Ron Winslow, 2005 Visiting Journalist
Visiting Journalist Program Home | Chelsea Conaboy, 2012 | Kevin Sullivan, 2011 | Dana Jennings, 2010 | Steve Damish, 2009 | Natalie Jacobson, 2008 | Barbara Walsh, 2007 | Jackie MacMullan, 2006 | Ron Winslow, 2005 | Donald Murray
The first Donald Murray Visiting Journalist:
Wall Street Journal medical writer Ron Winslow '71
Ron Winslow's week-long residency on campus in October 2004 inaugurated the new Donald Murray Visiting Journalist Program, which gives UNH journalism students the chance to benefit from the expertise of the program's distinguished alumni.
Ron has two titles at the Wall Street Journal: deputy news editor for health and science, and senior medical and health care writer. From 1978 to 1983 he was a journalism professor at UNH. During his 2004 visiting journalist stint, we kept Ron plenty busy. He spoke in every journalism class, held office hours, met with the editors of The New Hampshire, and gave a talk titled "The Bleeding Edge: A Journalist's Perspective on the Health Care Wars" that attracted lots of students, faculty, community members and Don Murray himself.
Among the long list of things that journalism students report learning from Ron: You can be a hotshot journalist and be nice. You can stay a Red Sox fan while living in New York. There's no substitute for deep, detailed reporting. You can use lots of numbers and technical info and still make people and plot the center of your work. Thanks to Ron, STORIFY, the Journal's word for finding the people who will bring an issue to life, is now firmly entrenched in the journalism-course lexicon in Ham Smith.
Ron's week as the first visiting journalist turned out to be a miracle of timing. A lifetime Red Sox fan, he got to watch on TV from a bar in Portsmouth as the Sox won the Series . . . during a lunar eclipse . . . on his birthday. Ron's wife, Larkin, reports that he was standing on a table and screaming. Ron claims it was only a bench.
Some of Ron's stories from the Wall Street Journal:
By Ron Winslow
The Wall Street Journal 8/2/01
DURHAM, N.C. -- Stephen Dedrick, chief of pharmacy at Duke University Medical Center, returned an urgent beeper message from his office one Friday morning to hear a startling report: His department had just ordered $250,000 worth of one drug, for delivery overnight from California. It was for a single patient. And it would last only through the weekend.
Even by the standards of the country's high-tech, high-cost health-care system, what followed was an extraordinary episode in American medicine. Over 34 days of treatment, the patient ran up a bill of $5.2 million. More than 95% of it was for drugs.
The patient, 69-year-old retired prison guard Slim Watson, had developed a rare disorder much like hemophilia. The only remedy was a complex regimen of blood proteins and other drugs that doctors hoped would halt his internal bleeding and restore his blood's ability to clot. Within days of his admission to Duke's 16-bed intensive-care unit, Mr. Watson was going through IV bags of clotting factor at a rate of $30,000 every four hours. The staff started calling him the million-dollar man.
Just getting the drugs to his bedside became a huge logistical challenge, involving pig farms in England, a biotech plant in Denmark and midnight trips to the local airport, where Duke staffers met planes flying in fresh shipments of medicine. Doctors, pharmacists and nurses went to great lengths coordinating Mr. Watson's care to make sure the highly perishable drugs were used with maximum effect and minimal waste. "This was like a transfer of gold from Fort Knox," says Peter Kussin, one of the intensive-care doctors.
Their treatment decisions had implications well beyond the fate of their patient. His extreme use of blood factors exacerbated a global shortage of one medicine, posing a risk that others needing it would be denied. And the case wreaked budgetary havoc as Duke Medical Center was in the midst of a cost-saving initiative.
There was little likelihood that reimbursement from Medicare and a private plan would cover all of the hospital's costs. "It was clear this was going to have an impact on our profitability," says William J. Fulkerson Jr., Duke's chief medical officer, who kept senior administrators abreast of the case as it progressed. "At the same time," he adds, "it was clear we were going to do what was best for the patient."
Mr. Watson, after a 31-year career in the Pennsylvania prison system, had retired and returned with his wife to their home state of North Carolina. They settled in a modest single-story brick home, where Mr. Watson started a garden growing Swiss chard and other vegetables. An Army veteran, he joined his local American Legion unit, serving for a time as its commander. Though bothered by diabetes, heart problems and psoriasis, he had no reason to foresee a medical crisis late last summer when he noticed some curious dark circles on his skin.
After a local hospital's tests showed he was anemic and bleeding internally, Mr. Watson was admitted to Duke Medical Center on Oct. 10. There, doctors diagnosed a condition called acquired factor VIII inhibitor. Antibodies produced by his immune system had begun attacking his factor VIII, a protein critical to blood clotting. Most hemophiliacs lack this blood factor congenitally. But each year, about 250 Americans with no previous clotting problems suddenly develop a factor VIII disorder, for reasons that are mostly a mystery.
Sometimes it is associated with cancer, but doctors found no sign of that in Mr. Watson. They couldn't figure out what caused his condition. But they determined he was bleeding somewhere in his gastrointestinal tract. And they told him early on that if they couldn't stop it, he wouldn't survive.
Still, the doctors were optimistic. Medicines developed over the past two decades have transformed treatment of bleeding disorders. About 75% of people with acquired factor VIII inhibitors are treated successfully, in most cases within a few days. "Usually you can get the bleeding stopped," says Thomas Ortel, a Duke hematologist. "Then you can treat the underlying cause of the antibody and the patient will frequently do fine."
One medicine is Hyate:C, a form of factor VIII derived from the blood of pigs. Made in Britain by Ipsen Biopharm Ltd., a unit of Paris-based Beaufour Ipsen Group, it has been available in the U.S. since 1986. But supplies have been crimped in the past five years by a virus infecting pigs throughout the world.
To avoid viral contamination, the company says it discards up to 90% of harvested pig blood in the initial stage of manufacturing. As a result, the blood of more than 20 pigs is needed to make one small vial of powder-like crystals. That is one reason Hyate:C's wholesale price is about $1,000 a vial.
A typical patient needs 15 to 24 vials just for the initial dose, Ipsen Biopharm says, with full treatment usually taking about 100 vials. "Whenever we get a [Hyate:C] patient, we know we're in for some big bucks," says John Kessler, Duke's deputy director of pharmacy.
Duke has had several patients with Mr. Watson's diagnosis in the past year. They all responded more quickly than Mr. Watson, one leaving the hospital in just 72 hours. Charges for these patients ran between $50,000 and $200,000.
Mr. Watson's case called for a second drug, a genetically engineered version of another blood factor, VIIa. Novo Nordisk of Denmark sells it under the name NovoSeven. In part because of the biotech drug's complex manufacturing requirements, NovoSeven costs $6,800 wholesale for one small vial.
Doctors also gave Mr. Watson steroids and a cancer drug. They frequently put him through a dialysis-like procedure called plasma pheresis, to try to filter out the culprit antibodies and allow his own factor VIII to revive. He needed repeated blood transfusions. And throughout his stay, he underwent numerous other tests and procedures aimed at finding out precisely where he was bleeding, in hopes that doctors could cauterize the area and stop it.
These tests were unavailing. When doctors inspected his colon, they found pooled blood but no lesions. High-tech X-ray and nuclear-scanning searches were inconclusive.
The doctors, nurses and pharmacists delivered all this care at a frenetic pace, and coordinating it became a daunting challenge. Once, a pheresis team gave Mr. Watson his blood-filtering treatment right after a nurse had given him a new IV bag of Hyate:C. Thousands of dollars worth of medicine was cleansed from his system and wasted.
Pharmacy officials, growing concerned about the intense use of expensive blood factors, brought the case to the attention of Duke's senior administrators. Like most nonprofit academic hospitals, Duke constantly wrestles with how to make ends meet while handling its various missions: care for both paying and indigent patients, plus ambitious programs of teaching and research. Squeezed by managed care and tight Medicare reimbursement, Duke's health system would have been in the red in fiscal 2000 but for investment income. On an operating basis, it lost $11 million on revenue of $1.11 billion in the year ended June 30, 2000.
Duke had just launched an initiative that sought to cut its projected fiscal 2001 drug spending by $4 million. As the Watson case grew more complex, one effect was quickly apparent: "It would take that initiative and throw it out the window," says Michael Burke, chief financial officer of the Duke health system.
Although Duke's top administrators rarely get involved in individual cases, this time they intervened. Mr. Burke asked for a special effort to document all decisions about care and account for every drop of blood factor, to put Duke in the best position for insurance reimbursement. Dr. Fulkerson asked his top specialist on blood disorders, Dr. Ortel, to oversee the use of blood factors. Staff members say none of the senior officials questioned the decision to treat Mr. Watson aggressively.
Despite the Hyate:C and his other treatments, Mr. Watson's bleeding continued after his first week at Duke. Doctors grew increasingly concerned that if they didn't stop it soon, he would turn irretrievably for the worse. Even though surgery could be fatal to a patient with bleeding problems, the doctors decided their best option was to remove the portion of his colon considered the most likely source of the bleeding.
Dr. Ortel's first major task was to order mega-doses of Hyate:C for Mr. Watson's postsurgical treatment. For several days after surgery, he went through it at a retail rate of more than $250,000 a day.
In the mixing room, where pharmacists and technicians prepare 2,000 custom doses of drugs a day, pressure was intense. Just 15 of the daily doses were for Mr. Watson. But each Hyate:C dose required as many as 30 vials, and fresh doses were needed every four hours.
As pharmacists reconstituted the powdered Hyate:C with sterile water, they had to take special care to prevent the mixture from frothing, which would reduce its potency. Just preparing Mr. Watson's medicines took up to four hours of staff time a day.
The pharmacy storeroom was busy, too. Duke keeps little Hyate:C and NovoSeven on hand. They are too costly and needed too seldom, and unused vials usually can't be returned. So throughout Mr. Watson's stay, the pharmacy had to get new shipments of at least one of the blood factors several times a week.
Hyate:C, which must be kept frozen until shortly before it is used, posed special problems: It had to be flown to Durham from Ipsen's distribution center in California packed in dry ice. Hospital staffers regularly made the 20-minute drive to meet planes at Raleigh-Durham airport, often in the middle of the night.
The task of coordinating much of this effort fell to Joanne "Bo" Latour, a clinical pharmacist who has spent her entire 15 year-career at Duke working with patients in the ICU. She attended the morning rounds at Mr. Watson's bedside, where Dr. Ortel and intensive-care-unit doctors reviewed his status and determined what tests, procedures and transfusions he needed that day. Dr. Ortel mapped out the blood-factor dosing plan, and then Ms. Latour worked with ICU nurses on timing of blood tests to make sure the results would be valid. She scheduled the pheresis team's procedures to avoid a repeat of the factor-cleansing mixup. She checked with the storeroom to make sure enough blood factor was on hand.
"This case tested our limits of being able to devote so much for one patient, without doing it at the expense of 700 other patients," says Mr. Dedrick, the pharmacy chief.
It was also a test for Mrs. Watson, 67, a tall, reserved woman who had worked as a clerical supervisor in a clinic. She visited her husband on the unit every day, often spending nights in the ICU waiting room. "It seemed like they were always doing something to him," she says. She was grateful for the care and particularly comforted that nurses were always attending to him.
She gave little thought to how much it all cost. "I was just hoping it would save his life," she says.
Shortly after Mr. Watson emerged from surgery, on his ninth day at Duke, the effort started to pay off. His blood count stabilized. His internal bleeding finally seemed to have stopped. For the first time since his admission, doctors, nurses and pharmacists began to think their patient had turned the corner.
To the staff on the 8200 unit, as Duke's ICU is known, Mr. Watson's progress was welcome news. The unit's 16 high-tech beds are nearly always full, mostly with desperately ill patients who have tubes in their throats and are unconscious or sedated. Doctors and nurses have few opportunities to get to know them.
Mr. Watson was different. Though seriously ill, "he was sitting up in bed talking to all of his health-care team," says Mr. Kessler, the deputy director of pharmacy. "He was not moribund with tubes and ventilators and at Death's door."
Despite all the procedures and discomfort, Mr. Watson rarely complained. When staffers passed near his room, he waved hello. He called one doctor "Smiley." He nicknamed a nurse "Sarge" after she took away a cracker he wanted to eat. He told Dr. Ortel he shouldn't have to come to work on a Saturday.
Though never told how expensive his care was, he knew of his "million-dollar man" nickname. More than once, he told his doctors he thought they should be spending the money on someone younger.
"He was very charming," says Loretta Que, the attending physician in the ICU during the early part of the case. "He appreciated what you were doing and he told you so." On weekends, Mr. Watson had a steady stream of guests, friends from his church and the American Legion in addition to family members, many in from out of state.
Staying comfortable was difficult. He used a trapeze-like bar attached to his bed to pull himself up and adjust his long frame. He was frustrated that he couldn't get out of bed. "That didn't suit him," Mrs. Watson says. "But he always stayed in a good frame of mind."
After the surgery, Mr. Watson's condition held steady for about five days. But on the sixth day, the beginning of his third week at Duke, he suffered a setback. His stomach hurt and his blood count dropped. The internal bleeding resumed.
Dr. Ortel determined that Mr. Watson was becoming resistant to the factor VIII from pigs, a common occurrence with extended use of the drug. He switched Mr. Watson to NovoSeven, the bioengineered blood factor from Denmark.
This one didn't pose the same delivery problems, but it had to be prepared more frequently. Mr. Watson continued to need transfusions, tests and procedures aimed at finding the bleeding source, all requiring intricate coordination. Once, Ms. Latour saw a technician from the mixing room deliver a $7,000 syringe of NovoSeven to the unit, but when a nurse went to use it, it was nowhere to be seen. After a nerve-racking search, Ms. Latour was about to order a remake when the syringe turned up, folded in the pages of the medical chart.
As costs mounted far beyond anything encountered before, even in other cases of acquired factor VIII inhibitor, Duke's pharmacists consulted colleagues at other institutions and scoured medical studies to see how any similar case might have been handled. "We found nothing that we could look to and say, at this level of cost, here are the guidelines," says Mr. Kessler.
On Nov. 1, Mr. Watson's 21st day at Duke, Dr. Kussin took charge of the ICU as part of a regular rotation among intensive-care specialists. Like others, he was immediately impressed with Mr. Watson's good-natured stoicism.
But within a couple of days, Dr. Kussin began to lose the enthusiasm shared by other members of the team for their patient's prospects. Mr. Watson hadn't regained bowel function after the surgery and he was being fed intravenously because he couldn't eat or drink through his mouth -- two critical indicators that he wasn't getting better. Doctors ruled out a second surgical effort to stop the bleeding. Even if surgeons could find the source, there was little confidence now that they could keep him from bleeding to death in the operating room.
With a fresh perspective on a case that others had been living with for three weeks, Dr. Kussin began asking the medical team during morning rounds how they felt about continuing the regimen of costly blood factors for Mr. Watson. Such questions are routine at the ICU, where 20% of patients die and many others are discharged to nursing homes where they won't recover from their illnesses. ICU staffers are often confronted with terminally ill patients hooked up to high-tech medical gear that isn't likely to do much good.
"There's a lot of waste," Ms. Latour says. "We talk about it a lot."
There are successes, too. During Mr. Watson's stay, Yvonne Spurney, nurse manager of the ICU, was herself a patient there, after aggressive treatment for cancer. She recovered and is back on the job. "We're not a glamorous unit," she says, "but we are people's hope."
When Dr. Kussin first posed his question about Mr. Watson, no one raised any doubts about continuing treatment. Though Mr. Watson wasn't getting better, he wasn't getting much worse, either. Kay Wellemeyer, a nurse on the unit, says she struggles with the ethics of high-cost care provided to comatose patients whose prospects appear dim. "I never felt that about him," she says.
Dr. Ortel also favored staying the course. Mr. Watson's heart, kidneys and other organs seemed to be holding up. Unlike some patients with coagulation problems, he wasn't bleeding from his nose or gums or even from the skin punctures for IV lines and blood draws. If they could just stop the internal source, Dr. Ortel reasoned, Mr. Watson would be in the clear.
Dr. Kussin deferred to Dr. Ortel and the others. As the attending physician, he says, he finds it's important "to let the rest of the team get comfortable that they've done everything they can."
NovoSeven, like the other blood factor, seemed to help, but not fully take hold for Mr. Watson. "There were times when he seemed to stabilize, and then he would start oozing again," Dr. Ortel says. "Just when we thought, `OK, we've turned a bend here,' the next lab result would be lower."
Then, on Nov. 9, Mr. Watson's 30th day at Duke, his condition suddenly worsened. His stomach and lower body swelled with blood. He became short of breath. His kidneys began to fail. After one last attempt to find a bleeding site, the medical team discussed the situation among themselves and with Mr. Watson's family.
"At that point, I think everybody agreed that we had tried everything we could," Dr. Ortel says.
Mr. Watson seemed to have had enough as well. "He said he got his spiritual side together and got his soul right with God," recalls Mrs. Watson, his wife of 46 years, tears welling. Over the next couple of days, his two daughters, his son, his two brothers and Mrs. Watson spent time with him one by one. "We told him if he wanted to go, he could," Mrs. Watson says.
The blood-factor treatment was stopped, and Mr. Watson was put on sedatives to ease his discomfort. On the afternoon of Nov. 13, with several of his family members at his side, he smiled and blinked. "Finally, he just closed his eyes," Mrs. Watson says.
In the end, what made the case so costly was the persistent uncertainty of its outcome. If Mr. Watson had been dying of another disease, use of blood factors probably would have been much more limited, his doctors say. If he had responded quickly, as often happens, he wouldn't have needed so much of them. For most of his stay, he was neither dying nor getting better. "Fifty-fifty cases are the toughest and most expensive to be in," Dr. Kussin says.
"As a business decision," treating Mr. Watson "wasn't a great one," Dr. Kussin concedes. He notes that "our hospital has always told us to spend what we need to take care of people." But as a physician who has also served as a senior administrator, he says, "This amount of money has never been put on the table before for one patient. When does a hospital have the right to say, `Time out'?"
Duke's insurance reimbursement from Medicare, plus a private plan, was $2.5 million. Hospitals have to accept this as payment in full. The family wasn't billed. In the end, owing to the complex way Duke bills for overhead and other expenses, it says it took a loss of $800,000 on the case.
The charges on the bill included $1.9 million for NovoSeven and $2.9 million for Hyate:C, the factor made from pigs' blood. Ipsen says it sold U.S. hospitals 10 million units of Hyate:C last year for 163 patients. More than 980,000 of those units, nearly 10%, were given to Mr. Watson alone.
Duke's final bill ran to 45 pages. The column where the charge for each item appeared wasn't wide enough for numbers higher than five figures and two decimal points. Daily six-figure charges for blood factors ran over into an adjacent column.
On the last page, the total reads: $214,333.50. The "5," as in $5 million, doesn't appear. The format couldn't handle a number that large.
(Copyright 2001, Dow Jones & Company, Inc.)
DNA Glitch Causes a Flaw In Babies, Then in Adults
The Appels' Misfortune
A Fruit Fly's Scientific Trail
By Ron Winslow
The Wall Street Journal 7/29/04
BATTLE GROUND, Wash. -- Eileen Appel and five members of her family, spanning four generations, were born with holes in their hearts. Each underwent surgery to patch up the hole and thought it was fixed. Years after the operations, her mother at age 48 and then her two sisters at 49 and 52 died. Just three years ago, her 35-year-old son succumbed as well. In each case, their hearts stopped without warning -- sudden cardiac arrest. Ms. Appel, 61, and her grandson Matthew, 20, both have had close calls. They now depend on devices implanted in their chests to keep the rhythm of their hearts under control. "We always knew there was something in our makeup that was wrong," Eileen says.
Scientists now have a name for it: a defect in a gene called Tinman. To the surprise of cardiologists, the same genetic flaw that caused the birth defect in all of the Appels also appears responsible for aberrant heartbeats decades later that can lead to heart failure and sudden death. The discovery of Tinman demonstrates a principle that scientists are encountering more and more as they pore over the genetic code of living things. "What we're learning is that Mother Nature has a limited repertoire of genes that can make organs," says Bruce Gelb, co-director of the cardiovascular genetics program at Mount Sinai School of Medicine in New York. "So she tends to use them for more than one aspect of development."
The identification of the Tinman gene also illustrates the interplay between basic research and patient care. The chance discovery of an unusual fruit fly in Michigan first put scientists on the trail of a culprit in heart defects, but it took careful observation of families such as the Appels to pinpoint that culprit's whereabouts.
So far, the work offers only limited benefits for people with Tinman mutations. Scientists are looking at potential targets for drugs that might alleviate effects of the mutation, although any treatment is probably many years off.
About one in every 125 babies is born with a structural anomaly in the heart. The heart has four chambers: two atria and two ventricles. People such as the Appels have atrial septal defects -- a hole in the wall, or septum, dividing the two atria of the heart. Other anomalies include a septal defect of the ventricles and a quartet of defects known as tetralogy of Fallot. In about two-thirds of cases, the holes in the septum heal on their own. But if they don't, they can sap energy, damage the heart muscle and lead to heart failure.
Today, thousands of children each year undergo hospital procedures to repair their abnormalities. Since the operations were first done in the early 1950s, advances in technology and technique have made it possible to patch up the holes without open-heart surgery in many cases. The procedures are an important reason why about one million Americans born in the last three decades with congenital heart defects are alive today.
For years, doctors have assumed that the repair was a cure. But over the past decade, cardiologists have been seeing some patients whose experience resembles that of the Appels. These patients had their hearts patched up during childhood and now are suffering new problems in their 20s and 30s, including heart-rate anomalies serious enough to require pacemakers and defibrillators. What's odd is that these problems usually involve the electrical signals that make the heart beat, not some leftover structural problem from the original surgery.
"There is a subset of patients where just having the surgery doesn't mean you're out of the woods," says Kenneth R. Chien, head of the Institute of Molecular Medicine at University of California at San Diego.
A recent Dutch study of 135 patients who had atrial septal defects repaired during childhood found that 8% had an irregular heart rhythm after an average of 26 years of follow-up, and 5% required pacemakers. A Canadian study published in 2001 tracking 242 patients with repair of the tetralogy of Fallot defects found that 29, or 12%, developed sustained heartbeat abnormalities later in life.
These long-term problems probably aren't caused solely by a single gene defect. Scars from surgery or a repair delayed beyond early childhood may raise the risk, cardiologists say, as can the role of other heart-related genes.
Commercial tests to detect the genes that might put someone in the high-risk subset aren't available, so it's hard for doctors to pinpoint the risk for a patient who had a heart abnormality repaired. Those with a family history of heartbeat irregularities and sudden death are at highest risk and should be regularly monitored, cardiologists say.
The heart is the first organ to form after conception, emerging by the seventh week as a four-chambered structure. The right side of the heart receives oxygen-depleted blood from the body and pumps it to the lungs. The left side takes fresh oxygenated blood from the lungs and pumps it to the rest of the body.
Because a fetus has its blood oxygenated by the mother's lungs, a small hole normally remains in the septum to let blood circulate efficiently through the fetal heart. Then, what Deepak Srivastava of the University of Texas Southwestern Medical Center describes as a "trap door" closes the hole around the time of birth.
Scientists believe this process is governed by a group of genes called transcription factors. They act like master switches, turning immature cells into specific parts of the heart. If the genes are defective, so is the heart's development.
In the late 1980s, Rolf Bodmer, a neuroscientist then at the University of Michigan, was examining fruit-fly genes in an effort to find master switches in the nervous system when he happened to find one that seemed active in the heart instead. Rather than cast it aside, he pursued the lead and eventually was able to observe embryos of fruit flies that lacked the gene. They didn't have a heart. He called the gene Tinman, after the Wizard of Oz character who lamented his lack of a heart.
A fruit fly heart is little more than a tube that circulates fluid around the body cavity. But soon after Dr. Bodmer published his discovery in 1993 other scientists found a corresponding gene in mice. By 1995 Australian researchers created a mouse without the gene. Such mice began to develop a heart in the uterus but it failed to progress into a four-chambered organ. The mouse fetuses died.
This led scientists to wonder whether Tinman existed in humans, and if so what its role was. A husband-and-wife team at Harvard discovered a surprising answer. In the mid-1990s, Jonathan and Christine Seidman started looking for families that shared a history of heart defects. They found a medical article from the 1970s that described a family in Pennsylvania in which 12 people over five generations had heart defects at birth, heart problems later in life or both. The Seidmans tracked down the article's author, who had retired, and through him the family. The Seidmans took blood samples from the Pennsylvania family but figured data from additional families would make their results more solid. That's when the Appel family with its history of heart problems entered the picture.
Eileen Appel was 14 and living in Los Angeles when she had a hole in her heart repaired. It was 1957, and she was told her chances of surviving surgery were 50-50. Her older sister had gone through it three years earlier. After their mother had the operation in 1960 at age 40, the three of them were featured in a local newspaper article as "boosters" for the annual Los Angeles County Heart Association fund drive. Eileen Appel's younger sister got the operation a few years later.
Their mother died suddenly in 1966, just 11 months after Eileen's son, Dennis, was born and discovered to have a heart murmur. Eileen, who worked as an administrative assistant in a government office, didn't have a symptom for 21 years following her surgery. One day in 1978, she began seeing black spots and stars while sitting at her desk at work. She went to the hospital in an ambulance and came out with a pacemaker in her chest.
"My sisters called me `bionic' and said I was paranoid about my health," she recalls. She had her pacemaker checked every year. Her sisters smoked and had high blood pressure, but never had pacemakers installed. They both died suddenly -- the older sister in 1990 and the younger sister in 1997 at age 52.
A doctor in Portland, Ore., who did an autopsy on the younger Appel sister mentioned the string of misfortune to Michael Silberbach, a pediatric cardiologist at Doernbecher Children's Hospital and Oregon Health and Science University in Portland. He had a friend who was working with the Seidmans at Harvard. Through that link, Eileen Appel was asked if her family wanted to join the Seidmans' study. She agreed, eager to know what was plaguing her family.
By 1998, the Seidmans had blood samples from more than 30 heart patients like the Appels and a similar number from family members without any heart problems. When all the samples were compared, it was a eureka moment. The people with heart problems all had mutations within a certain section of chromosome No. 5 of their DNA -- the place scientists had mapped the human version of Tinman, which is called Nkx2.5. Further analysis confirmed the gene as the culprit. These people had inherited one defective copy of Tinman and one normal copy from their parents.
By looking at what happened to the Appels and the other families, scientists concluded that the gene had a dual function: Before birth it directed the development of the heart, and after birth it maintained the electrical system that regulates heartbeats. The findings were published in the journal Science in 1998.
The next step was to figure out what was going wrong in the adults whose hearts were failing to beat properly due to the defective Tinman gene. A heartbeat is triggered by an electrical signal that causes first theatria to contract and then the ventricles. If the signals get mishandled, the contractions can go out of sync, forcing the heart to work harder and increasing the risk of irregular beats, heart failure and ultimately sudden death.
Mice with one mutated copy and one normal copy of Tinman -- the same as the people studied by the Seidmans -- would have been a natural model to study the electrical malfunction, but researchers hadn't found any obvious defects in such mice. At the University of California at San Diego, Dr. Chien had another idea. He engineered a mouse in which the Tinman gene was removed only in heart ventricle cells. The idea was to let the heart develop normally at first but disable the gene before it started playing its role in the heart's electrical system. Within 12 weeks of birth, the mice began to have irregular heart beats.
Their ventricles became abnormally enlarged, reflecting "a growth switch that was turned on and never turned off," Dr. Chien says. And the atrioventricular node -- a key switch that controls the movement of the electrical signal through the heart -- was small and abnormally shaped.
What wasn't known was what a Tinman mutation looked like in the human heart. Once again, it was time for the Appels to make a contribution to science.
One morning in 2001, Eileen's son, Dennis, raised himself from his bed on his elbows, tried to say something to his wife, coughed and slumped down on the bed. "It happened in a matter of seconds," says his wife, Vicki. "There were no signs." By the time paramedics arrived it was too late to revive him.
Dr. Silberbach in Portland asked the Appels for Dennis's heart. With their permission, he sent it to a pathologist in London along with the heart of one of Eileen's deceased sisters, which he had previously collected. The London pathologist found the left ventricles of the two hearts were substantially enlarged and the atrioventricular nodes were barely recognizable. Since the node is at the center of the heart's electrical signaling, that almost certainly contributed to the two Appels having died suddenly.
Around that time, Dr. Chien of UC San Diego came to Oregon to givelectures. He met with Dr. Silberbach and the two men discovered their mutual interest in Tinman. When Dr. Chien described the impact of the gene on the electrical systems of his mice, Dr. Silberbach replied that the effect on human hearts was the same. "It was a key moment," Dr. Chien says. "There's always a danger when you work with mice that the molecular mechanisms will be different than they are in humans." The two men agreed to incorporate the pathology findings on the Appels' hearts into a paper that Dr. Chien and his colleagues were preparing. The paper appeared April 30 this year in the journal Cell.
For all the progress, Eileen Appel and her grandson, Matthew, don't havea cure for their heart conditions. Eileen has a pacemaker that regulates her heartbeat while Matthew has a combination pacemaker and defibrillator to maintain a regular heartbeat and protect his heart from racing out of control or stopping. "I'm a normal person," says Matthew, who works at an electronics store. "If I could get rid of it, it would be great."
Further down the road is the potential for drug treatment. Dr. Chien has found that Tinman mutant mice had as much as 500 times the normal level of a growth factor called BMP-10 (for bone morphogenic protein-10). He wonders whether BMP-10 is causing heart tissue to proliferate excessively -- and if blocking BMP-10 through some yet-unknown drug could prevent at least some damage to the heart's electrical system.
It's too early to know whether that will pan out, but researchers believe that further studies of genes that control the heart's development will lead to targets for drugs. "People wonder why we study fruit flies, worms and zebrafish," says Dr. Silberbach. "Here, you've taken a gene you've found in a simple life form and identified it as a cause of important disease in humans. Then you study the mechanisms of the disease by recreating it in a mouse. It is a model for how the ideal genetic research should go."
(Copyright (c) 2004, Dow Jones & Company, Inc.)