Biochemist Bert Poolman: The Dutch Synthetic Cell

Biochemist Bert Poolman: The Dutch Synthetic Cell
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Wind turbines have replaced windmills in the North Holland farmlands outside Groningen, and Google now has a significant presence in the city itself. Otherwise Groningen looks like a page from Hans Brinker. One in every five residents is a student, many at the University of Groningen. It’s a culture where friends still share bike rides on the back fender. With cheese shops featuring shelves and shelves of wheels of exotic flavors from local dairies. And there are, of course, the canals for silver skates in winter. But inside the laboratories at the University of Groningen synthetic cell development is in progress---under the direction of biochemist Bert Poolman---which, if successful, could change the landscape far beyond this Dutch storybook setting (although it’s unclear just how). For now, Poolman says the goal is to better understand biology by bottom-up construction of a synthetic cell---”building systems, cellular systems, from molecular building blocks,” and he regards even a minimal living cell as “kind of a black box.”

I visited Bert Poolman in his office at the University of Groningen in late October. Poolman serves as program director of the Centre for Synthetic Biology and as scientific director of the Groningen Biomolecular Sciences and Biotechnology Institute. He also chairs the Membrane Enzymology group at Zernike Institute for Advanced Materials and at Groningen Biomolecular Sciences and Biotechnology Institute, in addition to his role as professor of biochemistry at the university.

Poolman and his team making a synthetic cell have recently been awarded €19 million by the Netherlands Science Foundation for their research. Bert Poolman is also a principal participant in the new Dutch Origins Center, which has received separate funding of €2.5 million.

Poolman’s research interests include synthetic cell development, i.e., “bottom-up construction of functional far-from-equilibrium systems”; bacterial cell-volume regulation; and traffic of membrane proteins.

He’s a member of the Royal Netherlands Academy of Arts and Sciences; a Faculty 1000 member; editor of the journal Molecular Biology; flagship manager of Synthetic Biology in the public-private research program BE-Basic, among other distinctions.

As a Fulbright Scholar a dozen or so years ago, Bert Poolman was a visiting professor in biochemistry at CalTech in Pasadena and before that a scientist at Genencor Inc. in San Francisco.

Other honors and awards include the Biochemistry Award of the Dutch Biochemistry Organisation; NWO Top-Go subsidy on membrane protein biogenesis; ITN-NICHE grant; ERC Advanced grant (partial list).

Bert Poolman’s PhD is in microbiology and his MSc in molecular biology and biochemistry---both from the University of Groningen and both cum laude. His undergraduate studies were in Switzerland at the University of Bern, with biochemical training at Medizinisch-Chemisches Institut.

Our interview follows.

Suzan Mazur: Are you starting from scratch? Jack Szostak told me in 2014 that he and his group were the only ones working from scratch.

Bert Poolman: There is a lot of labeling going on in synthetic biology: top-down, bottom-up. Here, what we call bottom-up is actually building systems, cellular systems, from molecular building blocks.

We don’t do the type of work let’s say that Craig Venter is doing, who is using living cells to make minimal organisms. We try to create life, molecular systems, by using well characterized building blocks and gradually increase the complexity [of the system] so that at some point we have a system that can grow, replicate and sustain itself.

Jack Szostak is also working from scratch because he uses---if you look at the membrane---he uses simple fatty acids to create membrane systems and determines their permeability and stability.

We use real lipids and more complex molecules, but we also include membrane proteins---channels and transporters---to catalyze the transport across the membrane so that we can also build up gradients. Our membrane systems build up osmotic pressure, like current living systems do.

So let’s say his [Szostak’s] molecules are a little more primitive than the ones we have, and they may relate to the ones that may have been at the origin of life. We take, in principle, any synthetic molecule as long as it has, say, properties that support the embedding and function of transport proteins.

Suzan Mazur: Why are you developing a synthetic cell?

Bert Poolman: The reason for us is basically to better understand biology. In making a minimal cell, you could also make it simpler and try to better understand what is needed. But we find that even a minimal cell is still very complex. It’s kind of a black box.

What we try to do is build up a cell-like system by working with fewer components. We then try to understand and to model all the interactions and reactions taking place so we have better control over our system. Of course, you’re then further from a system you could call “life.”

Suzan Mazur: I noticed in an article that Dutch Origins Center manager Jan-Willem Mantel sent me that you actually define life. Would you repeat your definition for “life” and let me know whether you think it’s important to have a consensus on what life is?

Bert Poolman: This is a tricky question. I’m not claiming I have a definition for life. However, we have a working definition for life in the context of what we are doing---building systems---which is: A system that can grow, replicate and sustain itself.

Suzan Mazur: Once you make your synthetic cell, it can only exist within a certain medium?

Bert Poolman: Yes.

Suzan Mazur: This is not something you want to make to send into space, to Mars?

Bert Poolman: I don’t know what I want to do in 10 years or so.

Suzan Mazur: Is that feasible? It would have to be kept in that same kind of environment.

Bert Poolman: For now it is a system that is contained in a specific environment.

Suzan Mazur: But you don’t know what’s going to happen until you’ve finished building it?

Bert Poolman: We’re building it on the basis of components we know. But, of course, components you know, if you put them together, may give emergent behavior that you would not have predicted.

But this is also one of the things we are looking for in order to understand biology in depth. You can do it in two ways. By studying living systems or by trying to make things, systems that have properties of life-like systems.

So, for instance, we also divide our work into modules. One of the modules is a metabolic processor. This is, in fact, the part that I’m mostly involved with---the self-organization of components, catalysis and confinement, transport of food and waste, and making a fuel system.

Suzan Mazur: Self-organization is the tricky one? It’s not really understood at this point.

Bert Poolman: No, but if we take simple vesicle systems, you can predict what you will see. That they are bright spherical structures. We can put skeletal structures in. One of our collaborators is reconstituting skeletal structures---and you get these invaginations. This is, of course, what you need for division.

We make sure that ATP is made. If we combine these two modules, we then have a system that can already basically produce two vesicles from one.

Suzan Mazur: How close at this point are you to making the synthetic cell?

Bert Poolman: We’re still decades away. This has to do with the middle part, what I call information processing. The most difficult aspect is probably protein synthesis, because protein synthesis involves more than 100 components. And to build a ribosome in vitro, from scratch, that is an enormous challenge.

So information is stored in DNA---although it could also be something else---it doesn’t have to be DNA. We need to replicate it because that’s something necessary for life. DNA is replicated to make a copy of itself for the daughter cell when a cell divides. But DNA also needs to be decoded or “read” to make new proteins. The process is one in which DNA is transcribed into RNA, which is then decoded by the ribosome to synthesize new proteins. This is something that all living cells do and that we try to reconstitute from molecular components, which is extremely difficult because of the many molecules involved, their complex assembly, and lots of processes we do not understand well.

Suzan Mazur: Albert Libchaber predicted in 2014 when I spoke with him for my book on origin of life that Vincent Noireaux---his former postdoc who has his own lab at the University of Minnesota--- would have a minimal cell within five years. And Jack Szostak announced at the 2014 World Science Festival in New York that he’d have “life in the lab” within three years. So far it hasn’t happened.

Bert Poolman: I know Vincent quite well. We collaborated in a paper.

I would say five years is very optimistic. But Vincent’s definition might be different. Vincent starts from pre-assembled ribosomes that he isolates and then he puts things together to synthesize protein.

But until he can do protein synthesis and have the same machinery make itself and make the ribosome itself---and the ribosome is very complicated. It’s not just protein, it’s also RNA---to make that cell and to let that fold into a new functional machine, I think that is still a very long way to go and will take more than five years.

Suzan Mazur: But it does seem to be moving along. There’s a ramping up of origin of life research and synthetic cell development. Is the interest real or is this just a way to dabble in basic research and get funded? Dieter Braun, also a former Libchaber postdoc, mentioned to me in our recent interview that a whole new breed of scientists has entered the origins field who are experimentally-driven. No more fishing expeditions.

Bert Poolman: I think the interest is real. The is due in part because certain things are now possible that were not possible in the past.

Suzan Mazur: What wasn’t possible in the past?

Bert Poolman: At some point we also need DNA to code the systems. The making of synthetic DNA has gotten quite a boost with the minimal genomes that Venter’s institute has developed.

The other thing is we can make observations now in a single cell or even at a single molecule level. If you think about the Nobel Prize a few years ago in chemistry, that was for super-resolution microscopy. Super resolution microscopy means that you can observe molecules in living systems with a resolution far better than conventional microscopy.

Suzan Mazur: The tools have improved.

Bert Poolman: The tools have improved in terms of microscopy, also in terms of analysis. If you think of mass spectrometry, the cells that we make are very small and the number of molecules that are on the inside are so small that you need very sensitive equipment to see what is going on. Mass spectrometry has improved tremendously. Super-resolution microscopy, mass spectrometry, synthesis of DNA, to name a few.

Furthermore, researchers from chemistry or true physics have entered biology in the last 15, 20 years, bringing with them their important skills and methods that have boosted the field further.

Suzan Mazur: With the coming together of the sciences, is there a need for a new language to replace obsolete terminology like natural selection, etc.

Bert Poolman: For me it’s a non-issue right now, the terminology.

Suzan Mazur: How many scientists would you say are now involved in synthetic cell development in The Netherlands and worldwide?

Bert Poolman: We received a grant of €19 million from the Netherlands Science Foundation last summer for our synthetic cell development project. The award went to 15 working groups---15 groups working in this area is substantial. We will probably appoint 70 to 80 PhD students. But some of our labs also have national grants and so the 15 groups could each include 10 to 20 researchers.

The 15 PIs [principal investigators] have already individually been working on aspects of synthetic cell development. But for the first time there is proper funding for tackling larger scale problems

Suzan Mazur: Where are the synthetic cell development labs? Here in the Netherlands; in the UK—John Sutherland and Matt Powner; in the US Jack Szostak and the Simons Foundation collaborators and Vincent Noireaux in Minnesota; Tetsuya Yomo now in China---

Bert Poolman: There is a parallel program to ours in Germany. Dieter Braun is part of that. There are groups in Switzerland.

Suzan Mazur: ETH.

Bert Poolman: Yes, ETH.

Suzan Mazur: How much money would you say is involved at this point---$100 million or so?

Bert Poolman: Probably around there. But five years ago it was virtually nothing. Yes---$100 million is substantial but only a fraction of what we will ultimately need.

Suzan Mazur: Your connection to the Dutch Origins Center is what at this point?

Bert Poolman: The previous government wanted to give the general public more say in the direction of science. It asked the public to submit questions and among the questions that kept coming up were those relating to origins of life. People had a strong interest in finding out where we come from.

Suzan Mazur: Is the Dutch public okay with synthetic cell development?

Bert Poolman: The majority of people responded positively to that. Of course, there are always some people who worry we might create Frankenstein-type monsters. But the public is very enthusiastic about arriving at a better understanding of origins of life. It was brought up so many times that we said let’s organize scientific teams who have an interest in the origins field---from geologists to biologists to astronomers to mathematicians, chemists and physicists. We also have philosophers participating.

We created the Origins Center as a virtual center. We got a little bit of money---a few million euros--- that’s being used mostly to organize ourselves within The Netherlands and to set up programs of collaborative research.

Suzan Mazur: Do you have any tie-in to Google and its computer system? I understand Google has a substantial presence here in Groningen.

Bert Poolman: Within our synthetic cell development program, which is separate from the Origins Center, people from Google are involved but this is mostly coincidental I would say.

Computer power is very important for us. We also have many people here who do large scale molecular dynamic simulations, to simulate a cell. That of course requires a lot of computer power.

The amount of computer power we need is high but it’s relatively small compared to what Google is now setting up in terms of facilities here for data storage. And it probably is relatively small compared to what the astronomers here are using as well.

Suzan Mazur: You’re doing both bench and computer chemistry?

Bert Poolman: My group is an experimental group. But one of my colleagues here is entirely computational. We collaborate a lot.

Often in computational studies you need to develop force fields and models and those need to be tested. My group sometimes tests those models so that they can be further built. In turn, we have experimental observations that are somewhat of low resolution, and we ask for help with computational simulations.

There’s an intimate interaction among computational people here at all levels---from quantum mechanics, atomistic, to mechanics.

Suzan Mazur: Seems like everything is going computational. Every scientific field is going into quantitative analysis.

Bert Poolman: Yes. There is some resistance and reluctance to it in some sciences, however. Of course, you cannot capture everything in a model, in an equation.

Suzan Mazur: Does the information that’s emerging on viruses at all affect your thinking about how evolution works?

Bert Poolman: Viruses are very good at self-assembling. A lot of what we do can be based on things that originally came from viruses, but work on viruses is not per se important for what we do.

Suzan Mazur: There are spinoffs possibly resulting from these investigations, useful in medicine, etc. You’re thinking along those lines?

Bert Poolman: We always use drug delivery as an example because the systems that we develop, can do sophisticated things already. We can already sense the environment. We can do catalysis in confinement.

Ultimately, if we understand the system, we can build it the way an engineer does---the way they build devices. Engineers can draw things on the drawing table and probably it will work the way they want. This is still our dream. We are far away from that with synthetic cell development. But once we are there, I would say the applications are limitless.

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