A Cabinet of Wonders

DNA is an elegant molecule. Purified, it strings like spider silk. Glassy clear, it hides reams of secrets: though we know its code—ATGC, the letters of its alphabet—we can't yet read it like a book. We may know what it says, but not what it means.

Yet a book is what the genome, the entire set of DNA in an organism, is often called: "life's instruction book," as the title of this year's Penn State Lectures on the Frontiers of Science put it.

Or it's a blueprint, the "blueprint for life." That analogy fails too: If the architect you hired to design your home brought you a blueprint that solely consisted of a long list of parts that began "windowwabeborogovestaircasedoorjubjub," wrote a commentator in Science, referring, with his Jabberwocky talk, to the amount of "junk" DNA in a genome, DNA that isn't genes, you might start to wonder if and when you will see your new house.

Having sequenced the genomes of 599 viruses, 205 bacterial plasmids, 185 organelles, 31 eubacteria, seven archaea, one fungus (yeast), two animals (worm and fruitfly), one plant (mustard weed), and one mammal (human), with the mouse, rat, zebrafish, pufferfish, and rice sequences well on the way, we now appreciate how complicated genomes are. (How is a genome sequenced? See "Sorting Things Out.") Our comparisons, consequently, are little by little becoming more realistic.

According to a reporter for the Associated Press, the human genome is like the telephone directory for a major corporation: "You've got lots of names and locations. But what does each of these people do? How do they work together to get things done? If something goes wrong, what employees or teams are at fault?"

Even more aptly, it is, in the words of the editors of Science, who named the genetics revolution the "breakthrough of the year" for 2000, "a cabinet of wonders."

Explains Londa Schiebinger, "A ‘cabinet of wonder' in early modern Europe was a splendidly crafted cabinet, itself made of rich materials, that the wealthy used to display natural and artificial oddities. The combination of divine and human craftsmanship displayed in the jumble of crystals, corals, shells, bits of bone, Amazon stones, or elaborately worked metals was to dazzle the observer."

pink-orange DNA against teal background

As Schiebinger, a professor of the history of science at Penn State, writes in Has Feminism Changed Science?, feminists looking at the Human Genome Project in the early 1990s took exception to the idea that sequencing DNA was "the ultimate goal of biology." The emphasis on simplicity, on "reducing things to smaller and smaller units," was a holdover from World War II, Schiebinger argues. "Physicists, fresh from the Manhattan Project, imported to biology the attitude that mysteries can be solved. By reconfiguring life as the mechanism of genetic replication, they concluded that life itself was not complex, but alluringly simple."

It's not.

That, ironically, is the first result of the Human Genome Project. When Science and Nature published the complete human genome sequence last February, Science lead author Craig Venter wrote of "a major surprise: We have found far fewer genes (26,000 to 38,000) than the earlier molecular predictions (50,000 to over 140,000)." He concluded: "The modest number of human genes means that we must look elsewhere for the mechanisms that generate the complexities inherent in human development."

The central dogma has long been: DNA makes RNA makes protein.

"It has always struck me as a curious term," said Nina Fedoroff, "since dogma is not what science is about. Science is about theories: human constructs which fall and are replaced with other constructs."

Fedoroff, head of Penn State's Life Sciences Consortium, organized this year's Frontiers of Science lectures, a series sponsored by the pharmaceutical company Pfizer Inc., on which the articles in this special report were based.

It's true, she explained, that "the information flow is from DNA to RNA to protein. Think of DNA as a library—a rare books library. All you get to look at are microfiche or xerox copies. DNA is copied into messenger RNA, which is transported out of the nucleus and into the cytoplasm—which is the rest of the cell—where it is translated or decoded and the outcome is a protein." The work of the nucleus is to maintain DNA, to replicate it, and to transcribe it to RNA. Outside the nucleus, a ribosome catches hold of this messenger-RNA and reads groups of three letters at a time. Every three-letter "word" stands for one of 20 amino acids. Following the RNA code, the ribosome stitches the amino acids into a chain, which then coils and folds into a protein. "Proteins provide structure or do work," Fedoroff explained. "Each protein is different by virtue of its amino acid sequence."

yellow DNA with red background

So far the central dogma holds true. But, "each gene, we thought, makes one protein. That was the gospel," noted Paul Berg, the Stanford Nobel Prize winner (and Penn State alumnus) known as the "father of genetic engineering." In a lecture at Penn State last April, he spoke of the impact of genomics on science and society. When the Human Genome Project was expected to find 150,000 genes, for instance, the pharmaceutical and biotechnology industries were highly valued on Wall Street. "Every gene represented a potential target for a drug. Then, when only 30,000 genes were identified, the pharmaceutical industry was immediately downgraded!" The human genome suddenly represented only a fifth as many drugs.

"Yet those 30,000 genes probably make on the order of 200,000 proteins. One gene can turn out eight, ten, 15 proteins," Berg said. "There's an enormous amount of science that needs to be done to figure out who talks to whom and when," that is, to learn the reasons why a gene is translated into one protein and not another. These tasks define the developing fields of proteomics (the study of proteins) and bioinformatics (the combination of computer science and molecular biology).

"That's where we are now," said Berg. "We have the basic parts list. That puts us at the very beginning of the start of the problem of what makes a human being and why we're all different."

The Human Genome Project provided other humbling surprises.

Of that string of three billion ATGCs, less than two percent is recognizable as protein-coding genes. These seem to cluster, leaving long stretches of "junk DNA" in between—at least, what used to be called junk. That some of this junk, the so-called Alu elements, also clusters in the gene-rich regions makes the designation suspect. As Berg noted in his lecture, DNA itself "was originally thought to be just baggage, just the structural component of a cell."

Another surprise is that some 200 genes in the human genome apparently come from bacteria. Directly from bacteria, not through millennia of evolution. It's startling enough, as Berg said, to know that "half the genes found in yeast are found in the human. And they're identical. You can take the gene from the yeast and put it into the human and it works perfectly well. What that tells us is that evolution has conserved information from the most primitive organisms to the most complex. What works in one place works everywhere."

David Baltimore of Cal Tech, writing in Nature, goes farther: "Apparently bacterial genomes can be direct donors of genes to vertebrates. So DNA chimaeras consisting of the genes from several organisms can arise naturally as well as artificially (opponents of ‘genetically modified foods' take note)."

Commenting on the news, one reporter quipped, "It is perhaps ironic that all humans, including those in the anti-GM lobby, are GM organisms." And it is perhaps coincidence that, the same week, the ban on genetically modified or "GM" foods was lifted by the European Union. "Gene-Altered Food Let In, But Europe Sets Strict Rules," the New York Times headline read. (The rules mainly involved labeling.)

orange and green background with DNA labeled

The final surprise of the Human Genome Project is that it changes how we think. Said Berg, "The implications and opportunities—as well as the concerns and problems—that come from it will convince you that it's at least as momentous as trying to put a man on the moon." From drug-design to issues of privacy, from family planning to food production, from evolution to environmentalism to medical ethics, the results of the Human Genome Project will color our arguments from now on.

One example is DeCode Genetics' plan to link three databases—medical records, DNA, and genealogies—for the entire population of Iceland. After months of debate over questions of privacy and ownership, the plan was approved; only ten percent of the population (28,000 people) still object, according to Gisli Palsson, an Icelandic anthropologist studying the project. The Icelandic state will receive fees and a share of the profits, recognizing, "the common-pool nature of the information involved," says Palsson, while the records in the three databases "will only be combined in the context of specific research projects, monitored by ethics committees and public officials." Already DeCode has located genes related to eight diseases, and Hoffman LaRoche, a major backer, is developing a schizophrenia drug based on the information.

So much was expected. But the project has already had other, unforetold consequences. Marilynn Ann Johnson is a retired curator of decorative arts from New York's Metropolitan Museum of Art whose grandmother had been born in Iceland. She reports, "Yesterday I received from Gisli and the DeCode project my Icelandic genealogy, tracing my ancestry back 500 years. How extraordinary is this miracle of the computer age!"

Londa Schiebinger, Ph.D., is Edwin Erle Sparks Professor of History in the college of Liberal Arts, 311 Weaver Building, University Park, PA 16802; 814-863-7303; lls10@psu.edu. Nina Federoff, Ph.D., is director of the Life Sciences Consortium and the Biotechnology Institute. She is the Willaman Professor of Life Sciences in the Eberly College of Science, 219 Wartik Lab; 814-865-5717; nvf1@psu.edu.

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Last Updated September 01, 2001