From Lithuania to Durban
Aaron Klug was born on August 11, 1926, in Želva, a small town in Lithuania, to Jewish parents, Lazar Klug and Bella Silin. His father had trained as a saddler but worked in his own father’s business of rearing and selling cattle. He had a traditional Jewish education as well as secular schooling, and a gift for writing that earned him occasional articles in newspapers in the capital. When Aaron was a baby, his father emigrated to Durban in South Africa, where members of his mother’s family had settled at the turn of the century, and the rest of the family followed when Aaron was two.
Durban was then a sleepy subtropical town, which Klug remembered as a fine place for a boy, with the beach and the bush close by. At Durban High School, run on traditional English lines, the brightest boys were steered toward Latin. Klug read voraciously and widely, and it was a popular book, Paul de Kruif’s Microbe Hunters, about the scientists who first identified germs, that made him want to study microbiology by way of medicine.
Physics, X-rays and Cambridge
At the University of the Witwatersrand in Johannesburg he began the pre-medical course, but a feeling that he lacked deep foundations drew him to chemistry, then to physics and mathematics, and he took a science degree. He moved to the University of Cape Town for a master’s degree, where he was lucky to find the X-ray crystallographer R. W. James, a superb teacher from whom he acquired a feeling for optics and the mathematics of diffraction. In Cape Town he also met Liebe Bobrow, a dancer, whom he married in 1948.
In 1949 a scholarship from the Royal Commission for the Exhibition of 1851 took him to Trinity College, Cambridge, and the Cavendish Laboratory. His doctoral work, under D. R. Hartree, was on a problem left over from wartime research: how steel changes structure as it cools. He then spent a year applying the same mathematics to how oxygen enters red blood cells. That brush with biology convinced him that what he really wanted was to work out the structures of biological molecules.
Rosalind Franklin and the shapes of viruses
At the end of 1953 Klug moved to J. D. Bernal’s department at Birkbeck College in London. There he met Rosalind Franklin, whose X-ray work had been crucial to the discovery of the structure of DNA and who was now studying tobacco mosaic virus, a rod-shaped plant virus. Her beautiful X-ray photographs fascinated him, and he found he could interpret puzzling features in them. From then on, he wrote, his fate was sealed. With Franklin and two research students, Kenneth Holmes and John Finch, he mapped out the general structure of the virus within a few years.
Franklin died of cancer in 1958, at only 37, and Klug took over leadership of her group. With Finch and Holmes he extended the work to spherical viruses. With the American Donald Caspar he developed a general theory of how such viruses build their shells from many copies of the same protein arranged in regular patterns, and his studies of how tobacco mosaic virus assembles itself from its parts led him to coin the term self-assembly. The idea, that the instructions for building a complex structure are built into its individual units, is now a basic principle of biology and nanotechnology.
Klug always credited the people around him. At Birkbeck and Cambridge he worked closely with Francis Crick, with whom he published a paper on diffraction by helical structures, and he said he learned by watching how Crick went about a problem. He also remained loyal to Franklin’s memory, carrying on the virus programme she had begun, with support from a grant from the U.S. National Institutes of Health. The Royal Society, electing him a Fellow in 1969, singled out his work on the structure of spherical viruses, which revealed new and unsuspected features of how viruses are built.
Seeing in three dimensions
In 1962 Klug moved to the newly built Medical Research Council Laboratory of Molecular Biology in Cambridge, the institute of Max Perutz, Francis Crick and Fred Sanger, where he would spend the rest of his career. There he faced a basic problem. The electron microscope could magnify viruses and other large biological assemblies, but its images were faint, flat and easily distorted by the heavy-metal stains used to give contrast, and the strong electron beam damaged delicate samples.
Klug showed that the seemingly poor, low-contrast pictures actually contained a great deal of hidden information, which could be extracted by mathematical processing borrowed from X-ray crystallography. His methods produced reliable images using very low radiation doses and without stains. Then he showed that by combining pictures taken from many different angles, a computer could reconstruct the object’s full three-dimensional shape. He called the approach crystallographic electron microscopy. It was adopted by laboratories around the world and is widely seen as a forerunner of today’s cryo-electron microscopy, which is now used to determine the structures of viruses, vaccines’ targets and drug targets at near-atomic detail. For this work, and for his structures of nucleic acid and protein complexes, he received the 1982 Nobel Prize in Chemistry, unshared.
Chromosomes, RNA and the zinc finger
Klug also turned to the packaging of DNA. Each human cell holds about two metres of DNA, folded into a nucleus far too small to see. Partly through discussions with Francis Crick, Klug’s group analysed the nucleosome, the bead-like unit in which DNA wraps around proteins, and the higher-order structures that compact it into chromosomes. The Swedish Academy predicted in 1982 that understanding this structure would be crucial to understanding how cells control their genes and, ultimately, cancer. His group also determined the crystal structure of a transfer RNA, one of the molecules that translate genes into proteins, in 1974.
In 1985, while studying a protein that switches on a gene, Klug and his colleagues discovered the zinc finger, a small, repeating fold held together by a zinc atom that grips DNA. Each finger reads a short run of DNA letters, and fingers can be strung together to recognize longer stretches. Klug saw at once that because the units are modular, new zinc finger proteins could be designed to target almost any gene. In 1994 his team published an engineered zinc finger protein designed to bind a chosen DNA site.
From zinc fingers to gene editing
That idea became a technology. A company spun out of his laboratory, Gendaq, was founded in 1999 and acquired in 2001 by the American firm Sangamo, and Klug served on Sangamo’s scientific advisory board. Joined to an enzyme that cuts DNA, designed zinc fingers became zinc finger nucleases, the first widely used tools for editing specific genes in living cells. They have been used in research animals, crop plants and human cells. In a trial that began in 2010, they were used to disable the CCR5 gene, which HIV uses to enter immune cells, in patients’ own white blood cells. In November 2017 a patient in California with the inherited disease Hunter syndrome received the first attempt to edit a gene inside the human body, using a zinc finger nuclease to insert a working copy of the faulty gene into liver cells.
Zinc fingers have since been joined by other editing tools, notably CRISPR, but they showed that precise gene editing in people was possible and opened the field of genome medicine.
Leader of British science
Klug was director of the Laboratory of Molecular Biology from 1986 to 1996 and President of the Royal Society from 1995 to 2000. He helped start research on neurodegenerative diseases at the LMB, and his input was central to understanding the role of the protein tau in Alzheimer’s disease. With David Rees he approached the Wellcome Trust about founding what became the Sanger Institute, a key contributor to the Human Genome Project. He was knighted in 1988, appointed to the Order of Merit in 1995 and received the Copley Medal, the Royal Society’s highest award. Colleagues remembered him saying that curiosity was the most important quality for a scientist, and described him as a strong but fair critic whose judgements usually proved right.
He also kept teaching. As a Fellow of Peterhouse, Cambridge, he supervised undergraduates himself for decades and served as a Director of Studies in natural sciences.
Jewish life and final years
Klug grew up in a Jewish immigrant family in South Africa and faced discrimination there. He remained religious throughout his life, and his friend and colleague Sydney Brenner observed that he became more religious as he grew older. He had close ties with Israel’s Ben-Gurion University of the Negev and the city of Beersheba, which he visited many times; in 2013 the university named its centre for structural biology the Aaron Klug Integrated Centre for Biomolecular Structure. South Africa honoured him in 2005 with the Order of Mapungubwe in gold.
He and Liebe, a choreographer and later a theatre director, had two sons, Adam and David; one of them died in 2000. Aaron Klug died in Cambridge on November 20, 2018, at the age of 92. His legacy reaches from the images of viruses on which modern vaccine design depends to gene-editing therapies that grew from a small protein fold he first noticed gripping DNA.
Sources & further reading
Aaron Klug, Biographical (autobiography), NobelPrize.org · Press release: The Nobel Prize in Chemistry 1982, NobelPrize.org · Aaron Klug (1926–2018), MRC Laboratory of Molecular Biology · Zinc finger proteins discovered by MRC-funded research used in first gene-editing trial, Cambridge Network · Aaron Klug, Jewish Virtual Library · Aaron Klug, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
A life of tikkun olam. This is part of tikkun olam, the Jewish idea of repairing the world, and every one of us can add to it.