A family of scientists
Roger David Kornberg was born on April 24, 1947, in St. Louis, Missouri, the eldest son of two biochemists, Arthur Kornberg and Sylvy Ruth Kornberg. His father, the son of Yiddish-speaking Orthodox Jewish immigrants in Brooklyn, would become one of the great biochemists of the century, discovering the enzyme that copies DNA. His mother, born Sylvy Ruth Levy, was also a biochemist and worked full time in her husband’s laboratory for most of their marriage, helping him isolate the first DNA-copying enzyme. Roger’s younger brothers also chose creative careers: Thomas became a biochemist and Kenneth an architect who designs laboratories.
When Roger was twelve, the family travelled to Stockholm to watch Arthur receive the 1959 Nobel Prize in Physiology or Medicine for his work on how DNA is copied when a cell divides. The family moved to California when his father founded the biochemistry department at Stanford. Roger studied chemistry at Harvard, graduating in 1967, and then returned to Stanford for a doctorate in chemical physics under Harden McConnell, completed in 1972. There, by studying how fat molecules move within cell membranes, he discovered that they drift sideways extremely quickly but flip from one side of the membrane to the other extremely slowly, findings still taught in cell biology.
Unwinding the mystery of chromatin
In 1972 Kornberg went to the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, to learn X-ray crystallography with Aaron Klug. Prompted by a paper by Francis Crick, he took on a problem Klug warned him was messy: the structure of chromatin, the material of chromosomes. Every human cell holds about two metres of DNA, packed into a nucleus a few thousandths of a millimetre across, wrapped around proteins called histones. Many scientists had given up, regarding the histones as a kind of sticky, shapeless glue.
Kornberg noticed a neglected paper showing that histones extracted gently, rather than with harsh acid, fell into neat pairs. With Jean Thomas he showed that two of them, H3 and H4, form a precise four-part unit. Thinking it over for days, he reasoned that chromatin must be built from repeating particles, each with two copies of four different histones and about 200 base pairs of DNA wrapped around the outside. Then he remembered an experiment in which an enzyme had chopped chromosomal DNA into pieces of a regular size. When he found a report measuring that size at 205 base pairs, close to his prediction, he was euphoric.
His 1974 papers described what is now called the nucleosome, the basic unit of DNA packaging in every plant, animal and fungus. Later work by others, culminating in a 1997 crystal structure, confirmed his model in atomic detail. The discovery opened one of the most active fields in biology: the study of how chemical tags on histones switch genes on and off, known as epigenetics. Several cancer drugs approved in recent decades act on the enzymes that add or remove those tags.
How a gene is read
After a period at Harvard Medical School, Kornberg joined the Department of Structural Biology at Stanford in 1978, where he has worked ever since. He turned from the structure of chromatin to a bigger question: how cells read their genes. Each gene is copied, or transcribed, into a messenger RNA that carries its instructions out of the nucleus to build proteins. In complex cells, the machine that does this is RNA polymerase II, an assembly of a dozen proteins.
Working with his partner in science and life, Yahli Lorch, he showed in 1987 that nucleosomes block RNA polymerase from starting to read a gene, revealing that the packaging of DNA is itself a way of regulating genes. To study the transcription machinery in detail, his laboratory spent years developing a working system from yeast, which many had thought impossible. A graduate student, Neal Lue, finally succeeded after discovering that ordinary chloride salt was poisoning the reaction. The yeast work showed that the machinery is fundamentally the same as in humans. Purifying the many proteins involved was its own ordeal. The yeast system gave a signal a thousand times weaker than the mammalian one, and for a long time every purification step after the second destroyed all activity. A postdoctoral researcher, Mike Sayre, broke the impasse by starting over with a new procedure, and in 1992 the group rebuilt transcription from five purified factors and the polymerase. Later, Lorch showed how a protein machine called RSC slides and removes histones so that DNA can be read.
Mediator and a picture of life’s copying machine
In 1990 Kornberg’s group found evidence of a missing link between the proteins that tell a gene to switch on and the polymerase that reads it. They called it Mediator. Isolating it took years, and when they finally did, in 1994, it turned out to be an assembly of about two dozen proteins. Mediator is now known to be central to gene regulation in all complex organisms, and changes in it are linked to cancers and developmental disorders.
At the same time Kornberg pursued the hardest goal of all: an atomic picture of RNA polymerase II. It was several times larger than any structure solved by crystallography when he began in the early 1980s. His group invented ways to grow flat, two-dimensional crystals of proteins on lipid layers, then large crystals, and in 2001 published the structure of the polymerase at near-atomic resolution, followed by pictures of the enzyme caught in the act of copying DNA into RNA. The images showed the DNA entering the machine, the new RNA strand growing, and the molecular clamp and ratchet that keep the process moving.
Why it matters
Transcription is necessary for all life; if it stops, the body dies within days, which is exactly what happens in poisoning by the death cap mushroom, whose toxin jams RNA polymerase II. Kornberg’s structures showed precisely how that toxin works. The Nobel committee noted that disturbances in transcription are involved in many human illnesses, including cancer, heart disease and various kinds of inflammation, and that understanding transcription is important for developing therapies based on stem cells, whose ability to turn into different tissues depends on which genes are switched on.
His work gave researchers a detailed map of the machinery they are trying to influence when they design drugs that turn genes up or down. In 2006 the Royal Swedish Academy of Sciences awarded him the Nobel Prize in Chemistry, unshared, for his studies of the molecular basis of eukaryotic transcription. He and his father became one of only a handful of parent-and-child pairs to receive Nobel Prizes.
Jewish life and Israel
Kornberg grew up in a Jewish family and, according to the German Jewish weekly Jüdische Allgemeine, remained a member of the Jewish community of San Francisco. Yahli Lorch is Israeli, and their three children, Guy, Maya and Gil, hold American and Israeli citizenship and speak fluent Hebrew. Since 1986 he has spent several months a year as a visiting professor at the Alexander Silberman Institute of Life Sciences of the Hebrew University of Jerusalem, which gave him an honorary doctorate in 2001, and the couple keeps a home in Jerusalem. He has called Israeli research world class and has spoken strongly against academic boycotts of Israeli scientists. The Technion awarded him its Harvey Prize in 1997.
Science and industry
Beyond the laboratory, Kornberg has served on the boards and scientific advisory boards of biotechnology and pharmaceutical companies in the United States and Israel, among them Teva, Protalix and Pacific Biosciences, and has chaired the scientific advisory board of Cocrystal Pharma, which uses structural biology to design antiviral drugs. From 2004 he edited the Annual Review of Biochemistry, one of the most widely read journals in the field. More recently his laboratory has worked on making tiny gold clusters to label molecules for electron microscopy, an idea that began with a graduate student and opened, he wrote, a window on a new realm of chemistry and materials science.
Character
Kornberg’s career shows unusual persistence. Some of his projects took the better part of two decades, and he worked for about five years, through repeated failures, before a visiting scientist made the first two-dimensional protein crystals work. He has said that the thin evidence for his nucleosome model was often pointed out to him, but that once his predicted DNA length was confirmed, he never really doubted it. He is generous in his Nobel autobiography in crediting the students and postdoctoral researchers who cracked each stage of the work, and above all Yahli Lorch, whose experiments on chromatin remodelling showed how cells pry nucleosomes apart so genes can be read.
Legacy
Kornberg answered two of the deepest questions in modern biology: how two metres of DNA fit into a single cell, and how a gene is actually read. The nucleosome he found is the foundation of epigenetics; the Mediator complex and the polymerase structures he solved are the reference maps for anyone studying how genes are controlled in health and disease. When the Nobel committee honoured him, one member said there was no doubt that his basic research would bear fruit for the good of humanity. It already has, in a generation of research on cancer, development and stem cells built on his pictures of life’s copying machine.
Sources & further reading
Roger D. Kornberg, Biographical, NobelPrize.org · Press release: The Nobel Prize in Chemistry 2006, NobelPrize.org · In bester Familientradition, Jüdische Allgemeine · Roger Kornberg, Jewish Virtual Library · Roger D. Kornberg, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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