Infection or immune tolerance

With his analysis of the antibody response, Ravetch created a paradigm change in immunology

April 27, 2018

Berlin – The Robert Koch Foundation will present the 2018 Robert Koch Award, which is worth 120,000 euros, to Professor Jeffrey V. Ravetch from the Rockefeller University in New York, USA. The award honors his groundbreaking work analyzing antibody response. Staffan Normark, Professor at the Karolinska Institute in Stockholm, Sweden, receives the Robert Koch Gold Medal for his life’s work, in particular for his work on the pathogenicity of pathogens.

The award and the honorary medal will be presented at an official ceremony on November 16, 2018 in the Berlin-Brandenburg Academy of Sciences and Humanities in Berlin.

Photos and CVs of the laureates:
>>Jeffrey V. Ravetch
>>Staffan Normark

For Jeffrey V. Ravetch, a childhood dream has come true. “I always had this hope as a child that one day I could say that I had researched a disease, understood how it works, developed a therapeutic drug to counteract it and had proven how this medication changes the course of the disease,” he told the BioTechniques journal in 2008. “Finally, I’ve succeeded.” With a recombinant gamma globulin, the US researcher opened up the possibility of treating autoimmune diseases such as arthritis or lupus far more effectively in the future than has been the case so far. The second and third generation of therapeutic antibodies against cancer would not exist without Ravetch. Some of them are already approved for use. Others are in the final phase of clinical tests.

All this is the result of decades of work on what is known as the “Fc fragment” on the antibody molecule and on its binding partners, the “Fc receptors”, which are found on the surface of many immune cells, including lymphocytes, phagocytes and natural killer cells. When Ravetch took over his first own research group at the Sloan Kettering Institute in New York in the early 1980s, he asked himself the apparently simple question: “Why do antibodies have an Fc fragment in the first place?” At that time, apart from its role in extending the half-life of antibodies in the serum and binding to complement, no important biological role was yet being ascribed to this structural element of the antibody molecule. However, Ravetch hit the bull’s eye with his question.

He succeeded in cloning the extended family of Fc receptors, which in itself was already a major challenge, considering the fact that techniques for isolating genes for rare proteins were still rudimentary at that time. Tests with knock-out mice showed that very different immune reactions could be modulated via members of the Fc receptor family. “It took a long time and a great deal of effort convincing the medical community of the fact that via these receptors, not only are inflammatory processes regulated, but also immunomodulation and immune tolerance,” Ravetch explains today.

For many phenomena mediated by antibodies, some of which appeared to be contradictory, there was finally a plausible explanation available, for example, for the presumed paradox in connection with the use of high doses of gamma globulins to suppress inflammation. It was already a long-known fact that such gamma globulins can trigger autoimmune diseases when they classify the body’s own cells as being “foreign” or mediate the killing of tumor cells and these are then attacked by immune cells. On the other hand, autoimmune diseases could be successfully treated with high-dosage intravenously administered gamma globulin preparations. How could that be?

Ravetch discovered that it depends on tiny molecular deviations (“sialylation”) in the Fc region of the antibody molecule whether the gamma globulin has an inflammatory or anti-inflammatory effect, since different members of the Fc receptor family reacts differently to the respective structural changes in the Fc triggered by sialylation. By clarifying this mechanism he has set the stage for the development of synthetic gamma globulin, a “hypersialylated” variant, with far greater potency than that of standard preparations pooled from thousands of plasma donations.

In contrast, different Fc structures binding to other members of the Fc receptor family are required for the killing of tumor cells or activation of the immune response. These observations have lead to the development and approval of new therapeutic antibodies against cancer based on the realization that key signals are transmitted via the Fc receptors that contribute to the mechanisms by which these antibodies can be used to treat cancers.

Controlling contradictory reactions via the same molecular entity, the IgG, was a revolutionary approach that led to a paradigm change in immunology. Rather than a invariant molecular structure as originally conceived, Ravetch revealed that the Fc can adopt many different structures based on changes in Fc glycosylation. These structural changes are translated into functional differences by their differential binding to members of the Fc receptor family. In a healthy immune system, activating AND inhibiting signals provide the right balance. However, if this balance is disturbed, the body’s own cells may come under attack, leading to autoimmune diseases or exacerbations of infectious diseases.

The huge potential of this groundbreaking research approach is far from having been fully exploited. Recently, Ravetch also included infectious diseases in his analysis of the antibody response, pointing out the role of Fc receptors in mediating the protective effects of anti-viral antibodies. New insights have already been gained from a range of animal models. The next goal is to develop better vaccines for people against diseases such as influenza. For Jeffrey V. Ravetch, this marks the closing of a circle.

Gold Medal for a great science mentor

When Staffan Normark looks back to the beginning of his career, he remembers a time when there was much that was simply “new and exciting”. Normark is one of the first researchers to clone a gene in Sweden. In 1980, aged just 35, he became the youngest professor at the university of his home town Umea. In 1983, he founded Symbicom, an early Swedish biotech company, which is now an affiliate of AstraZeneca. Normark had a sure sense for the incredible opportunities that opened up with the new molecular biology instruments. For a long time, he worked on the induction of “AmpC-beta-lactamase” in Escherichia coli and thus the creation of resistances to antibiotics. The beta-lactamases are bacterial enzymes that are able to split the “betalactam ring” of numerous antibiotics, thereby rendering it inactive. The enzymatic de-activation of antibiotics through beta-lactamases is regarded today as being the most common resistance mechanism.

Soon, Normark gained the reputation of a leading international expert on how bacterial pathogens bond to their host cells. The colon bacterium E.coli is responsible for up to 80 percent of all bladder infections. Normark studied the tiny hair-like appendages (“pili”) with which these bacteria – as though with tiny arms – attempt to cling to the cells of the bladder wall. His work led to the development of an experimental vaccine against urinary tract infections. Soon after the groundbreaking discovery by Robin Warren and Barry Marshall that Helicobacter pylori triggers stomach ulcers, Normark was the first to prove what enables this bacterium, whose role as a “stomach germ” had been hidden for so long, to dock onto the epithelial cells in the stomach lining.

Later, in 2005, he had the particular honor of giving the award ceremony speech when Warren and Marshall were presented with the Nobel Prize for Medicine. As a senior professor at the famous Karolinska Institute in Stockholm, Normark continues his work on the interaction between bacteria and their respective hosts. Recently, he has focused in particular on the molecular pathogenesis of infections through pneumococci, which can trigger life-threatening lung infections.

From 1999 to 2005, Normark was President of the Swedish Foundation for Strategic Research (SSF). As a member of the Nobel Assembly, he has already been involved in selecting Nobel Prize winners since the mid-1990s, and from 1996 to 2001, he was also a member of the Nobel Prize Committee. From 2010 to 2015, he worked as Permanent Secretary at the Royal Swedish Academy of Sciences, where one of his most enjoyable tasks was to telephone the winners of the Nobel Prize to tell them of their award.

The numerous awards that Normark himself has received include the “Nature Award” presented in 2012 for his exemplary mentoring. Former students who themselves now have a long and successful career behind them, praised his ability, among other things, to “tickle out” the best from them, while at the same time giving them as much freedom as possible. For him, an innovative idea was always more important than simply producing data. Philipp Campbell, who has edited “Nature” for many years, described Staffan Normark as “one of those unusual personalities who succeed in conducting top-level research themselves while at the same time creating an environment in which young researchers can develop their own creativity”.

About the Robert Koch Foundation
The Robert Koch Foundation is a non-profit foundation dedicated to the promotion of medical progress. It was founded in 1907 and is based in Berlin. The Foundation promotes basic scientific research in the field of infectious diseases, as well as exemplary projects that address medical and hygienic issues.

The Foundation confers a number of distinguished scientific awards each year: the Robert Koch Award – one of Germany’s most distinguished scientific awards, the Robert Koch Gold Medal, three awards for young scientists and, since 2013, the Hospital Hygiene and Infection Prevention Award.

Robert Koch (1843 – 1910), after whom the award is named, was the founder of modern-day bacteriology, for which he was awarded the 1905 Nobel Prize for Medicine and Physiology. From 1891 until his retirement in 1904, Koch was Head of the Institute for Infectious Diseases in Berlin.

Christine Howarth, Tel. +49 (0)30-468-11599, E-Mail: