Ambion: I’ve read where you maintain that science is about more than experiments — it's about a conversation. As you may know, Ambion is currently highlighting the endeavors of the RNA Tie Club on our website. What influence did your conversations with members of the RNA Tie Club have on your career, and how did the information and correspondences between the Tie Club members affect your views of the relationship between RNA, DNA, and protein and early days of molecular biology?

Dr. Brenner: Well, to tell you the truth, I knew very few members of the RNA Tie Club. I was one of the late additions to the Club. I believe I was “Val”. The people I knew were Francis, Leslie Orgel, Gamov and, of course, Watson. We were all working on breaking the genetic code, and through my interaction with the members, I was able to write a paper for the Club on the impossibility of all degenerate triplet codes. That was my theoretical contribution to the Club. Then after Francis wrote his paper saying that it looked like the coding problem being solved de novo was hopeless, we decided that we better get on and do other things. You know, we always pushed ahead with the experimental approach.

Ambion: I’ve also read that you consider creating a framework that brings ideas and scientists together to be very important to researchers today. How do you envision creating such a framework?

Dr. Brenner: One of the problems today is that everyone has become conventional. Nobody is willing to take any gambles; nobody is willing to take any risks. I think that we could fundamentally go to a situation where there is no more innovation. Of course, there is innovation now because there is just so much science such that innovation just happens. But if you want to favor innovation or stimulate it, you’ve got to let people do their thing without endless justification. You’ve got to take risks. Andrew Fire – the gentleman who discovered RNAi – for instance, worked in our lab in Cambridge. People were told to just leave him alone, and he was able to invent several things. But you ask what framework to use; well I say we should have the “casino fund”. I think everybody who gives money to science should give a tiny fraction, say 1%, into a casino fund and then that should be allocated to successful gamblers.

Ambion: You have discussed how in 1962 you believed all the classical molecular biology problems were either solved or would be solved in that decade. In retrospect, would you agree with that statement?

Dr. Brenner: Well, they were solved in principle. Of course we were wrong basically, there were a whole lot of new things to discover. For instance, we never expected that there would be introns. They were totally unexpected. And we also never expected there would be RNA enzymes – and so many of them. So it was a bit of an arrogant statement, but better to be arrogant then complacent.

Ambion: What do you believe are the big problems that need to be solved today, given current technologies?

Dr. Brenner: I think the first big problem is exactly how are we going to get all this data (from the human genome project) into knowledge? I think that is the thing that has become the great challenge. I believe it will have to be done by experiments. I don’t believe in all of these things that make millions of measurements and hope that something will emerge – things that I call “-omic science”. I don’t think that is going to be the way. I think we are going to need a theoretical framework in which to embed all of that in. And I think we can get to that point quite easily, really.

Ambion: In your Nobel laureate speech you commented on how one should focus on the “cell” rather than the “gene” as a basic unit of function, and that now we must focus on creating maps of cells and maps of how cells talk to each other. Could you elaborate on that?

Dr. Brenner: Yes, I think that thinking of the cell as the unit of function is important, and I call this project ‘Cell Map’. Genes don’t have function, per se. I don’t believe thinking of things at that level is the correct level of abstraction. Because if you look at any organism like us, the way you can interpret the function is in terms of the cells. Of course, the genes work within cells, but you have to have the picture that the body is built out of cells. In fact, we start as one cell and then after a successive many, many divisions, the cells differentiate, etc. This is all really old hat. There is a theory called the ‘cell theory’ that is about 150 years old. So I think studying the cell gives the proper perspective. You can then look downwards onto the molecule and upwards to the organism. So it is neither top down nor bottom up, rather it is middle out, and I think that is going to be the correct approach. So my thinking is, ‘thank you for the genome, now we are going to go and see which genes are active in which cells and when. That is the way we are going to be able to unify information.

Ambion: You also said that “humanity” should be of primary concern to researchers today. Could you elaborate on that?

Dr. Brenner: Yes, I think this is going to be a really exciting thing. For years we haven’t been able to do human science directly. But I think now that we can look at humans themselves, and we can look at their genes, why bother with the mouse? I call this project ‘Humanity’s Genes’ to distinguish it from the human genome. I believe nobody ‘has’ the human genome sequence and nobody will have that sequence. So, what I’m interested in is your genome, and my genome, and in all of those six billion genomes out there. I think this will open up a real way towards understanding human physiology.

Ambion: Do you believe scientific research as a whole changed significantly since your start over 50 years ago?

Dr. Brenner: Yes. I think it has expanded tremendously and become industrialized, in part. And, of course, part of me strongly regrets the industrialization. It does, of course, enjoy enormous funding. But I think at the end of the day when you think about it, it is going to be a man or woman in a room, having an idea, talking to others – and then trying to prove or disprove the idea by experimentation. I don’t think it is going to be the World War I approach, which is to get out there and attack. I don’t think that will work because that may deliver data, but not understanding.

Ambion: What is next for Sydney Brenner?

Dr. Brenner: Well, there are my two projects, ‘Humanity’s Genes’ and ‘Cell Map’. I plan to just get moving and try and do them. They are obviously very long term, and they will take decades to really accomplish, but someone needs to start. So that is what I want to do.

Ambion: Thank you very much for taking the time to talk to us. It has been an honor.

Dr. Brenner: It has been a pleasure talking to you. You know I have used Ambion’s products and I have got your catalog. Yes, I endorse your products; they work well.