“The field as such was not looking for such types of RNA-binding proteins.”
In this interview Matthias Hentze gives his perspective on pursuing an academic career and tells us about the discovery of "non-canonical" RNA binding proteins and the "Riboregulation" concept.
Where do you see the European research landscape standing, also in comparison to China and the USA?
There are many challenges. Europe is currently struggling more than maybe it was a few years ago. I hope it finds out of that phase. Regarding research, there are potential synergies that we should make use of but are not. In a lot of places in Europe, there is fantastic science going on, so on a small scale it is working well, but we are not obtaining a commensurate more structured and strategic benefit at the national or even continental level.
US research, I think, is currently going through a crisis. I hope it will recover soon, and I do not have any pleasure from a competitive viewpoint that now, by comparison, we are doing better because they have problems. I think the opposite is the case: The better the science in the US, the more exciting it is for European scientists to be part of that global community.
Both for US and for European research the way that science is tackled these days in Asia, you specifically mentioned China, poses a challenge. I think we have become in many parts of the west a bit complacent about our work habits. They have become a little less driven than at least I felt they were a couple of decades ago. In China, I see a lot of appetite to tackle things and to progress. Unless we somehow find a way to address that, we will fall behind.
I do not know how it is here, but at institutions like EMBL, that should be exemplary, that provide an amazing infrastructure and people with a key to work anytime 24/7 when they choose to, you are a bit surprised by how few people you meet if you enter labs on a Friday afternoon after five.
“I still think that everyone who decides for a career in science should think about it similarly to entering a professional sports career.”
Being a researcher at EMBL provides you the environment and resources to put it in soccer terms to play at the Champions League level research-wise, but doing so still requires personal commitment.
That is right: it requires personal commitment and also dedication. You do not play Champions League in soccer or Grand Slam finals in tennis if you are not passionate about it at every given moment, even on a Saturday or on a Sunday. That sounds very old fashioned, I know. I realize that not being in the lab does not mean that you are not working on your research, particularly now that data analysis has become a much larger part of experimental progress. There is a lot of data analysis that one can do in the comfort of home rather than in a lab where you have centrifuges running in the background. I realize that, but I still think that everyone who decides for a career in science should think about it similarly to entering a professional sports career: commit from day one, sweat it out, win when possible and enjoy.
You are a marathon runner: What are the parallels between running a marathon and research besides the endurance that both of them require?
Patience. I would certainly not be able to finish a marathon without it. You come to points where you wish it is over soon, and if you still have 15 kilometers to go, you have this urge to accelerate and get it done and over with quickly. If you do this with 15 kilometers still ahead of you, you are not going to make it to the finish line. There is a lot of this in science as well: you need the right patience and strategy to make it along a long distance.
I think the comradery and then the collegiality in sports is also very fitting to science. I have been in marathon races where somebody was pushed in a wheelchair and runners were taking turns to push the wheelchair forward. I think this is wonderful at the hobby runners' level and also when it happens in science: being ambitious for yourself but not against but together with others is a fantastic parallel not just between marathon running and science, but sports and science.
“You need the right patience and strategy to make it along a long distance.”
How did you become a basic scientist after studying medicine?
I started medical school because I wanted to treat patients, I finished medical school and I still wanted to treat patients. I then wanted to combine it with science becoming a physician-scientist in the area of gastroenterology and hepatology. I felt well prepared for the clinical part but ill prepared for the scientific part. Before starting with the clinical training, I decided to enter for two years into scientific training for which I went to the NIH, joining the lab of Rick Klausner.
I worked on a project investigating a human genetic disease, hereditary hemochromatosis, which failed miserably. However, in the process, I cloned a human gene called ferritin. That was in the mid-eighties, and I saw a paper from the mid-seventies that suggested that ferritin protein expression was regulated in a very unusual way. There were big changes in the amount of ferritin protein made when iron levels went up and down, but no change at the mRNA level. In the mid-eighties, it was totally exotic that you would have translational control.
That was the claim of the paper, and since I cloned the gene, I could actually test this directly and there were indeed big differences in protein output without any change in mRNA levels. Then I could stepwise identify the responsible regulatory element which turned out to be the iron-responsive element in ferritin mRNA. At the time, this was the first element in a mature mRNA shown to be regulating gene expression in a physiologically relevant way.
To cut a long story short, I then contributed to four 'Science' papers in two years: Two as a first author and two as a second author. Rick strongly encouraged me to pursue a scientific career, but I insisted on wanting to practice medicine. He then suggested that I go to EMBL to give a talk. I gave a talk and without even applying, I was offered a group leader position to my total surprise and I took it. I know, times have changed and this was a very lucky strike. And while this career change was totally unplanned and opportunity-driven, it turned out to be one of the best professional decisions that I ever made.
Would you still study medicine before entering a basic research career in the life sciences?
I would say, it did not hurt me, and even if people have an interest in biomedical science, I would advise them to consider studying medicine rather than biology, genetics or biochemistry. The reason is that only when you study medicine, you really have the chance to learn what medicine is about. This knowledge is very hard to acquire for a non-medic because non-medics do not have the same environment. When you are a medical doctor and you lack some fundamental scientific knowledge, and I have to admit that my chemistry knowledge still today leaves much to be desired, you are constantly in an environment with experts who can help and advise, while you contribute your medical knowledge.
“Interdisciplinary has become something you can almost not do without.”
What were the biggest changes you witnessed over your career how science is done and the scientific environment?
I think there is a scientific answer and a cultural answer to that. Scientifically speaking, of course, the 'omics'. I used to be a reductionist biochemist and now the omics and systems biology have a big impact, and one is even asking mechanistic questions in a totally different way. Also, the emphasis on physiological experimental conditions has changed dramatically. Those would be the two components of my scientific answer.
In terms of culture, interdisciplinary has become something you can almost not do without, which means that a single person and sometimes even a single lab can achieve much less. Therefore, there is less autonomy of individual labs than there used to be, but in turn, there are far more collaborations that are exciting and yield profound insights.
Is an academic career still as attractive as when you started your group?
You would have to ask the younger people this question. I think yes. It depends on what you want from your professional life. I think there is not a small fraction of people who would like to have a secure job ideally before the time they start their families, which is totally understandable. I think that academia the way we still practice it today, does not offer that. This situation deters talented young people because they prefer to take a track that is more predictable in terms of career outcome. One of the big disadvantages of an academic career, today in particular, is that if you make it is wonderful but if not that choice of a career path might retaliate. You may struggle, at least for some time, before you find your bearings in an alternative career. In that sense, academic jobs have become less attractive.
The situation may be somewhat different in areas where meaningful, high-quality start-up companies are active and recruit well-trained scientists. However, too few centers in Europe are currently successful in creating such environments. When I go to Boston or the Bay area, I see much more of that. I would say in those areas pursuing an academic career is potentially more attractive because you have great science, but you also have great alternative options.
“I know, times have changed and this was a very lucky strike.”
Is going from an academic career to an industrial career perceived as a failure?
For somebody in Heidelberg today, if they go to a company setting, I would not at all say that this would be looked at as a failure. I would definitely say that 15-20 years ago, it would have been looked at as your plan B, but nowadays not.
I would like to comment on how to judge failure: I think we should not only be judging outcomes but also paths. Somebody can take a very good path, learn a lot along that path, but the outcome is unsuccessful: that person has had a great learning experience, which could be useful for many things and just because the outcome was not successful, it should not be held against that person.
What advice would you give to young researchers?
Make up your mind about what you want and what would be your dream - and then try to pursue it with all that you have. Do not limit yourself by what you think would give you greater chances in the future based on probabilities, because these things change and your best guarantee to have a successful career is to work in something that you are truly passionate about. I am not recommending to be a dreamer, but to realize what your dream is and to pursue it in a strategic way.
“I thought “wow” if this is a general principle that would be quite amazing.”
Your group developed the RNA interactome capture method and applying it identified numerous novel RNA binding proteins: Were you surprised how many there were?
Absolutely. We actually did not develop the RNA interactome capture method as a way to discover or describe the RNA binding proteome as a whole. I simply wanted to know whether other metabolic enzymes could bind RNA. "My first protein", iron regulatory protein 1, which is identical to cytosolic aconitase, was an example of an RNA-binding protein, which is at the same time an enzyme, and where metabolic changes introduce switching between the RNA binding and the metabolic function.
I thought "wow" if this is a general principle that would be quite amazing. We need to connect cellular metabolism with cellular gene expression programs, and that would be a wonderful, potentially general way of how this could happen. There were papers reporting on a few other examples, like GAPDH and enolase, being RNA-binding proteins. I just wanted to know if this could be more a general principle.
So we thought of the RNA interactome capture method and Markus Landthaler's group - for different reasons - developed the same technique independently in parallel. Then we had the outcome and I was delighted to see how closely ours and Markus' data agreed with each other and that there were seventy or so enzymes. Far more than we bargained for, giving us more than enough to work on.
However, there were all these other proteins, and initially, when I saw them, they made me worry. How can that be? These proteins had nothing to do with RNA, as far as we knew. Do I expect them all to moonlight and have a second function or is something wrong with the technique? Do we have many false positives for some reason? I was really struggling with that for a while.
Until I had the thought that these findings connected well with the RNA world hypothesis and the origins of life. The role that RNA might have played very early in evolution was to regulate protein functions. Therefore, these proteins might not bind RNA to regulate RNA expression as trans-acting factors, for example splicing or RNA stability, but some proteins could be bound by RNA to be regulated by RNA, which we now call Riboregulation.
A reversal of roles?
Exactly, suddenly we realized that RNA-protein interactions could potentially exert the same type of regulatory functions that we are accustomed to from protein-protein interactions. From SELEX-derived aptamers we know that RNAs can evolve to bind to nearly any surface, including protein surfaces. So RNAs could have evolved to binding to proteins that lack recognizable RNA binding domains. This concept of 'Riboregulation' is what we are very excited about right now, and which we intensively investigate further.
“I think we should not only be judging outcomes but also paths.”
Why was the RNA binding capability of these proteins not discovered before?
In my opinion, about 30 years of RNA biology were mostly driven by looking for trans-acting factors that regulate RNAs. Researchers performed affinity purifications using RNA regulatory elements and looking for RNA-binding factors; or screening genetically for factors that influence RNA fate. So RNA-binding proteins that bind to RNA and regulate RNA were found: this outcome was inherent to the way they were looked for. Now we have what is commonly referred to as 'unbiased' approaches. And we not only 'rediscovered' these classical trans-acting factors, but also found those that would not likely have been found before, because they do not have those roles, and are instead regulated by RNA. The field as such was not looking for such types of RNA-binding proteins.
Might there be even more RNA-binding proteins that were missed by the interactome capture method? How many have we still missed?
I do not know. We currently estimate the number for mammalian systems to be somewhere between 1500 and 2000, and interactome capture has been devised to be low on false positives while accepting false negatives. False negatives can arise because UV crosslinking is very inefficient, and there might be circumstances when a facultative RNA-binding protein is not active in RNA binding; for example, it might only bind RNA in mitosis or under stress. Therefore, there are plenty of reasons for why we might still be missing some.
“If you make it is wonderful but if not that choice of a career path might retaliate.”
You discovered these metabolic enzymes binding RNA: On how many of these were follow up studies performed to reveal the mechanistic details?
Not many at all at this point and the exploration is just beginning. Cytosolic aconitase was there before and inspired the work. We have published a paper on a mitochondrial dehydrogenase, HSD17B10, but this is quite limited work. I have heard that around the globe, some groups are picking up some of these enzymes and study their RNA binding in more detail. However, I must also say that I am slightly disappointed. Our paper and that from Markus Landthaler were published in 2012, and if you had asked back then how much will we know in 2019, I would have expected more. I hope that this is still coming. We will definitely try to make our contributions and we are currently tackling several additional enzymes; however, this takes time.
What has been your impression of the NCCR RNA & Disease during your visit?
This is not a political statement: I think it is great. There is a good number of outstanding RNA scientists in Switzerland and the NCCR RNA & Disease brings them together. But it not only brings together the principal investigators but also the students. After speaking to them both in Bern and Zurich, I can say that they are really happy that the NCCR connects them. In Zurich, some students remarked that, in their view, there was limited connectivity of PhD students between different departments, but that those who are in the NCCR-run RNA Biology PhD program feel privileged because it provides a way that connects them creating a community that exchanges and benefits from each other. I cannot evaluate this statement, but I found it a very genuine statement. So from that angle, this program is providing fantastic glue towards not only connecting PIs but connecting communities and fulfilling a very important training purpose for the involved students.
Biography Matthias Hentze
After completing his medical studies at the University of Münster Matthias Hentze joined the lab of Rick Klausner at the NIH Betsheda in 1985. In 1989, he became group leader at the EMBL Heidelberg. In 1990, he obtained his habilitation from the University of Heidelberg and in 1998 was promoted to senior scientist at the EMBL Heidelberg. From 2005 - 2013 he served as associate director of the EMBL Heidelberg and in 2013 became its director. Since 2002, he is the co-director of the "Molecular Medicine Partnership Unit" of the EMBL and the University of Heidelberg. In 2011, he was awarded an ERC Advanced Grant entitled "Exploring the interface between cell metabolism and gene regulation: from mRNA interactomes to "REM Networks"".
Interview by Dominik Theler