20-Sep-2022 - Johann Wolfgang Goethe-Universität Frankfurt (Main)

Frederick W. Alt and David G. Schatz to be awarded the 2023 Paul Ehrlich and Ludwig Darmstaedter Prize

Laureates raised knowledge of the development of the immune system to a new level

Immunologists Frederick W. Alt (73) of Harvard Medical School and David G. Schatz (64) of Yale School of Medicine are to receive the 2023 Paul Ehrlich and Ludwig Darmstaedter Prize, as the Scientific Council of the Paul Ehrlich Foundation announced. The two researchers are being acknowledged for their discovery of molecules and mechanisms that enable our immune system to perform the astounding feat of recognizing billions of different antigens on first contact.

Both the antibodies produced by B cells and structures on the surface of T cells are able to capture antigens. Collectively, they are referred to as antigen receptors. In the first instance, their tremendous variety is thanks to different gene fragments combining at random to form functional genes. Almost 50 years ago, this principle was first demonstrated for the production of antibodies. However, the finer details of this somatic recombination remained largely in the dark until Alt and Schatz increasingly shed light on the subject. “The picture we have today of the diversification of antigen receptors in the immune system of vertebrates is above all thanks to the two prize winners,” says Professor Thomas Boehm, Chairman of the Scientific Council of the Paul Ehrlich Foundation. “They have raised our knowledge of the development of the immune system to a new level.”

Antigen receptors are proteins consisting of constant and variable parts. In each antibody, for example, two heavy and two light chains are joined together in a Y-shape. Which antigen an antibody can recognize depends on the variable parts in the arms of the Y. In each of our B cells, an antibody with different claws matures during its development in the bone marrow. In total, our body can build approximately ten billion different antibodies, although it has only about 20,000 protein blueprints in the form of genes. It achieves this by means of an extraordinarily daring procedure that makes cutting up and re-assembling the genetic information DNA on certain chromosomes of maturing lymphocytes the norm.

The enzyme complex RAG1/2 discovered by David Schatz and colleagues conducts these cuts at pre-designated sites. For the formation of the variable portions of heavy antibody chains, for example, these sites are located on chromosome 14. There, they flank relatively widely spaced segments in three different regions called V (for variable), D (for diversity), and J (for joining). RAG1/2 conducts cuts at a randomly selected segment from each of these regions for each antibody. Subsequently, DNA repair enzymes assemble a VDJ gene to encode a heavy chain variable region. Frederick Alt discovered the repair enzymes that work together to join the ends of the cut-out segments. In the next step of B cell maturation, the light chains are formed in a similar way, but only a VJ recombination occurs there in this case.

The RAG enzymes do not, however, wander aimlessly through the cell nucleus of immature lymphocytes. On the contrary, they draw the chromatin filaments together, in which the DNA is coiled up in a space-saving way, temporarily and again and again to form V(D)J recombination centers. There, they perform chromatin scanning. In this process, a chromatin loop, which can be more than one million DNA letters long, passes through the recombination center so that widely separated sections of text can be reliably linked together. The loop extrusion mechanism of V(D)J recombination elucidated by Frederick Alt elegantly explains how these loops are created and pulled through the recombination center.

Frederick Alt made further decisive contributions to the understanding of antigen receptor diversity. For example, he succeeded in showing that combinatorial diversity is increased many-fold by the enzymatic insertion of very short random DNA sequences, called N-nucleotides, at the interfaces of the gene segments to be joined. In B cells, antibody diversity is further potentiated by the phenomenon of somatic hypermutation. In this process, the normal rate of mutations affecting only one DNA letter is increased millions of times in the regions of the V segments by an enzyme. Alt, Schatz, and others showed how this enzyme performs its work with pinpoint accuracy. They thus provided a framework for solving the question of how B cells can take advantage of the enormous mutational capacity of AID for antibody maturation without running the risk of suffering tumor-inducing mutations.

Without the recombination-activating enzyme complex RAG1/2, the diversification of antigen receptors is impossible, the maturation of the lymphocytes is disrupted, and a severe immune defect is the consequence. It is all the more remarkable that this molecule apparently originates from a jumping gene – a transposon. These are selfish DNA parasites that crept into our genome at some point and can move from one place to another as jumping genes. Because of their uncontrolled distribution, they can be involved in the development of disease. RAG1/2, however, according to David Schatz's findings, descends from a transposon that all jawed vertebrates, including us humans, tamed for their own purposes very early in evolution. To prevent it from jumping on, they had to fix it in the genome. Schatz has shown which biochemical mechanisms enable this fixation. He was also able, on the basis of structural biological studies in an ancient invertebrate RAG gene to reproduce the act of transposition over several stages. He is thus giving science a fascinating look back at a revolutionary process at the beginning of vertebrate evolution: the development of the adaptive immune system in addition to already existing innate immunity. Building on this view from basic research, translational research will be able to open up new therapeutic perspectives for diseases in which our immune system plays a crucial role.

Facts, background information, dossiers

  • Paul Ehrlich and Lu…
  • immune system
  • antigen receptors

More about Uni Frankfurt am Main

  • News

    How do killer T cells know where danger is coming from?

    How do killer T cells recognise cells in the body that have been infected by viruses? Matter foreign to the body is presented on the surface of these cells as antigens that act as a kind of road sign. A network of accessory proteins – the chaperones – ensure that this sign retains its stabi ... more

    Laboratory study: effect of antibodies against omicron variants BA.1 and BA.2 wears off quickly

    The omicron variants BA.1 and BA.2 of the SARS-CoV-2 virus, which are dominant from about December to April, can undermine the protection against infection offered by vaccinations or survived infections after only three months. This is shown by a study from Frankfurt under the leadership of ... more

    How bacteria adhere to cells: Basis for the development of a new class of antibiotics

    The adhesion of bacteria to host cells is always the first and one of the decisivesteps in the development of infectious diseases. The purpose of this adhesion by infectious pathogens is first to colonize the host organism (i.e., the human body), and then to trigger an infection, which in t ... more

  • q&more articles

    From feast to famine and back – no problem for bacteria

    Bacteria are true survivors. In the course of evolution, they have developed numerous strategies to adapt to rapidly changing, uncertain environmental conditions. Their metabolism is much more sophisticated than that of human beings. Within minutes they can regulate their gene expression an ... more

    Why biosimilars and not biogenerics?

    Medicines produced using genetic techniques have existed since 2006, called “similar biological medicinal products” or “biosimilars”. Until a year ago, this was a fairly low-profile group, even in expert circles. This has all changed now, however, with the recent licensing of the first bios ... more

    Paradigm shift

    What would medicine be without drugs? But are these drugs being used optimally today? Not at all, as we now know thanks to the findings of molecular medicine. Because for the use of these drugs, it is important to observe two aspects: the disease and the patient. Only slowly is it becom ... more

  • Authors

    Prof. Dr. Claudia Büchel

    Claudia Büchel, born in 1962, studied biology at the University of Mainz, where she also received her doctorate and, in 2001, the qualification to teach plant physiology. After a postdoctoral research period at the Biological Research Centre, Szeged, she worked for four years as a research ... more

    Prof. Dr. Jörg Soppa

    Jörg Soppa, born in 1958, studied biochemistry in Tübingen and then went on to do his doctorate at the Max Planck Institute of Biochemistry in Martinsried near Munich. In 1990 he established his own research group there and held courses at the Institute of Genetics and Microbiology of Munic ... more

    Prof. Dr. Heinfried H. Radeke

    Heinfried H. Radeke studied medicine at the Hannover Medical School (MHH) and received his medical license in 1985. His Ph.D. thesis was recognized as the best research dissertation of 1986. After two years as an assistant physician at the Göttingen University Hospital, he began his career ... more

q&more – the networking platform for quality excellence in lab and process

The q&more concept is to increase the visibility of recent research and innovative solutions, and support the exchange of knowledge. In the broad spectrum of subjects covered, the focus is on achieving maximum quality in highly innovative sectors. As a modern knowledge platform, q&more offers market participants one-of-a-kind networking opportunities. Cutting-edge research is presented by authors of international repute. Attractively presented in a high-quality context, and published in German and English, the original articles introduce new concepts and highlight unconventional solution strategies.

> more about q&more

q&more is supported by: