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In Wake of Genetic Revolution, Questions About Its Meaning

by Eric Lander, PhDThe New York Times
September 12th, 2000

Labor Day has come and gone, and I am chagrined to find that I haven't made it through my summer reading. My list comprised only a single book, but a rather unusual one: the text is three billion years old, has six billion copies in print, runs three billion letters long (about one million pages), and is written entirely in four characters (A, T, C, G) with no spaces or punctuation. The book, of course, is a great classic, The Sequence of the Human Genome.

Just before the Fourth of July holiday, an international scientific consortium announced at a White House celebration that it had largely deciphered the DNA instructions encoded in the human chromosomes. I felt a special pride in the accomplishment, because my own scientific group at the Whitehead Institute Center for Genome Research was a major contributor to the effort.

Now that the hoopla has died down, we've all turned to the work of preparing a scientific paper to be submitted later this year describing the findings. The real challenge is ''annotating'' the sequence, attaching meaning to an otherwise boring string of genetic bits. Aided by computer programs, we're trying to parse the continuous DNA into distinct genes and discern each gene's role in making neurotransmitter receptors, bone proteins, stomach enzymes, reproductive hormones and so on.

We're trying to glean meaning from the breathtaking variations in the chromosomal landscape, from vast gene deserts to dense urban cores. And we're trying to reconstruct the glory days of ancient transposable elements that hopped around our genomes millions of years ago but have since fallen into ruin.

In effect, we're preparing the first edition of a guidebook, describing the landmarks of the human chromosomes, designed to shape the experience of generations of genome travelers to come.

Still, I'm aware that our work is just one of the many ways to breathe meaning into the human genome. So I was glad to visit the Exit Art gallery last week in SoHo for the opening of a different kind of genome annotation project, a show entitled ''Paradise Now: Picturing the Genetic Revolution'' by 39 artists probing the social meaning of genetics. The works tackle such themes as genetic identity, species boundaries, biotechnology, evolution and racism.

Scientific revolutions may start with dry, objective data, but their ultimate impact depends on human interpretation in a societal context. Scientific milestones set off a search, often a struggle, for the metaphors and images that will be used to connect the findings with our daily lives.

Galileo's discovery in 1610 that Jupiter had moons shook his world's foundations because it undermined the religious image of an Earth placed at the center of creation, with all heavenly bodies orbiting it. After a drawn-out battle, the image came to be replaced by a picture of humans alone on a small planet circling a mediocre sun in a backwater of an ordinary galaxy in an unimaginably vast and empty cosmos.

Intriguingly, the Vatican showed that it won't make the same mistake twice: when scientists in 1996 reported possible evidence for ancient life on Mars in a meteorite recovered from Antarctica, Roman Catholic officials swiftly said that such a possibility did not conflict with religious doctrine but revealed God's greater glory.

Likewise, the struggle over the meaning of the human genome is already under way. The language and imagery will be important because it will shape society's choices in the coming decades.

To what extent will we regard ourselves as constrained by our genes? Brain function, color perception, reaction times, rate of memory formation and personality are surely affected by slight sequence variations in genes encoding neurotransmitter receptors and biosynthetic enzymes. But do these gene sequences define limits that we must live within or influences that may, if understood, be overcome or turned to an advantage?

I already detect a naive biological determinism in some popular writing on genetics, stretching the science far beyond the data. Human beings may not be blank slates, but neither is there evidence that the chromosomes contain the legendary handwriting on the wall.

I'm suspicious of the language of limits. The gene pool has not changed significantly over the past 5,000 years, but human society and individual opportunity have been transformed. Moreover, history is littered with supposedly scientific pronouncements about the limits of women, African-Americans, Southern Europeans, Asians, Jews. Science has done a singularly poor job when it has sought to define limits on human potential.

To what extent will we seek to pigeonhole people based on their genes? Humans are a remarkably homogeneous species, with any two people, regardless of racial or ethnic group, being 99.9 percent identical at the genetic level. (By comparison, two random chimpanzees in Africa show a fourfold greater difference.) Still, the residual 0.1 percent translates to roughly three million spelling differences, with some conferring dramatically higher risk of Alzheimer's disease or breast cancer.

Will we see genetic variation as an economically efficient way to divide people based on group or individual risk of disease? Or will we say, ''There but for the grace of God go I,'' and choose to stand together?

Will we speak of genetic defects or genetic variants? Clearly, some DNA changes are unquestionably negative mutations, destroying the function of a crucial protein. But many of the common ones are likely to confer mixed blessings-- perhaps an increased risk of infection by one pathogen, but greater resistance to another. It's easy to slip into speaking of deviations from an ''ideal'' genotype, although population genetics instead suggests the image of a genetic tapestry is closer to the mark.

The hardest question is, To what extent will we decide to reshape the genes we pass to our children? Some of my close colleagues are already proposing ways to ''re-engineer'' what they view as an ''imperfect'' human genome--to prevent cancer, slow aging, or enhance memory--by modifying the human germline. These are serious goals, not to be lightly dismissed. Yet, I find it unsettling that we've only just skimmed the three-billion-year-old genetic text and already they're saying, ''Hey! I think I can improve on this!''

Safety is, of course, a major concern. Given the subtleties of human physiology, quick genetic fixes are likely to do more harm than good. And the prospect of a ''product recall'' from the human gene pool is too surreal to contemplate. But there will come a time when we can do such things safely, and it's not too soon to ask whether we should. Will we adopt the image of humans as a product of manufacture, rather than a product of nature? If we cross that fateful threshold, I don't see how we can ever return.

I part company from some of my colleagues here. While I'm strongly opposed to laws limiting scientific investigation, I would support a ban on modifying the human germline. Society could always repeal the prohibition if we become technically adept enough and morally wise enough. But we should have to rebut a strong presumption against tampering.

Meanwhile, I'm back home in my study sifting through genome analyses for the scientific paper. I have to explain periodically to my three wonderful children why Dad is holed up working on the weekend. I try to give them a sense of what I am laboring over. And, as I do, I find myself attempting to imagine the new world and new world view that they will inherit as a consequence of our science. And hoping that they'll be proud.

Copyright ©2000 by the New York Times Company.

Eric Lander, PhD is the Director, Whitehead Center for Genome Research



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