Imagine that certain forms of blindness could be cured. Or imagine that the body itself could produce a cure for some of its own diseases. These may be just some of the results of the National Centre of Competence in Research Molecular Systems Engineering (NCCR MSE). Its long-term goals are to create molecular systems and factories for the production of high added-value chemicals and develop cellular systems for new applications in medical diagnostics, therapy and treatment. Director Thomas Ward is aiming high: He wants to make Basel the leading hub for the next European flagship project. At stake: one billion euro.
Interview: Ralf Dümpelmann
Thomas Ward, you are the director of the NCCR MSE. How did you end up in this position?
Thomas Ward: During my work at the University of Neuchâtel we became curious about artificial metalloenzymes. For instance, we could take ruthenium ion that nature does not have much of at its disposal, and incorporate it in a protein to yield an artificial metalloenzyme. Pursuing this curiosity driven pathway, my group became more and more interested in biological questions. Ultimately I wanted to collaborate with molecular biologists – and this is one of the main reasons why I moved to Basel. When I arrived here nine years ago, the ETH Department of Biosystems Science and Engineering (D-BSSE) had just moved to Basel. That led professor Wolfgang Meier, then head of the Department of Chemistry at our university, to initiate talks with the D-BSSE which were very productive. In the end, he and co-director professor Daniel Müller set out for a National Centre of Competence and Research that ultimately got funded by the Swiss National Science Foundation (SNSF).
What was the goal when starting the NCCR?
Wolfgang Meier and Daniel Müller saw the opportunity to start a collaboration between biologists who relied quite heavily on chemistry and chemists who can provide the required chemical building blocks to address challenging biological questions. This is scientifically a very unique match. In my view this is also reflected in the most important aspect in the title of our NCCR – molecular systems engineering – namely the systems aspect.
Do you build artificial biological systems with the help of chemistry?
At the end of the road, we want to reproduce the properties and the complexity of a living system. There are two ways to get there. The chemical way is to take a compartment, put objects inside one by one and see what evolves. That is the bottom-up approach. On the other hand, a biologist takes a complex system and knocks out components, one at a time. In doing so, biologists focus on computing a system. And they are doing this very well. They can control things, even without fully understanding the molecular details of such systems. These two approaches meet at some point, and that is where our NCCR comes into play.
What could a potential end result look like? A small golem?
If you take the definition of what is life, there are a few features that we are definitely not trying to mimic. We are rather focusing on an artificial organelle, something that you could introduce into a living system and which would work in a living system, but which does not have all the features of a living system itself. I like to call such components molecular prostheses. It is like an artificial Lego block that fits into living systems. There we are already quite advanced.
Can you explain how the work of the NCCR is structured?
The network is planned to work over twelve years, split in three phases. There are roughly 30 groups associated with this NRCC, with some 20 in Basel. When there is somebody outside of Basel who has a competence that we need, they can be integrated to the network. That might be people in the Paul Scherrer Institute or at the University of Bern, for instance.
We are now approaching the end of the first phase of four years. The first step for us as chemists is to synthesise and assemble molecules into modules, an assembly of several molecules. For example, Sven Panke at the D-BSSE and myself synthesise artificial enzymes. Daniel Müller of the D-BSSE on the other hand manipulates pore proteins which allow to control the trafficking of substrates and products in and out of a cell. The goal is assemble an artificial organelle containing two or three enzymes and to introduce this prosthesis inside a cell. With that we can complement the natural metabolism of a cell with an artificial metabolism to produce new chemicals. At the end of the first phase, we ideally want to have solved the module’s problem. In the second and third phase, we can then focus on creating molecular factories and cellular systems.
Ultimately, a chemical factory could produce something that could be useful and a cellular system could be used to cure a disease. For both of these goals, you need a molecular assembly line, much in the spirit of what Henry Ford developed in the early twentieth Century, but at a molecular scale.
Do you already get a stable system out of these assembly lines?
Yes. The question is, however, how stable and for how long. We have systems that function in a cell for two weeks. Whether this is enough to cure a disease remains to be demonstrated.
What benefits may come out of it?
Our aim is to change the way biology and chemistry work in the long term. It is a risky strategy, but with a potentially high payoff.
What would be the high payoff?
You put a molecular or cellular system in the body and it treats or cures a disease.
When will that be feasible?
There are two systems, which are already very well advanced. Both were initiated and funded by the NCCR. Botond Roska of the Friedrich Miescher Institute for Biomedical Research has developed a system that can be injected into the eye to regain vision. This system will enter clinical trials in Winter 2017. It is based on genetic engineering, where you have to inject DNA so that your eye starts to produce pigments again. The other one is aimed at curing diabetes. Your fat cells are re-programmed into cells that are capable of producing insulin. They are then injected into your body and allow you to autonomously produce insulin when the body needs it.
Will these ideas be used in start-ups?
Yes. There are already two start-ups that were created in the past three years. The diabetes treatment is also seriously being looked at for a start-up. The SNSF wants to see things like that. It wants us to bring our research to an advanced stage.
You are organising the International Conference on Molecular Systems Engineering in Basel at the end of August. What is its main goal?
It is a challenge to organise such a conference because people who attend conferences like to talk to specialists in their fields. In our case, we want to apply our approach to a number of different fields. There will be outstanding speakers, but we have to convince people that it is worth looking at the subject from a broader perspective. The good news is that there are similar projects in Europe, in the Netherlands and in Germany. We will have a pre-conference, where graduate students from these other projects can exchange experience and ideas with students from the NCCR.
Is the conference a step to the European level?
Four years ago, the EU funded so called flagship projects. One of them was the Graphene project in Manchester, the other one the Human Brain project at the EPFL in Lausanne. These flagships have a budget of a billion euro. It seems that Europe will have a second round of such flagship projects in a few years. Our aim is to apply for the funding together with our partners in Germany and the Netherlands which would ensure the development of molecular systems engineering at a European level in the future.
In unique events the conference combines art and research. What is the idea behind this special mix?
It is about communication and ethics. We asked ourselves how we can talk about our research as it is quite complex for lay people to understand. One answer is to interact closely with artists and see if they can show their interpretation of what we do, and hopefully this would speak more to the public. We worked with artists hoping that they might rise interest in our research. Furthermore we can engage the public in a dialogue about ethical questions.
When will this dialogue start?
At our conference the argovia philharmonic will present a composition based on illustrations and videos we have provided them with. On the same day, we will also have a public ethics debate. We have brought in an editor of “Science” who will animate the debate and there will be three people debating. We hope one of them will be a bioethics officer of the Pontifical Academy for Life, the two others will be scientists.
What was for you the scientifically most exciting aspect of this NCCR?
When we started, we had a very broad approach and we had quite a number of curiosity-driven research projects. Without it, we would not have come as far as we did in these three years. For the second phase – we have just submitted the pre-proposal – we are much more focused.
What do you hope to achieve at the end of the NCCR?
If we only get one product in use this would already be a very nice achievement. Imagine, for example, that we could say: This NCCR has cured some forms of blindness.
Professor Thomas Ward, born in 1964 in Fribourg, is the director of the NCCR Molecular Systems Engineering. He heads the Ward Group at the Department of Chemistry of the University of Basel. The group’s research focuses on the exploitation of proteins as a host for organometallic moieties with applications in catalysis as well as in nano-biotechnology.
Ward studied organic chemistry at the University of Fribourg. He wrote his PhD thesis at ETH Zurich. He did a first postdoc with Roald Hoffmann at Cornell University in theory and then a second postdoc in Lausanne. He was then awarded an A. Werner Fellowship and moved to Bern where he obtained his habilitation. He moved to Neuchâtel in 2000 and to Basel in 2008. He was awarded a prestigious ERC advanced grant in 2016 and the 2017 Royal Society of Chemistry award in Bioinorganic chemistry.