Discovery of Split Genes
Dr. Phillip A. Sharp and Dr. Richard J. Roberts were awarded the Nobel Prize in Physiology or Medicine by the Karolinska Institute in Stockholm for their independent discovery in 1977 of “split genes.”
That discovery proved that genes can be composed of several separate segments. It shattered scientific dogma that had held that genes were continuous segments within DNA, the chemical basis of heredity. In making their discovery, the scientists worked in the laboratory with adenoviruses, which can cause colds and conjunctivitis, or pink eye.
Dr. Roberts did his award-winning work at the Cold Spring Harbor Laboratory on Long Island. Dr. Sharp also worked there before moving to M.I.T. in Cambridge, Mass.
“Everybody thought that all the interesting stuff had been discovered,” Dr. Roberts recalled yesterday. “In fact, there were several very prominent scientists who went on the public record saying that the age of molecular biology was dead and there were no more interesting discoveries to make.”
The discovery of split genes has been of fundamental importance for today’s basic research in biology, as well as for more medically oriented research concerning the development of cancer and other diseases.
The discovery has changed our view on how genes in higher organisms develop during evolution as split genes were frequent in higher forms of life, including humans.
The discovery also led to the prediction of a new genetic process known as splicing which led to the recognition of what are known as introns and exons, two different sequences in genes.
The discovery has given scientists a better understanding of how some hereditary diseases and cancers develop while other researchers have used the discovery to better elucidate a genetic form of anemia and one type of leukemia in which splicing errors occur.
The discovery of split genes “does not give us cures, but the possibility to know how we are going to do therapy with genes in the future,” Gosta Gahrton, a professor of medicine at the Karolinska Institute, told reporters in Stockholm.
Scientific understanding of genetics has constantly been changing, ever since Gregor Mendel grew sweet peas in a monastery garden and discovered factors responsible for dominant and recessive patterns of inheritance. Wilhelm Johannsen , a Danish biologist, called the factors genes.
For much of this century genes were defined as discrete elements arranged in linear order in chromosomes. The concept was based on studies of simple organisms, particularly bacteria and viruses that infect bacteria. Scientists assumed the concept also applied to higher forms of life.
But the concept was radically revised in 1977 as a result of the studies that Dr. Roberts and Dr. Sharp carried out on the genes of the adenovirus, which causes respiratory infections.
Although the genome of the adenovirus has many properties resembling human cells, its simple structure made it useful for studying the function of genes in higher organisms.
Dr. Roberts and Dr. Sharp sought to determine where different genes were situated in the adenovirus, and in biochemical experiments they found that one end of a messenger RNA in the virus did not behave as expected. By using the electron microscope, they then found that genes could be discontinuous, each present in several, well-separated DNA segments. Other researchers then found that such splitting was the most common gene structure in higher organisms.
“Everybody thought that genes were laid out in exactly the same way, and so it came as a tremendous surprise” that they were different in higher organisms, such as humans, Dr. Roberts said.
Dr. Walter Gilbert of Harvard University, a co-founder of Biogen, named the segments exons and introns. Exons are the vital biochemical sequences that contain the information to create a protein. Interrupting the exons are introns: long, rambling biochemical stutters that do not contribute to the construction of a protein. For that reason, they are often called “junk” DNA.
The average gene is composed of about 15 to 20 exons, broken up by lengthy introns. During the multistep synthesis of a protein, intron sequences are deftly clipped out and the exons are then stitched together into a continuous string of instructions that tell the cell how to propagate a complete protein. Possible Role in Evolution
Scientists suspect that the introns lying between the protein-making instructions, while serving no purpose in the current life of a cell, have been vital to the evolution of organisms. They suspect that the introns have allowed the exons to be easily shuffled around over time to generate an almost infinite variety of molecules.
Some of the estimated 5,000 hereditary diseases were a result of errors in the splicing process. The most studied of such diseases is beta-thalassemia, a form of anemia that is common in some Mediterranean countries. The disease occurs because of a faulty protein, beta-globin, which forms part of the hemoglobin, the main constituent of red blood cells. Small defects have been found in the genetic material of some patients, leading to errors in the splicing process and thus in the synthesis of poorly functioning beta-globin.
RSS
