From Scientific American
Not long ago I got an e-mail from Nikki. My high school friend turned lawyer now communicates solely by laptop, propped in an electric wheelchair, twitching her lip to activate her keyboard. She is fed through a stomach tube, and a ventilator breathes for her 24/7. If a fly lands on her face, she is powerless to brush it away. Nikki has amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease. So do 30,000 other Americans, of whom 8,000 die every year. Stephen Heywood, a six-foot-three carpenter from Boston, was 28 when his motor neurons began to fail. The earliest clue was subtle: he lost his first arm wrestling match in years to his older brother, Jamie. Then he couldn't turn a key in the front door of a house he was restoring. A year later he stumbled and pitched headfirst down a stairway. ALS is nothing if not relentless. Jonathan Weiner's latest book, His Brother's Keeper, is about ALS plus much more. Part biography, part autobiography, it deals with a family's journey into a previously unimaginable realm, Gen Xer Jamie Heywood's desperate desire to use genetic and stem cell technology to turn the tide of Stephen's disease, the author's coming to terms with his own mother's agonizing decline from another form of nerve death, and the current era of "anything is possible now" science. Weiner won the Pulitzer Prize for his 1994 book about evolution, The Beak of the Finch. In His Brother's Keeper, his prose is just as graceful and steady but far more personal and revealing. Like his subjects, Weiner is also on a journey. Clearly, a kinship links the author and the Heywood brothers. For one thing, they share eerily similar intellectual roots. Stephen and Jamie's father is a mechanical engineer on the faculty at the Massachusetts Institute of Technology (Jamie also graduated from M.I.T. with a degree from his dad's department). Jerome Weiner, Jonathan's father, is an engineering professor at Brown. In the course of the book, Weiner asks his father about Jamie's extreme makeover from high-tech entrepreneur to guerrilla bioscientist. His father replies by likening genes, DNA and protein to any other system--a pulley, a circuit, an engine. At which point the writer adds drily: if what has broken is nothing but a system made of molecules, engineers try to fix it. Unfortunately, ALS is not that easily fixed. When Stephen was diagnosed in 1998, the only FDA-approved drug for the disease was a glutamate blocker (glutamate is a chemical that carries signals between the brain and the spinal cord but also damages the nervous system when released in excess). Convinced that repairing the glutamate transporter protein system is a hopeful tactic for ALS sufferers, Jamie and his scientific collaborators Jeffrey Rothstein of Johns Hopkins University and Matt During of Jefferson Medical College plan to insert the corresponding gene in Stephen's cells. Until fate works against them, that is. A teenager with a rare metabolic disease dies after undergoing experimental gene therapy, Jamie's project is tabled, and During proceeds to plan B: injecting millions of stem cells into Stephen's spinal canal. I longed to hear more from two voices throughout this otherwise fine and moving book. Over a 25-year career, Robert Brown, the ALS specialist at Harvard Medical School who diagnosed Stephen, has led thousands of patients where no one wants to go: the edge of a cliff looking straight down. His perspective would have balanced Jamie's frantic race for a magic bullet. The other voice I missed was Stephen's. Not his matter-of-fact statements, which do weave through the narrative, but his inner thoughts. Was this omission dictated by Stephen himself or the author's delicacy, I wondered. The 1990s--officially deemed "The Decade of the Brain"--did yield remarkable new facts about the human nervous system as well as breakthroughs in ways of reengineering cells. What is both poignant and telling is Jamie's (and possibly Weiner's) notion that science might, as a result, rescue ALS victims on a specific timetable. Medical miracles do not obey timetables, even in an era of quantum scientific leaps. But there are other miracles in this book and in the lives of ALS patients. In 1999 Jamie Heywood launched a fledgling organization called the ALS Therapy Development Foundation. Today it is well funded and staffed, supporting a number of important research efforts. Stephen Heywood married and had a child, despite the inexorable progress of his disease. And Nikki, my dear friend, continues to engage with life: electronically overseeing her household; cheering husband, family and friends; attending her kids' school and sports events and a biweekly book club. In ALS, the triumph of the human spirit is the greatest miracle. His Brother's Keeper may focus on the promise of science, but the mystery of transcendence also speaks from its pages loud and clear.
Claire Panosian Dunavan is professor of medicine and infectious diseases at the David Geffen School of Medicine at U.C.L.A. and a medical writer.
From The New England Journal of Medicine
Jonathan Weiner is a talented science writer. He won a Pulitzer Prize for his book on Darwin's finches and a National Book Critics Circle Award for one on the genetics of behavior in drosophila. Here he tells the poignant story of Stephen Heywood, a carpenter whose right hand became weak in 1997; he was 28 years old. The diagnosis of amyotrophic lateral sclerosis (ALS) was confirmed later; only 5 percent of all people with ALS have symptoms before the age of 30. Also known as Lou Gehrig's disease, ALS is incurable and lethal. Stephen's brother, Jamie, was working as an assistant to Nobel Prize winner Gerald Edelman at the Neurosciences Institute outside San Diego, California. An engineer trained at the Massachusetts Institute of Technology, Jamie Heywood was hired to bring think-tank discoveries to market, and with his commitment to saving his brother's life, he came upon the idea of gene therapy. Weiner heard about the plan from a neuroscientist friend and was himself primed for the project. He had promised to write an article for the New Yorker, and he had a personal interest: his mother had been diagnosed with another nasty neurologic disease, a parkinsonism-behavior-dementia disorder, also incurable. Weiner contacted Jamie Heywood and rapidly became part of the project himself. He was attracted by the pursuit of an idea at "the edge of medicine," a fuzzy line where hope blurs with harsh reality. Jamie created a foundation to develop the idea. He enlisted the aid of two of the most outstanding ALS investigators: Robert Brown at Harvard, who had confirmed the diagnosis, and Jeffrey Rothstein at Johns Hopkins, who had found that the malfunction of a particular gene in ALS could result in the accumulation of glutamate, a natural neurotransmitter; an excessive amount of glutamate could be toxic to motor neurons. Jamie also found Matthew During, a Philadelphia neurosurgeon, who would insert corrective genes directly into Stephen's spinal cord. Weiner tells the story as though it were powerful fiction by focusing on the personal aspects of the case but not ignoring the social issues. In the end, gene therapy was halted when a teenage volunteer in a trial at the University of Pennsylvania died. So instead of the gene, Stephen's doctors injected stem cells into his cerebrospinal fluid; this was not harmful but gave no benefit. Some call it "guerrilla science" when families direct research themselves because they are impatient with the bradykinetic pace of conventional research. It can take years to develop an experimental approach, prepare an application for funding, wait until the application is reviewed and revised, and finally get started on the research. Stephen's family did not know how long he would live. In fact, he is still alive in 2004, but at the time it seemed that he might live only a year or two. They were understandably in a hurry. Rothstein was involved at two levels. His research findings had provided the idea of gene therapy. By the time that approach was scratched, he had become a leader in stem-cell research. Throughout the book, Rothstein is quoted as a voice of caution; animal experiments should precede human application, he warns, to ensure safety and to provide evidence of efficacy. In the end, Jamie Heywood raised millions of dollars -- a story in itself. His foundation's Web site now lists six doctoral scientists who focus on "high-throughput drug development" and screen thousands of compounds already approved for other uses by the Food and Drug Administration. The trick is to develop an assay that reliably predicts which drugs could be beneficial in treating ALS. Among the questions raised in the book are whether the company could raise more research money as a for-profit or a nonprofit entity, whether someone with a deadly disease can give truly informed consent to participate in risky human experiments, whether nonscientists can "pick something to do that the researchers in the field didn't pick," and whether conventional science is too timid in moving from laboratory to sick people. Can we learn from this experience? Stephen's hope rests on the remarkable progress made in the past decade and now accelerating worldwide. Most funding comes from the National Institutes of Health; private donors choose from organizations like the Muscular Dystrophy Association or the ALS Association, family sponsors like the Heywoods or the Estess family's Project ALS, or medical schools. Supporting fundamental ALS research is laudable in all these approaches. In the meantime, both of the Heywood brothers have married and had children. Readers will appreciate their fascinating story and will certainly join them in the hope that basic research will pay off. All of us who are engaged in patient care and research in ALS devoutly believe it will, but when? Lewis P. Rowland, M.D.
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