The Nobel Prize in Physiology or Medicine 1984
Niels K. Jerne, Georges J.F. Köhler, César Milstein
Presentation Speech by Professor Hans
Wigzell of the Karolinska Institute
Translation from the Swedish text
Your Majesties, Your Royal Highnesses,
Ladies and Gentlemen,
It is typical for the human mind that little thought goes to the functions of our body when we are healthy, yet acute interest frequently develops in times of disease. The immune system is a somewhat anonymous, talented and well-trained cellular society within ourselves which must function properly to maintain our health. The immune defence has the inherent capacity to rapidly recognize foreign material and can subsequently remember this contact for decades, thus creating the basis for vaccination. Through a clever usage of genetic material and large numbers of cells, the immune system within a single human being is able to produce defence molecules, antibodies, in billions of different shapes. The Nobel prize winners in physiology or medicine this year have all worked with the capacity of the immune system to produce specific antibodies.
Niels Jerne is the great theoretician in modern immunology. He entered the immunological arena comparatively late in his life and was 44 years old when in 1955 he published his first important theory of the construction of the immune system. Jerne proposed that the well-known capacity of the immune defence to recognize myriades of foreign molecules was something predetermined, already existing in the body when the very first contact with a foreign structure was made. What then happened was merely a selection amongst the naturally occurring antibody population resulting in an increase in production of exactly those antibodies which happened to have a good fit for the structure. Jerne's theory stood in great contrast to prevailing theories at that time, but it was rapidly confirmed and extended. We now know that Darwin's laws about natural selection indeed apply to the cells of the immune system: Those cells which happen to have received the property to produce a wanted antibody type will upon vaccination be rewarded with regard to proliferative capacity and survival.
Jerne took another known feature of the immune defence as the starting point for his next important theory, in 1971. The immune system always expresses a very strong defence of the private and unique features of the tissues within one individual. This behaviour creates great problems whenever attempts are made to transplant tissue from one individual to another. Jerne assumed that the molecules in the tissues that cause these reactions, the so-called transplantation antigens, must have their normal functions within the body of the individual. He proposed that one function of these molecules could be to serve as a specific driving force for the cells of the immune system, thus creating a large number of cells from which cells especially suitable to defend the tissues of the host would become selected. Special organs, such as the thymus, were assumed to serve as a combination of greenhouse and university for these cells. In this theory Jerne did predict to a great extent how the specificity of the cellmediated immunity is generated.
In the third great theory, in 1974, Niels Jerne introduced us to the mirror halls of immunology. The immune system is visualized somewhat like a gigantic computer where constant communication and regulation takes place in between the different components, the cells. The number of cells in such a network system in an adult human being exceeds 1012 (one million millions); and the system has through its capacity to produce billions of different forms of antibodies an enormous inbuilt richness with regard to structural variations. Jerne proposed that this should allow the creation of multiple complementary situations where certain antibodies would have select capacity to combine with their mirror images. Some antibodies would according to the theory then even mimic foreign molecules against which other antibodies would normally be produced during immunization. Jerne postulated that pairs of antibodies and their mirror images would spontaneously be produced during the development of the immune system, thus creating the possibilities for communication networks and regulatory equlibria. During immunization the foreign molecules would enter the mirror halls of immunology where the different pairs of antibodies and cells would perform their interdependent piruettes and separate the partners chasing away the mirror images. This change in equilibrium would then serve as a driving force, resulting in immunity. It is now well documented that network forces of the fascinating type that Jerne predicted do indeed exist inbuilt in our own immune systems. The theory also predicted the almost mind-boggling possibility that antibodies of the mirror image-type could replace the foreign material completely when inducing immunity. This is now a proven reality. Thus, it is for instance possible to induce a long lasting immunity against hepatitis virus by immunization with mirror image antibodies to the antibodies against hepatitis virus without ever using the virus in the vaccination.
In conclusion, Niels Jerne has via his visionary theories enabled modern immunology to make major leaps of progress. Several concepts in immunology now considered as self-evident have their roots in some of his pioneering thoughts.
In order to fully understand the importance of Georges Köhler's and César Milstein's discoveries we should first take some steps back. Sera from intentionally immunized animals or humans constitute very important tools in the hospitals as well as in research laboratories. They are used to diagnose infectious diseases, as well as to determine the concentration of a particular hormone in a sample. But every one of these immune sera contains a unique mixture of antibodies produced by a large number of different cells and their progeny and the various antibodies react in a similar yet distinctly different manner. Thus, each immune serum has to be tested to determine the special features of that particular serum with regard to its ability to distinguish between two related hormones, different bacteria, etc. Regardless of whether the immune serum is close to being perfect or not, it will always be used up, and it is then necessary to start again trying to produce a similar kind of serum. International standardizations of tests using immune sera have thus been greatly hampered.
The discovery and development of principles for production of the so-called monoclonal antibodies by the hybridoma technique by Georges Köhler and César Milstein have largely solved all the above major problems. And the story of the discovery of the technique also contains the moral of a saga, where the evil is put into the service of the good. How did this discovery take place? César Milstein is a highly prominent biochemist working for a long time in Cambridge in England. A major interest in his research has been to explore various facets of antibody production. Milstein used tumor cells which had arisen in cells of a type that normally produce antibodies. Such tumors also produce proteins which in all respects look like antibodies, although it is difficult to find suitable foreign structures to which they can bind. Milstein wanted amongst other things to study what would happen if two different tumor lines were allowed to fuse, e.g. what would happen to the production of the antibody-like proteins if for instance the tumor cells came from different species? Milstein constructed tumor cell lines allowing only hybrid cells between the two tumor cells to grow in certain defined tissue culture solutions. The systems worked and the hybrid cells produced large quantities of the antibody-like proteins, some of which at the molecular level could be shown to be hybrid molecules as well.
At the same time the young researcher Georges Köhler struggled in Basel in Switzerland to study normal antibody-producing cells in tissue culture. His research was in part frustrating as he could only get very few cells to survive for short periods of time. Köhler knew of the important studies of Milstein, and it seemed logical to see if normal antibody-forming cells could be fused with tumor cells to produce long-lived hybrid cell lines. If this was indeed possible the experiments of Milstein would indicate that they should then continue to produce their antibodies. At the same time the normally evil feature of tumor cells, the capacity to proliferate for ever, would now be turned into a very beneficial feature. Köhler went to Milstein's laboratory and together they wrestled with the problems and managed to solve them in a hectic two year period, 1975-1976. By that time they had succeeded to develop a technique allowing them at will to fish up exactly those rare antibody-producing cells that they wanted from a sea of cells. These cells were fused with tumor cells creating hybrid cells with eternal life and capacity to produce the very same antibody in high quantity. Köhler and Milstein called these hybrid cells hybridomas, and as all cells in a given hybridoma come from one single hybrid cell, the antibodies made are monoclonal.
Köhler's, and Milstein's development of the hybridoma technique for production of monoclonal antibodies have in less than a decade revolutionized the use of antibodies in health care and research. Rare antibodies with a tailor-made-like fit for a given structure can now be made in large quantities. The hybridoma cells can be stored in tissue banks and the very same monoclonal antibody can be used all over the world with a guarantee for eternal supply. The precision in diagnosis is greatly improved, and entirely new possibilities for therapy have been opened up via the hybridoma technique. Rare molecules present in trace amounts in complex solution can now be purified in an efficient manner using monoclonal antibodies. In all, it is therefore correct to describe the hybridoma technique discovered by Georges Köhler and César Milstein as one of the major methodological advances in medicine during this century.
Dr. Jerne, Dr. Köhler and Dr.
On behalf of the Nobel Assembly of the Karolinska Institute I would like to congratulate you on your outstanding accomplishments and ask you to receive the Nobel Prize in Physiology or Medicine from the hands of His Majesty the King.
From Nobel Lectures, Physiology or Medicine 1981-1990, Editor-in-Charge Tore Frängsmyr, Editor Jan Lindsten, World Scientific Publishing Co., Singapore, 1993
Copyright © The Nobel Foundation 1984
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