Genes offer sampling of hope and fear

Tribune staff reporter

It was supposed to be a simple bargain--an honest if somewhat bizarre deal struck between one of the last Stone Age peoples and the most technologically advanced society.

Soon after the Hagahai emerged from the cloud forests of Papua New Guinea in the late 1980s and made their first contact with the outside world, anthropologists stumbled across a remarkable secret flowing in the tribesmen's blood.The Hagahai, who have harvested yams and hunted wild boar along the remote Yuat River for millenniums, carried a rare virus in their white blood cells. It was a pathogen similar to ones that cause leukemia, but it did not harm the tribesmen.

American scientists wanted to understand why, so they made the tribe a quiet offer: Let the U.S. government patent their cells in exchange for half of the royalties from any breakthroughs in leukemia research derived from their blood.

The Hagahai, who by then were familiar with money, agreed. After donating a few test tubes of blood to the National Institutes of Health in Bethesda, Md., they promptly went back to stalking wild game.

If the story of U.S. Patent No. 5,397,696--for a DNA sequence dubbed "Papua New Guinea human T-lymphotropic virus (PNG-1)"--had ended there, it probably wouldn't rank as a footnote in the dazzling saga of the genetic revolution in the 1990s.

But the tale of the 1995 Hagahai patent and its bitter aftermath is far from forgotten in scientific circles. Instead, it has become the defining morality fable for one of the most intriguing and highly controversial new frontiers in human biology: the hunt for genetic cures in the DNA of small ethnic groups.

Buoyed by technical advances that make massive DNA testing economically feasible and spurred by the realization that humanity's genetic diversity is yielding to cultural assimilation day by day, researchers are scrambling to the most secluded corners of the Earth, hoping to tap the "healthy genes" embedded in the nuclei of the Cherokee, the Amish, Solomon Islanders, the Hagahai and others.

So far, the strange quest has fired the imagination of individual academic researchers and big biomedical companies. Probably the most compelling proposal on the horizon is the Human Genome Diversity Project, a plan put forth by a loose coalition of international geneticists to collect and preserve the DNA from 400 human populations and ethnic groups.

If funding is approved by Congress after a recommendation by the National Academy of Sciences, the diversity project could officially begin gene sampling this year, adding to a store of samples collected without government involvement.

"We've always known the strength of any species lies in its diversity," said Victor McKusick, a pioneering population geneticist at Johns Hopkins University who supports the global DNA-sampling effort. "Now, we're finally beginning to put those differences to useful work. These are truly exciting times."

To some, the case of the Hagahai genes proves otherwise.

When news of the New Guinea patent spread, howls of outrage sounded from human-rights groups.

Is human tissue, they asked, just another natural resource like timber or gold? If so, what government has the right to poach on a foreign country's genetic heritage?

Charges of "biopiracy" echoed in news reports across the Pacific. News releases declared that the United States had done the unthinkable and "patented itself a foreign citizen." Rattled by the publicity, Papua New Guinean officials summoned the U.S. ambassador for an explanation. The anthropologist who brokered the deal was hauled off a flight at Port Moresby, the Papua New Guinean capital, and interrogated like a spy.

What the Hagahai made of the fracas is not recorded. The NIH, however, was stunned: Though the blood still remains frozen in its freezers, it quietly dropped its claim on the intellectual property rights to the tribesmen's cells and the research is largely dormant.

Unique traits

Flaps over patenting biological material, especially DNA, are not new, but they are growing louder as science reaches out across the human family tree to pluck at exotic genes that could form the basis of new and expensive drugs.

The thrust of such "diversity research" has gathered momentum only in the last decade as experts began unraveling the biological mysteries of race and ethnicity. Along the way, they have discovered that different human populations have evolved unique resistances or susceptibilities to common diseases.

The key lies hidden within the 3 billion nucleotides of DNA within each of our cells that code for who we are, what we look like and how we function.

Though the similarity in all ethnic groups' DNA is boggling--all our blueprints differ on average by just one nucleotide in every 10,000--enough minute differences can accumulate over the generations to impart subtle advantages in warding off infections and illnesses. In effect, natural selection has thousands of such complex experiments running in diverse human populations all the time.

"We basically let Mother Nature do our work for us," said Georgia Dunston, a Howard University geneticist who has helped plan the gene survey proposed by the diversity project. "Why waste years of research trying to come up with cures from scratch? Evolution tells us that there are groups out there whose genes have been tinkering with ways to fight disease since day one."

How do beneficial genes settle out in different ethnic groups?

Scientists credit three elusive forces of evolution: time, isolation and group size.

It is difficult for unique traits to gain a foothold within large, dynamic populations, geneticists say, because they can be easily swamped or diluted by the constant influx and outflow of genes, the swirling of genetic tides.

Only in smaller, more stable populations--especially ones where oceans, deserts or mountains minimize outmarriage--can the subtlest genetic ticks become accentuated and magnified. In these cases, a positive mutation, such as one that imparts a tougher immune response, can percolate widely through the gene pool within a few thousand years.

The sort of biological solitude required for such differentiation, experts note, is increasingly rare in today's cosmopolitan world.

"You can't really go gene hunting in Chicago," said Alan Shuldiner, a geneticist at the University of Maryland who recently uncovered genes associated with obesity in Native American tribes. "There's so much intermixing and so much environmental variability that the job would be a nightmare. That's why remote populations make perfect laboratories."

One human experiment that has become legendary among geneticists is the village of Limone Sul Garda in Italy.

The medieval village, perched on a lake, was untouched by Italy's road system until the 1950s. Its gene pool remained largely unrippled by outside gene flow until that time. Researchers have discovered to their amazement that the residents, though they eat the same rich foods as neighbors, suffer almost no heart disease.

Geneticists have now isolated a peculiar mutation--thought to have first appeared randomly in a resident in the 1700s--in the villagers' DNA called the A-1 Milano gene, a localized oddity that appears to gird them against the ravages of atherosclerosis, or hardening of the arteries--one of the most common diseases in the industrialized world.

"You can imagine the sort of therapeutic potential discoveries like these have," said Robert Farrell, a professor of human genetics at the University of Pittsburgh who is studying diabetes and hypertension in different population groups. "That town has been combed by dozens of researchers looking for ways to translate whatever that gene does into some sort of synthetic drug. The payback would be amazing."

Yet it isn't just unique resistances to illness that diversity researchers are homing in on. Tight-knit human groups that suffer unusually high rates of inherited ailments also have caught the eye of gene hunters because they set the stage for mapping and understanding the workings of complex disease genes.

The granddaddy of all such population-specific disease studies involves the Pima Indians of Arizona and late-onset diabetes.

A desert people whose genes have adapted over the centuries to a lean, hunter-gatherer existence, the Pimas have been riddled by health problems associated with the switch to processed foods and a more sedentary lifestyle. The 6,000-member tribe suffers the highest diabetes rate of any ethnic group in the world. For 30 years, researchers at the NIH have been tracing Pimas' genealogies and drawing their blood, trying to crack the genetic underpinnings of a disease that afflicts millions worldwide.

"We'd really like to see some breakthroughs," said Viella Johnson, director of the hospital in Sacaton, the Pimas' tribal headquarters an hour drive east of Phoenix. "We've got families where half the people in them are diabetes patients. It's a plague."

In the brave new world of diversity research, places such as Sacaton--with its adobe huts melting into the Sonoran Desert and its dogs curled on a lonely main street--are becoming the unlikely new capitals of disease research.

So are the battered trailers and tents of Israel's Bedouin, who are being studied for clues to obesity and certain inherited forms of deafness. So are the small towns of Canada's Quebecois, who are the subjects of a quest for the genetic underpinnings of manic depression. And so are the remote villages of the Arhuacan Indians of Colombia's rugged Santa Marta Mountains, who, like the Hagahai, play host to a type of virus associated with leukemia and AIDS.

"The irony of all this is that by focusing our attention on the white European populations that can afford advanced medical care . . . we've been missing the boat on genetic variation for a long time," said Roger Rosenberg, a University of Texas researcher who is studying Oklahoma's Cherokees for their remarkable resistance to Alzheimer's disease, a fatal degeneration of the nervous system. "This is a whole new frontier."

If there were any doubts about the promise of such research, one need only follow the rainbow of human diversity down to the pot of biomedical gold--an economic reality that is triggering the most volatile debates over the commercialization of DNA from small and often poor populations.

Big pharmaceutical companies are quietly sinking millions of dollars into the sort of massive DNA surveying that purely anthropological proposals such as the diversity project have been pushing for years.

The stakes, even at this early stage, are tantalizing:

- Multiple sclerosis researchers supported by Genethon, a French biomedical firm, have discovered a remote population on Reunion Island in the Indian Ocean that seems to be immune from the crippling effects of the illness, even though they carry the disease genes. A "protective" genetic factor might be in play and, if ever isolated, could lead to lucrative new drugs for millions of MS sufferers.

- Asthma experts are testing a hotbed of bronchial disease on Tristan da Cunha island in the South Atlantic, where a third of the roughly 300 interrelated farmers suffer from the ailment. The California firm Sequana Therapies has signed a $70 million deal with Boehringer Ingelheim, a German pharmaceutical company, to help find the Tristanians' disease genes and develop a broad-scale genetic therapy from them. Sequana expects to announce the discovery of its first asthma-related gene as soon as next year, one of the first tangible returns from diversity research.

- In a breathtaking gene hunt that will dwarf the diversity project, the international biomedical company Genset signed a deal last year to sift China's 1.2 billion citizens for mutations that might have beneficial health effects. The company will focus on China's remote rural populations and its 40-plus minority groups. The value of the contract, like that of an unexplored mining lease, is incalculable but likely immense.

Which is why indigenous-rights advocates are crying foul.

"You've got this potentially lucrative traffic in human DNA zipping from lab to lab across the world and none of it benefits the donors," said Edward Hammond, an activist with the Canada-based Rural Advancement Fund International, or RAFI, a group concerned with biodiversity and tribal property rights. "There's just this huge potential for exploitation."

Ethics questions

It was RAFI that led the charge against the patenting of the Hagahai's cell line in 1995. The tiny organization, with a staff of about a half-dozen, has gone on to earn the wrath of academics and industrial geneticists for its David-and-Goliath campaign against diversity research.

According to RAFI and a shifting coalition of other indigenous groups, the expanding hunt for cures locked within the nuclei of the isolated peoples is an unsavory replay of an earlier genetic safari to the Third World.

In the 1970s, big agribusiness firms raided equatorial countries for lucrative crop hybrids that, with a bit of genetic engineering, later earned billions in profits--cash that rarely trickled back to the impoverished farmers who raised the strains initially, Hammond said.

"Today," he said, "the crop is human beings."

Declarations such as these have sent alarm bells ringing around the world, especially in the ethnically diverse nations of Asia. India, which launched its human-diversity project this year, takes the threat of "bioprospecting" seriously enough to declare its citizens' DNA a national treasure. Blood samples can't leave the country.

Meanwhile, RAFI's bioengineering crusade marches on, pushing for a ban on the patenting of human DNA, demanding that companies share profits with the populations who offer their genes for commercial research and lobbying the United Nations to regulate the burgeoning "human-tissue trade."

Medical-industry spokesmen dismiss such demands as wishful thinking. Without patents on DNA, they say, few businesses would invest in the research necessary to develop genetic cures.

"Do I have some theological objection to individuals participating in and benefiting from the economic upside of such research? No," said Kevin Kinsella, president of Sequana Therapies. "But the picture is far more complex than that. Gene discovery is just the first step in a 1,000-mile journey to find a therapy. It's a process that costs us millions and takes years of work. So how much does somebody who gets his arm pricked deserve?"

Kinsella noted angrily that the Tristan da Cunha islanders who are participating in his company's asthma studies are not "natives running around in grass skirts" but the descendants of British colonists. In exchange for the islanders' blood, he said, his company has promised to give back free drugs developed from the research.

Still, even those scientists who are most enthralled by the wondrous medicine cabinet opened by the foibles of human genetic variation say that serious moral questions will take years.

When a researcher walks tired and dusty into a village with his bag of syringes, who does he ask for permission to collect a population's DNA? The individual donor? The group's religious or political leader? Who owns a peoples'--not a person's--DNA?

And, more important, how can scientists possibly obtain informed consent--as is required by most governments--when they can't explain the profound repercussions of genetic testing to preliterate cultures?

"These are untested waters," said Dunston, the diversity project planner. "Scientists have to start by learning to treat people like people, not scientific subjects. After all, this whole exploration is about sharing what makes us human--scientists are truly part of the experiment in this case."

Dunston described one of the more serendipitous discoveries of diversity research that convinced her of its ultimate righteousness:

In seeking organ donors for African-Americans, doctors have found that in some cases tissue from whites is a closer match than tissue from other African-Americans.

The reason? African populations are so ancient that they have diverged into the most genetically variable peoples. Hence, the differences between two African-Americans could be greater than those between a white and an African-American, vivid proof that skin color can mask DNA affinities.

"It would be a shame to lose such insights to fears about commercialization of DNA," she said, worrying aloud that the diversity project, whose aim is pure science, is being sullied by the profit-driven motives of pharmaceutical companies. "This is medicine helping tear down old ways of thinking about race."

But some, especially those caught in the middle of the gene hunters, remain deeply ambivalent.

For Pennsylvania's Amish community, whose religious strictures against outmarriage have kept their gene pool unclouded for almost three centuries, the issue boils down to accountability and respect for the sense of ownership kindled by DNA.

"They came, they took blood, they made promises and they never reappeared," said Rebecca Huyard, a medical administrator in Strasburg, Pa., who remembers how disease researchers from Johns Hopkins University collected hundreds of genetic samples among the farming folk of Lancaster County in the 1970s and 1980s.

"Eventually, people here got fed up with it. They wondered where their blood was going. It was, after all, our blood, our DNA."

Huyard, who is Amish, said she and her devout, buggy-riding neighbors fear that their molecular inheritance--the building blocks of their biological identity--has somehow slipped beyond their control. She hoped that Amish DNA samples weren't being shared without the donors' knowledge. She also bemoaned the lack of awareness about a momentous scientific quest that, however noble, is speeding ahead almost without public debate.

"Now, we don't trust any of them anymore," Huyard said. She added that if diversity researchers showed up again in the silo-studded hills of Amish country, they probably would be turned away politely but firmly at farm doors.

What she didn't know was that several biotech firms have acquired Amish DNA and are interrogating it for clues to everything from Alzheimer's disease to diabetes. That Amish DNA, frozen and cultured in petri dishes, sits alongside thousands of other human cell lines in laboratories and refrigerators around the world.

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