"Genetics in the 21st Century"

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By:Aaron Hall

According to Eric Lander, "People today are now living through the most stunning information revolution, unlike anything before in the history of science." He compared its importance to the chemist Mendeleev's critical observation around 1869 that all the elements of matter could be organized in a very simple table. With this discovery, Mendeleev laid the foundations for the chemical industry and for much of chemistry in the 20th century. The biological sciences and industry are now experiencing the same thing, Lander stated. Instead of a periodic table, the 100,000 human genes constitute a finite list that will be complete in the near future. This list will help biologists and scientists understand the tremendous diversity of the human race and determine the causes of disease.

People are variable, Lander said, and every possible DNA sequence and DNA change that can exist probably does exist somewhere in the world. On the other hand, he continued, there are only two or three common variants of most human genes. If two people were selected at random from the audience and a particular gene were sequenced from each, the odds are one in two or one in three that the two sequences of the coding regions would be identical. This reflects the fact that the human race descended from a small population in Africa only 10,000 generations ago or about 200,000 years. Small populations have relatively few variants, and the mutation rate of one in a billion bases is so low that 95% of all the genes in the audience have not undergone a single mutation in all those years. Even though any two human chromosomes are nearly identical, the little differences in DNA sequence can be used to trace the inheritance pattern of chromosomes and localize particular genes to particular subregions. Finding genes in this manner requires good genetic, physical, and sequence maps. The Human Genome Project has been making very good progress in these three tasks, Lander said; the genetic maps are essentially finished, and more than 97% of the genome is well covered in physical maps that can be used to isolate disease genes. Sequencing is heating up, with about 10% of the sequence expected to be finished by the end of 1998.

The process of producing 3 billion letters of information (the DNA base sequences) requires extraordinary automation and cooperation around the world. Bizarre machines are being built, Lander said as he showed a picture of a machine at Whitehead nicknamed the Genomatron, which can set up 100,000 PCR reactions in an hour. This reflects a 1000- to 10,000-fold increase in capabilities over only 4 or 5 years ago, when a student might set up 10 to 100 reactions in an hour.

What are we making of this information revolution? he asked. How far have we come toward understanding the remarkable differences among humans, the basis of different traits? Finding gene associations for rare Mendelian disorders like cystic fibrosis or Huntington's disease is a piece of cake these days, Lander stated. Over 1000 relatively rare disorders already have been mapped to specific chromosomal regions --almost all of them within the last 10 years, and all within the last 14 years. About 140 have been specifically isolated and cloned.

For common diseases, the challenge has been to tease apart the contributions of multiple genes associated with complex conditions. The most progress has been made by looking for rare Mendelian subtypes, but there are as yet no good published subtypes for asthma, schizophrenia, and bipolar disease, for example.

Human genetics eventually may come down to just one very large table of variants or traits common to the population. People already are talking about collecting all the roughly 300,000 variants (3 for each of the 100,000 genes) and genotyping everybody. This is what genetics may look like in the 21st century, Lander continued.

He showed some examples of extreme claims, particularly those in supermarket tabloids, regarding genes and how they determine what kind of work a person may do, whom he will marry, or how much money she will earn. As the audience laughed, Lander pointed out that if the subject were Alzheimer's disease or thrill seeking, it's not clear where the public would draw the line regarding behavior or other traits that might be explained by genes.

"We have to make the advantages of this genetic revolution available for biomedical research and yet still fight what I think is the danger of a naive biological determinism and the consequences that could have for society. We need a different model. The right model, for me, is captured on a poster [showing two people] I'm very fond of from the Musée de L'Homme in Paris, from an exhibit they had some years ago: 'Tous parents, tous differents.' It can be translated two ways: 'All the same, all different,' or 'all related, all different.'"

Genetic variations influence our lives, he concluded, but they don't constrain us, nor do they shape us in the choices we can make as a society. What has happened so far in the information revolution will seem like nothing when compared to what will flow from the sluice gates of human genetics projects around the world over the next decade or so. We must explore "how to manage the information," Lander said, "and the choices and consequences of what science has to offer."

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