ASTHMA
Asthma Island
Search for Genes Takes Doctors to the End of the World
By Michael Gibbons
While busily transforming the world into a global village, humans committed a small oversight. They forgot about Tristan da Cunha.
Serious stamp collectors know the name Tristan da Cunha. Few others do. It’s a smidgen of an island of volcanic rock far off the southern tip of Africa. It’s a new synonym for remote.
“You go to the docks and see the ocean and you know that for thousands of miles there is nothing,” Noe Zamel, MD, twice a visitor to the island, says in awe. “It’s a tremendous sensation to be in this place and watch the ocean. The sense of isolation is almost like being in a capsule out in space–except you are part of the planet.”
Tristan da Cunha is home to 90 families, not quite 300 people altogether, Anglos, descendants of a British garrison stationed there in 1816 in case Napoleon tried to escape from the island of St. Helena.
Isolated and inbred, 56 percent of them have asthma, making this society a naturally occurring asthma genome project. Dr. Zamel, a pulmonologist, arrived here, as he likes to say, “looking for the genes of asthma at the end of the world.”
He may find them. DNA samples he took from 272 Tristanians are now under the scope at a San Diego research lab. They may help reveal the genetic underpinnings of the breathing disorder that afflicts 15 million Americans and millions more worldwide.
If that happens, people throughout the global village will know the name Tristan da Cunha.
HISTORY
Exuding affection, Dr. Zamel gave colleagues at last year’s meeting of the American College of Chest Physicians this tour of the island and its people:
Tristan da Cunha’s volcano peak rises dramatically 6,760 feet high. Only two of its 60 square miles are flat, walkable and habitable. The island takes its name from its discoverer, a Portuguese explorer who spotted it in 1506 on his way to Madagascar.
To foil any attempt by Napoleon to leave St. Helena, the British maintained a heavy military presence all around him, including stationing troops on Tristan da Cunha. After an expensive year of feeding and clothing them, however, Britain decided to withdraw. One Scotsman, William Glass, chose to remain on the island, along with a small number of others. Glass, who had brought his wife and four children with him, became governor of the island and sired 12 more children.
Currently, seven families constitute the population, descendants of Glass or others who, over the years, arrived on the island by shipwreck or of their own free will. As time passed, cousins couldn’t help but marry cousins. Today, everyone is everyone else’s cousin 50 times over. Each face has the same high cheekbone structure, each body the same deportment. One photo of 12 islanders sitting on a long bench has an eerie repetitive quality to it; all heads tilt forward at precisely the same slight angle, as if they emerged from a human copier machine.
“Tristan is sort of the pinnacle of isolation,” notes Colin Stine, PhD, a geneticist at the University of Maryland, who’s conducting his own search for asthma genes. “It’s in the middle of nowhere. It’s a population in which second and third cousins almost look like identical twins.”
“A MODEST BUT NICE LIFE”
Tristan society consists of a few roads that connect about 90 homes, a tiny shopping area, a school with usually about 30 students, an Anglican church, a three-bed medical building, a government building, a community center and a cement factory. Homes are made of cement because wood is so scarce. A generator provides electricity; propane heat allows cooking and heating.
Temperatures range from 4 degrees Celsius in winter to 24 degrees Celsius in summer.
Tristanians catch fish, plant potatoes, onions and other vegetables, raise cattle for milk and sheep for meat and wool. Until 1947, they had no economy or currency. But they had one natural resource, the sea, so they began catching and exporting lobster, which now nets them nearly $1 million annually. They also, like inhabitants of many exotic places, sell cancelled commemorative stamps to collectors, who know them as the most expensive stamps in the world. Tristanians suggest topics for the stamps, such as when the Queen Mary visited the island, then Great Britain’s post office prints and distributes them, and ships some cancelled stamps inside commemorative envelopes to Tristan, for sale.
Together, lobsters and cancelled stamps allow Tristanians to enjoy “a modest but nice life,” said Dr. Zamel, a Brazilian who now lives and works in Toronto.
Every Saturday night, islanders dance to country rock at the community center. The bar opens each evening for socializing and games until 11 p.m. After church on Sunday people gather at a café.
Men and women alike serve three-year terms on Tristan’s Council. Every five years a representative of the British school system arrives to inspect the school, which students attend until age 15. The only telephone on the island sits on the desk of an official representative of the Queen of England who serves for three years. Mail arrives by ship every three to four months.
VOLCANO ERUPTS
In 1962, Tristan’s volcano erupted and spewed sulfur and sand down to the sea, forcing inhabitants to relocate to Southampton, England, where a barrage of physical and psychological tests, overwhelming and off-putting to the stressed-out visitors, first documented their high prevalence of asthma. Stamps were printed to commemorate the islanders’ uprooting–along with their triumphant return to their beloved home a year-and-a-half later.
Dr. Zamel, in London at that time on a research fellowship, followed accounts of the islanders and never forgot about them. So when, about six years ago, tools became available to study asthma genetics, Tristan da Cunha came instantly to his mind.
He set off for the island in 1993 from Capetown on a 180-foot-long tanker bound for the South Pole. During a week of rough seas, the ship at one point tilted 51 degrees–two degrees shy of capsizing. “For a few seconds, I and my research associate just looked at each other and we felt, ‘That’s it,'” he recalled.
Finally they spotted the island and its cinematic volcano peak, now dormant, drained like a lanced pimple, still coated with lava residue from 1962.
A sign greeted Dr. Zamel as his boat docked: “Welcome to the Loneliest Island.”
Tristanians eagerly participated in the study, from an elderly man of 94 to a 5-year-old. Six days a week, from 8 a.m. to 8 p.m., Dr. Zamel and his staff performed methacholine challenges to assess them for broncho-hyperresponsiveness and took four tubes of blood samples from each–DNA from 272 islanders.
Technicians packed the samples in ice for the trip back to Capetown. Dr. Zamel’s hard luck at sea returned: He passed a kidney stone en route.
On the second expedition in 1996, technicians brought two centrifuges to extract blood cells right there on the island, froze them and shipped them to North America from Capetown. Those cells are now defrosted and “growing happily” in a lab in San Diego, said Dr. Zamel, a professor of medicine who oversees the PFT lab at Mount Sinai Hospital in Toronto.
PRELIMINARY RESULTS
Based on history and methacholine challenge, 21 percent of Tristanians showed strong evidence of asthma, 35 percent showed partial or questionable evidence of asthma and only 44 percent appeared asthma-free.
Almost 80 percent were atopic to D. pteronissinus, 71 percent to D. farinae, 41 percent to house dust, 48 percent to feathers and 42 percent to cat fur–even though all cats were captured and removed from the island in 1972.
AxyS Pharmaceuticals Inc., the San Diego firm genotyping the DNA samples, says it has identified one novel gene in a region of DNA. Researchers are now using cell models and developing transgenic animals to study how this gene expresses itself and mutates.
Dr. Stine, who is studying asthma genetics in an isolated Dutch population, says the search for asthma genes could lead to potent, personalized asthma drugs.
“Half a dozen drugs exist now to treat asthma, but the same drug that works well on one asthmatic may prove ineffectual on another,” he says. “One speculation is that if we knew which genes were involved, we could say, ‘You have asthma gene 1, therefore this beta-agonist will work on you,’ and so on. That’s the hope. We could tailor therapies to each patient’s genetics.”
Dr. Stine finds the Tristan project promising but will reserve judgment until he sees something published.
“It’s got potential,” he says. “From a genetic perspective, (Tristanians) show linkage disequilibrium over a long distance…About two years ago, the San Diego group announced they had found a gene. That would be exciting if it’s true. But they haven’t released the name of the gene to the public. And we don’t know what the chromosome is. The proof of the pudding is when you put it out for public consumption.”
The pudding may be in the oven now. Dr. Zamel has his hopes high–as do the people of asthma island.
“When we have this gene well known and well established,” he said, “the Council of Tristan da Cunha has decided to issue a commemorative stamp to celebrate the finding of the gene.”
Any medication resulting from the research will be free of charge to Tristanians for life and delivered personally by Dr. Zamel. But even if the venture fails, he intends to return.
“Once you go to Tristan you have this bug,” he says. “You have to keep coming back.”
Michael Gibbons is associate editor of ADVANCE.
