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The daring act of sequencing the human genome


Inside-out genetics gives faster results
Sydney Brenner Scientist
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And so our job then... and every classical genetical thing, whether it was in phage or bacteria or C. elegans (Caenorhabditis elegans), and that is the way I began... began with a mutant hunt. You hunt for mutants and then you classify them. The way you classify mutations is you put them into the same organism and you see whether they complement each other. If they fail to complement you can say those mutations are in the same gene. If they complement, you know you've got different genes. And so you can conduct this exercise and come out and just say well, for movement I think we've got to have at least 10 genes that specify movement because I have 10 genes of paralysed mutants that show lack of movement. And these genes then, it's now up to you to show how they work. That of course was the difficulty with developmental biology... is one didn't know how to get into the system until we could clone the genes. Right. Now, what we could now do was effectively clone genes, sequence them, therefore we... we didn't have to do the mutant hunt. We could actually find the wild-type genes, they were there. And then we could ask — it's been called reverse genetics, but it's wrong — then we could ask what happens if I make a defect in this gene? Right, now. And then I'll see what the effect is on the organism. Basically what it is, it's not reverse genetics but it's inside-out, because the whole history of biology we pursue functions from the outside, from the phenotype, from say, finding people that suffer, that have... that are bad at high altitude, to discover by going through that they have abnormal red blood cells, to show they have a protein that has an abnormal way of aggregating, to finally showing that there's the protein with one amino acid change, and that's the sickle cell mutation. And that took... decades to do. Now we can start at the other end, which is to find the wild-type gene, since we know the genetic codes we can just write down the protein. And since, as information collects about proteins and what they do, we may be able to... to get much faster to map this in terms of phenotypic function, right. So here's the new approach to genetics. What does it do? It liberates us from the life-cycles of organisms. We had been bound to always do crosses, always our experiments depended on taking genotypes apart, seeing what happens and putting them together and seeing what happens. One generation at all times. And of course when we got experimental organisms, they had to have easy life-cycles, they had to have rapid ones so we could do a lot of experiments... didn't have to wait a year or two years for the answer. In that case we might well have forgotten what the question was by the time we got the answer. And I can remember giving my first lecture on this, in the... in about 1986, ‘87, in which I said, I've come to... you know, we have now been liberated from the tyranny of the life-cycles of organisms, from their modes of reproduction. We can do genetics now on everything, anything. Giant redwoods, grapes, and most important, human beings.

South African Sydney Brenner (1927-2019) 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.

Listeners: Lewis Wolpert

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.



Listen to Lewis Wolpert at Web of Stories



Tags: Caenorhabditis elegans

Duration: 4 minutes, 33 seconds

Date story recorded: April-May 1994

Date story went live: 29 September 2010