Fruits of Genome Sequences for Biology

![Figure][1] CREDIT: AAAS When I first became interested in genetics in the early 1960s, DNA had just taken center stage. We studied its chemical and physical properties, and we understood that inferences about genes and genomes (yes, this word was used then) were actually about information encoded in DNA sequences, which we could not read or interpret. By the 1970s, we had learned how to use recombinant DNA technology to manipulate DNA in bacteria and viruses, which allowed us to recover (clone) sequences encoding proteins from any organism (including humans). The next step became obvious (and controversial) even before it had been reduced to reality: expressing these coding sequences in easily cultivated cells and producing pure recombinant proteins in quantity at reasonable cost. This enabled production of previously rare protein therapeutics and allowed biologists, biochemists, and structural biologists to study pure proteins. One would have thought, after these developments, that when the possibility of sequencing entire genomes was first raised, it would be regarded as an obvious next step with great promise for science and medicine. Instead, it was met with much skepticism; in the beginning, I was among the skeptics. Unlike the controversy over recombinant DNA, which revolved around issues of safety, opposition to sequencing the human genome was driven by concerns about the extreme cost (estimated then at $3 billion) and effort required. The opposition (including me) felt that diversion of these kinds of resources to “big science” might so distort the nature of our scientific community that the cost would outweigh the benefit. There was no consensus then around the benefits of the genomic sequences, for science or for society. In 1988, a National Research Council study (on which I served), proposed a compromise whereby much smaller, and therefore cheaper, genomes of genetic model organisms would be sequenced first. The critical argument for me, and indeed for much of the scientific community, was that the sequences of the model organisms could be interpreted through experimental work, yet the homology among similar proteins in diverse organisms would allow us to transfer much of the biological interpretation to the human genome. Genomic sequences of many organisms, not just the human, would allow us to read and ultimately interpret the information in DNA in all of them. So it turned out. The benefits for science have been nothing short of revolutionary. The fears of big science around sequence technology have largely dissipated. Today, individual investigators outsource routine sequencing to a thriving service industry at an astonishingly modest cost. Data-release practices introduced during the human genome sequence project facilitate reuse of existing data in place of pointless and expensive repetition. This has spread to the functional genomics community and beyond. As with all technology development, some issues remain, such as the cost of computational and sequencing infrastructure, which is still beyond the means of individual small laboratories. These can be dealt with well short of big science by modest increases in funding for shared facilities. When I began my career, I never imagined that someday I could simply look up a gene's coding sequence; find its orthologs in other organisms; and order, from a service organization, a mutation to my specification for an experiment to reveal gene function. Yet this is now our world, the direct result of a collective agreement to make genomic sequencing a priority in the last decades of the 20th century. It was a very good decision. [1]: pending:yes