

In The Lost Art of Healing, Lown recalls the simple advice he received from a Siberian physician — “Every time a doctor sees a patient, the patient should feel better as a result” — and spends most of his book trying to convince his readers that physician-patient dialogue is the only reliable way to ensure a positive medical outcome. “I know of few remedies more powerful than a carefully chosen word,” writes Lown. “Patients crave caring, which is dispensed largely with words.” I took care of Lillian before reading The Lost Art of Healing. When I read Lown’s memoir a few years later, her case kept popping into my head. My colleagues and I published the largest case series of fibrillary glomerulonephritis patients treated with rituximab to date, and Lillian is the clear outlier, the only patient with advanced kidney failure who responded to the drug. We had no explanation for her success. Lown probably would argue that my optimistic words were a key player. “I attempt to discover a silver lining in the cloudiest situation,” he writes. “This has little to do with truth or falsehood. It flows from the deepest intent of doctoring, to help a patient cope when a condition is hopeless and to recover whenever it is remotely possible.”

A new study in the Proceedings of the National Academy of Sciences, entitled “Myeloid differentiation architecture of leukocyte transcriptome dynamics in perceived social isolation,” lends support to Lown’s message. The investigators, led by Steven Cole at UCLA and John Cacioppo at the University of Chicago, used questionnaires and samples from the Chicago Health, Aging, and Social Relations Study to show that “perceived social isolation,” a behavioral science term for loneliness, activates a series of genes that promote inflammation and weaken our immune systems. Their findings were confirmed in a macaque model, in which the loneliest monkeys not only expressed high levels of pro-inflammatory genes but also, when challenged with simian immunodeficiency virus, were unable to clear the virus as quickly or effectively as highly sociable monkeys.

We are firmly planted in the genetics era of medicine, from President Obama’s Precision Medicine Initiative, announced in the 2015 State of the Union address, to the ubiquitous ads for 23andMe, the for-profit company that promises a detailed genetics report in exchange for $199.00 and a sample of saliva. Many doctors, including me, believe that our genes are the ultimate determinant of our health, and we are rapidly accumulating the tools to identify these genes for every patient. Yet many doctors, including me, have underestimated the role of epigenetics, which is the study of gene expression modification (as opposed to alterations in the genetic code itself). In other words, the DNA we inherit from our parents influences our health, but these genetic variants sometimes will only surface in the right — or, perhaps I should say, wrong — environment. Epigenetics explains why identical twins, with identical genes, can have wholly different disease profiles. And epigenetics is the key to understanding the findings from Cole and Cacioppo’s study.

The genes and gene products promoted by loneliness are part of what these investigators call our “conserved transcriptional response to adversity,” more commonly known as the fight or flight reaction. These are not uniquely 21st-century responses, but rather the same reactions that our earliest ancestors manifested in times of stress. What is 21st century about this study is how “stress” has shifted from an onrushing, bloodthirsty woolly mammoth to a high score on the UCLA Loneliness Scale, which asks participants to answer “often,” “sometimes,” “rarely,” or “never” to statements like “I am unhappy doing so many things alone,” “I feel starved for company,” and “People are around me but not with me.”

¤

“There is no one I can turn to” is item #7 on this loneliness questionnaire. When Lillian first came to my office, her local nephrologist had just told her there was nothing he could do to help other than send her to my clinic. At that visit, I told her how little we knew about her disease and its possible treatment. She came alone to that appointment and returned by herself six months later. No friend or family member was sitting next to her as I reviewed her labs and lack of response to the medication. From my end of the consultation desk, I only passed her a box of tissues. Our relationship dynamics changed the moment I told her I would re-dose the medicine and she would get better. Her face brightened. She smiled as she wiped away her tears. I had not given up on her. I had not abandoned her. Within seconds, her perceived social isolation diminished, and she was on the road to recovery.

This is not medical hocus-pocus, according to Lown, who ritually put his hand on a patient’s shoulder at the end of an appointment and said, “You’ll be fine.” He’d seen his own mentor, Samuel Levine (or SL, as Lown calls him throughout The Lost Art of Healing), do the same thing and watched his patients “be fine” despite grim diagnoses. Cole and Cacioppo’s study is just the latest and one of the more scientifically rigorous demonstrations of how this kind of physician-assisted optimism can help patients. Previous reports have linked loneliness with higher rates of heart disease, cancer, and viral infections. In contrast, high/optimistic scores on the Life Orientation Test, a questionnaire to assess a patient’s outlook on life, have been associated with fewer heart attacks and fewer complications after cardiac surgery.

¤

The most refreshing part of Lown’s memoir, two decades after its publication, remains his optimism about what a doctor can do for his or her patients simply by taking a genuine interest in their well-being. In this vein, the just-published Placebo Talks: Modern Perspectives on Placebos in Society serves as an interesting companion read to The Lost Art of Healing. Placebo Talks wastes little space proving the existence of what is now a well-established “placebo effect.” Instead, this anthology draws experts from the fields of medicine, psychology, neuroscience, and anthropology to explore the “improved performance that some individuals experience when they receive what appears to be appropriate help, that may actually be specious, for the situation they are in.” Indeed, most of the authors in this collection replace the term “placebo effects” with more specific language, such as “context effects,” “meaning effects,” and “care effects.” This last idea — the care effect — could serve as a tidy encapsulation of Lown’s art of healing.

In their chapter “Placebo science in medical education,” Natasha Campbell and Amir Raz call physicians “walking placebos” and use language that could easily fit in Lown’s memoir:

One can be both a scientific physician and a walking placebo; that is, a physician’s bedside manner and personality can be as scientifically informed and astute as their knowledge of, for instance, the treatment of respiratory infections. Through this perspective, we frame the distinction between curing and healing: physicians can cure abnormalities of the body and heal the problems that arise from a patient’s subjective experience of those abnormalities. […] [P]hysicians have the ability to change expectancy, experience, and outcome by capitalizing on certain conditioned social cues and choosing words wisely, in order to create an optimal healing environment.

The patient, according to Irving Kirsch, the Associate Director of the Program in Placebo Studies at Harvard Medical School, arrives in the doctor’s office laden with expectations (“response expectancies” is the technical term), and the doctor can either foster or negate those expectations. Lown, the eternal optimist, assumed his patients arrived with faith in his abilities to make them better, but Kirsch (anticipating, perhaps, the recent research on perceived social isolation) describes in his chapter how hopelessness, too, is an expectancy “that a negative state of affairs will not get better, no matter what one does to alleviate it.” This latter phenomenon is what placebo experts dub the “nocebo” effect. Reading through Placebo Talks, I wondered how much of Lillian’s lack of response to the initial course of therapy was a nocebo result, just as I wondered how much of her success with the second course of therapy could be attributed to a caring effect.

I realize that many of these ideas and concepts come perilously close to paternalism, a taboo subject in modern medicine, where phrases like “Doctor knows best” or “Trust me, I’m a doctor” are reserved for ironic T-shirts. What’s fascinating about Lown’s memoir and, even more so about the various entries in Placebo Talks, is that these authors openly embrace a certain type of paternalism. In fact, more than one placebo expert uses the analogy of a parent kissing “better” a child’s “boo-boo” to explain the expectancy effect of a successful placebo therapy. In a chapter entitled “Justifying deceptive placebos,” the ethicist Bennett Foddy argues that the placebo effect, deployed when a doctor expresses genuine concern for a patient, “involves a special case of deception, which is not subject to the same ethical objections as other forms of clinical deception,” provided that the doctor’s goals in deceiving the patient are shared by the patient.

So how does a doctor, like me, know what a patient, like Lillian, wants? The poet Claudia Rankine, in Don’t Let Me Be Lonely, defines loneliness as “what we can’t do for each other.” I suspect that Lown and the authors of Placebo Talks would assert that patients don’t want their doctors to let them feel that version of loneliness. Patients want their doctors always working toward some helpful intervention that reaches across the loneliness abyss separating the sick from the healer, even if this intervention is nothing more than an expression of empathy. “As every parent and child knows,” science writer Steve Silberman relays in his Placebo Talks entry, “a mother’s kind words or a ride on a father’s shoulders can be marvelously effective medicine — and the need for that kind of attention from someone we trust is something we never outgrow, even when the problems that ail us become enormously complex and daunting.”

¤

It’s reassuring to know that, along with their short white coats, stethoscopes, and scrub suits, medical students are being handed a copy of The Lost Art of Healing at the beginning of their long paths toward becoming a doctor. It’s reassuring to me as a doctor when I think about who will be my future colleagues, but it should also be reassuring to the future patients of these student physicians. Most patients want their doctors to heed Lown’s message. For example, a study at MD Anderson Cancer Center asked patients with a diagnosis of advanced cancer to watch one of two videos (the video assignment was random). Each video showed a professional actor, portraying a physician, discussing treatment and prognostic information with another professional actor, portraying a patient with advanced cancer who had received several lines of chemotherapy, had poor performance status, and was not a good candidate for additional therapy. In one video, the physician provided explicit information about the lack of further treatment options (video A: less optimistic). In the other video, the physician added vague information about possible future treatments, including a statement considering the possibility of further treatments if the patient improved in functional status (video B: more optimistic). The actors deliberately acted the same way in each video, with the same body language and delivery of both messages. After watching the videos, the patients were asked to rate the physicians’ compassion and professional performance. The physician-actors from video B (more optimistic message) had significantly better compassion and trustworthiness scores than the physician actors from video A (less optimistic message).

One interpretation of this study is that higher perception of compassion is associated with greater trust in the medical profession. Another interpretation is that physicians may be reluctant to give bad news because they don’t want to be seen as uncompassionate and untrustworthy. I’m not sure which interpretation applies to that afternoon in my office when I told a crying and lonely patient that I would re-dose a medication that clearly had not worked. Just as I’m not sure whether that second course of therapy helped or, in light of the results from the recent Proceedings of the National Academy of Sciences study, whether her recovery was due to an epigenetic change in her inflammatory genes initiated by my promise that she would get better. Perhaps Lillian and I were together harnessing what cultural anthropologist Daniel Moerman, in Placebo Talks, calls “the power of medicine’s ritual, narrative, and performance, which, more and more often, seem to trump its ‘evidence-based’ remedies.” Years after that appointment, when it was clear that Lillian’s recovery was going to be sustained, I reminded her about the episode in my office just before the second course of rituximab. She remembered that day as clearly as I did. I confessed I’d been bluffing and had no scientific reason to believe the drug would work. “Oh, who cares?” she said. “Whatever you did worked.”

¤

Andrew Bomback is a physician and writer in New York. His essays have recently appeared in The Millions, Vol. 1 Brooklyn, Ohio Edit, Hobart, Entropy, Human Parts, and Essay Daily.