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The New Immunology

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The New Immunology
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Peter Medawar never accepted the honorary title “father of transplantation[1]”, which many of his peers bestowed on him. He rather emphasized that no bridge led directly from his findings into the realm of modern organ transplantation[2]. Yet he was happy and proud that he had succeeded in proving the feasibility of such a bridge by showing “that organ transplantation between genetically different individuals was theoretically possible”, as he explains in this lecture. “This gave an important boost to moral because until then many people, particularly geneticists, because they are so much wiser than we are, had said that it would never be possible to transplant organs from one individual to another.” So, Medawar literally was a pioneer in the conquest of a hitherto inaccessible field of medicine. He was not on his own, however, as he mentioned in his banquet speech on occasion of the Nobel Prize Ceremony 1960: “I should prefer to remember not the giants upon whose shoulders we stood, but the friends with whom we stood arm in arm. Let me therefore pay tribute to two men who began as my students but who soon became close and dear colleagues in so much of my work: Rupert Billingham and Leslie Brent. And let me also pay tribute to a man whose great synoptic grasp of the fundamental problems of biology has at all times illumined all our thinking: Sir Macfarlane Burnet.”[3] For Medawar, it went without saying to share his Nobel Prize Money with Billingham and Brent. Medawar started the work that would win him the Nobel Prize in Physiology or Medicine 1960 together with Burnet “for discovery of acquired immunological tolerance”, after he had been classified “D” by the British recruiting board in 1940. “It was my singular good fortune that I was too large to fit either into an aeroplane or a tank”[4], 1.95 m tall Medawar remembered later. Instead of sending him to war, the Government assigned him to support the surgeon Thomas Gibson to find out whether foreign skin could be transplanted to patients with burns. As a result, both discovered the basis of immune rejection, namely “that the destruction of the foreign epidermis was brought about by a mechanism of active immunization”.[5] Ten years later – drawing on fundamental theoretical considerations by Frank Macfarlane Burnet and experimental work by Ray Owen – Medawar and his group demonstrated in experiments with mice and chicken that grafts are not rejected if foreign cells from the future donor are introduced into the future recipient when it is not yet immunologically mature, i.e. during its foetal or neo-natal life. This proof of acquired tolerance[6] “came as a blinding beacon of hope”[7] that the immunological barriers to the transplantation of foreign tissue could be overcome. Prompted by Medawar’s discovery and spurred by Burnet’s theory of clonal selection, the old chemistry centred immunology was gradually replaced by a “new immunology”, whose most important feature Medawar characterizes in this lecture as “the interpretation of the immunological response in terms of the population dynamics of lymphoid cells”. Elegantly, his lecture captures the essence of immunology’s transformation into a modern science. A “very great lesson” could be learned from that transformation, Medawar says. Immunology’s “snail-like progress” during the first half of the 20th century was due to its self-concept as an applied science. The “new immunology” that quickly became the “most rapidly moving of the biomedical sciences”, in contrast, was initiated by scientists whose main motivation was “to achieve understanding of natural processes and not to solve pressing practical problems on an ad-hoc basis”. Therefore, Medawar advocates basic research with “experiments intended only and primarily to enlarge the understanding”, whereas he criticizes “the modern tendency to treat the financing of research as if research were a branch of the retail trade, as if a customer could order the results that he wanted.” Joachim Pietzsch [1] Starzl TE. Peter Brian Medawar: Father of transplantation. J Am Coll Surg. 180, 332–336 [2] cf. Kyle RA, Shampo MA. Peter Medawar – Discoverer of immunological tolerance. Mayo Clin Proc, 78, 402 – 403 [3] https://www.nobelprize.org/nobel_prizes/medicine/laureates/1960/ medawar-speech.html [4] cf. Sir Peter Medawar: lives of a scientist. New Scientist 12 April 1984, 14 – 20. [5] Gibson T, Medawar PB. 1943 The fate of skin homografts in man. J. Anat. 77, 299 – 310 [6] Billingham RE, Brent L, Medawar PB. 1953 ‘Actively acquired tolerance’ of foreign cells. Nature 172, 603 – 606. [7] Starzl, l.c.
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Transcript: English(auto-generated)
Mr. Chairman, ladies and gentlemen, the new immunology. The term, the new immunology, was first used by Sir Macfarlane Burnett to describe the immunology which has grown up in the last 10 years.
The immunology of which the three central concepts are, first, the biology of self-recognition, second, the molecular basis of information transfer in biological systems, thirdly, and perhaps most important,
the interpretation of the immunological response in terms of the population dynamics of lymphoid cells. But before describing the great revolutions of thought which have led to the inauguration of the new immunology, I must try to answer
your unspoken question. What was the old immunology? The old immunology was, above all, an applied science which was regarded as a branch of bacteriology. The syllabus of immunology was part of the small print
in the syllabus of bacteriology departments. From a theoretical standpoint, immunology was treated as coextensive with the actions and interactions of empirically defined entities called
antigens and antibodies. The antibodies were thought to be of various different kinds. Agglutinins, which caused the aggregation of bacteria or red blood corpuscles, precipitins,
which formed insoluble compounds with protein antigens, and lysins, which brought about the rupture of the cell membrane, and opsonins, which affected microorganisms in such a way
as to make them vulnerable to the phagocytic action of polymorphs and macrophages. All these reagents were functionally empirically defined and were thought to be separate, each from the other.
Biochemists used to laugh at immunology and immunologists and treat immunology as more of a hobby than a science. All this has changed very greatly now, and I proceed to describe the four great revolutions of thought which have led to the instatement of what
Burnett called the new immunology. The first great advance was that which was made possible by the inventions and discoveries of Tiselius and Svedberg. By the use of electrophoresis, which Dr. Yalow has described,
and ultracentrifugation, it became possible to characterize antibodies physiochemically. Antibodies are globulins. The class of globulins as a whole, which includes antibodies, is now called immunoglobulin.
These discoveries were followed very soon by those of Landsteiner and Horowitz, who showed that only part of a foreign, that is a non-self molecule, excites an immune response. The determinant group only is responsible for exciting
the immune response. To each determinant group that corresponds one antibody. If, as Horowitz showed, a molecule carried two determinant groups, then two antibodies corresponding to them were formed.
The specificity of immune reactions, which was the principal study of Karl Landsteiner in the latter half of his life, that is to say the unique pairing, one to one, of antigen and antibody, was now explained by the exact matching of the molecular configurations
of antigen and antibody. There was a complete abandonment of the distinction between agglutinins, precipitins, and lysins. Now we think of these entities as so many, not as different substances, but as so many
different manifestations of the action of an antibody. All are interconvertible, one into the other. The work that originated in the techniques of Tiselius and Svedberg reached its peak in the research of Edelman and Porter, which has now given us
a virtually complete understanding of the molecular structure of antibody. Chronologically, however, the next advance came from biologists. McFarland Burnett and Meduwa and his young friends saw the biology of self-recognition
as a central concept of immunology. The study of transplantation showed that not all immunological reactions are manifestations of the action of antibodies. Immunological reactions proved to be of two different kinds.
There are humoral reactions mediated through soluble immunoglobulins in the blood, mediated through antibodies. And there are cellular immune reactions in which the recognition of antigen and the reaction upon
it are the work of lymphocytes, lymphocytes which James Gowans showed were long-lived and recirculating cells. Lymphoid cells are the agents of both forms of immunity. Both humoral and cellular immunity
are mediated through the actions of lymphocytes. One great family is responsible for antibody formation, and these are called B cells. B is short for bursa, the bursa of fabricius of chickens, or its equivalent in mammals.
On the other hand, another class of cells, the thymus-dependent cells, or T cells, are those which are responsible for cellular immunity. The discovery of tolerance by a joint theoretical and practical operation of McFarlane, Burnett, and as I say,
myself and my friends, showed that organ transplantation between genetically different individuals was theoretically possible. This gave an important boost to morale, because until then, many people, particularly geneticists,
because they are so much wiser than we are, had said that it would never be possible to transplant organs from one individual to another. But we were able to show that it could be done, and this gave a tremendous boost to surgeons and immunologists working on the transplantation problem.
A recent development of transplantation biology, which is that upon which I am now working, is the recognition that some cancers arouse a defensive reaction similar to that of graft rejection. It is not exactly the same. Many disappointments have been caused by the assumption
that tumor rejection and graft rejection are essentially identical processes. They are not identical, but they have a family likeness which may be enough for us to build upon. An innovation of principle, which
illustrates the great fertility of the new immunology, is that which is embodied in network theory, which I shall spend just a moment explaining to you, because it is one of the newest things in the new immunology. In immunological reactions, organisms
react to non-self substances, substances which are completely new to the reacting system. Suppose, then, an antigen is introduced into the body for the first time. Then the antibody which that antigen causes to be formed
is itself a protein new to the body. And therefore, it should produce an antibody against itself, an anti-antibody. And the antibody formed against this antibody. Are you following me, my friend?
The antibody formed against this antibody will in turn form another antibody, an anti-antibody. Jernes network theory envisages that immunological control is achieved through this network of interacting antibodies.
A simple and brilliant idea, which is already the basis of attempts to diminish or to augment the immune response, and which is already beginning to put it within our power to do what all immunologists want above all else to do,
to regulate the immune response, to boost it or to diminish it as the need arises. Ladies and gentlemen, I believe that a very great lesson is to be learned from the history of immunology. And this is why I have spent so much time on it.
Immunology today is in some ways the most successful or the most rapidly moving of the biomedical sciences. Its developments have led to recognition, interpretation, and in many cases, the cure or radical improvement
of immunological deficiency diseases and other diseases caused by miscarriage of the immunological process, diseases which include myasthenia gravis, dermatomyositis, many forms of allergy, and also of autoimmune,
that is of immunologically self-destructive diseases. The immunological deficiency diseases are caused by the failure of either cellular or humoral immunity or of both.
In addition, the new immunology has made possible the transplantation of organs such as the kidney and will one day make possible the transplantation of lungs and hearts. People often want to know when will it be possible to transplant hearts and lungs.
The answer is that they will inevitably come if the need for them is judged to be sufficiently great and if the competing demands on the limited resources of money for health care can be reconciled with the provision of heart transplantation and lung
transplantation. There is no theoretical obstacle to the transplantation either. Need and money are the limiting factors. But perhaps the greatest possible benefaction of the new immunology lies in the interpretation of the natural defensive mechanism against malignant growth.
This is still a matter for the future, though very few of us have any serious doubt that there is a natural defensive mechanism against malignant growth. The combination of improved immunological and microbiological techniques is rapidly
leading to the extinction of such virus diseases as poliomyelitis and smallpox. Within the lifetime of most of the people present in this room, both these diseases will be abolished. And the genetic information contained in the viruses responsible for them
will be lost unless it is preserved in museums erected for the purpose, which is because even in an age of nostalgia, this is carrying sentimentality too far, perhaps. But from the standpoint of the history of ideas,
what has been especially remarkable about immunology is not its explosive growth today, but its snail-like progress between the discovery of complement by Borde in about 1900 and the great biophysical discoveries
that led to the interpretation of the nature of antibodies. The reason, I believe, is this. Immunology grew up, as I said, as an applied science. Its only purpose was thought to be to provide ad hoc solutions of practical problems, particularly in the domain of microbiology.
The new immunology was invented by zoologists, biochemists, biochemists, biophysicists, geneticists, and microbiologists. The motivation of their work was to achieve understanding of natural processes
and not to solve pressing practical problems on an ad hoc basis. The greatest methodologist of science, Sir Francis Bacon, made a distinction between experiments of use, corresponding roughly to applied science, and experiments of light, experiments intended only
and primarily to enlarge the understanding. Much of Bacon's writing is a plea for the prosecution of experiments of light, a plea for the advancement of learning. He would have been deeply shocked by the modern tendency
to treat the financing of research as if research were a branch of the retail trade, as if a customer could order the results that he wanted and pay or support only those scientists who could or profess to be able to provide the answers.
We need, of course, power over the environment to make the world a better place to live in. And we need understanding upon which our power over the environment is founded. For Bacon was the first person to teach what the history of immunology so clearly
illustrates, that the power comes from the understanding. Thank you.