The Nobel Prize in Physiology or Medicine 1987.
"for his discovery of the genetic principle for generation of antibody diversity"
Susumu Tonegawa (1939 - ) received the Nobel Prize in Physiology or Medicine for working out the mechanism of generating antibody diversity. This was one of the fundamental problems in immunology—and, indeed, all of biology. How do antibodies recognize so many different antigens?
We now know the answer thanks to Tonegawa and his coworkers. The genes for antibody proteins are constructed in antibody-producing cells by recombining bits of DNA from several different locations. Millions of different permutations can be constructed to create a random library of antibody molecules. The chance that one of these randomly constructed antibody molecules will recognize a new antigen, such as virus, is very high.
This is one of the most significant Nobel Prizes of the 2oth century. Tonegawa's discovery deserves a lot more attention that it normally gets.
The presentation speech was delivered (in Swedish) by Professor Hans Wigzell of the Karolinska Institute.
Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,
The defence of our body against infections is carried out by the immune system, a talented cellular society with a capacity to distinguish between self and non-self and with a memory capable of remembering a previous contact for decades. The system is managing this through the inbuilt capacity in a single human being to produce billions of different forms of protective molecules, antibodies. The Nobel Prize of this year is given for the elucidation of the unique capacity of the immune system to produce this enormous diversity of specific antibodies.
Susumu Tonegawa is the great molecular biologist in immunology. In a series of ingenious experiments carried out in the middle of the 1970's he solved the problem how our limited genetic material is capable of generating the diversity required to create protection against established as well as future disease provoking microorganisms. When Tonegawa did his experiments at the Basel Institute of Immunology in Switzerland other scientists had already generated a-considerable amount of knowledge regarding the features and functions of antibodies. But this knowledge had also led to uncertainty and even confusion. Antibodies are proteins and their structure is strictly ruled by genes, by the DNA in our chromosomes. When Tonegawa carried out his experiments it was commonly believed that each protein, each polypetide chain, was governed by its gene in a relation one to one. But at the same time calculations on the number of genes in the chromosomes in man determining proteins gave a number probably below one hundred thousand genes. They should suffice to all the proteins in the body, to the hemoglobin in the red blood cells, to the pigment in our eyes and so on. Only a minor part, maybe one percent, could probably be used for the creation of antibodies. Around one thousand genes being able to create billions of different forms of antibodies? The equation seemed impossible to solve.
Our antibodies are made up of two sorts of polypeptide chains, short and long ones. Tonegawa did first acquire a toolbox, filling it with the best precision tools there were of hybrid-DNA nature, developed new methods and started to study the actual construction of the genes determining the short chains of antibody molecules. He discovered something entirely new and revolutionary in genetics. On the chromosome where the gene for the short chain was expected to be located, there was not one single, but a string, of pearls of genes. One special gene resided at one position whereas two other sets of variable genes create two gene families, in all maybe around one hundred genes. When a cell should start to make antibodies - this was preceded by a gene-lottery.
One member of the largest gene family selected at random was cut out from the chromosome and moved close to a member of the second gene family, whereafter they created a functional gene for the short chain together with the solitary gene. Three and not one gene participate in the creation of the short chain of antibody molecules. Each member in one family can probably be linked to any one of the members of the second gene family, increasing variability by multiplication. The results showed beyond doubt that our body has the capacity to carry out advanced recombinant DNA processes. The intelligence of Nature can also be seen as the studies went on. The recombination of genes and their coupling together do not occur in exactly the correct manner. While such relative misfits should in other systems be bad, here they constituted yet another mechanism of increasing the diversity of antibodies. Experiments by Tonegawa as well as other scientists also revealed that the same genetic lottery principle did apply to the generation of the long chain although here the number of variants were even larger. Four different genes could be shown to create these chains together. The number of variant short chains should then be multiplied by the combinatorial possibilities of the heavy chain to give the variation at the antibody level, a fact which will also drastically enhance the diversity of antibodies.
The equation was in essence solved. A few hundred genes are used by the body in a new, revolutionary way and can thus generate billions of different antibodies. Through this genetic lottery the immune system is always prepared to react against known as well as unknown microorganisms. The economic usage of precious DNA is compensated by wasting more dispensable material. Every minute our body produces several millions of white blood cells - lymphocytes. Each one of these has undergone the hybrid-DNA procedure and is prepared with its own, unique antibodies. If not called upon to react they will rapidly die. If, however, they make contact with the fitting foreign structures they receive a reward, i.e., they are allowed to proliferate and live longer. After the great randomized gene lottery natural selection will pick the winners, thereby generating specific immunity, the cheapest and most efficient protection there is against infections.
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.
[Photo Credit: Nature]
[Figure credit: The figure showing immunoglobulin gene rearrangment is from carthage.org]