Like Phoenix from the ashes

With his discovery of regulatory T cells, Shimon Sakaguchi revealed the secret of immunological self-tolerance.

8 June 2020

The 2020 Robert Koch Award goes to the Japanese immunologist Shimon Sakaguchi / German infection biologist Thomas F. Meyer receives the Robert Koch Gold Medal

Berlin – The Robert Koch Foundation will present the 2020 Robert Koch Award, which is worth 120,000 euros, to Professor Shimon Sakaguchi at the Immunology Frontier Research Center (IFReC) at Osaka University (Japan). The award honours his groundbreaking work on regulatory T-cells. Professor Thomas Meyer, Director of the Department of Molecular Biology at the Max Planck Institute for Infection Biology (MPIIB) in Berlin, will receive the Robert Koch Gold Medal for his life’s work, in particular for his achievements in the field of molecular infection biology.

The award and medal of honor are expected to be awarded on November 13, 2020 as part of an official ceremony at the Berlin-Brandenburg Academy of Sciences in Berlin.

Photos and CVs of the laureates:
>> Shimon Sakaguchi
>> Thomas Meyer

Robert Koch Award
The “regulatory T-cells”, for whose discovery the Japanese Shimon Sakaguchi will be awarded the 2020 Robert Koch Award, are regarded as peacemakers of the immune system. This is because they prevent defence cells patrolling the body from attacking the body’s own tissue. If these cells do not function properly, they can cause autoimmune diseases or allergies. If they are missing completely, patients might even suffer from a number of autoimmune diseases at the same time, as is the case with IPEX syndrome, a rare hereditary disease. For a long time it was a matter of dispute whether such guard cells, to which we ultimately owe the selftolerance of our immune system, existed at all. But Professor Sakaguchi held on to the idea with admirable persistence – until he actually succeeded in capturing them.

The story began in the early 1970s, when Sakaguchi was still studying medicine at Kyoto University. Around this time, the existence of so-called suppressor T-cells, which specialise in slowing down immune system activity rather than igniting it, was first suspected. Sakaguchi was so fascinated by the idea that he made it the subject of his doctoral thesis. According to the British immunologist Daniel M. Davis, the result was a discovery of tremendous importance. Sakaguchi had surgincally removed the thymus glands of three-day-old mice. In the thymus, the T-lymphocytes mature, which are responsible for the body’s cellular immune response. The animals then developed autoimmune diseases, which subsided when Sakaguchi administered immune cells of healthy mice from the same inbred strain. So there had to be special cells among these immune cells that, according to Davis, could stop immune reactions and deal with an autoimmune disease.*

However, the initial hype about the suspected suppressor T-cells soon collapsed again, not least because the technical means to differentiate them from other T-cells were not yet available. There was hardly any funding left for research on the topic, and in the end it was downright frowned upon to even deal with it. Sakaguchi was one of the few who did not loose sight of their goal even during this phase, which lasted for more than a decade. And this perseverance paid off. In the end, Sakaguchi succeeded in identifying the suppressor T-cells, which were renamed “regulatory T-cells (TReg )“ a little later, by means of a special surface antigen. He removed these cells from mice with the help of genetic manipulation. As a consequence, autoimmune diseases occurred, including inflammations of the thyroid, stomach, pancreas, salivary gland, ovaries, kidneys and joints. These diseases could at least be alleviated by the timely administration of regulatory T cells. Like a phoenix from the ashes, the guardian cells came back into the lime-light.

Sakaguchi’s 1995 article from the Journal of Immunology, in which he reported on his discovery, is one of the mostcited papers ever published in this highly acclaimed journal. The researcher, who has already been considered a candidate for the Nobel Prize for Medicine, was also instrumental in the further clarification of molecular biological relationships. The milestones of Professor Sakaguchi’s achievements include his groundbreaking work on the importance of the transcription factor FoxP3 for the development of regulatory T cells and on the importance of mutations in the FoxP3 gene for the development of autoimmune diseases.

It started out as basic medical research. But the possibilities for clinical application were obvious. Some are already being pursued very actively. For example, it is not only possible to strengthen regulatory T-cells in the case of autoimmune diseases and allergies, but also after organ transplants, in order to reduce excessive rejection reactions. The opposite is true for cancer. A significantly increased proportion of regulatory T cells was found in tumour tissue, suppressing a potential immune defence against tumour cells. So in the case of cancer diseases, it would be important to curb the activity of regulatory T cells in order to enable the immune system to act more effectively against the tumour.

Shimon Sakaguchi has been awarded many international prizes, including the William B. Coley Award (2004), the Keio Medical Science Prize (2008), the Medal of Honour with Purple Ribbon (2009), the Canada Gairdner International Award (2015), the Crafoord Prize (2017), the German Immunology Award (2019) and the Paul Ehrlich and Ludwig Darmstädter Prize (2020).

*Daniel M. Davis: The Beautiful Cure: The Revolution in Immunology and What It Means for Your Health. University of Chicago Press, 2018

Always up to date
Milestones in infection biology and a bridge to cancer research
The Robert Koch Medal in Gold is awarded to a scientist who stands out in seminal research of infectious diseases and has accumulated a wealth of research experience like no other. More than once, the infection biologist Thomas F. Meyer was far ahead of time when it comes to setting landmarks in the research of infection biology, even reaching out towards discoveries on the origins of cancer.
Using the model of “pathogenic Neisseriae”, he commenced with investigating the intriate courses of bacterial infections and their underlying mechanisms. He discovered how bacteria change their surface in order to undermine the immune system and pursue multi-pronged infection strategies. He also gained valuable insights on fundamental questions of infection biology such as, for example, how pathogens transport weapons to their surface aimed to reprogram the cells of the host organism, how they horizontally exchange genes in order to arm themselves, and how they penetrate host cells, where they successfully proliferate. Many of these early discoveries from Meyer’s laboratory now represent textbook knowledge, forming the basis for similar observations in a large number of other pathogens. In retrospect, it becomes clear how systematically and consistently the researcher has proceeded with his scientific approach.
Realizing that an infection always depends on two partners, the pathogen and its host, the researcher formulated a provocative hypothesis early on. According to that hypothesis, infectious bacteria and viruses can be eliminated by blocking functions in human cells in addition to the standard application of antibiotics or antiviral substances, respectively. In his follow-up work, therefore, Thomas Meyer dealt with the roles of host components in infection processes, thereby developing the concept of “host-directed” therapy. In addition to the use of vaccines and antibiotics, this therapeutic approach has now become a modern third pillar in the fight against pathogens. It also has the advantage of reducing the development of resistance to antibiotics, and it can be employed quickly to test and repurpose medicines for other diseases, such as cancer, against infectious diseases.
The question of the fate of the onceinfected host cells seamlessly followed – are the cells damaged during the event of infection, the cause of which could be a possible origin of further diseases in the human body? For example, the gastric pathogen “Helicobacter pylori” is known not only to cause gastritis and ulcers, but also to cause stomach cancer in the long term. Therefore, Meyer is now seeking for a fingerprint, a genetic signature, that could prove the connection between infection and cancer. In fact, his latest research does not only underlie the importance of Helicobacter in the development of gastric cancer, but also sheds light on the effects of bacteria that damage the human genome with a genotoxin. Meyer found that a toxin called “colibactin”, which is released by the bacterium Escherichia coli, causes characteristic mutations in human intestinal cells which can be detected in a subgroup of colon cancer patients years later – based on the discovery of this genetic signature there is now, for the first time, direct evidence for the causative role of a bacterial infection in human cancer development.
Meyer has maintained his fascination with getting to the bottom of things and treading innovative paths for decades. As early as the 1990s, he started growing organ-like structures to better understand infection processes and the development of cancer cells “in vitro”. To date, such “organoids” have been manufactured from epithelial cells of the stomach, the fallopian tube, the cervix, the prostate, the gallbladder and the lungs. These in vitro models can serve as a replacement for extensive and expensive animal experiments. He had already used the latter for studies with influenza viruses. Since these native human cells also express the ACE-2 receptor, which serves as the entry gate for the novel SARS-CoV-2, the researcher now is using them as test systems for potential Covid-19 drugs that are in dire need. Once again, the researcher is at the leading edge of research – thanks to his extraordinary ability to innovate.
The recognition for Meyer’s great life work is reflected in many notable publications and prestigious prizes, including the Otto Hahn Medal of the Max Planck Society (1981), the Heinz Maier Leibnitz Prize of the Federal Ministry of Science and Education (1986), the main award of the German Society for Hygiene and Microbiology (1989), the Max Planck Research Award (1993) and the Aronson Award of the State of Berlin (1996). With the recent award of an advanced grant by the European Research Council, he will now be able to pursue his pioneering research on the role of infections in driving human carcinogenesis.

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.

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