In this episode my guest and I discuss the beautiful alchemy that is metabolism and how it can be used to accelerate sustainable bioproduction. Joining me is Jan Krüsemann, a postdoctoral researcher at the Institute for Biochemistry in Berlin and an all around interesting and lovely person. We chat about metabolism being not merely a biological process but also a sophisticated mechanism through which life transforms various substrates into energy and essential biomolecules. We discuss how enzymes, the catalysts of metabolic reactions, facilitate these transformations, enabling the efficient use of resources in nature. We then touch on the ways in which evolution builds systems like metabolism and why that limits their usefulness for biotechnology. That is until we view metabolism not as fixed pathways but as a toolkit with which we can create new things.

We then examine the potential of utilizing these metabolic processes to construct a sustainable circular economy that minimizes reliance on fossil fuels and harmful industrial practices. The conversation also touches on the innovative approaches being developed to harness the capabilities of metabolic pathways, emphasizing the necessity for a paradigm shift in how we view bioproduction and resource utilization.

Takeaways:

• This podcast episode delves into the intricate relationship between metabolism and sustainable bioproduction, highlighting how enzymatic processes can reshape industrial practices.
• Our conversation with Jan Krüsemann elucidates the innovative approaches researchers are employing to leverage metabolic pathways for a circular economy.
• We explored the concept of metabolic mimicry, where bacteria are designed to produce desired compounds while maintaining their growth balance, offering a more sustainable production method.
• The discussion emphasizes the necessity for a paradigm shift in how we perceive and utilize biological processes, advocating for a harmonious coexistence with nature instead of exploitation.

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  • How growth-coupled selection could rebuild metabolism
  • Jan Krüsemann: Institut für Biochemie - Charité – Universitätsmedizin Berlin

What is up, Brad fans, How you doing?

How you living?

My guest today is Jan Krusmann, a scientist postdoctoral researcher working at the Institute for Biochemistry in the Sherite in Berlin.

He is also part of a larger group of researchers in a field that I've been following for a while now that is all about using metabolism, metabolic reactions to make stuff to build sustainable circular economies using bioproduction.

And we'll get into what that means and a definition of metabolism in the conversation.

But in short, metabolism is how all life on the planet takes the things that it consumes, sunlight, sugar, carbon, other plants and animals, whatever, and turns it into energy and the proteins and molecules that make up their bodies.

So it's really this beautiful alchemy when you think about it, a powerful way in which nature has evolved to transform matter into energy and the molecules that make up life in a way in which life can use energy from the breaking of bonds or store energy within these chemical bonds.

And to do all of this amazing stuff, there's a fascinating class of molecule called enzymes.

They're needed to mediate these reactions because many of them would be highly energetic, would release so much heat that it could burn up a body, for example, or they would just take forever to do.

But enzymes buffer and assist the reactions.

And enzyme design is actually very interesting.

And we're now using enzymes to do different things in industrial chemistry.

This is another offshoot of this research that we don't even get into today.

But it's a field that's rapidly developing because of our ability to design proteins and enzymes with AI and other software.

But when it comes to bioproduction, using biology to make stuff instead of industrial systems based on fossil fuels, humans have actually been doing this for quite some time.

Fermentation is probably the most well known example where you use yeast to break down sugar to produce ethanol or some other metabolite.

But in terms of current, let's say large scale bioproduction, there are some narrow uses right now, some narrow markets where bioproduction is used to make pharmaceuticals or precursor molecules for some other production process, maybe some detergents, things like this.

But this field that I've been following that Jan is a part of is about doing more with metabolism.

And I actually first met Jan while writing an article that will be linked in the show Notes about his former supervisor and mentor, Aaron Bar Evan, who had a unique way with metabolism and believed we could do so much more with the enzymes and reactions found in nature, or that we are now able to design ourselves a lot of current Bioproduction is based on sort of trouble tweaking what nature has already evolved using the chemical reactions, the metabolic reactions that exist in nature.

And bar Evan and now Jan and many others believe that these reactions are not fixed.

And by using the components of these reactions as a toolkit, entirely new reactions and things can be made meaning.

If we want to go from molecule A to C, how can we get there using these tools rather than relying on what nature has already evolved?

And this is very powerful because as Jan and I discuss, nature doesn't work this way.

Evolution doesn't decide on a goal and then find the most optimal solution for that, but we can.

Nature rather is iterative.

It builds up patchworks of updates and sidechains that deal with new environments or conditions just well enough to keep the organism alive.

But again, humans as rational designers can take these tools and use them to make new things.

And that's what's exciting to me about this field and why I'm interested in covering it.

I'm also interested in this technology because I think it's one of those fields that has the potential to really transform the our ways of life for the better.

Similar to the guest on last episode, Rachel Armstrong, this technology also says we can utilize more of the resources that naturally occur around us without the need for extractive or harmful global industrial processes based only on fossil fuels.

As Jan describes it, he's attempting to build the technology to replace the the old way so that when our politics and our economics finally catches up, we can say there is a viable system in place to switch to and this new system is more sustainable, works better with the resources we have to produce the things we want with less waste, without needing harsh reagents or a ton of energy from burnt fossil fuels.

So this is a really great conversation and a super exciting field, again, from the tech standpoint, the genomics and the biotech that goes into this, but also from a scientific process or philosophy standpoint.

And by that I mean people are being very clever about the experiments they run and the technological solutions they're trying to achieve.

There's a real art to this.

There's a real creativity to it.

And that gets covered in the article I wrote about Jan's supervisor, who perhaps his greatest gift was his ability to see how to use these tools in a very clever and unique way compared to what everyone else was doing with him.

So again, it's a great representation of the creativity that's involved in science.

And another one of those what ifs we've talked about previously what if we just thought about metabolism differently?

What if we just tried to do something new?

What if we could replace the old with something better?

And as always, before we get to.

The conversation, please, like, subscribe, follow, review wherever you are, seeing or hearing this, it really helps a lot.

And now my conversation with Jan.

Thank you so much for taking the time to join me today.

It's a pleasure to see you again.

How are you?

I'm really good.

I just got home from a wedding in Poland and a lot of sun, a lot of nice people, good food.

So really relaxed.

All right, well, ready to get back into the lab, I'm sure.

And that's.

Yeah, let's start here.

We've spoken before.

I interviewed you for a story that I just wrote.

It'll be out.

We'll link to it and stuff in the show notes.

But your work involves metabolism, synthetic metabolism.

And I think it's your supervisor, Stefan.

He really got me interested in this whole field.

And then we worked on this article together about your former supervisor, Aaron Bar Evan, and his ideas and what we can do with metabolism.

And there's a lot going on here.

It's a very fascinating topic.

So I wanted to bring you on the podcast to elaborate on this for my audience.

So I think maybe the best thing to start with is just what is metabolism?

How would you define it?

And then we can go into sort of the science that you're doing from there and how you got interested into this topic.

I think people have heard of the word metabolism, but maybe they don't think about it beyond something that our body does.

So how would you define this thing that all life does?

Metabolism?

I mean, it's basically magic to me, too.

It's the way of biology to control catalysis.

So thermodynamics defines what reactions are possible, what compounds can be turned into each other and at which ratios they then exist.

And metabolism is then what happens if you throw enzymes into this mixture, because these still have to adhere to the principles of thermodynamics, but they can suddenly speed up processes that would normally take thousands and hundreds of years.

And they have adapted over time.

And so when I think of metabolism intuitively, what I always think about is a map that looks a bit like a roadmap that is also attached to every empty space in our lab where you have certain inputs, carbon sources that then go via this roadmap.

And at each intersection of this roadmap sits an enzyme that kind of turns a metabolite into another one.

And this is what here Metabolism.

What I think of, which is really interesting because sometimes I'm maybe I'm finding out something about myself or during sport and I realize that.

Yeah, yeah, true.

I also have a metabolism which is very complicated and that's what people usually think about this kind of human metabolism.

But when I hear metabolism, I think of this like, magic way of.

Yeah, bending catalysis and, and like really always this visualization of this roadmap of metabolism.

And it's really like, I think when people hear metabolism outside of like the scientific context, they think exercise, they think their weight.

You know, some people, oh, I have a fast metabolism, I have a slow metabolism, but.

And that kind of scratches the surface because really, like, for me, my understanding was, okay, metabolism is how life takes, you know, its inputs.

So, you know, plants take sun and sugars and the things they get from the soil.

We eat things, carbon basically.

And metabolism is what transforms that into our energy and like the stuff that makes, makes us right.

So it's like this really, it's like this life giving sort of things.

Not to sound too, you know, spiritual about it, but it really is.

And you mentioned a couple words there, catalysis and enzyme.

And I think these are important ones that we should probably unpack as well.

So catalysis, when you say catalysis, what is your, what are you talking about in this chain of, you know, how, how organisms take the things that we ingest and turn that into energy and, you know, the stuff that makes up our bodies.

How does catalysis play a role?

And then enzymes.

So I'm a biologist.

It's very important to note there might be chemists in your audience who listen to my definition and be like, actually so a small disclaimer.

I have a very intuitive understanding of catalysis and of metabolism, which is kind of arose anecdotally from the different projects that I've been doing, focusing on different angles and special islands in metabolism.

But catalysis really to me is this change of one substrate into another and at an increased rate.

So it's already a very, probably a very biological view at it.

But to me, when I think catalysis, I never think catalysis without an enzyme.

It's always, I always imagine, directly think of enzymatic catalysis, especially because most of the chemistry that I think of is organic chemistry.

And so I think of an enzyme that through interaction with the different metabolites manages to somehow create a certain molecular tension that then speeds up the catalysis of a process that usually happens maybe very Slowly, if you just put everything in a bucket of solvent or water.

Yeah.

So catalysis is really the changing of one thing to another and then the enzymes come in.

Because this, and this was something that blew my mind.

I mean, I think I found this out like relatively recent in my life, which is, you know, let's say a couple, five, six years ago, but I had never really thought about.

I also studied biology, but more ecology and more in a broader, a bigger picture rather than the sort of, this sort of chemical nature did a bit of genetics and stuff like that.

But these reactions that happen in our cells, like all the time, they're happening all the time in our cells to create energy, you know, to take carbon and change it into these different things.

Some of them, as you say, go slowly, but some of them also release a lot of energy.

Right, like that.

That could be like lethal.

Like it cause an explosion in a lab or something.

And that's why you have these enzymes that moderate these reactions.

If I'm correct, you could jump in and correct me if I want.

They speed things up, they absorb energy.

They do these things that allow your body to do things that, yeah, in a lab would be incredibly difficult and incredibly complex.

Too much energy take too long.

And so these enzymes are these really like amazing class of molecule that life has evolved to do these reactions.

There's two really interesting images there.

Like, one thing that we also learned I think very early on in our biology bachelor was when you take a cube of sugar and you light it on fire and it really burns and the same energy gets released when we eat that cube of sugar and our body metabolizes it just at a much slower rate and much more controlled.

Where the energy is in the best case, not just freed as heat, but instead stored in chemical energy.

And also our body releases heat because even though we managed to store quite some energy in chemical energy, which can then be used in a later process, we still release some heat.

So a view on our body could actually be seen as a huge AC for our mitochondria because the fact that we are at 37 degrees or kept at 37 degrees is only because we are cooling the energy producing process of our mitochondria, which actually would heat up much more if we weren't cooling them actively the whole time.

It's like you hear these metaphors for the mitochondrion stuff like the power plant of the body or of the cell, the powerhouse, the engine, all these things.

And we think of those things and those things all produce he and it's the same.

So it's like you really do have, like, this biological furnace going on in your.

In your body that.

And then you need all of these, you know, chemical reactions, these enzymes, these different things to buffer that and then contain that, but also to capture that energy, right?

Like, that's the energy that's released from some of these reactions gets stored in other molecules to then be broken apart and released and to do other work.

And it's really, it's quite amazing when you think about that all of this is going on every single cell of your body all the time.

Yeah, yeah, absolutely.

It's completely fascinating.

I managed, luckily still to still sometimes stop and just look at the kind of metabolism that I change with my work, but also as just nature made it already and it never stops to fascinate me, honestly.

Yeah.

And so then this is like, you know, this is the progression as we move towards.

So there's this fascinating thing that, that, that nature has evolved, right?

And it's, you know, animals, we have our version of it.

Plants have a sort of different version.

It's doing the same thing, but they use different molecules, they use sunlight as an input, you know, all of these things, photosynthesis.

So life on this planet has figured out how to use these reactions.

And the idea that enzymes evolving like that, to me is just because the enzymes are so key here, right?

Like, you can't.

You can't contain the power of these reactions and, or the speed.

You know, you need to speed them up, you need to slow them down.

You can't do that without enzymes.

So the fact that these reactions exist in nature, if you put these things together, you know, in a.

In the right conditions, they will react, the molecules will react.

But then that evolution found a way to add this side component is amazing.

It's pretty incredible.

So then we have.

We can look at it as scientists and say, okay, look at this amazing web of things that are going on.

Well, what can we do with it?

Like, how can we, how can we use this?

How can we tweak this?

And this kind of gets a bit more to the applied stuff that you do.

So what was your first, you know, introduction or that sort of light bulb coming on moment where you were like, oh, this is really fascinating from, like, just a biology standpoint, but also then the sort of, let's go further, let's explore this.

What can we do?

What gave you that spark?

Why do you now do what it is that you do?

First, one note on enzymes, I think that's also Always really important to say.

You mentioned already Aaron, my basically sub supervisor, he wrote a paper already I guess 15 years ago, which is called the Moderately Efficient Enzyme.

Yeah, because how enzymology is taught is usually that.

Exactly.

These are these like miraculous machines that operate near the metabolic speed limit and they are like these.

Every enzyme is perfect and it's super amazing how it works.

But that is really not the truth.

There's, there's some outliers that are really efficient and that kind of show what enzymatic catalysis can in theory achieve where, where they just catalyst catalyze reactions at an insane rate.

But then these are mostly the outliers and we, with a lot of research, we focused on those in, in central metabolism.

Enzymes that have to carry a lot of flux.

But often for nature it's good enough if the enzyme works a little bit.

And then this also brings me a bit there.

Then there is also not much need for nature to optimize it further.

It only needs it as good as it is.

And if there's maybe a special component that is produced, let's say an odorant or so, the enzyme doesn't need to be as efficient as one thing that supplies energy to the cell which has to carry as much flux as possible.

Good enough to get the job done and keep the organism moving, keep it alive.

Yeah, yeah, exactly.

And that also then brings up this curiosity.

Well, it's a curiosity but also a need because now at some point we want to use enzymes for industrial processes and then we need enzymes that are just the best catalysts possible.

And so now then we need to start optimizing those suboptimal enzyme and see if we can somehow improve them because they were not evolved to fulfill the needs that we ask of them.

But that's maybe already I'm a bit teasering the, the later stages.

You asked more about the, the entry point.

Yeah, sure, sure, yeah, yeah, because, but I think that's a good point to make because.

Yeah, and I get lost in this too, you know, and I think people do as well, you know, this like the power of evolution and you, and we think of it as like this, this really optimized, like life.

It must be so optimized, you know, to do this, this.

It's incredible, you know, like it's, it's so mind blowing, right.

That evolution could even produce something as complex as you and me and all this stuff.

But in fact it is quite a sloppy process.

Right.

Like it's, it's just, it's iterations and so it's.

It's.

And sometimes, you know, when the environment changes and the organism has to adapt to that, it just sort of glues on another.

Another, you know, side reaction or side piece or something to solve that problem.

But it's not the most efficient way that you would like, if you were a rational designer, you would like, maybe do it a different way.

Right.

But it's just this sort of cobbling together of things that kind of work good enough to keep the organism alive and keep it going, which is beautiful in a sense as well, you know.

Absolutely.

I have a very nice analogy.

I learned this in my bachelor in Biology, which helps to understand also why then sometimes kind of suboptimal systems and why.

Why this is the outcome of something so beautiful like evolution.

Because it is really only stepwise.

And the analogy is our keyboard.

So the keyboard that everyone uses around the world, there are small adaptions, right.

Between English and German, for example.

But it is.

It was developed at a time where typewriters were existing that had, like, these little.

I don't know what they're called in English.

Like the hammer.

Yeah, the hammer, exactly.

And so at the time, it was very important that letters that are coming often close together, in a word, that they would be separated on the keyboard so that the hammers wouldn't get stuck.

The typewriter was invented, and it was a revolution.

Right.

Everyone would get trained on this.

And already within, I think, 10, 20 years of the first typewriters being rolled out and the keyboards being optimized to work with the typewriters, it got an upgrade, which was a ball now that turned and would print the letters, and you wouldn't have the hammers anymore.

And this ball could have allowed for a completely different keyboard because you were not constrained anymore with the distance of the hammers.

But all the secretaries in the world were already trained on this keyboard, and it would have taken them way longer to change to a new keyboard than just staying with the same keyboard.

And today, mostly what we do, or a lot of the texts we write are even with our thumbs on a touchscreen, where it is even more absurd that the design of this keyboard was basically determined back then when it was about not hammers, not getting stuck.

Right?

Yeah.

And that is exactly what evolution does.

Right.

Like there could be, if we were now, today, to develop a keyboard, we could come up with such smart ways of organizing it so that a thumb can reach the letter as well.

But what's the point?

Everyone knows how the keyboard works.

And we learned how to type with 10 fingers.

And making this step requires much more effort than just maybe smaller steps of maybe separating the keyboard on your touchscreen or something and adapting.

And that's exactly what evolution does.

Like a really nice example is Rubisco.

So it's the enzyme that performs about 99% of carbon fixation in the world.

It's all in the end.

And that all plants have trees, some plankton also have it.

And this enzyme evolved at a time when the CO2 concentration in the air was about 60 to 70%, 2 billion years ago.

And then something happened which was the great oxygenation event.

So a lot of carbon from the air got fixed, and basically the plants made their lives very difficult themselves and they kind of took all the CO2 from the air.

And now our CO2 concentrations are 0.005 or.

I don't know exactly rising for sure, but way lower.

So now this enzyme has a problem already since a couple of thousand million years.

But now this enzyme has a problem because it has a side activity where it doesn't just grab CO2 out of the air and converts it, but it has a side activity with oxygen.

And now the oxygen concentration is much higher.

So sometimes it performs a catalysis with an oxygen atom and not a CO2.

And what happens then is it makes a toxic byproduct which costs the cell a lot to recycle and so on.

So it is estimated at about 30% of energy loss occurs because of the site reaction, which was not important at the time when it evolved, but now it is a problem.

And so what does nature do?

It doesn't do a big step and invent a new enzyme.

No, because all the rest of metabolism is already fixed around this key CO2 fixating reaction.

So it has to come up with other ways, maybe better detoxification mechanisms, increasing the levels of CO2 keeping out, like maybe making organelles that kind of keep out the CO2.

So a lot of tinkering around, exactly what you said of patching kind of updates on the thing, instead of saying, no, I throw out my computer and I get a new one.

Yeah, yeah, yeah, yeah, yeah.

It's fascinating.

And I guess this is, again, it's leading towards this idea then.

And maybe this is a good place to sort of, before we get into your inspiration and your path on it is just to say, people, we've.

Humans as scientists and engineers and whatnot, have realized that we can use these processes, we can use some of these reactions.

Right.

And so this is bioproduction.

And you mentioned it we can start to use enzymes for industrial processes.

So taking what we normally do with fossil fuels, we take carbon from that's stored in fossil fuels, and we make plastics, we make fuels, we make pharmaceuticals.

You know, we make everything with this.

Well, what if we can do that in a cell?

Like, the cell is doing these things, it has the components to really change matter, you know, to take carbon and change it into different things.

So then people had the idea, well, what if we, what if we direct the cells to kind of build the things that we want?

And that's already a very complicated thing to try and do.

But that's sort of the avenue in which you and your colleagues are working is this, this bioproduction.

And, and then I guess this is where you can maybe describe your interest in it, what got you into it.

But then also.

Sort of.

Well, and then maybe we can get into.

Yeah, like, you know, there's a tinkering with what nature has already done and then there's this optimization and then there's making something brand new, which is exciting.

So, but let's get to what was your introduction to this topic?

What made you sort of say, this is what I want to do, this is what I want to focus on.

So in general, I'm just super fascinated by biology.

I'm epicenter.

Say we make the difference between rubber boot biologists and lab coat biologists.

Yeah, right.

I was a rubber boot biologist.

Exactly.

I'm also total rubber boot biologist by heart.

Like, if I see a, a forest somewhere or a stone, I look under it, I investigate the bugs.

I get absolutely fascinated by all of this.

And so I did this rubber boot biology bachelor where we went out and did ecology and all these things.

And then only by chance, and maybe a bit of trusting my gut, I got into this bachelor thesis where I would work on synthetic biology.

I can't even say anymore what was the exact reason.

I mean, back at the time, I was not at the stage where I would read papers and inform myself.

I mean, I was a little party animal in Berlin.

And so I, I somehow, via friends, got this, got this contact of someone who did a bachelor thesis at an Max Planck institute in this group of this guy.

And it was apparently fun.

I was like, all right, I apply.

And that then changed everything because I got into contact really with synthetic biology, got fascinated by this idea of not just studying biology, but also taking the parts and building it together in a new way.

And all the ways this allows you then even to circle back and do basic research because you create Maybe setups where enzymes perform jobs that they usually don't.

And then you see, ah, they can actually do this.

It was just never found out with conventional methods.

And it was also just this feeling of I had my own project which I could work on very independently.

And this feeling of suddenly you're not just doing a task with a predetermined end like in, in the Bachelor, but you're actually advancing human knowledge.

That was something so fascinating to me.

And that, yeah, I don't know where.

What I would be doing now if I hadn't taken that bachelor thesis.

But I got completely hooked.

I mean, I did a little detour for, to Zurich for my master, but then I knew immediately I want to.

Want to go back and do also my PhD in that.

And that's really.

Yeah, what, what continues to fascinate me, this looking, not just looking at metabolism and saying, wow, nature did a good job.

Cool, let's study this.

But thinking like, how can we do this better?

Almost a bit this like human audacity of the hubris.

Yeah, yeah, exactly, exactly.

But yeah, it's not, it's not per se better.

It's more like more fit to our needs in a way.

Yeah, I think that's the kind of.

Again, it's really the way that I see it or the way that, you know, when you talk about it and other people that I've, in your.

Your colleagues and stuff that I've talked, it's.

To me the best sort of way that it fits in my mind is that it's like once you realize that biology has these tools, right?

They have tools to do reactions, enzymes, catalysts, all of these things, right?

It's then just saying, well, rather than viewing them as this is the pathway, you know, but a cell can take this and it can turn it into this.

If I delete a gene here or I delete a gene there, maybe I can get it to sort of, you know, make a similar compound.

But it's all kind of within the same thing.

But if you look at these things and say, no, this is a toolbox, and then challenge the question or, you know, pose the question, this is what I'm starting with, this is what I want on to end with.

What tools can I use to make that transformation, to make that chemical transformation?

And then it's a process of discovery, trial and error optimization, all this stuff.

But it's really this sort of.

Once you kind of just change your mindset to say these, these are the tools that are available now, pose the problem and here's the tools, I think, of that.

I don't know, this is an old movie now, but Apollo 13, you know, the, the with the spit there, the spaceship going to the moon, and they have all these problems and stuff.

But basically the.

The NASA engineers said, like, this is what's on board this.

This is the tools we have to fix the problem.

This is all there there is on the capsule, on the space, on the.

The lunar lander or whatever.

Figure it out.

This is what you have.

Figure it out.

And I think it's kind of the same thing because it's like this is.

These are the biological enzymes we have.

What can we do with them?

Yeah, yeah.

I mean, sometimes what we even do is we even outsource this task.

So what we.

It's like the core of our work is to make evolution work for us.

So we.

Depending on the exact experiment.

But what we sometimes do, we are the NASA engineers and we say we create a kind of status or like a setup where only a specific enzyme can survive.

A specific optimized enzyme, right?

And then we put our cells that have maybe different variants that have maybe a mutagenesis tool or something, put them in a container and let it rest and, or like rest and shake or whatever.

Right.

But basically let evolution happen and screen all the potential options that you cannot really think of in your brain and let evolution figure out with the tools it has to get to the solution we want.

That's actually, then we really try to be.

To be in this position most of the time where we have to define the right settings that then gives rise to a certain property.

And we don't have to figure out the way, but we let really the beauty of evolution and nature figure out the way there because it is just so much better at sampling.

Yeah.

Yeah.

And this is, this is the other thing that I found really, really interesting when diving into this world is that that's exactly it.

And it's so.

It's like setting the table, like building the machine, or machine, maybe not the right word, but yeah, you set the conditions for the cell that.

It's like in order for you to survive, you have to do this thing that, that I've decided that I want that the outcome that I desire.

But then you just give it all of these different tools, enzymes, options, and say life will figure it out because really that's the.

It's.

It's like water running down a hill, right?

Like, it will find.

It will find the path of.

Of least resistance or, you know, the quickest Way to, you know, get it done, right?

Because the cell life wants to live.

And if, if those are the conditions it will evolve to do it.

And then kind of takes away a lot of the trial and error work for you guys.

The question that I have, and this is maybe kind of loops back to what you're saying, because you can do.

You end up doing basic research.

So you have a.

You have an applied problem that you want to solve.

I want X product, or I'm trying to make X chemical or whatever.

I give the conditions and I let the cells evolve their way to that solution.

But then there's kind of this black box, right?

Like this mystery.

Like you don't really know how the cell did it.

You could kind of go back and maybe start to tease it out.

But these are very complex reactions and enzymes involved and all this stuff.

So what would you.

What's your comment on that in terms of like, it's.

There's a.

There's a balance of getting the solution you want, but then also understanding how you got that solution.

Because it's a bit of a mystery sometimes.

It always starts as a mystery.

And often it feels like detective work.

But it is an essential part of our work also.

We call it reverse engineering.

First we let nature figure out a way, then we have a solution.

And what we then usually do is we send our.

In this case, it's bacterial strain, usually that then can perform a certain task or has an optimized enzyme.

In the best case, we send it to sequencing and we find out all the different mutations that nature has made.

And because it is such a stochastic process, there will be some in there that are not essential for the new ability that maybe just by accident happened.

So what then the cumbersome task is to maybe in a strain, insert single mutations, compare them.

If we don't find the desired ability, try to try to compare them.

Also of course, with the available literature, with our available knowledge of the different enzymes, come up with hypothesis then and kind of test them.

Because you will never be able to just publish a result by just saying like, yeah, evolution found its way.

We don't know how it works, but it works.

Trust us, it does it.

But whatever.

Yeah, exactly.

So.

So a lot of the work that our everyday lab work is actually this detective work of having a strain that maybe does something now and figuring out how it does it.

And that is then what comes back a bit to basic research.

Because often the ways the cell finds.

And we're working with E. Coli mostly, which is the Best studied bacterium on the planet.

But even there, we only understand only the surface.

It feels like often enzymes may be annotated to catalyze only one reaction.

But actually most enzymes are very promiscuous and they have also kind of lower.

They're called sometimes moonshine reactions with other substrates.

And if the evolutionary pressure is right, this moonshine activity might require only one or two mutations to become relevant to the cell.

And suddenly they can carry flux, which they would not do in a.

In a natural setup.

And so that's why we.

How we always find out something about different angles of metabolism, even without having engineered it, by just kind of creating the settings where suddenly properties arise in a natural system that would otherwise not.

Not happen.

Yeah.

And this guy, like, goes back to the.

The moderately efficient enzyme, Right.

Like, if you have an enzyme that is so good, so optimized that doing its.

It's one thing when the environment changes, it's not flexible enough to adapt.

So by having all of these sort of pretty good enzymes that can kind of bind to this one, but they can also maybe kind of bind to this one by having that sort of, I don't know, sloppiness is the wrong word maybe, but it's like a.

Like an inherent, you know, flexibility.

Like a playground.

Yeah, yeah.

Then you can.

That's how.

That's how you get adaptation.

Right.

Like so.

And that's interesting because it is now we're looking at, you know, there's.

There's so much more possibility, Right, because life evolved to survive in the conditions that it's presented with.

Right.

And that's the conditions on our planet for the last billion years or whatever.

But there's other things.

There's other conditions.

We can now create new conditions and put life in it, and it finds a way to live and evolve.

So do you ever view this.

This is maybe a bit of an aside, but do you ever view these, you know, these strains that you're creating to do these things that you're manipulating?

Would you consider them like new forms of life, like different species?

Is.

Is there.

Is there a discussion about that?

Or is it just like it's E. Coli that we've adapted to do something else?

Right.

But it's not necessarily found in nature.

Right.

Yeah, it's interesting.

I think my view there is a bit more humble of saying, no, it's really an adapted E. Coli and it's still quite far away from a synthetic life form.

There is this whole branch in synthetic biology that tries to do really this kind of create Life from bottom up.

Where you really think, okay, what are the principles of life?

It needs to be able to divide, to mutate, to store genetic information, and which are really.

There's so many efforts around the world who are trying this.

And if they would manage this, I think really, and only this, I would consider a new life form and not an adapted life form.

Yeah.

And that makes sense to me.

But do you.

Is it an important distinction, do you think?

Does it matter?

Good question.

I think it matters a bit also in the.

In, in a way to also communicate that it's not that scary what we're doing.

Because of course, I mean, what we haven't gone into yet so far.

Like, we talked mostly about the fascination of doing what we're doing, but there's like.

Synthetic biology by itself is not so known, but genetic engineering, this term has a really bad connotation.

It's got a lot of baggage.

Yeah, exactly, A lot of baggage.

And a lot of the success stories are not attached to it.

Why we get or why we can produce certain medicine in our food technology, like the vitamins that are added into our food.

There's so many success stories.

The vaccines, although there might be a big overlap between people not liking vaccines and genetic.

Yes, it's similar community.

Exactly.

I mean, but, but, but still, I think there's, there's also distinctions.

But yeah, like the, the fact that we got so fast to a COVID vaccine is, is a success story, an absolute success story of synthetic biology.

But people don't make this connection so much in their head.

And so for me, it's always when I tell the people, like, because sometimes I, I tell them what I'm doing and I say, okay, I have these, I make these bacteria.

And sometimes when I want their attention, I say, I make these super bacteria that are turning CO2 into products.

And then sometimes they think and they're like, okay, but do you want to take over the world with this?

Or whatever.

But then I compare them a bit more to.

It's a bit more, I think, than a breed, than an actual different life form.

So I compare it to if you release a Chihuahua in a forest compared to what a wolf usually does in a forest.

And if you release a Chihuahua, it's dead within a couple of hours.

I would say, yeah, hunted by a wolf, probably.

And, and the same is with my, with my bacteria.

Like, they are really good for a certain task of converting something into something else under given conditions.

But if I would drop my bacteria, even though it's not legal, if I would drop them outside, they would have no chance to survive because they are really just an adapted E. Coli in the end, with some very specific functionalities that are only useful to me and really not for itself.

Yeah, yeah, exactly.

Or.

And not.

Not in the context of the pond in the forest.

Right.

Like in the context of the lab where I'm trying to get it to produce, you know, a new polymer or something, whatever it is.

Right.

But I think this is interesting and I hadn't thought too, too much about this, but now that we're here, the way in which we talk about these things actually, you know, does matter for this, because I think one of the big challenges we're facing right now with technology that you and your colleagues and people like you are developing is that we're showing that we have the ability to replace at least some things that we would normally do with fossil fuels.

Right.

We.

We have the power to do that, but there's cost and there's, you know, there's all of these, you know, arguments, political arguments, economic arguments that have to be made.

So we really do need a way to talk about these things in order to sort of, you know, convince the public, convince our politicians, convince, you know, businesses to adopt these new ways.

Right.

So it is important the way we talk about this.

You look at genetically modified organisms in crops, right?

This would be one of the big ways that we could help, you know, feed, you know, underprivileged communities or, you know, deal with climate change.

You're talking about Rubisco, things like that.

But there's a resistance, you know, in some areas of society to these things.

There's also the thought of, like, you know, we're.

We're, you know, just sort of.

People don't think of bacteria maybe in this way, but like, you're kind of.

You're enslaving it.

You're grabbing these bacteria and you're.

You're really forcing them to kind of, you know, to change their biology and stuff.

And is this just another iteration of humans sort of dominating the planet, you know, exploiting the planet?

Obviously, we're talking about it in ways of, like, we can use these bacteria because it's much more sustainable, much greener than fossil fuels.

But we're still, you know, so I don't know, there's this thing.

How much do you.

Do you get?

Do, do people in your orbit, do you guys talk about these kind of things or is this.

Am I just kind of going off here?

No, no, no.

There's so many.

So many Thoughts to the point you are raising.

I mean the first thing is that with genetic engineering it's important to distinguish between.

It's a different process if I engineer a plant and really release it to the environment than engineering a bacterium that is contained in a bioreactor and is not made to survive in the environment.

So and that's something that is important to distinguish in the public discourse.

But let's stay with more my case because there it's interesting, you don't really inter.

Have to, you don't necessarily even have to interact with the society because the people I really would need to convince, they only listen to money.

If I go to a company that makes plastic tomorrow and I can tell them, hey, I, I can, with my bacteria, I can make the precursor you need for your plastic for half the price and I make it from waste, I don't have to convince them like money talks.

And that that's also really something that, that where really the whole field has seen a drastic change.

If five years ago we were just into the COVID pandemic.

Synthetic biology had a big hype and biotech startups had a big hype.

Money was really easy to get and it was super easy just with a, with a story of saving the planet to raise millions of dollars.

And then a lot of biotech companies crashed because they were not economically feasible their business models.

So the bigger challenge for my line of work is actually to somehow compete with existing processes only on a pure economic base.

And maybe you can have separate arguments of maybe my, my mode of production is more resilient because you don't rely on the import of a precursor from another country.

But which comes back to an economic argument, economic stability.

And there I think the big difficulty is in times like these to fight against existing power structures, which is just, I mean fossil fuels are still heavily subsidized, which is insane in the kind of.

Most people don't think about that.

No, exactly.

And so we're not just.

We don't just compete with processes that have been optimized over the last 200 years.

We also compete with the power these players have, their special interests.

Exactly.

There were more delegates from fossil fuel companies sent than from all of the African companies, sorry, countries combined.

So there's this insane power and money that tries to stick to their success and to their investments which they have made.

And so these are more the difficult kind of structures we have to fight and less about the public acceptance.

So what I'm doing with my bacteria, I think the only person who I Heard like, who I talked to personally who was like, disagreeing with it was border guard in the US I entered in Iowa and she was really like, like, yeah, this isn't right.

We shouldn't be doing this.

This is not what God wants.

Yeah.

And I went on of nearly getting fired for.

For not taking the vaccine and so on.

That was.

That's my one anecdote of.

Because, like, this thing of making bacteria work for us is something.

I think that that is, if you really go into the details, supported by a lot of people.

And then the interesting part is what you mentioned is dominating nature.

We have to be a bit careful how we talk because it can sound like this.

But the funny thing is that actually the line of research we do is way less thinking of dominating nature, but rather balancing it.

So my free time, I give science slams and I have.

I have a science slam and we always have to tell a funky story there.

So science slam instead of poetry slams.

They're not poetic.

They're more just like explaining with some funny pictures.

Many people use cat pictures to win the audience's liking.

And there I compare existing production with bacteria which exist.

So these are already totally economically viable for a lot of products.

This is a bit.

I'm missing the good English term in German, like forced labor, where usually you grow your bacteria and then you have a point where you have a lot of bacteria and then you add an inducer molecule which then tells the bacteria to now produce, and then they produce, produce, produce.

They kill themselves because they are forced to produce, and then you harvest the whole bacteria and then you start from new kind of.

Yeah.

And the way we do it actually is we do something, I like to call it metabolic mimicry.

So there are some processes in nature where cells also produce when they grow.

The most successful is actually ethanol production.

So the way humans have produced ethanol over the years is they put yeast with some substrate sugars and so on, and they just create anaerobic conditions where the yeast now has to turn the substrate, the sugars into ethanol.

And it's also totally forcing it with the anaerobic conditions.

But we're using a mechanism in metabolic mechanism that exists where the yeast really takes the substrate, converts it, and is producing and kind of balance it with its own growth.

And we're really looking at this and adapting the same mechanism, growth, coupled bioproduction, and turn it and use it kind of for other substrate to product combinations.

Where now we can turn methanol into a plastic precursor, but not in this, like, forest.

Now you have to produce until you die method, but really in a way where the cell biomass formation and the production is inherently balanced by the specific metabolism that we design.

Right, right, right.

So that, that maybe sounds a bit better than I make them produce.

Yeah, no, for sure.

And I think it's like.

And I was just, like I said, I was just kind of thinking of these things in my head because I think this is one of the things that, like a previous podcast guest that I just had on was talking about, you know, using.

She was an architect of a doctor that became an architect, but looking a lot at like, you know, chemistry, matter.

These things are not fixed.

They, they react given the conditions, you know, so when you kind of realize it's again, this idea of, like, once you kind of have this shift in perspective where, you know, matter and chemistry doesn't have to just go one way.

Right.

We can, it can change based on the context.

It's actually very liberating and you can do a lot more.

And so she was into biodesign and, you know, using, you know, bacteria or living things to, to build our, our, our world.

Right.

So you have like, biosensors in your home.

You know, your, your home could be more like a coral reef that, that, that, that reacts to the environment and reacts to you rather than, you know, taking all of our energy and fixing matter into concrete so that it doesn't move ever again.

And it's the same kind of thing.

So in a way where you're like, you're really manipulating bacteria and, and sort of, you know, you could view it as like, we're really getting in there and like, changing these things and, and getting them to do what we want them to do.

But you're also looking at, well, what is the environment that we have, what are the things that we have available to us and how can we use those better?

And so it's.

When you, when you with it, with a change in perspective, you know, of what chemistry can do or what these molecules can do and how they react in different contexts and stuff, you can start to unlock new possibilities, right?

And you can look at, well, what are the problems that we want to solve?

What are the things that we have available to us and use those, how can we use those in better ways?

So it's not this domination, it's not exploitation, it's rather what is available to me.

We have an excess of carbon now in the atmosphere.

Well, can I use that?

Can I use that by getting a bacteria that can then assimilate that carbon?

Take that Carbon and turn it into something useful.

Right.

So it is more harmonious in that sense rather than this sort of one way exploitation of the resources that we have.

Which I think is, that's an interesting story and a story that I think people can get on board with.

But it's also, as you say, the economics of it are always going to be the biggest, you know, decider.

I guess.

Yeah, but, but that's still why, I mean, on a very superficial emotional level, I believe so deeply in our work and also in the long term economic success.

So right now I'm working on founding a startup and actually turning our research into reality.

Because I see this as the only way of actually making it real, just by publishing about it.

I don't think any big chemical producer will read this and be like, yeah, okay, we change all of our production based on this guy's publication.

Right.

And of course right now I mostly have data from the lab and we maybe have some modeling.

But what this already suggests is that this more harmonious way of producing is actually also more economically viable because it allows me to better scale my process.

Usually when I go from lab scale to pilot scale to production scale, there's years of optimization between them because every time you need to again, kind of optimize the bacterium for these new conditions.

While if I have a strain that just loves to produce and that's just really good at producing and kind of has it balanced by itself or it just knows, knows how to balance it itself, I have way shorter development times because now it's not so important to it.

Whether it's in a shake flask or in a huge bioreactor, these are things that we will now have to demonstrate in real world.

But we're just kind of intuitively, I'm really looking forward to see the success of this in real life.

Yeah.

And I think that makes a lot of sense.

You know, when you were talking about, we were talking about evolution, like just sort of finding the way and, and then it becomes this.

Yeah, it's not driving the bacteria to death, you know, just squeezing every last production out of it.

It's.

You've created conditions and a strain in which it's happy to do this for.

For lack of a better word, you know, like it's.

This is how it, you know, this is how it grows.

It grows by producing the thing that we want it to produce.

And so then, yeah, at each stage when you kind of have to change the conditions a bit, going from a vial to a giant bioreactor, it's it's happy to do that and it can maybe adjust a bit again with evolution, but it's all pointed in that direction.

So the, this is the other thing that you know, and this is kind of my introduction to this world was seeing these bits of data, right?

Seeing the paper that got published in Nature, whatever, that's like, oh, we now have a bacteria that can do these anaerobic fermentations, but in aerobic conditions.

Isn't that neat?

Right?

And that's cool.

But then it is this next step, it's like, how do we actually build this into something that changes how we produce the things that we need to produce?

And I think that that's a really big challenge.

But I see yourself and some of your colleagues and stuff as being.

You're really forward thinking in terms of like wanting to take on that challenge.

Because in my job of science journalism, I've met many, many, many scientists, usually older, that are just, I just make the papers, I just, I just do the data and I just publish the papers.

It's up for someone else.

So what are your thoughts on, you know, scientists themselves becoming more maybe involved in, in the, the commercialization aspect?

I think to some people, some scientists, that's a dirty, it's a dirty word.

You know, like it's, it's not, it's not where the, the purity of science or whatever.

But I, I disagree and I think it's like we need more, more scientists to be more actively involved.

So what are your thoughts on that?

And then what are the things that you as a scientist, you know, realize when it comes into shifting into that world?

Holy.

There's a lot of things I don't know about this side of the, the equation.

Yeah, it's a very interesting shift.

And I'm still not, I still have this kind of ivory tower, like comfort of saying like, yeah, science is nice if it's pure.

And then if you, if you have to now suddenly make it work in a capitalistic world, it's more like dirty work.

So I myself really, I'm still not fully transitioned to.

When I, people ask me what I do to really say with a lot of comfort, yes, I'm making a startup, I'm turning this into reality.

It's still, it's still a process because yeah, it comes back to your question.

What do I think if more.

I think sometimes scientists are also good if they can just be scientists and hand it over into someone to someone else's hands because.

Exactly.

It is a different job.

I mean it needs to go hand in hand.

But I would be happy if I could just stay in the lab and keep just being curious and not having to worry too much about all these other factors that then suddenly play a role.

But yeah, that's not what it is like in the world, unfortunately.

And I think I'm also going to enjoy it because it's really nice to.

It's somehow exactly so real and less theoretically thinking about what would be good, but really integrating it into this complex system of what companies are out there already working on.

What are the waste streams?

For example, in my publication I wrote about glycerol using glycerol as a waste stream.

And it used to be a waste stream maybe 20 years ago, 15 years ago, and it was very on vogue.

And I can still in a paper from two years ago.

Right.

It's a waste stream and we need to find ways to valorize it.

But as soon as you look really in the using it economically, you realize and everyone who is also in the real world can directly tell you it's not a waste stream anymore.

As soon as something is a waste stream, there's a lot of industries interested in valorizing it.

Right.

So especially for, for refined pure glycerol, there's a high need now in the cosmetics industry and so on.

And it's actually not even cheaper than sugar.

And it, it's.

I could easily write this still in a paper and wouldn't be too criticized for it.

But then if you look in the real world, it's, it's a completely different story and it's somehow even, yeah, way more honest in trying to not save the world, but maybe be a part of this by saying, okay, I actually face the world as it is and try to integrate my tech there instead of just speaking out of the ivory tower and being like, hey, we have to use glycerol because it's a waste stream.

Yeah.

But I think that, you know, we can kind of link it back maybe to the same things that we were talking about in these sort of patchwork, sort of step wise things.

Right.

Like you could try to like you say from the ivory tower, say that's it, no more fossil fuels.

Like let's just totally get rid of it and build something new.

But that's not necessarily how the world works or the best way to maybe approach the problem.

Whereas if you sort of start like, well what is, what's one thing that we can, that we can pick off the, the fossil fuel, you know, process?

Well, let's pick that one off and start there.

And we get that.

And then piece by piece we start saying, okay, well now we can do this one and now we can.

We know, but it's.

I don't know, I think that that makes sense.

Like, it seems like a realistic and a very logical approach.

Approach.

But when you get into discussions, bigger discussions about climate change and all of these things, it doesn't feel fast enough, it doesn't feel urgent enough, it doesn't feel, you know.

Yeah, it absolutely doesn't.

And, but that's also why I always say what we right now is society need a societal change.

Right?

We need to see.

I mean, I'm really, I'm really quite tough on this.

I think we need to see billionaires as a disease and really do what is necessary to take away this weird wealth distribution we've been seeing over the last year of going to the more powerful and to them who are really polluting the planet and not the poor people who have to suffer the consequences.

I think we need absolutely political change right now.

And I want to be a part then of the system that comes after.

And I believe that I'm developing technology already now for hopefully a system that is fixed, but without that in place, we're like, I mean, I'm not alone with saying this, right?

The Antonio Guterres says this, the head of the un, we're on right highway to climate hell right now and I'm not going to fix this.

I just like to think of it like, I mean, I'm also politically active and so on.

Like, and I think really there's the bigger lever, but I'm more thinking of still developing positive alternatives because if you're only against something, it's not really leading anywhere.

So I think it's always better to be ready to say this is bad and we have something better here than just saying this is bad.

Because then people can easily say, yeah, but you don't have any alternatives.

And what we have to do right now is kind of demonstrate that our technology also works in industrial settings.

Probably not for large volumes yet, because it's really only economic if you produce in large volumes, which needs a lot of investments.

But even for small molecules, it can already be a success to show this works and then going this bit by bit way while hopefully the rest of society takes on the rest of the battle and doesn't just be like, oh yeah, the scientists will save us.

Yeah, no, it's a good point.

And I think it's again, yeah, there's a holistic view there's a lot of different things you need to do technology, you need the economic side, you need the political side.

And I think, you know, I definitely agree with you that like the way that our, you know, let's say Western capital systems are, the incentives aren't really there for, you know, to implement these things.

We talked about fossil fuel subsidies and the fossil fuel industry's representation at climate talks.

Right.

So it's, it's.

But that's, that's where I am hopeful because like the scientific things we were talking about, where there's just a change in perspective and you unlock a new thing, I think the same is true in the political arena.

And I think people are getting sort of fed up with this idea or this, you know, what we're seeing of all our resources going one way, not for the benefit of us, but rather for the benefit of a few.

And if we can just recapture our governments, our politics, the mechanisms that we have to say, hey, we're not diverting resources to that anymore and we're going to divert them into something else, you're ready to go with viable technologies that are there.

So I totally agree with that.

As we wrap it up here, we've been talking for like an hour already, so this is, I appreciate your time.

Do you want to elaborate on the startup that you're doing?

Like, what is the goal?

Like what is the product, what area you're focusing on?

Or is it too early to bring that in yet?

So we're still in stealth mode, which means.

Exactly.

We're talking to customers, we're talking about co developing, we're talking to big industry while at the same time also investigating our own production lines.

But even there, what I can say is it's going to be growth coupled.

So really this is the heart of our research and this is what we know how to do well and we really believe that this can transform the bio industry.

But I cannot share any molecules yet we're targeting because.

Exactly.

That's always.

Until it's done public, very sensitive and we're still running tests in the lab and so on and so forth.

But I can say that I'm working with.

My co founder is in Paris, Nadine, absolute amazing person, also a synthetic biologist by training.

She ran startup before or like was as a CIO employed there.

And it's really nice to have, I mean I'm in Berlin, she's in Paris.

To really from the beginning think this of a European project of really like especially in Europe now with the things going on in the US really like thinking about, okay, what can we do to become more independent resource wise.

And we should not just outsource everything to China because it's, it's cheaper there, but we need some capacity of bioproduction here because it gives independence.

Like if China wants to go to war.

Exactly.

If China wanted to go to war with, with Germany, it could just stop the, the delivery, be the deliverable of all antibiotics and we would, people would suddenly start dying from diseases and all these things are just like in a, in a globalized world you need some sort of independence.

And it's really nice to think this as a European project from the, from the beginning and not as a national project.

And really thinking of how can we use the diversity we have in Europe also.

Yeah, no, I think the current political situation could be viewed as, you know, like there's all these crises that we're dealing with and everything, but there's also a lot of opportunity.

Right.

And it's a way, you know, maybe some people are waking up to something things and again, if you're ready to go with a technology that says, hey, this is a problem that just come up, I can solve that problem, you know, then it's, then you're ready to go.

So that's great.

I'm, I'm really looking forward to, to following along and seeing your, your company take off and you know, maybe we can join again to, to discuss that.

But I really appreciate your time and I appreciate your perspective.

You have a nice way of talking about these things and, and also indulging some of my tangents as I go off on.

I appreciate it for sure Lily.

Like, thanks for, thanks for the conversation even just this is also inspiring to me and I, I just.

The nicest thing you can get as a scientist, someone interested in your work.

It's like the dream to be able to talk about what you think and research for, for an hour.

So thanks a lot.

Yeah, yeah, no, no, I'm, I, I agree.

I hear you.

It's like artists and scientists, it's the same thing.

There's so many, there's so much overlap and one of them is like gratitude of somebody paying attention.

Yes.

Okay, well, we'll be in touch and yes, please come on anytime when you have updates and stuff.

We'd love to hear it.

So thank you, Jan.

It's been a pleasure.

Thank you very much.

Bye Brad.

Thank you all so much for tuning in.

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This show is produced, written, edited, recorded, all by myself, Brad Van Peridon.

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Bye for now.

I.