South African Sydney Brenner was awarded the Nobel Prize in Physiology or Medicine in 2002. His joint discovery of messenger RNA, and, in more recent years, his development of gene cloning, sequencing and manipulation techniques along with his work for the Human Genome Project have led to his standing as a pioneer in the field of genetics and molecular biology.
The acridine experiments went on, and they made various interesting predictions. So just to give you an example, you could start with a mutant which you arbitrarily labelled 'plus', then all the suppressors of it would be ones that would be minuses. So when you add a plus and a minus you come back to zero again. Now, I have to say that this concept of a frame or a phase – we called it phase-shift, it turned to be frame-shift later on – was so foreign to people in genetics that we had endless problems trying to explain this work to people, right? And so just going on with this… so now… now you can go… you can start with a suppresser, and it must be symmetrical. So if you start with a minus suppresser, then its suppressors must be plus. And so you then can create arrays of, as they were called, uncles and aunts, cousins, brothers, sisters, and you can see how they relate and you can map them and you can do this. It soon… it became very clear to us very quickly that we could use this to determine the size of the code. All we had to ask is how many of these could we put together and so come back to the normal phase, because you see according to this, two pluses would be a minus if it was a triplet phase. And so the question was: how do you do this experiment uniquely? And the experiment had to be done uniquely in the following way. You make doubles... you make doubles by brute force. So we take, say, three mutants, A, B, C, in a row, and we make a combination A and B. And A and B is mutant, and we make the combination B and C, and B plus C is mutant. Now, we cross those phages together, there is no way a normal phage can be produced, because they both share B. But of course you get wild-type functional phage come out, and that must be the triple: A, B, C. So we showed we could actually construct a triple, and therefore the triple showed that the code was phase three. Now, this I think is the kind of apotheosis of a genetic analysis, because you have to consider what you're doing here. You're taking these viruses and you are just mixing them together and you're simply recording plus, minus. And from this pattern it seems mad that you could deduce the actual triplet nature of the genetic code. But that's just simply the logic of how the information is transferred, that it is a non-overlapping code of these, and of course awoke us, well at least awoke me, to the idea that topology could, you could do these things at the kind of topological level. And so let me just say that to the geneticist this was very hard to stomach. You could take a mutant – you could a set of mutants and you can show first, you could add them in certain pairs, they were still mutant. Other pairs, you just restored the function. Furthermore, you could take these, pair them in many ways, they were still mutant, but if you put three together they came back to normal. And if you did four, five, they were still mutant, then we went as far as six to make it normal, and then after that it got a bit boring. And formally what we showed, and there were some things there, formally what we showed that the code is a multiple of three. It's 3n bases, where n is likely to be 1. And that was deduced completely by this experiment.
Title: Using frame-shift to determine the size of the genetic code
Lewis Wolpert is Professor of Biology as Applied to Medicine in the Department of Anatomy and Developmental Biology of University College, London. His research interests are in the mechanisms involved in the development of the embryo. He was originally trained as a civil engineer in South Africa but changed to research in cell biology at King's College, London in 1955. He was made a Fellow of the Royal Society in 1980 and awarded the CBE in 1990. He was made a Fellow of the Royal Society of Literature in 1999. He has presented science on both radio and TV and for five years was Chairman of the Committee for the Public Understanding of Science.