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The History of Everyone and Everything

He invented 'genetic geography' and tracks human migrations around the globe. But critics now charge that Luca Cavalli-Sforza wants to go too far.

Photo: Jason Grow

BRANCHING OUT: Cavalli-Sforza envisions a global DNA bank that would help researchers fill in the human family tree.

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By Mitchell Leslie

From the beginning, we humans have refused to stay put. Our earliest wanderings took us out of Africa, the birthplace of our species, and across the globe. Some groups migrating into Asia turned left and colonized Europe, supplanting the Neanderthals who lived there. Others veered right and rambled across Asia, then into Australia or the Americas. By the time modern civilization dawned, around 12,000 years ago, humans had settled every region except inhospitable Antarctica and some remote islands. And as populations continued to swell, new migrations got rolling, imposing their own patterns on top of the old ones.

Fascinated by these ancient journeys, an Italian scientist in the 1950s had an idea: trace mass migrations not just through archaeological digs, but by tapping into the genetic clues in modern people's blood. His fresh approach launched a new realm of research, blending historical and anthropological perspectives with an emerging understanding of genetics. As the father of what he calls "genetic geography," Luca Cavalli-Sforza has spent a lifetime deciphering the travelogue of our footloose species. He has, in effect, used genes to reconstruct the history of humankind.

Now 77 and an emeritus professor of genetics at Stanford, Cavalli-Sforza is considered one of the world's most distinguished geneticists. From his first forays in genetic geography to his recent studies of the Y chromosome, he has been a driving force in human genetic research. "It's amazing how many people follow after he's initiated a field," says mathematical biologist Marc Feldman, a Stanford professor who has been a longtime collaborator and friend. "The first to a field is usually Luca, and then the field is quickly occupied by people who are going to ask the same kinds of questions."

Cavalli-Sforza's efforts to uncover human migrations and to understand their causes have earned him a drawerful of scientific accolades, including membership in the U.S. National Academy of Sciences and the Royal Society, Britain's foremost scientific organization. And he has received another kind of recognition -- stacks of hate mail from white supremacists -- for his well-publicized insistence that DNA studies can serve as an antidote to racism because they reveal an underlying genetic unity that cuts across racial groupings, making race a scientifically meaningless concept.

How is it, then, that Cavalli-Sforza now finds himself accused of cultural insensitivity, neocolonialism and "biopiracy"? Late in his career, as he struggles to organize his most ambitious project yet -- a sweeping survey of human genetic diversity -- why are some people calling him a racist?

In his third-floor office at the School of Medicine, the books are shelved neatly and the papers organized in orderly stacks. With ruddy cheeks, thinning white hair and an unassuming demeanor, Cavalli-Sforza looks more like a kindly grandfather than a high-powered scientist. He speaks fluent English with a vague European accent, leaning back in his chair and interlocking his fingers as he talks.

The word that best describes him is "gentlemanly," says Peter Underhill, who heads his lab. Cavalli-Sforza lives up to his billing during our interview, offering to share his lunch of sushi with me. Later, as the afternoon sunlight dims, he bounds out of his chair to turn on the overhead lights so I can see my notes, apologizing that he hadn't noticed the darkness before.

If concern for others is one of his guiding principles, it's also a quality he seeks in his colleagues. When he and Underhill first met for Underhill's job interview nine years ago, "he never questioned my capabilities," the younger researcher recalls. "What he was most concerned about was if I was a nice person."

A hallmark of Cavalli-Sforza's work has been his collaborative approach. He has teamed up with archaeologists, linguists, anthropologists and mathematicians, building a reputation as a sort of alchemist who can transmute drab data into valuable insight. "Working with him one-on-one is one of the best ways to get educated. You see his thought processes," says Feldman. "He is unafraid of pursuing an idea that doesn't look promising."

The man who is fascinated by migrations is an immigrant himself. Cavalli-Sforza was born in Genoa and studied medicine at the University of Pavia. He practiced medicine for a couple of years in the 1940s before leaving the profession in frustration over the primitive conditions in the local hospital. Antibiotics were not available in wartime Italy. Though a physician could make a good diagnosis, he recalls, the prognosis was rarely good.

So he switched to genetics, first studying bacteria. He came to Stanford in 1971 as a refugee from burdensome administrative duties at the University of Pavia, where he headed the 100-member genetics department. Cavalli-Sforza made it clear he would join Stanford only if he wouldn't have to chair the department.

His title is now "active" emeritus professor, a designation unrelated to the fact that he bicycles to work. "What I like is my work," he says with a little smile, explaining why he has no intention of retiring. Cavalli-Sforza remains insatiably curious about the human story and is still trying to refine our understanding of it. By studying additional groups, he says, "I believe we can get a very, very careful reconstruction of the history of humanity and the forces that cause change."

Already he has assembled a detailed account of our wanderings by comparing genetic overlaps across populations. To geneticists, a "population" is essentially a group of people who are more likely to marry one another than to marry anyone outside the group. Cavalli-Sforza has focused on groups that haven't mixed much with others, because intermarriage could dilute the genetic signals of ancient migrations. Examples include the Navajo, the Basques and the Saame people (Lapps) of Scandinavia.

When he first began this work in the early 1960s, DNA-probing technology was crude. Because he couldn't look at DNA itself, he looked for proteins encoded by genes. Nowadays, he and his colleagues read the genes directly, quickly determining the sequence of DNA "letters."

In the early 1970s, Cavalli-Sforza used genetic geography to overturn an assumption about one of the biggest transformations in human history: the advent of agriculture. All humans lived as nomadic hunter-gatherers until about 10,000 years ago, when people in the Middle East started to take up a new way of life, planting crops and domesticating animals. Archaeological remains show that agriculture spread north and west into Europe. Cavalli-Sforza wondered: did it spread by word of mouth, or did it travel with the farmers themselves as they settled new areas?

Most archaeologists believed that farming populations tended to stay put. Cavalli-Sforza, however, suspected that they migrated, carrying their know-how with them. The ages of relics unearthed in old farming villages suggested that agriculture had spread at a very regular rate of about 1 kilometer per year, he found. This was a reasonable migration rate for a group of people, but it still didn't prove that early farmers moved. So Cavalli-Sforza turned to genetic analysis. First, he and his colleagues ransacked the scientific literature to collect data on 39 traits among populations scattered across Europe. Then, using statistical techniques, they created what looked like contour maps, except that the contour lines connected places sharing similar genetics rather than similar elevations.

Viewed as a "topo" map, the genetic landscape looked something like this: rising over modern Iraq was a high plateau, which gently sloped away to the north and west, reaching its lowest point in far northern and western Europe. What this showed is that people in, say, Greece are genetically more similar to people in Iraq than are the distant Swedes. That's not earth-shattering. But the fact that any DNA similarity turned up between Middle Eastern and Northern European groups confirmed a genetic connection between the two -- something that could arise only through migration.

The farming "wave" was more like a steady trickle, with hunter-gatherer traditions slowly dissolving through intermarriage between the two groups, he says. At least one clan, however, may have escaped complete assimilation. These were the ancestors of the Basques. Now numbering some 1 million in northern Spain and southern France, Basques are genetically and culturally distinct from other Europeans. Cavalli-Sforza and other geneticists think they descended from Europe's early hunter-gatherers, retaining their distinctness for thousands of years in part because of the mountainous isolation of their homeland.

After analyzing Europe, Cavalli-Sforza's team went global, constructing a genetic landscape for the world. This revealed a series of mass migrations that have driven human history (see map). Each was triggered by a population boom that sent people searching for new homes. And each was catalyzed by technological change, from agriculture to oceangoing ships. The work was synthesized into a hefty, 1,000-page atlas of genetic diversity, The History and Geography of Human Genes (1994), which one admiring scientist called "a history of everything about everybody."

Cavalli-Sforza, however, says the tome is far from complete: "This is a book that, five or 10 years from now, will have to be rewritten, analyzing the new data -- I hope."

New data? That's where the controversy comes in.

He could walk away from science right now, leaving a potent legacy. Instead, Cavalli-Sforza has an ambitious plan. And this time, his proposal has become what Law School bioethicist Henry Greely calls "a lightning rod for genetic issues."

In a letter to the journal Genomics in 1991, Cavalli-Sforza and four other prominent geneticists called for a massive survey of human genetic variety to create a DNA bank encompassing thousands of populations. The bold project would capitalize on rapidly advancing DNA technology. Researchers would fan out across the globe, collecting samples of blood, hair or saliva from which to extract DNA. Some would be analyzed right away; other samples would be preserved for future study in the form of "cell lines" stored in centers around the world.

Planners conceived this Human Genome Diversity Project as a necessary supplement to the better-known Human Genome Project, then just getting under way. The Human Genome Project, scheduled for completion in 2003 at a cost of $3 billion, aims to locate and decode all 100,000 or so human genes and to assemble that information into a standardized map showing the position and DNA sequence of every gene. However, since its samples come from just a handful of Western scientists, the map isn't intended to reflect genetic diversity.

By contrast, the similar-sounding Human Genome Diversity Project aims to compare a few snippets of DNA that tend to differ among a broad range of individuals. Its cost is estimated at $25 million to $30 million for five years. Cavalli-Sforza and the dozens of other planners foresee far-reaching benefits, both practical and intellectual, from such an inclusive collection. The project would improve our understanding of human genetics and diversity, while answering questions of history and evolution. And it could help pin down genes linked to diseases like cancer and diabetes.

In their call for action, proponents stressed the need for cultural sensitivity, noting that many of the populations in question had been exploited or oppressed in the past. But they also urged a quick start, because many distinct groups (such as the Hadza of Tanzania, the Yanomame of the Amazon and the Yukaghir of Siberia) were dwindling. Now is the time, they wrote, to "grasp a vanishing opportunity to preserve a record of our genetic heritage."

The proposal won support from geneticists and some anthropologists, who saw it as a logical way to pull together irreplaceable data. But it also drew sharp criticism. Project planners, most of them white academics, were denounced as gene pirates, neocolonialists and racists by some who believed the project would backfire on minority groups. One Australian aboriginal group came up with the name "vampire project" to describe the plan.

Greely, who chairs the project's ethics subcommittee, says he expected opposition. But, he adds, "I am surprised by the way it has been entangled in a host of concerns that it doesn't have very much to do with." One contentious issue is patenting: who would profit on any commercially valuable discoveries? Here, the project ran afoul of existing tensions between developed and developing countries over intellectual property, as well as worries over the patenting of genes. Some have charged that Western companies have made off with plants, ancient medicines and other traditional knowledge and then locked up their "discoveries" with patents, never compensating the countries of origin. Critics of the new project say it would allow comparable "biopiracy" in the human genetic realm. For example, companies might trawl the data for patentable genes that could lead to new medicines.

Anthropologist Jon Marks, a visiting associate professor at UC-Berkeley, attacks the planners' "colonial" assumption that indigenous people would simply cooperate as cell donors. This high-handedness was evident, he says, in a meeting held in 1992 at Penn State, where anthropologists, linguists, geneticists and archaeologists selected roughly 500 populations, many on the verge of disappearing, to study in the first phase of the project. No representatives of these populations were invited, Marks says. "They organized a meeting to try to get blood out of natives' veins and into Palo Alto as expeditiously as possible," he says.

Project supporters insist that the guidelines in their model ethical protocol would protect donors from exploitation and ensure them a share in any profitable discovery. But the stringent protocol hasn't alleviated Marks's concerns or those of Edward Hammond, project director for the Winnipeg-based Rural Advancement Foundation International, which promotes sustainable agriculture and works to protect intellectual property rights of indigenous people. Hammond's group leveled a darker charge: that the data could pave the way for genocide by uncovering population-specific genetic traits that "unscrupulous parties" could use as targets for biological weapons.

Though some of the most vituperative assaults have been directed at him, Cavalli-Sforza acknowledges no wounds. But it's clear that speaking of the controversy saps his energy. As we talk about it, he sinks in his chair until, several times, he's on the verge of slipping out of it, and he removes his glasses frequently to rub his eyes. His sense of humor vanishes.

He stands by the original plan. Worries about economic exploitation are baseless, he says, the result of misunderstood intentions: "We don't want to patent anything. We are very much against patenting DNA." As for the bioweapons concern, he says it's groundless because most genetic differences are between individuals, not groups. Almost never does one group have a trait that is missing in the rest of humanity and that could therefore be a target for a selective weapon, he says.

In fact, genetic similarities tend to belie traditional ethnic or national groupings, Cavalli-Sforza observes. He takes this idea of deep genetic unity even farther to argue -- and this is a key message of his work -- that races don't exist; they cannot be scientifically defined. His stance on race has drawn vicious attacks from white supremacists, but its scientific logic, echoed by most in his field, is difficult to rebut. People tend to fixate on external differences -- skin color, facial features, hair texture -- when in fact these are malleable characteristics that evolve relatively swiftly, Cavalli-Sforza explains. Our physical differences actually represent ancestral adaptations to different environments. The obvious differences in skin color, for instance, relate to the intensity of sunlight at different latitudes.

Even if ethical objections can be soothed, the Diversity Project faces an uncertain future. After all, $30 million is a lot of money to raise. Greely says the effort will get off the ground, although "it won't be the universal, simultaneous kind of project that originally was hoped."

Cavalli-Sforza is less lawyerly: "It will be done."

He notes that international collaborators have begun collecting data, even if not under the project's umbrella. For instance, his lab joined with scientists from other countries last year to gather blood samples from people in Eurasia (see sidebar). The Chinese have launched a genetic evaluation of their 56 nationally recognized ethnic groups, and even the Human Genome Project has taken a recent interest in genetic variation, preparing to search for subtle differences in a broad sample of the U.S. population.

Instead of fretting over the Diversity Project, Cavalli-Sforza has done some of his most important work in the last five years, mining a rich and untapped vein of genetic information on the Y chromosome, that sliver of DNA that makes half of us male. Having succeeded in reassembling so much of our past, he is driven -- some might say consumed -- by the missing pieces of the puzzle.

Meanwhile, human migrations go on, remixing our genes. And while this continual churning is erasing traces of past migrations, Cavalli-Sforza is finding a fertile source of data in a migration close to home: the influx of immigrants into California. "A lot of the world," he says, "you can get right here."


Mitchell Leslie writes for the Medical School's news bureau.

 

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