Judging DNA

Courtesy of National Library of Medicine Marshall W. Nirenberg, laboratory chief of biochemical genetics at the National Institutes of Health's National Heart, Lung, and Blood Institute, received a Nobel Prize in 1968 for helping to interpret the genetic code and its function in protein synthesis. Q: How did the discovery of the double-helix structure relate to the cracking of the genetic code? A: George Gamow, the physicist, told me he went down his driveway to pick up the mail one day and found this issue of Nature that had Watson and Crick's article in it. He opened it right at the mailbox. And immediately he thought of a code, of a genetic code based on the sequence of deoxynucleotides in DNA. Q: Without the double helix, would it be difficult to crack the code? A: At that time--when I first started, I didn't know--I thought that amino acids were encoded into protein by nucleic acid, but I didn't know whether it was DNA or RNA. I didn't know if a code existed. The first question was: Does DNA or RNA stimulate the amino acid incorporation into protein in cell-free extracts? Q: What were the implications of obtaining the genetic code? A: I was really struck by the fact that [since] we knew the code, we could program robotic machinery [in the cell] to carry out the instructions. I was struck by the potential for programming cells with synthetic information, RNA or DNA. Q: Was gene therapy what you had in mind at that time? A: Yes, and I predicted that it would take 25 years to develop the technology to get the nucleic acids into the cell and to get them read. It was exactly 25 years later that the first experiment was done with humans. Courtesy of James Darnell Laboratory James Darnell, Vincent Astor Professor at Rockefeller University, pioneered gene regulation through his discovery of the cell-signaling route, the JAK-STAT pathway. Q: How was the discovery of DNA received in the scientific community? A: DNA was not always known and recognized as the hugely important area it was to become. Around 1957-58, [Bob DeMars] recognized what this 'new wave' of bacterial genetics was all about. At the time word hadn't seeped into biology that this was the molecule to pay attention to, and most of the scientists at the National Institutes of Health didn't know or care what DNA was. DeMars gave lectures to bring the NIH community up to date on the transfer of genes between cells, transduction, and the importance of DNA, and I think this is what finally awakened interest in the cell biology community--that DNA was a repository of information that could be moved around and change the phenotype of the cell. I don't think this was appreciated until [the] Nobel [committee] recognized it in 1962. Q: How did the discovery relate to your own work? A: We showed that polyA was added in the nucleus to long RNA molecules and later found that the polyA-terminated nuclear molecules also had a 5-prime cap. We didn't think of the possibility that the mRNA came from the long molecules by splicing. That concept was implied from [Phillip] Sharp and [Richard] Roberts' Nobel-winning discovery (physiology or medicine, 1993) that adenovirus [Ad] mRNAs bound to scattered sites on the Ad single-stranded DNA with long unbound loops. It really showed that the information in our DNA was scattered and had to be collected by RNA splicing. Courtesy of UCSB Public Affairs Robert L. Sinsheimer is chancellor emeritus at the University of California, Santa Cruz, and professor emeritus at UC-Santa Barbara and UC-Santa Cruz. Q: How has the discovery of the DNA structure changed biology? A: To be truthful, I don't see the double helix as being such a seminal event.... It was one in a series of events that would make a kind of regular progression. Q: Why has the double helix received so much attention? A: It's a pretty structure. I don't mean to downplay it. It took a lot of ideas that were sort of amorphous and gave you a solid model on which to focus these ideas. In a way, some of the more recent developments, to me, have been more surprising in that they came almost out of the blue. Q: For example? A: Splicing. And then programmed cell death; I don't think that was anticipated by anybody. More recently, RNA interference. Q: Historians often link the DNA discovery to the Human Genome Project. What led you to propose the project? A: I was acquainted with big science, what you can do with huge amounts of money. And it occurred to me ... 'what could you do if you put a lot of money into a project, what would be worth doing?' It seemed to me what we really needed was to have a biological database of whole genomes that would provide a solid foundation for development of cellular and other forms of biology. And the natural thing to think about was the human. In one way it might've made more sense perhaps to first talk about doing bacteria or Drosophila or something like that. But you weren't going to get the money. The human had its obvious medical implications and for that you could get money. Courtesy of Susan Lindee Susan Lindee, an associate professor of history and sociology of science at the University of Pennsylvania, wrote The DNA Mystique, a study of popular images of DNA, with sociologist Dorthy Nelkin. Q: How has science changed in the 50 years since the discovery of the DNA structure? A: Watson and Crick didn't have the kind of lavish corporate and government funding widely available to people doing research on DNA today. I think a young biologist/geneticist starting out today can expect to achieve a lot more than Watson and Crick might have expected to achieve, because of the power of technology and the power of the institutions. Q: How do you feel Watson and Crick facilitated this change? A: What Watson and Crick did was very important, but they were building on what a lot of other people did. And to isolate that one moment of discovery and say that this is the point of transformation from the past into the future--OK--that's a choice you make. Watson ... built that moment with that autobiography and he did that very effectively.... He was marketing himself [while marketing] science as kind of an exciting and maybe even sexually liberating experience, and he was great at it. Courtesy of John Harris John Harris, Sir David Alliance Professor of bioethics at the University at Manchester, is a member of the United Kingdom Human Genetics Commission. Q: How has the discovery of the DNA structure affected bioethics? A: I cannot think of a single area of bioethics that hasn't been influenced by it. Privacy is one issue that now has a new dimension. Now with the ability to do genetic profiling noninvasively from saliva and not blood, someone can lurk around the bar, take my drinking glass, and run a test from my saliva. So these issues of privacy and confidentiality have shifted from keeping information secret, to punishing the misuse of information. Q: What are some of the other new issues in bioethics? A: The new issues of bioethics have to do with the possibilities of intervening in people's genomes through gene therapy, genetic manipulation, and cloning. I think that is a huge shift in the sense and responsibility of who we are. We've operated up to now [with the belief] that ill health was a matter of chance. We're now starting to feel more responsible for our state of health and about our genomes. We no longer look at ourselves passively as the products of evolution, but possibly the authors of future evolution. --Brendan Maher, Eugene Russo, and Hal Cohen contributed to this report. Correction:The image of John Doebley, professor of genetics, University of Wisconsin, Madison, was incorrectly used for John Harris in this story. The corrected image is provided above.

Judging DNA

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