Saturday, July 01, 2006

A Story of Science, a Story of Grief

Billy’s Halo: Love, Science and My Father’s Death

By: Kevin J. Tracey M.D.

Bill McKernan lived an extraordinary life as a British entrepreneur, successful businessman, expert golfer, widely liked friend, and beloved husband. He was his daughter’s hero. In Billy’s Halo: Love, Science and My Father’s Death, Ruth McKernan, Ph.D., an accomplished scientist who has spent her career studying the biochemical workings of the nervous system, details the numerous roles she was forced to assume at the end of her father’s life. She was the child of a sick parent, but also a worried mother, helping her own child cope with what was happening to a beloved grandparent. She was the communication liaison between her family and medical teams that spoke a complex new language rife with upsetting predictions, and she was a grieving scientist, grappling with uncertainty about the clinical data stemming from the disease processes ravaging her dad.

This book is McKernan’s chronicle of Billy’s illnesses, dissected into simple, factual prose, not at all unlike what you might find scrawled in the margins of Ruth’s laboratory notebook. Unlike a sterile lab notebook, however, Billy’s Halo places the science within the context of Billy’s life and times through anecdotes that bring both Billy and the science to life. The result is a compelling summary of what Ruth came to understand about her father’s life-threatening infection and leukemia.

Ruth, a neuroscientist at a British pharmaceutical company, remains first and foremost Billy’s daughter, writing to memorialize his achievements and successes. We learn of his roots when, after barely surviving hospitalization in intensive care for a septic infection, Billy leads his family on a final visit to Blairgowrie, in a farming region of Scotland, where he lived when he was a boy. Raised a postman’s son, Billy was justifiably proud of the business he founded and nurtured, Molecular Products, Ltd., a major manufacturer of chemicals that either absorb or produce breathable gases. The success of his company supported a comfortable lifestyle for Billy and his family. Nearing retirement, he passed business operations to his children so that his company would continue to provide for their families.

Ruth writes courageously as she describes her pride in her father’s accomplishments and her love for him, poignantly noting that his death crystallized these feelings. She credits Billy for providing the tools she needed to develop her scientific career of experimental design, data analysis, and teaching—the same tools that she applied to exquisite advantage in writing Billy’s Halo.

SEEKING HOW AND WHY

A perusal of the table of contents unveils chapter headings that promise a book with treatises on topics of singular complexity, including “Memory,” “Consciousness,” “Stem Cells,” “Genes,” “Stress,” and “Time.” The book lays bare overarching questions in these divergent fields, spanning cell biology, physics, immunology, biochemistry, and neuroscience. Ruth covers it all, because that is where her father’s story led her.

Billy’s problems started when he developed a bacterial infection in a pimple on his face, just under his left eye. Unfortunately, his immune system’s response to that typically trivial problem spun wildly out of control, spilled over into the bloodstream, and put him in a coma. He spent days in the intensive care unit, hovering close to death. Like the rest of her family, Ruth was overwhelmed by the suddenness and magnitude of the bad news that came daily from the doctors and nurses. Billy’s problems seemed to go only from bad to worse, when one organ after the next began to fail, as if they had teamed up and decided together to stage a revolt against all things homeostatic.

Writing later, she recalled: “With the benefit of hindsight, and my father’s unusual symptoms notwithstanding, everything begins to fit, such that, in the words of Sherlock Holmes, ‘a hypothesis gradually becomes a solution.’ Once I have done substantial reading, it becomes clear to me that everything my father endured can be accounted for by a bacterial infection. All the symptoms, the trauma, the whole gamut of bodily catastrophes, could be laid at the door of the dishonorable microbe and explained by ‘streptococcal toxic shock,’ a cascade of events that happens so frequently these days that it has officially become ‘a syndrome.’” 

“With the benefit of hindsight, and my father’s unusual symptoms notwithstanding, everything begins to fit, such that, in the words of Sherlock Holmes, ‘a hypothesis gradually becomes a solution.’ ”

This insightful description reveals the duality of this book: it is both Ruth’s heart- rending story about grief and loss and the product of her scientific inquiry and reading in search of the underlying cause of her father’s disease. Her father has been attacked by microscopic invaders that laid him close to death, and Ruth remains intolerant of partial, dogmatic, unsatisfying, and simplistic explanations. This great man could not possibly have been defeated by a pimple. She enters the fray by reading and writing, and her book reports her answers.

Motivated by her desire to understand Billy’s demise and explain it, she brings the science to life, with explanations that arise like a wellspring from her grief. As a scientist, Ruth knows no other way to proceed. She is driven by the need to understand what she knows, what she does not, and what is unknown by all. Her writing is discerning, objective, and accurate, rendering transparent her quest for answers about what happened to her fallen hero.

A DAUNTING ENEMY

The word “syndrome” originates from the Greek word for “a tumultuous concourse running together.” As defined by Stedman’s Medical Dictionary, a syndrome is “the aggregate of symptoms and signs associated with any morbid process, and constituting together the picture of the disease.” Billy developed his syndrome of toxic shock from an infected pimple, but I have seen patients who developed toxic shock syndrome from other types of infection, as in a case of complicated childbirth. Early in the disease, the patient with the pimple and the patient with the post-childbirth infection look quite different from each other. Once the signs and symptoms are full-blown, however, the original problem that incited the syndrome may be rendered meaningless, like a scratch on the face of a wounded soldier with a shrapnel injury to his heart and brain. Other problems take center stage.

Indeed, if all of the personal identifiers were magically sponged away or hidden from view, so all that remained was the clinical signs of the “syndrome,” then it would be impossible to distinguish one patient from the other as they lay in intensive care. Both would have a bright red rash on the face, fever, shock (dangerously low blood pressure), coma, failure of the kidneys, lungs, and liver, and intolerance of food. These aggregate constellations of seemingly unconnected signs and symptoms form the clinical picture of the syndrome.

Researchers studying the various syndromes caused by infection have begun to uncover proof that unifying mechanisms may explain these apparently unrelated biological failures, and that, surprisingly, the source of the problem lies within the immune system, not with the bacteria. Billy’s syndrome was started by infection with a “dishonorable” streptococcus that caused “toxic shock syndrome,” but infection with usually innocuous bacteria, such as E. coli, can also initiate similarly devastating syndromes, with names such as “septic shock” and “severe sepsis.” 

The uncontrolled attack kills indiscriminately, as bacteria and normal tissues alike become casualties. Even a relatively few bacteria replicating in a pimple or deep inside a bodily recess can switch the immune system into this frenzied, wild attack that damages the body’s own organs.Since the time of Pasteur and his germ theory of disease, scientists have recognized that bacteria can be the underlying cause of illness and that human diseases can be treated by eradicating the invading bacteria. Today’s antibiotics are extremely powerful, and the majority of appropriately treated bacterial infections can be cured with these drugs. But sometimes the antibiotics do not prevent the bacteria from aggravating the immune system to the point that it responds by suddenly throwing absolutely all the weapons it possesses at the germs. The uncontrolled attack kills indiscriminately, as bacteria and normal tissues alike become casualties. Even a relatively few bacteria replicating in a pimple or deep inside a bodily recess can switch the immune system into this frenzied, wild attack that damages the body’s own organs. Like firing a rocket-propelled grenade to kill a mosquito, weapons are activated in full regardless of whether there are five or five billion bacteria in the affected area of the body. Deadly molecules fill the region, attacking with impartiality, and the damage continues unchecked and unimpeded. Therein was Billy’s larger problem.

Once these so named “sepsis syndromes” have evolved to the stage of organ damage, antibiotics do not prevent that damage or improve the chances for survival. Antibiotics can eradicate the inciting germs, but if the bacteria have already activated the immune system attack, antibiotics provide little benefit. A deeply ingrained tendency in medicine is to focus on things that can be readily explained and understood, so doctor-family discussions at the bedside of a patient with a sepsis syndrome inevitably concentrate on the status of the pimple, or the pneumonia, or the urinary tract infection. Often these discussions studiously avoid the immune system’s fundamental, causative role in damaging the body. Usually the names of the syndromes are not even spoken; attention instead is rigidly fixed on the body part that may have been originally breached by germs.

Often these discussions studiously avoid the immune system’s fundamental, causative role in damaging the body. Usually the names of the syndromes are not even spoken; attention instead is rigidly fixed on the body part that may have been originally breached by germs.

Scientific advances in the past 20 years have begun to change this situation, and knowledge is spreading about the identity, function, and structure of molecules that damage the organs and kill the person affected by a sepsis syndrome. This new way of thinking about sepsis, in which the immune system supplies the damaging molecules, has emboldened scientists to develop therapies that neutralize the problem. Knowledge about these molecules and pathways has enabled the development of experimental treatments that can cure severe sepsis syndromes in mice and rats.

For example, it has recently become possible to cure severe sepsis in laboratory animals by administering an antibody that binds to a protein molecule named HMGB1. The goal would be to impair the production of HMGB1, which appears to play a lethal role in sepsis. High levels of this protein are released into the bloodstream during sepsis, and it begins to accumulate in the body’s organs. When this occurs, it causes the cells lining the organs to separate from each other and come apart, the result being a leakage of the normally intact barriers within organs that are critical to their function. As the physiological barriers between individual cells fail, water in the blood leaks into the air sacs of the lungs, urinary toxins and bile ooze back into the bloodstream, and bacterial products from the intestines leach into the general circulation. Even worse, as the damage in the organs progresses, the injured cells themselves release more HMGB1, adding to the problem and worsening the state of organ failure. The result is a widespread degeneration of normal physiology that underlies the clinical signs and symptoms of severe sepsis. In the future, it may be possible to prevent the damage caused by HMGB1 using antibodies that have been shown to prevent sepsis syndromes in laboratory animals. These experimental drugs are now being developed for clinical studies.

Despite the abundance of promising studies in animals, the reality is that this knowledge did not benefit Billy and cannot yet benefit other people who face a similar onslaught from a septic infection.

Despite the abundance of promising studies in animals, the reality is that this knowledge did not benefit Billy and cannot yet benefit other people who face a similar onslaught from a septic infection. Years of additional clinical work are needed before we will know whether HMGB1, or some similar molecule, is the cause of severe sepsis in humans and whether drugs that target its activities can be as effective in preventing organ damage for these people as they have been in laboratory animals.

SCIENCE AND THE EXPERIENCE OF LOSS

In Ruth’s account, we first meet Billy when he developed sepsis, but we soon learn that some years earlier he had been diagnosed with chronic lymphocytic leukemia, a cancer of the immune system that causes an accumulation of white blood cells. Ruth delves into the pathological underpinnings of this disease, explaining cell birth and cell death and the various ways in which cells can kill or be killed, including a form of cellular suicide termed “apoptosis.” Cancer develops if cells either are born too fast or fail to kill themselves on time. The reader is led through fascinating discussions of cellular biochemistry as Ruth seeks to understand the very end of Billy’s life.

In the end, Ruth confesses that her dogged pursuit of understanding the processes of death and dying did not ease the pain of her loss: “While Billy lay dying, I sought solace in science. But being a scientist spared me nothing; it provided no shield against fate, no defense against grief. Knowing how emotion affects memory could not keep out the vision of those last few breaths. Knowing how genes and development together could mold personality could not make me love my father more. No matter what we understand of the human mind, it doesn’t change what we are.”

The inspired writing and heartfelt stories give insight into how science and medicine move forward, often driven by the very personal motivation of the compulsive and curious investigator.

Though I recommend this book to everyone, I suspect that it will be most sought by students of science and medicine, and by patients, survivors, and families who are dealing with the same illnesses as Billy, sepsis syndromes or chronic lymphocytic leukemia. The inspired writing and heartfelt stories give insight into how science and medicine move forward, often driven by the very personal motivation of the compulsive and curious investigator.

Excerpt

From Billy’s Halo: Love, Science and My Father’s Death by Ruth McKernan. © 2006 by Ruth McKernan. Reprinted with permission of Joseph Henry Press.

I marked off the hours and willed myself to sleep last night, just to make time pass. By six o’clock I gave up and called the Intensive Care Unit for news. Hesitatingly, I called my mother, knowing that she would dread the sound of the phone. But I need not have worried: while I had waited until six, she did well to wait till five. And now I’m back there at his bedside because, well, what’s the point of being anywhere else?

I’m staring at the consistent lack of expression on my father’s face. He is totally unconscious. There is no jot of emotion, no pain, no frustration—no frown, no muscle tension at all. Being unconscious puts him in a state of unremitting peace, like a Morandi still life—reality with the color wrung out—or a silent 1950s home-video frozen in one restful black-andwhite frame.

…[S]tudying consciousness is one of the most exciting things going on in neuroscience today. It is now academically acceptable to work on the enigma of consciousness without being branded a heretic or heathen. For most of this century, scientists were reluctant; consciousness was a scientific taboo, the domain of philosophers. Before my father’s illness I would have said that the topic is ripe for research, back in vogue, a legitimate problem of biology and physics, like any other. But now, reducing it to a question of science is too impersonal to bear. It’s like watching a man drown while only reflecting on how hydrogen bonds make the water molecules around him liquid rather than gas.

It is noisily quiet in here with no human sound between the bleeps and clicks of cardiac monitors, infusion pumps and respirators. There is nothing else to do but think: think about how little we understand of what distances my father’s state so far from my own.



About Cerebrum

 
Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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