At the country’s largest treatment and research center for cystic fibrosis, time slips away for a patient and his wife, while a doctor and his staff work obsessively to give it back.
The slide into third was ugly. John Anderson knew it was going to be bad, knew it instinctively, because he’d played enough ball in his 30 years to recognize that the blonde woman’s approach was disastrous. In recreational softball, most days you go home with a bruise or a scrape or two, nothing major. This wasn’t going to be that kind of night for Lisa Hampton, he was sure of it.
She turned the corner at second and prepared to slide into third, and Anderson, who was playing second base, prepared to hear the snap of a ligament or the crack of an ankle. Dust flew. Anderson cringed. Then he looked up. Darned if this Lisa girl his friends had wanted him to meet didn’t pop right up like a Little Leaguer, good as new, defiant as the devil, ready for the call to come home.
“That’s what first caught me about her,” said Anderson. “Something about the way she bounced back so quickly. I said to myself, ‘This is someone I’d like to meet.’ ”
They talked after the game. He invited her out on the first of many dates. Then one evening, nervously sitting on his couch, he figured it was the right time to let her know. So he pulled out a newspaper clipping and told her about the research treatment he was about to undergo at UNC. He told her, not knowing if she would turn and run or stay and listen, that he was a man walking around with a child’s disease. He was sliding, too, he said; and he didn’t know how ugly it could get.
One night in March, just two months earlier, Anderson, an elementary school physical education teacher, got in his car and drove himself to the hospital in Hickory. That was his way – independence. He felt no need to trouble anyone else; after all, this was just a small stomach problem, his problem. He was certain the doctors could fix what was wrong with him and send him home. He discovered that he had a bowel blockage. That was fixable. What they couldn’t fix was what had caused it: the fluids that couldn’t flow though his body, the oxygen that couldn’t get through to his organs, the impurities that wouldn’t wash out, and the way all three of those things eventually would conspire to end his life.
“When the doctor first told me I had cystic fibrosis,” said Anderson, “I just looked at him, shrugged my shoulders and said, ‘OK. So?’ I didn’t know what it was.
“And he looked back at me and shrugged his shoulders, too, and threw his hands out, palms up, and said something to the effect of, ‘I don’t know what can be done for you.’
” ‘I don’t know what can be done for you,’ ” Anderson says once more, 20 years later, the same bewilderment stretching beneath his watery eyes and across the thinning, ashy skin of his 50-year-old face.
And then he shrugs his shoulders. Just like that.
Oh, but those three words, that shrugging – they imply a simplicity, and there is nothing simple about this disease.
There are some things that we know about cystic fibrosis. We know, for instance, that it is a genetic disease, a cruel gift of one defective gene from each parent. We know that one in 31 Americans is an unknowing, symptomless carrier of the defective gene. We know that if both parents are carriers, their children stand a 25 percent chance of being born with CF; a 50 percent chance of becoming a carrier; and a 25 percent chance of being a non-carrier.
We know that it causes lung airways to fill with a sticky mess of impenetrable mucus that leads to deadly infections and that it can create a litany of digestive problems.
We know that it cannot turn itself off – yet.
But for all we know about cystic fibrosis – and compared with 60 years ago, that knowledge is considerable – it is the unknown that still kills about 400 people each year, without fail, in a most injurious and methodical fashion. It is the unknown that makes the clock tick faster for both patients and researchers. Nowhere is this ignorance more haunting, more palpable, than in a little corner of the world off of Manning Drive in Chapel Hill.
Richard Boucher is today the director of UNC’s Cystic Fibrosis Research and Treatment Center because of his middle daughter. That fits the scenario with a disease like CF; those who live within its grasp usually do so because it has achieved a personal hold on them. For although it is the most common fatal genetic disorder in the United States, CF afflicts only 30,000 people nationwide – just 0.01 percent of the population. That’s hardly the sort of consumer base that attracts scientists and pharmaceutical companies looking for glory or profit.
And Boucher, a Yale graduate with a Columbia medicine degree, was studying the much more common and treatable problem of asthma in 1977. He was a young man with a young family, completing pulmonary medicine and research fellowships at the Royal Victoria Hospital and McGill University in Montreal, when his path in medicine began to turn toward an orphaned disease.
“My daughter, just before we came down to Chapel Hill, had four right upper-lobe pneumonias in the first year of life,” said Boucher, who also is a Kenan professor of medicine at UNC. “I hadn’t a clue what CF was about then. But if I had, I would have been terrified. That’s a very common finding in kids with CF.”
Boucher’s daughter tested negative for cystic fibrosis. Boucher went back to studying asthma in athletes. In Chapel Hill, he started looking at the airways of asthmatic lungs vs. normal lungs, using probes to discover how salt and water were regulated there and what role they played in triggering asthma attacks.
And then, one day in the lab, something made him think of CF; of how devastating he’d learned it was; of how 1,000 sets of parents that year would be told that their child might live long enough to walk but never to drive; of how he and his wife, if not for the grace in their genetic dance, came close to joining them.
He wondered: What if? And then he said, Why not? It might just work. He used the same electroprobe-like device he had employed in asthma patients in the lung airways of CF patients. “Sure enough, CFs [salt and water regulation] were different in a way we hadn’t expected, and wildly different than normals,” said Boucher. “At that point, asthma sort of disappeared off the radar.”
Boucher’s entrée into the CF world in the early 1980s coincided with the beginning of the era of modern understanding of the disease, which had long confused those few researchers who bothered to study it seriously. Until then, there were few leads about what caused CF and little funding to facilitate the research. Gradually, things were starting to change.
Although CF has been around for centuries, it was first named in 1938 by a New York doctor after hundreds of infants and children were brought into hospitals during a particularly steamy summer, their foreheads crusted with salt. Whenever mothers detected salty sweat on their children, it was an indication that they had the fatal disease.
CF causes the body to produce an abnormally thick, sticky mucus, due to the faulty transport of sodium and chloride (salt) within cells lining organs such as the lungs and pancreas. In the pancreas, the mucus prevents enzymes from reaching the intestines to help break down and digest food, a problem treatable with oral supplements.
But in the lungs, where oxygen is distributed, the mucus build-up cuts off the air supply that organs need to function, placing strain on the heart. Meanwhile, bacteria settle into the mucus in the lungs, yielding the deadly infections that kill 95 percent of patients.
Still, mucus build-up wasn’t an issue in the sweat glands, which meant that CF’s attack on the body wasn’t caused solely by an overproduction of the sticky mess. That’s what stumped researchers.
“The thought had been that it was sort of something that was in the blood,” recalls Boucher. But his probe tests, which measured electrical charges across epithelial cells – cells that line tiny membranes that cover surfaces of the body and its organs – found the same large negative charge across all the epithelial cells in surfaces affected by CF. For the first time in history, all the organs ravaged by CF had been linked by a common abnormality. That was 1981.
Today, UNC is renowned for both its treatment and its research in CF, thanks in large part to Boucher’s guidance. In 2000, Boucher’s $5.1 million in National Institutes of Health grants put him on the top 10 list of federal funding in all areas of basic research nationally. And its teams have made some large contributions toward the fundamental bank of knowledge that CF centers worldwide now draw from as they continue to work on the disease, including developing the first CF mouse model in 1992.
Its infrastructure reflects national prominence in every facet of cystic fibrosis study. UNC’s CF care center is one of eight Therapeutics Development Centers, designated by the nonprofit Cystic Fibrosis Foundation to coordinate clinical trials of new treatments. It is home to the first-of-its-kind CF National Bioinformatics Center, where genomics research conducted around the world is consolidated in a central location to promote sharing among scientists. The UNC care center has been part of the 10-member CF Research Development Program since it began in the 1980s as a cooperative effort among scientists to maximize their collective expertise on the disease. It is one of seven CF Foundation-designated Gene Therapy Centers, and it recently won a grant for proteomics research.
It’s an impressive list. But what UNC hasn’t done is hit the research jackpot. It hasn’t come up with an original, approved treatment that stems the disease’s tidal wave.
“They’re one of the first research centers in the United States credited with laying the groundwork for the kind of knowledge that has been used to learn more about this disease,” says Bob Beall, president of the Cystic Fibrosis Foundation, a bulldog-like charity that distributes $60 million in grant money each year. “That’s been picked up by others and exploited elsewhere. But it would be wrong to say that they have developed anything at UNC that has contributed directly to increasing the life span of CF patients.”
“He’s right,” says Boucher with a good-natured laugh. “He’s absolutely right.”
Beall reserves his accolades for treatments such as DNase, an aerosol enzyme treatment that reduces the stickiness of mucus; as well as antibiotics like the TOBI inhaler, a tobrimycin solution that lessens lung infections. But Boucher, who calls Beall a good friend, said he isn’t bothered by the powerful foundation head’s statement. His laugh doesn’t imply nonchalance. It’s merely the confidence that he has in his current work talking. Twenty-five years after the scare with his daughter, Boucher said he and his lab are so close to saving CF lives, “so tantalizingly close, that it’s maddening.”
Boucher favors the much slower path of prevention to the quicker return-on-grant-investment remedies that the CF Foundation sometimes seeks.
“Right now, what the CF world is best at is killing bacteria in the lungs. This is why these kids get IV antibiotics, and they get these inhaled antibiotics like TOBI or whatever,” Boucher says politely but dismissively. “But in our view, these are important treatments, and we use them here. But they are rescue-type therapies. They try to rescue patients from the mucus thing. What we would like to do is deal with the front-end problem and prevent it.”
Ultimately, the way to do that is with gene therapy. When the mutation in the gene responsible for CF was found in 1989 after 10 years of study by Francis Collins ’77 (MD), now the head of the Human Genome Project at the NIH, and Lap-Chee Tsui at the Hospital for Sick Children in Toronto, the world may have thought a cure would soon follow. CF doctors and patients knew it wouldn’t be that easy.
Still, in Chapel Hill, they were among the first to try. And they made history in 1995 when they published a study in The New England Journal of Medicine that outlined why they failed.
Because it takes two abnormal genes to set CF into action, gene therapy for the disease revolves around the idea that replacing the defective cell with a normal copy will fix all that is insidious about CF. Boucher and the other researchers used an adenovirus, which seeks out cells to attack, as the mode of transport for their healthy cell, applying it to nasal airways of 12 patients who were kept in isolation for 15 days.
“It just turned out that the body’s innate defense mechanisms are awfully good against keeping foreign DNA out of the body,” says Boucher. He is now co-directing, with UNC Gene Therapy Center head Jude Samulski, new gene therapy studies in lung disorders, thanks to a $9.2 million grant received from the NIH last December.
“It will work. It’s just going to take some time,” he said. “It may take another five to 10 years, but the study was successful in one sense because we proved what didn’t work. We know that now. It helped the whole scientific community move on.”
What he didn’t know
John Anderson knows something now, too; it’s the same thing that his first doctor believed. He should have died 48 years ago. That’s what happened to children born in 1952 with cystic fibrosis. You lived for maybe two years before your lungs gave out. In truth, CF had been chasing Anderson for some time; he just never bothered to look over his shoulder.
“I can distinctly recall sitting in first period every day in high school, and just coughing the whole time,” he recalls. “And then it would stop. I wouldn’t have it the rest of the day.” He had no other symptoms to alarm his parents, save for nasal polyps he had removed that were attributed to allergies, so they assumed there was nothing more to it, and their son assumed his cough was just part of who he was. They had little money to spend on medical checkups, but John was never seriously affected by the disease. His mother suffered a miscarriage between John and his younger brother, Walter, but to the best of his knowledge, none of his relatives ever had CF.
So John grew up strong and by all accounts healthy, playing Little League in his Miami neighborhood, running track, living for athletics. He earned a degree from Lenoir-Rhyne College, got a dream job teaching physical education in Hickory and relished the independent life of a bachelor.
Until that night in March 1983. It was difficult for John to know at first what shape his future would take. He said as much to Lisa, who now works from home as a freelance office manager for medical clinics. He feared the disclosure would be too much for her.
“I was worried,” he says. “I didn’t even know at the time what I was in for, and I didn’t know if it would change the way she felt about me.”
For several years after his diagnosis, Anderson still had no serious trouble. He took two weeks off from work and then went back. He and Lisa spent much of their time enjoying the same kinds of team sports and physical fitness that had brought them together. The knowledge that he had CF didn’t slow John from the normal course of adult life; in fact, if anything, it may have deepened it for him.
He didn’t know, he said, just how much he needed Lisa until he met her, how important companionship was in life. Before he got sick, “I never had much use for marriage,” he said. “But I guess it just puts life into perspective. I know now that I never would have survived all these years without her.”
It wasn’t until 1996 that he took a turn for the worse. That was when the catheter that had been inserted in his chest to pump in the more-frequent antibiotics now needed for his lungs became infected with aspergillus. The medicine doctors used to treat the fungus, amphotericin, is so powerful that it can cause kidney damage. In Anderson, it did. He is now on dialysis.
Anderson is one of 200 patients under UNC’s care at its Adult Cystic Fibrosis Clinic, which is in itself an existential triumph. Thirty-nine percent of CF patients in the U.S. are older than 18, and about half live into their mid-30s, thanks to research that has produced better treatments, better care and a more visible fight against CF. Soon, said Anderson’s physician, James Yankaskas, adults will represent the majority of people with cystic fibrosis.
There are about 60 such adult treatment centers in the United States today; the one in Chapel Hill is not only the largest, and one of the first; it also is widely hailed as the best. “It’s the environment in which care is given that makes UNC so good,” says Bob Beall. “They have a full-team approach.”
Adult CFers’ burgeoning numbers caused health-care providers to re-think the way CF patients were treated beginning in the early ’90s, when Yankaskas and colleague Michael Knowles, co-directors of the UNC program, foresaw the demographic shift and drew the blueprint for the adult center in Chapel Hill. Typically, the only physician a person born with CF ever saw was his pediatrician – and by the same token, pediatricians were the only doctors with specific medical training to deal with CF and know when to recognize its symptoms.
“Most people would rather be treated in an age-appropriate facility,” says Yankaskas. “At the places where they are slow to develop adult programs, what happens is the adults just leave and they find care somewhere else.”
The effects of living with CF longer create unique concerns. Adult CFers build up immunity to antibiotics used to treat infections in the lungs, even as their lung disease gets progressively worse; diabetes and osteoporosis are far more common; and most men – 98 percent of them – are sterile because of a blockage in the vas deferens leading from the testicles to the penis, which results in a condition that resembles the vasectomy procedure.
John Anderson is one of them.
“We talked about that from the beginning,” says Lisa Anderson. “I just didn’t want to bring a child into this world who would only have a father for eight or 10 years. And then just me. I didn’t think I could do it. But then, in the end, it didn’t matter.”
And therein lies the other category that makes an adult patient different from a child. As CFers age, issues of marriage, family, work and college combine with their disease to create new potential conflicts and unusual social stresses. For example, only 27 percent of CF adults are married, compared with 56 percent of the U.S. population as a whole. Most patients need some help with physical therapy – which can consume as much as four hours out of each day – and other treatment factors as they decline. At UNC, physical therapists, psychologists and social workers team with doctors, nurses and researchers to help guide patients through CF adulthood.
The greatest problem can be the transition itself.
“It’s a really difficult process,” says Kathy Hohneker, the CF adult program’s nurse coordinator. “The pediatrician may be the only person dealing with cystic fibrosis that the patient knows, and certainly the parents have a huge bond with the pediatricians.”
Hohneker, Yankaskas and the rest of the adult team work closely with the pediatrics unit at the Cystic Fibrosis Center to make the transition smooth. Once a CF patient is deemed ready for the adult program, typically at age 18 or whenever life circumstances dictate, they set up crossover meetings between the pediatrician, the adult physician assigned to the patient and the rest of the care center’s team.
The Adult Care Center, in fact, wears a lot of hats. UNC also helped pioneer the double lung transplant, a relatively new transplant procedure that was first performed in 1985. Adult CFers who have less than a year to live often consider double-lung transplant, which can add several more years to a patient’s life.
While their transplant preparations are coordinated through a separate team of health-care workers at UNC, their CF is treated by the Adult Care Center. Carolina has more than 10 years experience in lung transplants in general; it has conducted about 200 such procedures overall and more than 100 double-lung transplants – the second-largest number in the country.
But transplant also can add complications, such as organ rejection and lymphoma, a type of cancer that results from Epstein-Barr antibodies; and, the waiting list can extend as long as 28 months – often longer than a patient’s health can afford. Additionally, about 4 percent of CF patients, including John Anderson, are not eligible for transplant because they suffer from Burkholderia cepacia, a bacterial lung infection with unique manifestation in adult CF patients. B. cepacia strains are resistant to antibiotics, show a more severe case of lung disease and are highly infectious to other CFers. As a result, the CF Foundation prohibits patients such as Anderson from attending events they sponsor, and he must wear a mask when walking the CF clinic hallways at UNC. He and Lisa manage his health primarily from their home in Hickory.
Through the course of his 20-year battle with the disease, Anderson has learned how important research volunteers are in the fight to find an answer to CF. His very association with UNC came as a result of his answering a call for so-called “adult CFers” for clinical trials he noticed in a newspaper shortly after his diagnosis. Since then, he has contributed his time to several studies, often combining the research with regular visits to the UNC clinic.
Taken together, the pediatrics, adult and lung transplant units at UNC offer CF researchers such as Boucher, Yankaskas and Knowles access to a great deal of practicable knowledge about the disease. One reason the CF Foundation named UNC one of eight centers nationwide to conduct foundation-sponsored clinical trials is because of its enormous size – about 550 CF patients in all. That advantage, says Beall, is underestimated in importance.
“Getting people to participate in research could be the most limiting factor as we move forward in the process [to treat CF],” says Beall, who reports that 1,122 CF patients nationwide participated in foundation-supported trials in the first quarter of 2002, down from 1,612 two years ago. “We don’t have a big group out there to begin with – it’s not 8 million or even 2 million people we’re talking about. It’s 30,000. And they can’t be too sick to participate in some of these trials – it’s a very difficult obstacle.”
Charlie Tolchin, a 34-year-old Washington, D.C., resident who received a double-lung transplant from UNC (at the recommendation of Beall) five years ago, says patients understand the door swings both ways: The reason UNC provides the best care in the country is precisely because of the research it conducts with help from patients.
“No question,” says Tolchin, who worked for the CF Foundation as an intern and is a member of its Advisory Task Force on Adult Issues. He was diagnosed at age 5. “The things they are doing there are mind-blowing. And because all these brilliant researchers at UNC are on rotation to treat patients in the clinic at least one month out of the year, that translates into patient care.
“The folks treating CF patients there know everything there is to know about the disease because they have to. They just have to. They can’t push the envelope if they don’t know where the edge is.”
Boucher is quick to point out that his team seeks a balance when treating patients. The goal is to find a treatment routine that is comfortable and effective on a personal level. Nutrition is a key, because the pancreas, due to blockage, can’t process natural enzymes that break up food. Exercise helps strengthen lungs in some cases. And antibiotics and physical therapy, including percussive therapy – that wretched beating of one’s body to loosen the mucus – are all important if they work for a patient.
“But at the end of the day,” Boucher says, “it’s about clearing that stuff out of the lungs. And you’d love to be able to substitute antibiotics with clearance. If I know that ultimately there’s a problem with too little salt and water on the airway surfaces, I’m asking myself, How do I restore that? And that’s when you ask patients to sort of take an adventure with you and find out what works.”
A man of metaphors
When you work on a disease as emotionally draining as CF, it becomes an obsession. Boucher not only describes how CF functions in the body with the intimacy bestowed upon a family member; he lives it the way an artist sees filled canvases outside his car window, the way a novelist proofreads cocktail conversations.
“You know when you get on one of those plastic sliders at the edge of the beach when you’re a kid?” he asks. “If the plastic slider is the mucus that your lungs naturally produce, and a big bacterium hops on that slider, if you have just the right amount of water at the edge of the beach, you’ll slide forever. And that’s how you clear out impurities. Essentially, CF kids are missing that sort of lining lubricant layer of water on their lung surfaces. Basically, their bacteria are hopping on that slider up in the sand – they’re not going anywhere.”
Boucher and his lab have been working on that slider problem since he first got into CF research. Short of getting gene therapy to work, he believes fluid transport holds the key to developing a quasi-cure for CF. In other words, fixing the balance of salt and water that flushes out the mucus that traps the bacteria that leads to the lung disease that kills most CF patients should be just as effective in most cases as fixing the gene itself. (See related story)
After 10 years of research that involved failed studies and carefully checked doubts and counterpunches from other teams of scientists, in July 2001 Boucher succeeded in proving himself correct: The fix for getting the fluid back is getting more salt into the lung. Those findings support what Boucher’s lab believes will be two enormously beneficial treatments for CF patients, the kind of breakthrough therapies that Beall has been waiting to see from Chapel Hill.
But for all the funding help UNC gets for its various CF undertakings, which includes more than $2.3 million so far in 2002 alone from the CF Foundation plus NIH grant money, getting a treatment from the petri dish to the drug store is an expensive and arduous undertaking. Ten years of research, in addition to at least five years of treatment development and clinical trials, translates to a great deal of patients lost to time and a lack of funding.
Sometimes, to save his patients, an M.D. must pretend that he has an MBA.
“Right now,” says Boucher, “if Glaxo were going to be interested in something, there would have to be a $700 [million] to $800 million market for it. CF is about a $50 [million] to $100 million market. It truly is way off the radar screen of the big pharmaceutical companies. So then you’re stuck.”
To get the most promising of his ideas for treatment through the pharmaceutical development pipeline more quickly, Boucher co-founded INSPIRE pharmaceuticals. The Durham biotechnology outfit’s main reason for existence was to take Boucher’s research and transform it into a correcting treatment for that salt problem in the lungs. INSPIRE, which is an amalgam of displaced workers from Glaxo’s takeover of Burroughs Wellcome in 1995, came up with INS37217 and is now ushering it through clinical trials. Within the next three years, Boucher hopes it will be saving lives.
INSPIRE has since gone public – before the stock market became unfriendly -and has added new developing drugs to its reservoir for respiratory conditions such as bronchitis. So three years ago, when Boucher was ready to send another of his potential breakthroughs through the treadmill, he was turned away by his own creation. Somewhere, Frankenstein author Mary Shelley must have smiled.
“This is where a scientist learns there are two views to the world, and that both of them are reasonable,” says Boucher. “The view from INSPIRE at the time was that for balance, they couldn’t have two CF programs that would amount to two huge sums of money spent on high-risk programs. So Christy [Shaffer, the CEO], was very straightforward, and we agreed to disagree.”
And to move forward. Determined, Boucher just started himself another boutique biotech firm in the same mold to fast-track his new research. This one he called CyFi Inc. Like INSPIRE, it also is based in Durham and is managed by a former Glaxo scientist, Ross Johnson, who had been the president of Durham-based HIV biotech Trimeris. Although INSPIRE and CyFi work on different tasks, both companies know each other well, Boucher says.
“University researchers just don’t have the time or expertise to go through the drug development process. We just wanted this one bad,” says Boucher of the new potential treatment. “There’s a community with CF, and there’s this idea in my group that we want to do something on our watch. We’ve felt privileged to study this disease.
“It’s just a bad rap that these kids get. They’re choking all the time, they’re coughing up all of this putrid pus. It’s just not fair. They tend to be very bright, very motivated kids. And they get to be your peers after a while.”
There is a level of egotism in science, of course, just as there is in recreational softball, just as there exists in all forms of competition within the human spectrum. It manifests itself in the race for grants and in the race for results and in the race for firsts. But soon enough, last year’s success fades from the memories of all but those who achieved it, and in the end you are left with one lasting question: Have we fixed the problem? And “fixed” is a very different concept from “treated,” no matter how you define the word “cure.”
The CF Foundation believes a cure will come in the form of a combination of three areas – gene, protein repair and drug therapies. Two of those UNC has been working on for years; the third, proteomics, it’s just starting on in a big way, although earlier than most of its peers.
Jackson Stutts, an associate professor of medicine, received a $1.79 million grant from the CF Foundation’s therapeutic discoveries arm to study protein interactions in the CF gene – the Cystic Fibrosis Transmembrane Regulator, CFTR. That comes on the heels of last year’s announcement of a $25 million anonymous gift to begin the Michael Hooker Center for Proteomics at UNC. The donor phoned Boucher expressing a particular interest in how proteomics could help cure CF.
And it could truly be the holy grail. When the Human Genome Project was completed, it was merely the beginning of discovery about the architectural makeup of human beings. Sleeping underneath the 35,000 genes that create us are about 1 million proteins that actually do the heavy lifting. Just one protein produced by the CFTR gene is missing from the roll call in a CF patient; that one protein is responsible for everything that goes wrong.
But it, in turn, interacts differently with other proteins in different organs of the body to create wildly varied CF symptoms. What’s more, the type of interaction varies from person to person, creating 1,480 different types of mutations in the CFTR gene.
“It’s very hard to identify a unified theme,” says Boucher. “It’s only once that you understand the whole context – the furniture in the room – that you really understand the disease. It’s just an amazing hierarchy they achieve. It’s humbling.”
The mutation John Anderson was born with, for example, may be among the most intriguing. In the words of his wife, Anderson has been “confounding doctors and defying the textbook” on CF since he was diagnosed. It is precisely because they don’t understand him that Yankaskas and others at UNC are so interested in his participation in research studies. What they could learn from Anderson, in fact, could be a genetic bonanza. Because something, some force inside him, stifled CF until he was a grown man. It was as if a child-safety lock had been applied to his disease’s trigger. And that may mean that he has some so-called “good gene mutations” that compensated for the bad ones for many years, keeping him healthy until now. Proteomics could help figure that out.
But Yankaskas and Boucher both caution that the payoff for proteomics – if there is one – will be measured in decades, not years. “The development of science and better treatments is incremental,” says Yankaskas, a former aeronautical engineer who designed the cockpit for the Blackhawk helicopter. “It’s not usually a game-winning home-run. It’s a series of people working hard and getting things together, questioning the old results. You can see the results of that scientific process already if you just look at the improving survival of individuals over the last 40 years.”
Living longer, of course, means living longer with CF. That’s OK with most patients, says Beall. “Just think about waking up each day and knowing you have a disease that will kill you,” said Beall. “These people live their lives as fully as they can. They want to.”
Because we know what gene causes CF, parents can be tested – or have their unborn children tested – for the CF gene now, if they have the money for the procedure. It’s a tempting, but difficult, choice.
“If you put yourself in someone else’s shoes … ” says Yankaskas. “I know families who have multiple children with CF, and they have just a horrendous existence and die at age 3. If those people want to have a bigger family, but know there’s no way they’d put another child through that – that’s easy to understand.
“On the other side of the coin, for John’s parents to have said, ‘Forget it. We’re not going to carry this child to term,’ wouldn’t be the right thing. He’s had a pretty productive life.”
Anderson says Yankaskas unequivocally is responsible for keeping him alive this long. “I’ve had a good life,” he says. “I couldn’t have asked for anything more. I was able to go to college, have a career teaching, play ball, get married. I’ve done a lot. I’ve had a lot more successes than failures.
“There are worse things,” Anderson continues, his breath rattling beneath the words. “I’m not in bad pain. I have discomfort, but it’s not like the pain that cancer patients go through. It’s more mental sometimes than physical.”
He pauses to consider a phrase rolling around in his mind, one it seems he’s not quite sure he wants to say out loud. CF patients do not kid themselves about their circumstances; but, for as long as he has been preparing to say such things, to understand such things, to embrace this blasted reality of his – I don’t know what can be done for you – Anderson’s face now says that he simply cannot believe it’s true. That, unlike the Bouchers and their daughter, no one is going to tap him on the shoulder and tell him that all of this was just a sick mistake.
“Sometimes,” he begins slowly, “I can’t catch my breath, and I’m afraid that I won’t be able to. And I start to panic.”
One breath at a time
Cystic fibrosis does not begin to hurt you one day because you smoked too much or consumed too much, and it is not a disease that attacks just one organ. What cystic fibrosis does throughout your life is steal the breaths to which human beings are entitled, one by one, until none of your organs can breathe at all. This is almost always how one dies from CF; at the end it is a battle of supply – when there is only one breath remaining, and the disease gets to it first.
“People tell me I don’t look sick,” Anderson says, pausing, hoping for affirmation, “and that’s good, I guess. But I feel sick. I sure do feel sick.
“This past fall and winter was when my breathing got really bad,” Anderson said. “And I started to get really down a lot. They gave me a drug for anxiety, Paxil. My appetite is decreased, too. I used to be able to eat a whole large pizza by myself. I could eat two meals in one setting normally, sometimes three.
“Sometimes,” John said, looking across the living room at his wife, “Lisa’s surprised I haven’t choked myself in the middle of the night, with all the things that are attached to me. I’ve got the oxygen tank on one side and the dialysis machine on the other.”
“I walked in one morning,” said Lisa, picking up his thought, “to what we call his ‘medical room’ where he sleeps, and I just had to laugh. The prongs to his oxygen tube had come out of his nose, and they were just hanging there off the side of his face. So I tucked them back in.”
She giggles loudly, compensating for John’s stifled laugh through pursed lips and crinkled, wet eyes. These are the terms of negotiation as worked out between his considerable sense of humor and his weakening lungs: Laugh, but not too hard. These are the terms of endearment shared between a man and the woman he wasn’t supposed to live to love, the companion he thought he didn’t need – a chuckle shared at the expense of a disease. In sickness and in health.
They no longer share their bed, but they share CF – John physically, and Lisa managerially.
“Sometimes,” Lisa said, “he coughs so hard when he gets up in the morning that he strains his neck muscles.”
“It’s always worse when it’s either really hot or really cold,” he says. And then his voice grows grave. “Now here lately, I try to clear my throat, and nothing seems to happen. Nothing comes up. I don’t know why that is.”
She left one day this past summer to run some errands, and he asked if there wasn’t something he could do to help while she was gone. She thought about it a minute and pointed to a bowl of green beans on a table in the family room. “You could string those, if you wanted,” she told him. She figured that was better than the vacuuming he’d tried to do in the past to help her keep up their home on a five-acre horse ranch – a small task that didn’t call for much in the way of muscle or oxygen or energy.
“OK,” he agreed.
When she came home a bit later, the beans were still sitting on the table, untouched. The understanding that curtained Lisa Anderson’s face bore the greater meaning of the moment. The strings attached had proven themselves to be … not too daunting an exercise in itself, nor too dull … but a painful reminder that so much of what life had become for John now was dull and unexercising. She shook her head gently at the still-fresh memory. A slide from second to third. Waiting for the call home. Just like that.
“I know,” he says slowly, “I know they’re never going to find a cure for it in my lifetime. But I’m donating my body to UNC when I die. If they can open me up and find out better what causes this, find some answers, I would much rather they do that than lay me cold into the ground.”
Reading such statements, the kind that are usually reserved as thoughts, may be uncomfortable to those who don’t have CF. It may seem crass, all this talk about body parts as commodities, as pieces to be transferred and ogled and considered under fluorescent lights by people in white coats who never owned them or breathed in them, of “cases” that are different from each other, of life reduced to medical terms. But orphans cry loud and openly and in unison because they must. Theirs is a desperate, not disparate, search for answers, and there is no time to be polite. The CF community gives itself up unlike any other in medicine, both in life and in death, with unrelenting hopefulness. It knows no other way to be.
“I mean, it used to be impossible that the gene would ever be identified. That was science fiction. Doctors said it would never happen. And then it did,” said Charlie Tolchin. “It tells you [that] you should never believe the conventional wisdom. You should not buy it when someone says, ‘It will not happen in your lifetime.’ You should not believe that. Let’s always say, ‘What if?’
“Doctors don’t know everything,” he says, “but the really good ones – the ones who find the answers – know how to admit it.”
Copyright 2003 UNC General Alumni Association
Published in Carolina Alumni Review November/December 2002.
Sidebar to “Breathing Lessons”:
Is the new mouse the ticket for CF research?
At times, reaching a breakthrough in cystic fibrosis research can feel a lot like winning the lottery – only to wake up the next morning and hear about the guy in Peoria who claims he has the right combination of numbers. So you go back and see if your six was really just an upside-down nine the whole time. You make sure. And then it happens again a few years later, same guy in Peoria.
Breakthrough, go back, make sure. Breakthrough, go back, make sure. Catchy rhythm if you’re dancing, but when you’re trying to solve one of science’s most maddening mysteries and thousands of lives are at stake, not so much.
Eventually, you just have to believe in your six. You have to believe you have the disease’s number.
And that’s precisely what researchers at UNC’s Cystic Fibrosis Pulmonary Treatment and Research Center are betting on after their announcement in April of finally creating a genetically engineered mouse that mimics the course of CF lung disease. Few searches for answers in medical science are as competitive as the one that would explain why people born with a single defective gene are fated to die by age 30. By fits and starts, answers have revealed themselves, notably the discovery of the gene that goes awry in people with cystic fibrosis, the so-called CFTR, in 1989. But 15 years have passed, and that treasure map has yet to yield its gold.
For years, researchers at UNC and elsewhere believed that CF patients could not clear the thick mucus that builds in their airways because they lacked the miniscule layer of fluid there that healthy people have, fluid that moves inhaled debris along, with the aid of coughing. In CF, the mucus just sticks, clogging airways like a bathtub drain filled with scum and leading to 95 percent of all CF deaths. The reason, the UNC team said, was that the airway cells had too little salt, or sodium chloride, which acts as a magnet for water and helps move it across airways.
The CFTR gene regulates the amount of sodium absorption and chloride secretion in airways – those two actions have to work together to create just the right amount of salt. But in CF patients, the chloride channel doesn’t hold up its end of the bargain, leaving sodium to play an aimless game of one-man Ping Pong and leaving a mess in lung airways.
Without chloride to regulate its actions, sodium absorption skyrockets and fluid levels drop.
At least, that’s what UNC thinks.
Enter Peoria. A team of researchers at the University of Iowa published a paper in 1996 that showed utterly different results from UNC’s. The problem wasn’t low fluid that might be fixed by adding the salt and water back into the airways. The problem with CF, Iowa said, was that the fluid already was far saltier in CF patients than in normal lungs; that, indeed, that salt was blocking the lung’s innate warriors against bacterial agents. It wasn’t a matter of over-absorption but of defective absorption.
Go back, make sure. The tango with Iowa, dubbed the Salt Wars and continuing in 1998 and 1999 after successive papers by UNC and Iowa (both further supporting their dueling hypotheses), is no dance party. It makes treatment options – adding salt or taking it away – a matter of life, death and millions of dollars in research money. But even in normal lungs, the layer of fluid on airways is so thin, just seven-thousandths of a millimeter in depth, that extracting it from organisms for study in lab cultures can alter it.
That’s why the creation of an over-absorbing mouse that mimics the mucus plugs and bacterial infections of a CF patient has many scientists excited. UNC’s previous attempt at a mouse model in 1992, in which the defective CFTR gene was bred in the animal, failed because the mouse’s airways responded differently to the gene, never developing deadly infections. Richard Boucher, the director of UNC’s CF center, says the new mouse, which has a fully functioning CFTR gene but over-absorbing sodium channels, can be used to test more effective treatments – not only for CF patients but for people who suffer from asthma and chronic bronchitis.
“The question is, how much more definitive can you get?” added Marcus Mall, the principal investigator on UNC’s latest finding and a German postdoctoral scholar who came to UNC specifically to create the mouse. “The whole salt war argument in Iowa was all made by cell culture. This one is the first time in an in-vivo model, a living model, that you have hyper-absorption of salt and water.”
And the word from Iowa? Not so fast.
Jeffrey Smith, associate professor of pediatrics at the University of Iowa and one of the school’s prominent CF scientists, said leaving the CFTR gene in – giving the mouse a functioning chloride channel to go along with rigged sodium over-absorption – will result in less fluid simply because chloride helps quicken absorption. Even normal lungs would have clearance problems in such a setup, he said.
“I don’t disagree with their data,” said Smith, who thinks UNC is ignoring Iowa’s research. “They’re doing good science. But they’ve stacked the cards against the mouse, and it doesn’t reflect what truly happens in a CF lung.”
Boucher said he values Iowa’s work; if not for Smith’s 1996 findings, UNC might have assumed its hypothesis was correct and never endeavored to make this new mouse model, would have “just put it in cruise control,” as Boucher explained. Still, he said, “Operationally, we decided a few years ago that you just have to move on.”
They have moved on, creating therapies based on their low-volume hypothesis that are being tested in humans by a small pharmaceutical research firm. One, INS37217, posted unexpectedly positive results in studies reported in late April.
Smith also is moving forward with research to further Iowa’s hypothesis. The Salt War may be turning into more of a Cold War, but that’s OK with scientists – as long as a cure is left standing.
“Science is very competitive,” Boucher said. “But it’s better that way. It makes you think. And as long as it’s done the right way – and on both sides, that’s true here – it’s useful for the field.”
Copyright 2004 UNC General Alumni Association
Published in Carolina Alumni Review, JulyAugust 2004