 We were unable to actually isolate a gene. What is responsible for turning these on or turning these off? But the cancer virus itself had RNA as a genetic material. Well, let's take a look at this. Is this really dangerous? Once you had sent fused the DNA molecules, it was extremely laborious and difficult. The present guidelines which prohibited... When I finally was called upon to testify, by this time it was one o'clock in the morning. And this was the starting of the biotechnology revolution. The underlying problem in biology, after discovering the genetic code and the metastrophotic synthesis, were actually the question, how do you actually turn a gene off and on? How do you control DNA? Jacob and Mano approached this problem with a combination of genetics and physiology and a little bit of biochemistry, but mostly genetics and physiology, to try to understand a very simple system in bacteria, the system that bacteria have for using the sugar lactose as a source of their carbon and energy. But back in the mid-1960s, we didn't know what any of these genes did, and we didn't know in the case of the oppressor whether the gene made an RNA molecule or a protein molecule, or what. We wanted to get more into the details. Some of us doing genetics, especially Gilbert doing biochemistry, how do you study a gene in biochemically? You need to have at least partially purified that gene. John Beckwith came to work with me first, and he actually worked on genetic suppressors. He was a great performer in that area. And so what he decided at one stage was to say, well, I'll purify the lack gene. The basis of our being able to isolate the lack gene comes from the structure of DNA itself. And what we had done was to isolate two viruses. If we took apart the DNA strands, the two DNA strands of each of these viruses and slapped them together, the lack genes would form very nice pairs because they were identical to each other, they were complementary to each other to form these tight bonds. So what you ended up with was a structure in which you had black genes forming a nice double helix, but these two other strands of the virus sticking out and not forming the tight bonds. And we were actually able to visualize that on a microscope. And first of all, there were beautiful pictures because they were exactly what we had predicted, which was very nice. And this is the first time a gene had been taken out of a chromosome and purified in a test tube. We called a press conference on the day that the paper was published and announced our discovery. But at the same time at this press conference we also talked about some of our ethical concerns about genetic manipulation. And so the media reports, which were worldwide on our finding, were a mix of reporting genetic advances and suggesting how close we might be coming to curing genetic diseases, et cetera, which was a bit of a stretch. But I mean, down the road it's related to that, certainly. John Beck with electrifying feet demonstrated that you could obtain a single gene from a bacterium. However, his approach was not useful for obtaining genes from higher organisms, including human beings. But then in 1970, Howard Tenman and David Baltimore came along and independently discovered an enzyme called reverse transcriptase that enabled a genetic information in an RNA tumor virus to be integrated into the DNA of a cell. The day I did the first experiment and I got this little lip, my wife actually was working in the lab there and I sort of turned to her and showed it to her and she said, no. She said, that's just background noise. And I said, well, you know, maybe it is, maybe it isn't. We'll have a look and concentrated the virus and that was the whole story because now we were tenfold over the background there was no question that it was real. And I just more or less told everybody in sight about it because it was really very exciting. However, this was just a day before Nixon bombed Cambodia. And sent me and everybody else out into the streets. So I went on strike for a week after having discovered the reverse transcriptase as actually the first thing that I did. And the experiments weren't complete yet. I froze away the experiment in progress. Came back after a week and then finished that experiment and a few others to nail it. So once Baltimore had reverse transcriptase he realized that you could use it to transform the messenger RNA back into, say, the DNA of any gene including a mammalian gene. So we had captured genes, mammalian genes for absolutely the first time in history. And this was in some ways the starting of the biotechnology revolution because now companies could do that insulin, whatever you wish. And the reverse transcription to this day is the way to capture a messenger RNA. So once you could isolate genes scientists wanted to manipulate them, play with them, try to figure out what they do. Two of the scientists who had this ambition were Herbert Boyer and Stanley Cohen. They were at a scientific conference in Waikiki, Hawaii in November 1972 and they found themselves together munching corned beef sandwiches in a deli late one night. They got to talking about this problem and they decided they might have a way to accomplish this purpose. It's involved using things called restriction enzymes that cut DNA at a specific place. So once they could cut it then they could insert the DNA of interest in a plasmid and put the plasmid into a bacterium and watch what the DNA does. It was a natural collaboration and as we talked about this we realized that this would be a very exciting scientific opportunity. So we decided at that time to collaborate in trying to reconstruct plasmids. The experiment went as follows that Stanley would send us the DNA. We'd cut it up, put it back together again. We'd send that DNA to Stanley. He would transform it into the bacterium. He would send those bacteria back to us. We'd take out the plasmid DNA, cut it up and look at it in the gel. That was sort of the division of labor. And so Bob Helling and I when we did the first analysis of what we thought was a recombinant DNA molecule we stained the gel and it was late afternoon and went to the dark room and turned on the black light and there was this picture and it was very evident that we had re-assorted the fragments of DNA, successfully recombined them and we had recombinant DNA molecules. Now these results, exciting as they were, didn't necessarily mean that we could use this to clone pieces of totally foreign DNA. We immediately thought that well the next thing we need to do to really prove that this is going to have some impact beyond microorganisms that we needed to put a piece of what we call eukaryotic DNA. That is DNA that comes from an organism other than a microorganism like an elephant, a human or what eventually turned out to be our first demonstration was with a frog DNA. It was clear when we did that experiment that it was now possible to transplant genes from virtually any source into bacteria and that was a very exciting potential because it was apparent to Herb and to me that this meant that one could study genes from complex organisms, one could eventually clone all of the genes of the human genome or from any organism and study them individually. In the summer of 1973 Herb Boyer gave a talk at a Gordon conference and it was clear that you could take DNA from anywhere from a human cell, from a banana, from a fish, you name it and put it into a little bacterial plasmid and grow the bacteria up and you would have enough molecules to be able to do chemistry on these things. But as soon as that was apparent, the same day that he gave a talk several of the younger people there immediately raised the question as to whether you could in that way make things that might be dangerous. The questions led to a moratorium unprecedented in the history of science. It also led to a meeting, an international meeting to which scientists came from all over the world in Asilomar, California in 1975 to discuss this problem. The people who were there were frankly conflicted. On one hand they wanted to avoid the moral taint that had befallen the scientists who participated in the atomic bomb project but on the other hand they wanted to get on with recombinant research. Their exercise and social responsibility led them to include the press and there was considerable open debate. I remember feeling as though I never knew what was going to happen. I didn't know what the right way to proceed was and here I was a member of the organizing committee. It was just a tremendous amount of science to get your arms around. It was huge public issues for which we had no background or training. We talked all this through and came out saying in this case we don't know enough. I was absolutely certain that this is also safe and that was a wrenching thing for people to say because what we were really saying to ourselves was we're not going to do certain kinds of experiments until we've gone through a whole process of convincing ourselves that we don't have a we're not letting some genie out of the box here. At the end of Asilomar the great significance was that we felt that experiments could go forward and could go forward with some sense of assurance that we weren't going to be doing really nasty stuff. If we hadn't invited the press to Asilomar then the stories would have been less good than they were. The information would have been less precise than it was. We would have been in worse shape than we were. Well the National Institutes of Health which was the principal federal agency that would sponsor recombinant research took the Asilomar guidelines into account when it began drawing up its own rules for the conduct of recombinant research. The NIH issued its rules in June 1976 and they were designed to protect public health and safety. However a number of people, scientists, laymen and government officials around the United States were suspicious of these guidelines. Their main reason for suspicion was that the guidelines had been drawn up by the same people who were going to be doing the research. This apprehension expressed itself quite forcefully in Cambridge, Massachusetts. The City Council held hearings on recombinant DNA and they then set up a committee to evaluate the potential dangers of this research and the committee was made up of citizens of across the spectrum of the city including scientists and experts but also ordinary citizens working, housewives, etc. At the time of the great Cambridge crisis of post-asilomar and the mayor of Cambridge egged on by some of my friends was trying to ban recombinant DNA in Cambridge. I must say that I've been surprised recently to find myself being put among those who are not concerned. I've been concerned and I continue to be concerned. I feel... When I finally was called upon to testify by this time it was one o'clock in the morning and it was a circus. There was music, there were flags, there were demonstrations and there were several different Nobel Prize winners arguing different sides of the issue to the Cambridge City Council. There were only two libraries of clones in Cambridge. One was our yeast library and the other one was Tom Maniatis' CDNA what we would now call CDNA libraries and we were both basically chased out of town for a while. In the end MIT defended me and that was great but Tom had to move to Cold Spring Harbor to continue his work for a while. There was no possibility to the fact that if a community of scientists say there might be danger here that the general public is going to hear there is danger here and we saw it all in the chambers of the City Hall in Cambridge in Congress and in the press. We saw every bit of it and you have to go through it. I don't see any way we could have avoided that. It's not the answer to getting public acceptance. You just got to go through a messy process.