After my Nobel Prize, which was for chromatin, for doing nucleosome structure and also for methods for the image, what I call three-dimensional electron microscopy, reconstruction electron microscopy, which were developing techniques, I became interested in what was then called active chromatin. So I looked around and chose a problem in Xenopus the frog because it looked to me like a system where you could study active chromatin, which is chromatin where the DNA is going to be transcribed. So I became involved in transcription, the way that DNA makes RNA. I was lucky to find that the system I studied—I discovered a new class of proteins, which I called zinc finger proteins. This turned out to be—I realized they were something very special. I spent the last twenty years working on them. Indeed, I knew they would be a powerful research tool. But now I make synthetic zinc finger proteins which can target any gene in the body, any gene in the cell, with high affinity and high specificity. One of my zinc finger constructs is actually in patients trying to cure a disease.

What happened is that I read about a protein called transcription factor-3a, which interacted with the genes for 5S RNA. Moreover, it interacted not only with the gene but with the product of the gene which was RNA. That was intriguing structurally. Also the main attraction was that there was lots of material present early in Xenopus, you know, the toad Xenopus _____. So I wanted something where I could get enough for biochemical and structural studies. Now you see most molecular biologists were working either with genetics or with electrophoretic gels with smaller quantities. I wanted something with large, where I could extract large quantities. Now most transcription factors are present only in small amounts in cells. This was a conscious decision because of the practical reason.

What I didn’t know was that this system—so we began to do biochemical studies to extract the material and to grow crystals because I was a crystallographer, but also do biochemical work first because I do do biochemistry. Its nonsense to call—you know, my generation already, we were biochemical crystallographers. We made our own preparations. We didn’t wait for people to give them to us. That’s what used to happen many years before. Perutz never crystallized hemoglobin because it was already being done before. The people who worked on enzyme structure, it was already being done.

So I found—I put on a student in 1982 after my Nobel Prize, I put on a student to try to extract the material. We ran into all sorts of difficulties. I realized and found, in fact, that in order for the protein to be stable it needed a metal. I can’t tell you—I deduced that there had to be a metal. Then we found what the metal was. It was zinc.

Then later on the sequence got published and I could see in the sequence repetitive elements. We had also biochemically tried to break the protein down, TF3a, into smaller units in case there was already—there were domains. I found together with my student Jonathan Miller that there were repeating units. In the sequence I could see the repeating units. Most of the repeating units contained amino acids which bound zinc. So I proposed that there’s a novel type of structure for binding, for recognizing DNA: a series of repeated modules which we called fingers, and the fingers, this is the DNA double helix, and each finger binds to three bases—that’s what was shown later, three bases on the DNA. So it’s a remarkable system because each finger recognizes three bases and the bases are different. So it reads the sequence. Now there are many other proteins which recognize DNA, but they are always dimmers with the symmetry of DNA. This doesn’t have any symmetry. So it’s a unique system. So that’s why I pursued it. Then I realized that it would be useful for research.

So we began trying to put more fingers together. But you can’t put—when you start putting more fingers together to recognize a long sequence of DNA because what you want is to recognize a sequence uniquely, uniquely. In other words, it mustn’t recognize anything else. So this means very high affinity and it means having a long target. But if you start adding more fingers they get out of the register. The register of the fingers doesn’t match the spacing of the DNA bases which are recognized. So I began doing protein engineering to try to adjust the phase. So for five or six years we did protein engineering and solved the problems. Now we can target 18 base pairs, a sequence of 18 base pairs and the chances of that sequence of 18 base pairs occurring anywhere else in the genome is very, very small. So we have single gene specificity. This is now being developed by a company called Sangamo who bought—we had the MRC patents, who developed the patents.

In Nature two weeks ago there was a remarkable paper which showed they could correct a genetic defect in SCID cells. SCID is Severe Combined Immunodeficiency Disease. So it’s very exciting. I never used the word exciting before. It is an American word and we don’t tend to use such words in this country. But it is quite exciting to have one’s constructs in patients.

It was written by the Sangamo people. I wrote parts of it, but I’m not an author. I’m thanked, I’m thanked for writing it. I wrote quite a lot of it actually. Well, because I’ve only got a small group here now. I’m called a retired worker here. Retired worker, that’s an oxymoron. It doesn’t make sense. It means I’m retired from my post, but not from my work. So I have a small research group. So we couldn’t do such things, make large quantities of a material. So this is—anyway, that’s what I’ve been doing for the past twenty years.

Aaron Klug is chemist and biophysicist and winner of the Nobel Prize in chemistry. After completing his BSc at University of Witwatersrand in Johannesburg, he attended the University of Cape Town on scholarship where he received M.Sc. degree. In 1949 he moved to Cambridge in England, he studied molecular structure of steel and wrote a thesis on the changes that occur when molten steel solidifies, for which he earned Ph.D. in 1952.

In 1953 he obtained a fellowship to work at Birkbeck Collage in London, where he met Rosalind Franklin. They worked together to determine the structural nature of the tobacco mosaic virus. After Franklin's death in 1958 he continued his work on viruses together with Kenneth Holmes and John Finch. In 1962 he accepted a position at Laboratory of Molecular Biology in Cambridge.

His major contribution to scientific research was the development of crystallography electron microscopy for which he was awarded Nobel Prize in Chemistry in 1982. He was knighted by Queen Elizabeth II in 1988.

More Information: Wikipedia, Nobelprize.org