The next level: Single-cell analysis

As BIH Visiting Professor, Giuseppe Macino regularly visits Berlin – where, together with Professor Angelika Eggert and Professor Nikolaus Rajewsky, he’s working in a Europe-wide consortium on the future of single-cell analysis: that is, the technologies for analyzing single cells. We met with the three researchers in December 2018 and were able to take a look inside the (as yet unfinished) new building of the Max Delbrück Center for Molecular Medicine (MDC) on the campus of the Humboldt University in Mitte, Berlin. The Berlin Institute for Medical Systems Biology (BIMSB) will move into the new facility in spring 2019.

We have sitting in front of us a molecular biologist, a systems biologist with a background in physics and an oncologist. What has brought you together?

Macino: We met in New York in 2005. There, we decided to conduct a few experiments together and that collaboration ultimately led to an influential article at that time. That not only sealed our collaboration, but above all our friendship. What unites us is that we share a very similar concept of what science actually means.

And how does it all fit together in terms of content?

Rajewsky: As you can’t conduct experiments on the brain in neurobiology, for several years now my laboratory has been working with organoids. To do this, you take cells from the patient and reprogram them to become stem cells which then develop into a miniature brain. This can be used for studying diseases or for conducting experiments. We are doing this with single-cell analyses methods. Giuseppe Macino works with organoids in cancer research. I became aware of Angelika Eggert because she’s not only a dedicated clinician, but also very well connected in the field of basic research. As a cancer expert, she studies brain tumors in children and likewise produces organoids for that purpose – so you don’t have to be a genius to see that this expertise ought to be brought together. Similarly, the EU flagship initiative LifeTime brings together these very hot topics in modern biomedicine: single-cell analysis – that is, the molecular study of single human cells, organoids, which can in turn be broken down into individual cells, and artificial intelligence. Giuseppe Macino initiated the Italian Epigenome Program, which is focused on the same topics and whose development I’ve followed over the years. The BIH Visiting Professors Program of Stiftung Charité allowed us to bring him to Berlin in order to jointly initiate concrete steps and launch the flagship.  

Macino: Our experiments can only be conducted in a few laboratories with suitable equipment. Nowadays, the technologies are so complex that we not only need researchers to conduct the experiments but, after that, also the right people to analyze the data generated. Collaboration with the laboratory that’s one of the foremost pioneers in the field of bioinformatics worldwide is essential for our project.

The Human Genome Project, to which your respective projects are in a sense connected, was associated with great hopes. Looking back, which expectations have been fulfilled and which have not? What has changed in single-cell analysis?

Macino: The Human Genome Project is one of humanity’s most important achievements. The idea alone was revolutionary. At first, everyone was excited. We thought: “At last we’ll be able to read all the genes and understand how cells function.” Not long afterwards, we were forced to face the fact that every cell is different – even when all the cells are using the same genome. For example, in cancer cells completely different genes are used than in healthy cells. Apart from that, we also know that the DNA is organized differently in each cell. We now need to discover the mechanisms that control which set of genes is used and which isn’t used.

The next level: Single-cell analysis
Prof. Dr. Giuseppe Macino

Funding program

BIH Visiting Professors

Funding period

2018 – 2020

Project title

Single-cell genetics and epigenetics of patient-derived tumor and brain organoids

Research area

General genetics

Institution

Max Delbrück Center for Molecular Medicine (MDC), Berlin Institute of Health (BIH)

 

Since 2016

President and founder of the School in Bioinformatics at Sapienza University, Rome, Italy

Since 2012

Director of the National Flagship project EPIGENOMICS of the Ministry of Education and the National Research Council, Italy

2007 – 2016/2009 – 2015

President of the School in Biotechnology and Director of the Department of Cellular Biotechnology and Hematology, Sapienza University, Rome, Italy

Rajewsky: Looking back, it was of course naive to believe that we’d be able to heal all diseases through decoding the human genome. Nevertheless, the project has had a massive impact. Recently, a corporate consultancy firm estimated how much revenue was generated by every single dollar invested in the project. From an economic viewpoint, it was one of the best investments ever made in science. When you look at how diseases are treated today, many therapies are already based on the results of the Human Genome Project. Patients with tumors that no longer respond to conventional therapies can have their DNA sequenced to check which medications will work and which will not. We don’t claim that we’ll be able to cure cancer or Alzheimer’s with our project, but we are expecting groundbreaking effects similar to those of the Human Genome Project.

So what can single-cell analysis deliver that the Human Genome Project wasn’t able to do?

Eggert: The developments in the field can be compared to a computer game. At the first level, you have to carry out a certain task. That task was the Human Genome Project. Once that task has been successfully completed, you get to the next level and are faced with a new, more complex task. The single-cell methods and the LifeTime consortium are that new level. We’re already working on the Human Cell Atlas, but it’s limited to the descriptive level – a bit like a map on which you see an ARAL sign, but don’t know that it stands for a service station. In order to know what the sign means, you have to discover the function. Single-cell analysis is the degree of precision necessary to, for example, advance further in the field of oncology. Up to now, cancer has been regarded as an organ that grows in our body. In reality, the tumor contains not only tumor cells, but also vascular cells and immune cells. Even the tumor cells differ from one another. Single-cell analysis offers the hope that we’ll be able to treat the different cell types of tumors with greater precision in future.

Rajewsky: You could also describe single-cell analysis as an extremely good microscope, but not in a visual sense. You look inside the cells and can distinguish between individual products of the genome there.

In 1901, Wilhelm Conrad Röntgen won the Nobel Prize for developing the first method of being able to look inside the human body. It was suddenly possible to see structures, bones and tissue. Today, we’re so far advanced that we’re able to look inside the cell itself.

Professor Eggert, why are you, as a clinician, so interested in basic research?

Eggert: In my team, we work with brain tumors and other tumors of the peripheral nervous system. We began to create organoids of our cancer patients because we saw the necessity for it. However, only basic researchers can develop new approaches regarding all the things that can be studied using these organoids. Personalized medicine is already furthest advanced in the field of oncology, but there’s also a huge need for it. Cancer still constitutes a deadly disease, and the cure rates are not as high as we’d like.

We’re sitting in a building that will be opened at the beginning of next year in order – among other things – to bring the MDC’s basic research closer to the Charité. What does this mean to you?

Rajewsky: Each time I come here, I’m overcome by the thought. I once used to sit at my desk in Buch, thinking that there ought to be a place like this. Now, nearly ten years later, it’s just about to open. The site of the new location is central and important. Until now, unfortunately research institutes in Berlin were scattered. There are historical reasons for this, but it’s not in keeping with the nature of modern research, which involves interdisciplinary cooperation for which geographical proximity is essential. Coming from Buch, it was not practical to visit Angelika Eggert in Wedding on a normal workday. Now, it will be a ten-minute drive and the collaboration can proceed much more intensively. In addition, we’re located on the Humboldt University campus. We need young people to come to us, learn and at the same time bring new ideas to our laboratories. The MDC’s basic research will have much closer contact with the clinic – so this is a very dynamic time. It’s important to me that it should be a place where people feel at home. Scientists go for a meal together in the evening, have a chat – and suddenly get new ideas. So, they go back to the lab and get down to work again. The most important ideas are, by definition, impossible to plan. You can, however, plan an environment that increases the probability of hitting on such ideas.

Macino: ...which is why a good coffee machine is so important! (laughs)

Rajewsky: In fact, finding the right coffee machine is a small research project in itself.

Macino: One day, I got an e-mail from Nikolaus Rajewsky in which he asked for recommendations for coffee machines. So, I went to my favorite café in Rome and asked: “Toni, which is the best coffee machine?”

So, you were able to influence the equipping and designing of the building?

Rajewsky: Normally, in Germany, from the moment you invite bids for a building contract, you no longer have any chance to influence anything – so you have to draw up a bid invitation that’s as detailed as possible. We were very lucky. The winning architects, Staab Architekten, are known for working closely with the scientists. To tell you the truth, I’ve probably been involved in working out every detail that you can see here. One of the features closest to my heart is a room that’s been specially designed for very different people to come together.  You can not only hold discussions there, but also concerts and other events. The idea behind it is that it should be a meeting place – for life scientists, clinicians, politicians, investors, the public and artists. There’s nothing like that in Mitte yet. The idea here is for people to come into contact with ideas and people that don’t come from their usual environment. I believe that’s very important for the communication between the different actors. People outside the laboratories ought to understand what goes on inside them. At the same time, the world out there can also be an inspiration for the scientific community too.

Macino: In the LifeTime project, too, we want to invest energy in communicating with the outside world and to regularly provide students, professors and other target groups with new information on our projects and results. And particularly physicians, who have no contact with basic research. Medicine is increasingly becoming molecular medicine, but it’s not yet being taught accordingly at university – so there’s a huge gap in that respect.

Professor Macino, as a BIH Visiting Professor you’re new to Berlin, unlike your colleagues. Have you already made any discoveries here that have nothing to do with your research?

Macino: After arriving in Berlin, the very first thing I got myself was a bicycle. I’ve even ridden it all the way to Buch a couple of times. But what I do miss in Berlin are hills – like those in Rome. That’s why it’s so easy to cycle here – it’s so flat that the bike almost goes by itself.

When you compare the city to Rome, what’s the first thing that springs to mind?

Macino: You want me to compare Rome and Berlin? (laughs) Rome is in many respects a very beautiful city – but also a complicated city. In Berlin, it’s much easier to feel at home. I’ve been here almost a month and I like it very much – even the daily journey to Buch. When you come from Rome, it’s easy to find your way around Berlin. You can find everything you need. In short – I already feel almost like a Berliner.

 

November 2018/MM