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Infobytes: Book Review

A CHRONICLE OF ONE FAMILY'S QUEST TO CURE ALS

Appel, Stanley H. MD

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Dr. Appel is Professor and Chair of the Department of Neurology at Baylor College of Medicine in Houston, TX.

His Brother's Keeper: A Story From the Edge of Medicine By Jonathan Weiner. 368 Pages • Ecco 2004

Don Quixote, meet Jamie Heywood. Seventeenth-century life and literature, meet 21st-century medical hubris – sometimes exercised by scientists practicing at the edge and sometimes by what one might do to save his brother's life. Don Quixote's quest is to destroy injustice, especially the final injustice – death. It is hard to think of someone better qualified than Jonathan Weiner to chronicle Jamie Heywood's quest to cure his brother Stephen's amyotrophic lateral sclerosis (ALS), and forever postpone this final injustice.

Weiner is a gifted science writer, author of the Pulitzer Prize-winning The Beak of the Finch, which chronicles two Princeton scientists recording changes in the beaks of finches in response to changes in weather and vegetation in the Galapagos Islands, and provides compelling evidence that Darwin's theory of evolution is as relevant today as in the past.

Now, in His Brother's Keeper: A Story from the Edge of Medicine, Weiner tells the tale of two brothers. Jamie, an MIT graduate, had never met a challenge he couldn't overcome. He is working at the Neurosciences Institute in La Jolla, responsible for turning the think-tank's ideas into money. His younger brother Stephen is unique in a family of academic overachievers. He is relatively laid-back and into physical challenges; and he is the one who develops ALS. Thanks to Weiner's eloquence, we have a unique rendering of this modern-day parable of passion and hubris, questioning whether we understand enough to engineer cures for diseases molecule by molecule, even if there were sufficient money, conviction, and bravery to stand at the edge.

Weiner sets the scene: “By the last decade of the twentieth century, the power of understanding had reached a point at which it was possible to view all of life as a project in molecular engineering, and the saving of life as nothing more than engineering and genetic carpentry.” With the birth of the cloned lamb, Dolly, we have reached the age of “irrational exuberance” in medicine and science. Weiner's introduction is worthy of a futuristic space odyssey moved to the present.

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THE DIAGNOSIS

In 1997, Stephen was working full time as a carpenter when he began to notice weakness in his right hand. By late 1998, further progression resulted in the full pattern of ALS. Jamie was sitting alone in an office he shared at the Institute when Stephen called from Boston to tell him that he had been diagnosed with ALS. Jamie's response to the news, poignantly described by Weiner, was to type the keywords “prognosis” and “ALS” on his computer. After he left the office, he was drowning in his emotions as he sat with his wife Melinda at sunset on a cliff overlooking the Pacific, chanting, “Let Stephen be healed! Let Stephen be healed!”

Melinda called Jamie “the Repair Man.” To save his brother's life, Jamie was determined to find the cure. He set a goal that would be daunting for anyone else, but not for him. Is this exaggerated self-confidence or true devotion? Jamie would educate himself to find that cure. He returned to Boston, set up a private foundation, the ALS Therapy Development Foundation, and committed himself to developing the ultimate repair.

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GENETIC ENGINEERING

In 1999, genetic engineering was the answer he was seeking. But, what was the gene that needed to be replaced in ALS? He was soon convinced that the defective glutamate transporter in ALS patients, reported in a series of elegant papers by Jeffrey Rothstein at Johns Hopkins, was the right target. He enlisted Rothstein's help as well as that of Matthew During, who had just arrived at Jefferson Medical College in Philadelphia to head the CNS Gene Therapy Center.

Money needed to be raised, and the first fund-raiser featured Melinda, who had earned her way through Wellesley as a belly dancer. Jamie reveled in demonstrating how to insert bills into the sequined girdle with the same gusto as orchestrating the scientific enterprise.

In the spring of 1999, there were many genetic engineering successes to emulate, all of them in mice. Progress in humans had minimal, if any, success. Nevertheless, Jamie was convinced that packaging the glutamate transporter gene in a viral capsule, then injecting the particles into his brother's spinal cord was the answer. Matt During would develop the construct, and a neurosurgeon would do the injections. What was most amazing was Jamie's ability to convince so many scientists to follow his lead, which Weiner euphemistically portrays as “the rhythm of the charming sell.”

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THE ‘SALES PITCH’

As the narrative unfolds, we realize that Weiner himself was not immune to Jamie's sales pitch. He became close to the Heywood family, and accompanied Jamie on his many trips from Boston to Baltimore to Philadelphia, asking himself whether he was viewing hype or science at the edge. Was Jamie in way over his head? This was particularly difficult for Weiner to answer objectively, when he realized he had a personal stake in the outcome of Jamie's quest. Weiner's own mother had begun showing signs of a neurodegenerative disease characterized by frontal dementia and parkinsonism that was subsequently diagnosed as possible Lewy body dementia.

“If Matt During could make a vaccine against ALS, I wondered if he could also make a vaccine against Lewy body dementia,” thought Weiner. In true entrepreneurial spirit, Matt During was quick to oblige for a price. He told Weiner he would need $10,000 for the animal tests. Weiner began ruminating on how his work as a science writer could actually save his mother, and “clear up whatever had fouled her inner weather for the last dozen years.” Unfortunately, none of these wishes were ever realized.

Money was clearly a focus for both Jamie and Matt. They needed it to realize their dreams of a gene therapy for ALS, and quickly learned that at least half of the gene therapy trials were financed by private funds. This was 1999, and irrational exuberance on Wall Street had spread into everyone's thinking. So, Jamie and Matt decided the best way to proceed was to form a biotech company.

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REALITY INTERVENES

Reality intervened in the unfortunate outcome of an adenovirus-encapsulated gene-therapy study that had been devised by Dr. James Wilson at the University of Pennsylvania to treat a young man with ornithine transcarbamylase deficiency. Following the infusion, the patient developed severe inflammation and acute respiratory distress, shutting down his organs. The patient's father decided to remove his son from life support, and his son died. Gene therapy trials throughout the country came to a screeching halt. It did not help that Wilson had a large stake in a biotech company that stood to profit from the gene-therapy trials.

Jamie and Matt still had not been able to develop the appropriate construct for ALS, and their dream of an ALS gene therapy was put on hold. Ever the entrepreneurs, they switched to stem cells as a therapy for Stephen as well as for other ALS patients. Subsequently, Stephen's own hematopoietic stem cells were injected into his CSF. Fortunately, there were no untoward effects of the therapy, but neither was there any benefit.

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HYPE AND HOPE

In this modern-day parable of hope, Weiner found it difficult to distinguish between hype and hope. What initially seemed like hope was ultimately transmogrified into hype. Weiner wanted Jamie to save Stephen, but he recognized in the writings of The New Yorker staff writer, Jerome Groopman of Harvard Medical School, the conclusion he reluctantly had to accept: “Expect progress, not miracles. Dreams become reality through hard labor at the laboratory bench and at the patient's bedside. Promises are fulfilled by cobbling together increments of knowledge drawn from the many corners of biology and medicine. A roller-coaster ride is dramatic and dizzying, but ultimately returns us to our starting point. Genuine scientific progress is made on a steady chugging train that at times feels frustratingly slow, but delivers us to our destination.”

Jamie is the focus of the story, the quixotic elder brother who seductively intrigues and charms us, but ultimately leads us back to our starting point, looking for “the cure.” Tremendous resources had been raised and expended, and it is hard to define the true progress that was accomplished by Jamie's efforts.

The real hero is Stephen, as he lives with ALS and struggles in courageous silence despite inexorably progressive weakness. Stephen personifies the ALS patient that many of us dedicate our professional lives to helping. He is the unrelenting optimist willing to do everything to help others, the truly “nice guy.”

Early on, Weiner catches the spirit of the ALS patient: “Jamie was masterminding a war, while Stephen was calling friends from Alaska to Corfu to tell them the news [of his diagnosis] and make plans to get together. His friends could not understand how he could keep his good nature.”

In the final scene, Stephen has lost his ability to speak. He is sitting in his motorized wheelchair with his son Alex in his lap, content to hear his computer read aloud each page from the Maurice Sendak book, Where the Wild Things Are. As this magnificently rendered true-life tale ends, we wonder about Jamie, but we know that Stephen is comfortable where he is.

Figure. His Brothers...
Figure. His Brothers...
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©2004 American Academy of Neurology

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