Professor Wolfgang Baumeister from Max Planck Institute of Biochemistry in Munich, Germany, spoke to SciTech Europa about his work on cryo-electron tomography, macromolecular complexes, and visualising supramolecular architecture.
Structural biology and cryo-electron tomography
Professor Wolfgang Baumeister, a Director and Scientific Member at the Max Planck Institute of Biochemistry, Germany, focuses his research onto cellular machines called ‘macromolecular complexes’. Understanding how these complexes are structured leads to a better understanding of the processes taking place inside the cell. This has wide-ranging implications in chemical, physical, engineering, and life sciences – all of which are important to the work that takes place at Diamond Light Source, the UK’s national synchrotron facility.
Baumeister’s team developed a technique known as cryo-electron tomography (cryoET) in which samples are frozen to about -150°C before being measured at different angles to produce a 3D model.
However, perhaps what he is known best for is the fact that in 2000, his team succeeded in mapping macromolecular complexes in intact cells for the first time, which acted as a real turning point in proving the effectiveness of cryoET. Along with a host of other awards during his career, Baumeister was rewarded for his lifetime of pioneering research with the Ernst Jung Gold Medal for Medicine in 2018.
Here, he speaks to SciTech Europa about his work on macromolecular complexes and visualising supramolecular architecture.
Is there any single reason as to why you decided to focus your career on structural biology?
It perhaps began during my years as an undergraduate student. At that time biology was not a very modern science (by which I mean it was very descriptive). One day, I discovered in the institute an abandoned electron microscope, and went on to fall in love with electron microscopy.
Having been the Director of the Max Planck Institute since 1988, how would you describe the evolution of the available technologies?
The idea to do something like the electron tomography of unstained biological material had been around for a while when I began, although first attempts were rather non-impressive as much of the key technology was yet to be developed. For example, there were no frozen hydrated samples, cryo had not yet been invented, and image processing was at the very beginning – there was hardly any digital image processing back then; it was basically analogue optical processing which doesn’t take you very far.
When we started to do tomography, there was a lot of disbelief. It wasn’t just a matter of developing software to automate the data acquisition process but also knowing how to make the electron dose which the sample is exposed to acceptable. That required hardware developments. It may well be that we started a little bit too early, but just a couple of years later computerised goniometers and so on became available.
Nevertheless, it took some six or seven years until we could show that we were able to automate the entire process of data acquisition to the extent that the electron dose is tolerable to the sample. And then it took another couple of years basically to convince the community.
There is new potential even now to improve the entire workflow that is needed to make the best of electron tomography. It is not yet available commercially as it should be, namely in the form of a seamless and robust workflow. We are also waiting for an integrated workflow that will enable many cell biology labs to really go into the field of electron tomography; the entire workflow is still a very specialised thing can only be done at a relatively few places because samples are, for instance, too thick to be transparent to the electron beams, meaning that you have to thin them. This technology is not yet fully developed, so it remains a barrier.
Furthermore, cell biologists are not used to making huge investments such as those which are needed to do electron tomography. In order to have a full flat lab that can do cutting-edge electron tomography you need an investment of in the region of €10m, which is still a major hurdle for many institutes. Similarly, the running costs are also quite high.
You are interested in researching large macromolecular complexes. Can you explain what they are and why you are you interested in them?
Macromolecular complexes are simply assemblies of several individual protein subunits, which work collectively to achieve a certain task. It is very rarely that biological functions can be performed by, for instance, individual molecules, than by the interaction between many molecules. In the case of macromolecular complexes, they are drawn from many units which each perform a certain role.
The important thing is that many of the interactions which underlie cellular or biological functions exist only transiently, and so if we do what is normally done in structural biology – if we take a cell apart and purify all of the components – then we lose part of the information about the interactions, and that is key to understanding their functions.
This, then, highlights the importance of cryo-electron tomography – which allows a still image to be taken from which a 3D model can be created, thereby allowing these interactions to be visualised more than ever.
What else is special about this technique? Why is it so important to researchers like yourself?
Because traditionally structural biology deals with isolated purified molecules, and we then lose the information about the interaction networks that give rise to cellular functions, we want to get away from this extreme reductionist approach, which looks just at the building blocks, to get to the larger picture of their interaction in a functional cellular context. We want to bring structural biology (or, as some people call it, ‘structural biology in situ) into the context of the cell (others call it ‘structural cell biology’) which didn’t exist before.
Our goal is to eventually bring cellular structural biology to a similar resolution level to that which can be achieved in synchrotron particle analysis.
At Diamond, the eBIC facility is dedicated to biological research, with numerous of cryoEM and cryoET tools. What effect do you think that facilities like this will have on the life sciences and your own research? And what impact does making this more accessible have on the greater scientific community?
Accessibility for the larger scientific community will be its biggest impact.
In order to start a lab that can do cutting-edge research along these lines takes, as previously mentioned, a minimal investment of some something like €10m, and while that might be affordable for larger institutions, it cannot be achieved everywhere, and that leaves those teams out there who have interesting and challenging problems at a disadvantage; they need access to this technology.
Synchrotrons are a great place to host distributed centres which can do everything; they have the infrastructure, they have a traditional structure made up of visitors collecting data, and so when making the technology more accessible to the larger community, they really work.
What challenges have you experienced as Director of the Max Planck Institute when it comes to realising your vision of a workflow that stretches across facilities and perhaps even across countries?
20 or 30 years ago, the field of cryo-electron microscopy hardly existed. At that time, it was difficult to recruit outstanding young scientists. Now, cryoEM has become so tremendously popular that we are flooded with applications; there is a huge interest in this, meaning that it is much easier to find the visionary people required to make this happen.
So at the start, how did you go about finding the people that you wanted to be part of your vision and actually putting his building blocks in place?
The technology has always been driven by people with a background in physics, meaning that it was not a big problem for me as I am also a professor in the Physics Department at a technical university; I had access to very good students with a physics background to get the technology developed.
Even now, roughly half of our graduate students and post graduate fellows with a physics background are recruited into the lab. Yet, there is a good balance of those with a physics background and those who are driven by solving a biological problem.
Was this interdisciplinarity something you had envisaged from the beginning?
Yes, it was always the intention to be really interdisciplinary. As I have said, we have always had the best people from physics, chemistry, and biochemistry backgrounds join the team, and that has been a large part of the fun; we have even included mathematicians on occasion, too!
As I have mentioned, the technology is usually proven by people with a physics background; but it is very important that they don’t develop things in isolation when confronted with the real problems that come from biology.
At the recent American Association for the Advancement of Science meeting in Washington DC, you presented (along with some of your colleagues from Diamond) a session on ‘Cryo-Electron Tomography: The Promise and Challenges of Structural Biology in situ”. What did you talk about there?
I began with a brief retrospective discussion of the beginnings of Cryo-Electron Tomography, before talking briefly about the recent technology developments and what they enable, such as focused ion beam technology. I then moved on to applications and their implications, before focusing on the molecular machinery of protein degradation and intracellular protein degradation. I also mentioned some of my recent quite successful work on neurodegenerative diseases, where I am visualising the molecular architecture of neurotoxic aggregates inside neurons.
Is there any one sort take-away that you would like the average person to who is interested in science to get from the research that you have done throughout your life?
I am still fascinated by seeing and visualising supramolecular architecture because I think that is the essence that underlies biological functions. The fun is in using these technologies and being the first one to get a glimpse of this molecular architecture.
Professor Wolfgang Baumeister
Max Planck Institute of Biochemistry