The Nobel Prize in Physiology or Medicine 1978
Werner Arber, Daniel Nathans, Hamilton O. Smith
Presentation Speech by Professor Peter
Reichard of the Karolinska Medico-Chirurgical Institute
Translation from the Swedish text
Your Majesties, Your Royal Highnesses,
Ladies and Gentlemen,
"Their research opens up the possibility to copy human beings in the laboratory, to construct geniuses, to massproduce workers, or to create criminals." This is a quotation from the presentation on Swedish television of this year's laureates in medicine. The presentation was not made as a joke. Let me for now, however, leave this Frankenstein-fixation of the news-media. Reality is remarkable enough, without such excursions into science fiction.
The discoveries of this year's laureates mark the beginning of a new era of genetics. Genetics started as a science more than 100 years ago with the experiments of Gregor Mendel who showed that our heritage is packaged into genes. Each gene directs a particular function and is faithfully propagated from generation to generation. The second era of genetics started about 30 years ago when Avery succeeded in transferring with DNA a hereditary property from one bacterium to another. Thus, genetics became molecular, and our concept of both genes and their functions acquired a chemical basis. We realized that the gene is a piece of DNA, and that DNA contains the genetic code for the synthesis of specific proteins. During this period many fundamental discoveries were made in molecular genetics, as witnessed by the fact that six Nobel prizes in medicine were awarded to scientists working in this field in the last 20 years.
These discoveries originated mostly in experiments with bacteria and viruses, but usually the results could be directly extrapolated to man. However, man depends on many biological processes directed by genes, which do not take place in microorganisms. So we must ask how do our genes direct the development of a single fertilized egg cell into a complete individual with many different organs? What mechanism forces the cells in one organ to retain their specialized functions? We know that disturbances in normal development give rise to diseases and malformations. During the 1950s and 60s scientists worked very hard to answer these questions but apparently knocked on a closed door. This door has now been opened wide by our laureates, whose discoveries started the third era of genetics.
The difficulties in this field of research were mainly due to the large amount of information contained in our genes and to the enormous length of the DNA molecule. We can compare the DNA of a single human cell with a book containing all the information for the development and function of the cell. The text written on one page of this book might then correspond to one gene containing all the information necessary for the synthesis of one protein. The whole hook consists of 1 million pages and would occupy about 100 meters in a book shelf. The whole book is faithfully copied at each cell division. One mistake in one letter on a single page may result in disease or death. Changes in the text can be caused by the action of chemicals or viruses and this may result in cancer, malformations or hereditary diseases. The scientist wants to be able to read the book and to localize and identify any misprints. He first tries to find the correct page with the interesting text, but in doing so he realizes that the pages of the book are glued together. How can he separate the pages without destroying the text?
Restriction enzymes are the tools which make it possible to open the sealed book. Werner Arber discovered these enzymes in the early 1960s when he analyzed an apparently obscure phenomenon in bacteria, discovered 10 years earlier by Bertani and Weigle, called host-controlled modification. In a series of simple but elegant experiments Arber showed that this phenomenon was caused by a change in DNA and apparently served to protect the host from foreign genes. Foreign DNA is degraded, and Arber postulated that bacteria contain restriction enzymes with the capacity to recognize and bind to recurring structural elements of DNA. At these locations the DNA-helix is severed: the pages of the book are separated.
Hamilton Smith verified Arber's hypothesis. He purified one restriction enzyme and showed that it could cleave foreign DNA. He determined the chemical structure of the regions of DNA which were severed by the enzyme and discovered certain rules which later could be applied to other restriction enzymes. Today maybe 100 such enzymes are known. They all cleave DNA, each at different, defined regions. With their aid, these giant molecules can be dissected into well-defined segments which subsequently can be used for structural investigations or in genetic experiments.
'The last step in this development was taken by Dan Nathans. He pioneered the application of restriction enzymes in genetics and his work has been a source of inspiration for scientists all over the world. He constructed the first genetic map using restriction enzymes by cleaving the DNA from a monkey virus. The methodology devised by him for this purpose was later used by others to construct increasingly more complicated maps. Today we can write the complete chemical formula for the genes of the monkey virus that Nathans started to investigate.
The application of restriction enzymes has revolutionized the genetics of higher organisms and completely changed our ideas of the organisation of their genes. In contrast to the DNA of bacteria, the DNA of higher organisms is not a contiguous structure coding for one protein. Instead, genes contain "quiet" regions alternating with regions containing the genetic code. Restriction enzymes have also been used for genetic engineering. With their aid we can selectively remove parts of the genetic material and transplant genes into a foreign background. In this way genes from higher organisms have been transferred to bacteria, and in certain cases such bacteria can be used to produce human hormones. In the near future we can expect many products of medical importance to be synthesized.
These experiments gave rise to the earlier mentioned fears of copying human beings in the laboratory. Such fears are due to a complete ignorance of the content of genetics and the nature of man. A similar misunderstanding once caused the distortion of Darwinian evolution theory to social Darwinism. I would like to illustrate this with the following example which I take from the geneticist Dobzhansky: "Whereas birds, bats and insects became fliers by evolving genetically for millions of years, man has become the most powerful flier of all, by constructing flying machines, not by reconstructing his genotype".
Dr. Arber, Dr. Nathans, Dr. Smith: The discovery of restriction enzymes started off an avalanche in molecular genetics. Their application made possible the detailed chemical analysis of the organisation of the genetic material, and this has in particular in higher organisms given unexpected but far reaching results. At long last we are in a position to tackle successfully the basic problem of cell differentiation. Your work has pioneered this development. On behalf of the Karolinska Institute I wish to convey to you our warmest congratulation and I now ask you to receive the prize from the hands of his Majesty the King.
From Nobel Lectures, Physiology or Medicine 1971-1980, Editor Jan Lindsten, World Scientific Publishing Co., Singapore, 1992
Copyright © The Nobel Foundation 1978
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