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A Lasker 35 years in the making
How Bob Roeder’s discovery of three mysterious enzymes led to a transcription machine so complex it still hasn’t been fully mapped
BY JOSEPH BONNER and ZACH VEILLEUX
The journal Nature originally rejected Bob Roeder’s landmark 1969 discovery – made when he was a graduate student – that three different cellular structures work together to read the information encoded in DNA. “They told me it wasn’t of wide enough interest to the scientific community,” Roeder remembers. “That was my introduction to both scientific publishing and scientific politics.”
Today, it’s hard to find a biomedical scientist who hasn’t shown an interest in Roeder’s research. The genetic transcription machinery he identified is the mechanism by which every line of genetic code in the human body is expressed. In a sense, anyone who studies biology studies transcription.
That first Nature paper (the journal’s editors eventually reconsidered) identified, in animal cells, three enzymes called RNA polymerases, which directly copy DNA – a discovery that gave birth to our understanding of how genetic information is processed and interpreted in each of the body’s cells.
Consider the fate of a muscle cell. Genetically speaking, it’s no different from a skin cell, a brain cell, or any one of the 200-odd other types of cells in the human body. In fact, though their shape and function differ dramatically, each of the body’s cells contains an identical set of genetic instructions. The difference is largely determined by which of the cell’s specific genes are expressed or “read” by the cell’s machinery, a process known as transcription.
The RNA polymerases Roeder originally discovered are the machinery that carry out this process. His first experiments involved sea urchin embryos. By combining their dissolved nuclei with amino acids containing radioactive tags, he was able to measure the activity of various enzymes as the DNA transcription process unfolded. His original charts from the experiments clearly show three distinct enzymes at work.
In subsequent research carried out at Washington University School of Medicine in St. Louis, he showed that these three enzymes recognize and read the information encoded in distinct classes of genes. The first enzyme, RNA polymerase I, transcribes DNA into ribosomal RNA; the second, RNA polymerase II, transcribes DNA into messenger RNA; and the third, RNA polymerase III, transcribes DNA into transfer RNA. Messenger RNA encodes proteins while ribosomal RNA and transfer RNA are involved in the synthesis of proteins.
Other details soon followed: Each of the polymerases contained at least nine proteins. Some of those proteins showed up in all three polymerases while others were unique to their particular enzyme.
That was just the beginning. In the late 1970s, Roeder developed a new system of studying transcription that would open up an entire field of science. Called a cell-free system, it allowed Roeder to purify RNA polymerases and other components extracted from cell nuclei, and study them in a test tube as though they were still in a living cell. In effect, the technique allowed scientists to “view” transcription machinery in action.
The development of cell-free systems led to the rapid-fire identification of hundreds of transcription “activators” and “repressors” over the following two decades. The discovery of activators, sets of proteins that bind to specific DNA sequences and enhance the transcription process of certain genes, and repressors, which perform the opposite task to inhibit a specific gene’s activity, was a key milestone in the study of gene expression.
Scientists now believe that activators and repressors are the triggers behind not only cell differentiation, but dozens of other physiological processes that occur throughout the body every day. The code is sitting there the entire time, but only the activators and repressors know – and signal to the rest of the components – which parts to read, when to start reading, and when to stop. They play important roles in such processes as cell growth and division and immunity, to name a few.
“What Roeder gave us was a detailed understanding of the molecular events that occur in normal cellular processes and in disease states such as cancer,” says Rockefeller University President Paul Nurse, a past Lasker – and Nobel – recipient himself. “Ultimately, the application of these findings may lead to new drugs that selectively switch genes on or off for the treatment of diseases such as cancer, heart disease, Alzheimer’s and AIDS.”
And there’s another layer of complexity: Soon after his discovery of activators, Roeder and his colleagues discovered coactivators, large protein complexes that provide a bridge between activators or repressors and transcription machinery. “What began to emerge is that these coactivators, like the RNA polymerases, are incredibly complicated machines,” Roeder says. They can be either ubiquitous, in which case they monitor many genes in a variety of cells, or they can be specific to one particular cell type. Coactivator OCA-B, for example, first isolated in Roeder’s laboratory, is unique to B cells, a type of immune system cell that makes antibodies.
The task now, which Roeder’s lab has already begun to make a dent in, is to define specific physiological roles for each of these coactivators. “We need to understand not only the mechanisms underlying normal gene activation, but to relate these to important medical problems. More precise knowledge of coactivators offers the potential to understand the diseases that occur when the process goes awry, and could lead to more specific  drugs with fewer side effects,” Roeder explains.
Given an hour, Roeder can diagram the entire history of his 35-year scientific odyssey on a white board – but it takes a half-dozen colored markers to do so. Each component of the transcription process has dozens of subcomponents, many of those have subcomponents themselves, and still others remain uncharted. The result is an intricate, multi-colored pattern of pieces that dwarf the tiny strand of DNA they exist to transcribe.
Ultimately, that’s what Roeder discovered. The genetic code itself is the simple part. The real complexity of life is knowing which parts to read.

September 25, 2003



 

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