Building "a small universe:" the very model of a laboratory

In the early 1960s Klaus Rajewsky began creating what later became, as he calls it, a "small universe”: the immunology department at the Institute for Genetics in Cologne, where he would remain for 38 years. It's a model of how excellent science can be done against a changing landscape of ideas, technologies, and careers, producing generations of scientists who have gone on to become leaders in their fields. Inspired by the culture of science they experienced in his lab, many of them have maintained close contacts with Klaus and drawn on those experiences in creating small universes of their own. This "extended family" will come to the MDC on Nov. 4 for two days of events in celebration of his 80^th birthday. The festivities will begin on the 4^th with a symposium entitled "Mechanisms of Molecular and Cellular Immunity 1964-2016." The next day the circle will draw closer in an invitation-only symposium of five talks called "New Scales," at the Berlin-Brandenburg Academy of Sciences, followed by a concert and dinner.

In this recent interview, Klaus reflects on the experiences that inspired him and how they guided more than five decades of research. He discusses the elements that he considers essential for excellent science, lessons learned when he left Cologne to work for ten years at Harvard and since establishing his laboratory at the MDC after that, along with the values that shouldn't be forgotten as the landscape of science rapidly changes. In 2013 he wrote a wonderful retrospective of his work in Cologne that is the best testimonial to the way these ideas have generated groundbreaking insights into the immune system, a number of diseases, and the development of new gene technologies.

There have been many biographical films about scientists recently, and they usually open with a key, formative event from their early lives. What would that scene be for you?  
I think it would be a seminar room in Paris, in the early 1960s, at one of the seminars of the lab of François Jacob and Jacques Monod that took place several times a week. This was the peak time for their work on bacterial genetics. The room was small but was always packed so full that people had to sit on the tables and windowsills, smoking and engaging in unbelievable discussions. These meetings would start with a talk, followed by heated arguments that often left the speaker forgotten in a corner. I had come to Paris to do a postdoc on lactic dehydrogenase isoenzymes and was trying to use antibodies to characterize them. At the time antibodies were starting to be used as research tools, but very little was known about their origin, or the immune system overall, and many of the ideas that were floating around turned out to be wrong. Very soon afterwards I would be completely drawn into this topic, at just the time some of the very basic concepts in immunology were starting to be established. Due to my background, I didn't understand a lot of the science that people were arguing over in that small, smokey conference room. What struck me, though, was the tremendous intellectual excitement and passion that was generated in this free atmosphere of argumentation. This spirit is something I never forget, and the experience strongly influenced my decision to join a molecular biology research lab in Cologne.

How did the Cologne institute develop?
The institute was created by Josef Straub and Max Delbrück, who was then working at Caltech in the USA, and its organization was strongly influenced by Delbrück’s experiences with research in the US – particularly the culture of small labs with an informal atmosphere and very little hierarchy. Many of the researchers and professors who were appointed in Cologne had just finished postdocs in the U.S. and were returning. It was a very interesting period in which we were getting postdocs from all over the world. The then famous annual Phage Course organized by the institute (later growing into the Cologne Spring Meetings) was attended by a whole generation of future molecular biologists in the country. I started my own minute operation inside one of the molecular biology groups in the institute, as an immunologist overseeing twelve rabbit cages. But within a few years we grew into an immunology department and what I liked to call our “little universe”. Embedded into a German-speaking environment, we had decided early on that English would be the lab language – which was important with the arrival of increasing numbers of foreign postdocs with whom we could only communicate in English. In this situation we all flocked together, organized an extended system of weekly discussion groups, where the various scientific projects were discussed in much detail, and there were extensive joint social activities among the group members outside work. All this generated a very special atmosphere in conjunction with exciting science – surely one reason that so many former lab members are coming to our meeting in November!

How did the scientific focus of the lab evolve?
I became very interested in immunology because it related to general problems like memory, self and non-self, and learning. I thought that studying the immune system might give insights into these matters. At the time I started, T cells hadn't been discovered, and antibodies were considered key to immunity. Niels Jerne, one of my scientific mentors, developed the concept of the idiotypic network of antibodies, a pretty philosophical, but fascinating concept incorporating the memory and learning aspects of the immune response. We spent a long time working on what ultimately turned out to be a dead end – at least at the time. The network idea didn't really hold the promise that it seemed to. It didn't strike at the center of what the immune system was probably really doing – fighting infections. At the time we considered that a sort of pedestrian view of things! Some of the people who are coming to the upcoming meeting started working within this earlier framework, and have witnessed the incredible changes in thinking and experimentation that have occurred within the field.

A more "philosophical approach" has significantly changed the way certain problems were considered at various times – thinking of early conceptual work on the gene, for example... Are there questions today which could benefit from this abstract way of considering things?
I think the main thing that has changed between then and now is that at the time, there were very few experiments you could do. We simply didn't have the tools necessary to approach many of the questions we were most interested in. As a result there was a tendency to propose grand schemes that couldn't be tested. An example of this is the Brenner-Milstein model of the generation of antibody diversity by somatic mutation, which was published as a Nature paper, in the absence of experimental evidence. Today if you would have this sort of idea you'd need to provide some evidence for it. There is so much you can actually do nowadays that it has become unfashionable to propose hypotheses without testing them. This change involved the arrival of fundamental advances in technologies which allowed one to do molecular analyses. That had such an impact on everything because it finally gave you methods that produced solid results that told you how something really worked. For example, with respect to somatic mutations, you could actually begin to identify them in the genes. That became so overwhelmingly insightful that it changed the entire way we approached things. It was truly a major, major shift.

Your article describes another fundamental change that occurred, which you were directly involved in: bringing genetics into the game.
That was something similar. You have to realize that at the time I came to Genetics Institute, in 1963, most of the advances in genetics were coming from groups working on bacteria and bacteriophages, and yeast. I was truly envious of this. But in the systems I was working in, almost nothing was possible, except for breeding experiments with genetically distinct strains of rabbits (the experimental animals I started with) or mice. Then came the breakthrough of embryonic stem cells, with the prospect of their genetic manipulation. As an immunologist, working at the Genetics Institute, it became obvious to me that I had to work in this direction, and we started on it immediately, as the only way to marry the two worlds. For us and of course many others it was the lucky accident of being in the right place at the right time. When we began there was no guarantee this would happen.

You stayed in Cologne for a long time – until mandatory retirement forced you to leave. Today that sort of long-term association with a single institute is unusual for a highly successful scientist...
Yes, and there were a lot of reasons that this happened. One was the character of the institute, which was completely unusual at the time. Part of this had to do with the values that inspired Max Delbrück to structure it in a certain way. Another was the type of people the institute attracted – many independent thinkers and unorthodox personalities – who didn't want to work in the classical German university type of structure. This was an opportunity to interact with interesting people at many different levels, and I think I stayed there so long mostly for these reasons. Over the years I got quite a few interesting offers, some of which would have left the lab "swimming" in money. In Cologne we were living off the DFG; we had to bring in our own funding. But I have never really suffered from this; the lab never had to face a truly threatening shortage of funding. Today this might only work within a framework such as Helmholtz or Max Planck, but at the time we somehow managed. The path I chose allowed me to continue spending most of my time thinking about experiments, looking at data and talking to people. I was never a Dean, never belonged to the DFG Senate or held such a position at the university. I was asked, of course, but at some point they stopped approaching me – through some sort of unspoken mutual understanding that it wouldn't have been in the interest of either of us!

Most scientists have to work within structures that they have inherited from the past, often when scientists were working in a different way. What's happening on a daily basis in labs such as yours is now changing so fast... Do you see the need for some further type of change that would improve the quality of research? 
Today's trend of "big data" is very important, of course, and requires some changes in the ways people work together. But I still think that the most productive way to do science is to assemble a congenial group of people who like talking and working together. When I think back, that was always the crucial component of my scientific career. At some point in Cologne we had a group – a "band" – of people that was absolutely outstanding and truly inspiring. We had somehow overcome the problem of mutual criticism becoming personal. It only worked by establishing a scientific spirit of openness, allowing blunt discussions about what was going on. This was wonderful, and I think this particular spirit of bringing people together remains the main element in any scientific activity and the most important means of developing science. You always want people who speak up and challenge you. When I hire someone, I look for the best qualified, most independently thinking individual. That was easy at a place like Harvard Medical School, which attracts the best of the best from China, from India, from all over Europe. It's not a given everywhere in Germany, due to many environmental factors. I don't know why it worked so well at the time in Cologne, but over time we began attracting people who were unbelievably qualified from America, from Japan, from Europe... They flocked around us.

Today the landscape of scientific careers has changed in some worrying ways – what is your take on the situation?
During the period in Cologne, everything was still growing; it was an expanding situation which made for a lot more opportunities in science. When I look at the people who have come through my lab, I find more than eighty academic group leaders, others have been successful in industry, and so forth. There are very few who have “disappeared” from science. While I was in Boston I was asked to lecture at two German graduate schools, which were extremely selective – the bar for admission was set very high. I had the opportunity to have lunch with the students, and we talked about careers. The vast majority said that they did not intend to continue in science – which is a sign of the extent to which things have changed. The issues were the extreme amount of work and time investment it would take to succeed in such a competitive environment, when at the end there was little chance of getting a position... I was completely shocked. If I had asked the students in my graduate program in the US the same question, the answer would have been totally different. I went through many learning experiences when I moved to the United States – at the age of 64. The psychology there is very different. In the U.S., it is very clear that you have to take your career into your own hands from the beginning to the end. Apply to the best graduate program and best lab for your PhD, continue as a postdoc in a top lab, and then set up your own lab in a prestigious place – it’s all your responsibility, in the limits of your ability! Here, on the other hand, people often think that they need to be taken care of. The system over there also concerns itself more broadly with the theme of education, ensuring that students truly acquire the skills they will need for a successful career. Many of the foreign students who arrive in Germany, for example, don't have sufficient English or writing skills, which they will need constantly, but they are not challenged (and supported) because of this. I would like to see a requirement that students deliver half-year written reports about what they have done, where they present the data and monitor their progress so they know where they stand and whether they are able to express themselves. That would make things much simpler for their thesis later on – they could just put everything together in the end; and they would be aware of the progress of their work throughout.

With age comes this vast experience you have accumulated in science – has this changed the way you think, somehow, or the way you approach problems?
I think the main thing that happens involves decisions about just any of your activities. You try to make them as efficient as possible. I notice this when I write a text – you don't want to waste the time of struggling with ten different drafts of something! This efficiency issue becomes ever more important as you get older. One thing that has always been important to me, and which I have always tried to protect, begins to require more effort: not to be drafted into all kinds of activities, to preserve an amount of time in which you won't be disturbed. I never allowed my secretaries, for example, to make a real schedule for me, because I didn't want to become the slave to my calendar. That's changed now, but I still try to protect some time.

How does this concept of efficiency play out in terms of decisions about the direction of your science? What's the difference between a question that you find interesting and worthy of pursuing, and one that you find less so?
Perhaps in the past I would have tended more toward broad topics that might take a long time. Nowadays I have become more... realistic? I tend toward projects that I think we can get finished in the foreseeable future. And one thing that I feel is a very important consideration in science is to try to give up things, when you see they don't work. Hans Clevers has recently written about this: the importance of finding the right moment to quit when something isn't working out, so that you can follow up on things that produce results. There's a profound insight behind this: we can't predict nature. Thus, many approaches will necessarily lead to dead ends. This raises an issue for young scientists who are just entering the field: everything is doable. There are hundreds of ways to acquire thousands of datasets. Somehow this leads people to think that a goal of their work could be to generate "resources". This may be fine, but consider from the beginning which biological problems your data resource will help you to solve, and be aware that many such resources are never used. When decades ago we developed techniques to sequence antibody genes in single cells, we did so in order to determine antibody affinity maturation in germinal centers and the origin of B cell lymphomas and of Hodgkin’s disease; and Cre/loxP-mediated conditional gene targeting allowed us to address the function of key genes in specific subsets of cells in the immune system and beyond.

What are you most proud of, when you look back on your career?
One thing was certainly the way we developed the immunology department at the institute in Cologne, continued in the U.S. and now back in Germany: this idea of building a context, an environment of intelligent people who like to talk to and challenge each other while considering what makes good science. We'll experience some of this when some 150 people who went through the lab come back together here in November, continuing the sorts of discussions that have been going on for many years. That has generated a unique value that I am proud of.

Contribution picture: Klaus Rajewsky in the lab. Picture by David Ausserhofer/MDC.