Unlocking Enzymes' Potential by Locking Them in Place with James Weltz

What if we could harness nature's most precise chemical tools and make them work in industrial settings? James Weltz, co-founder and CSO of Cascade Bio, reveals how enzyme immobilization technology is transforming chemical manufacturing by stabilizing delicate biological catalysts.

From his childhood exploring chemical plants with his industrial hygienist father to his groundbreaking PhD research, Weltz shares the journey that led to Cascade Bio's revolutionary polymer brush technology. This innovation allows enzymes to maintain their remarkable catalytic properties while anchored to solid surfaces – converting them from fragile biological molecules into robust industrial catalysts that can operate in continuous flow processes.

The implications are profound. While enzymes have long promised atomic precision in chemical transformations, their instability has limited industrial adoption. Cascade's technology preserves nearly 100% of enzyme activity during immobilization (compared to just 1% with conventional methods), allowing these biocatalysts to withstand higher temperatures, function in organic solvents, and operate continuously for much longer periods.

Weltz walks us through real-world applications already making an impact – from nitrile hydratase producing acrylamide for rubber manufacturing to penicillin G-acylase creating antibiotics at massive scale. More exciting possibilities await, including true recycling of plastics and remediation of "forever chemicals" like PFAS. The conversation extends to multi-enzyme cascades that perform complex chemical transformations outside cells, potentially recreating cellular pathways in industrial settings.

The melding of computational protein design with robust immobilization technologies may finally deliver on biotech's promise of "infinitely scalable, atomically precise" chemical manufacturing. As Welts puts it, these innovations could transform how we produce the materials our modern world depends on – making them compatible with human and planetary health.

Join this deep dive into the cutting edge of industrial biocatalysis, where nature's chemical tools are being reimagined for a more sustainable future.

(00:00) Introduction to Enzyme Immobilization
(00:18) Welcome to the Climate Biotech Podcast
(01:09) Meet James Weltz: A Leader in Enzyme Immobilization
(01:43) The Potential of Enzyme Immobilization in Climate Biotech
(02:21) James Weltz's Background and Early Influences
(08:31) Understanding Enzyme Immobilization
(10:03) The Importance and Benefits of Enzyme Immobilization
(19:41) Challenges and Innovations in Enzyme Immobilization
(24:10) Case Study: Lipase Enzymes
(25:25) Dramatic Improvements in Enzyme Technology
(25:45) Enzyme Stability and Industrial Applications
(27:22) The GPT Moment for Enzyme Work
(28:09) Exciting Examples of Enzyme Applications
(30:48) Community Questions: AI and Enzyme Design
(39:18) Challenges and Opportunities in the Enzyme Industry
(41:38) Future of Enzyme Technology and Rapid Fire Questions

Transcript

[00:00:00] James Weltz: Essentially, enzyme immobilization is taking enzymes, these nature's catalysts and converting them from a form where they work in a cell. And making them look a lot more like catalysts that chemists and chemical engineers use at scale today, 

[00:00:18] Daniel Goodwin: Welcome to the climate biotech podcast, where we explore the most important problems at the intersection of climate and biology, and most importantly, how we can solve them. I'm Dan Goodwin, a technologist who spent years transitioning from software and neuroscience to a career in climate biotechnology.

As your host, I will interview our sector's most creative voices from scientists and entrepreneurs to policymakers and investors. 

 I've been a big fan of James Weltz and Alex Rose from Cascade biocatalysts for a long time. Enzyme immobilization is probably one of the most important things we can solve in biotech.

That's my personal opinion, but I think it's really important. And Alex and James are leading from the front on this. So I've wanted to have this geek out for a long time. What I'm going to do is just give a couple words about James's background and then get out of the way. And then we're going to have a really fun conversation about this aspect of climate biotech.

James is a leader in this idea of enzyme immobilization. And he had completed his PhD on this topic before co founding Cascade Bio. One of my personal biggest dreams for climate biotech is the idea of a chemical factor that fits in your hand. Cells do a magnificent array of molecular reactions and a cubic micron, but we've been so far away from that in deployment.

One of the things people hear me say a lot is, the potential of biotech is infinitely scalable, atomically precise, and that sounds good, but we haven't really accomplished either in deployment yet. And I look to this idea of enzyme immobilization as being one of the big steps forward in that, and so really excited to have this conversation.

What we're going to be talking about today is this idea of pairing enzymes with synthetic substrates. You can think of that a molecular glue to trap and protect the enzyme in place. And that could be one of the foundational unlocks. And I think from the outside looking in, that's a totally counterintuitive idea.

And that's exactly what we're here to have this conversation with. So James Weltz, it's wonderful to have you here. Who are you? Where did you grow up?

[00:02:14] James Weltz: Yeah. Thanks, Dan. And what an honor to be here. This is a really exciting opportunity to come and nerd out with you on enzyme immobilization. I'm James Weltz. I'm co founder and CSO of Cascade Bio and I'm a chemical engineer by training. But really I'm a product of my environment and I've been really lucky to have some really great environments growing up.

I think something, outside of my formal education and chemical engineering, a really formative experience growing up was My dad is an industrial hygienist, which is essentially workplace chemical safety, and he's an entrepreneur. So my summers growing up we're kind of split between in the analytical lab, testing drinking water for lead or building materials for asbestos.

We're going out into the field and seeing how chemical manufacturing is done. At scale today everything from a plant burning landfill gas to create steam and electricity to, the factory making cookies in continuous processes. It was, really a formative set of experiences that led me on my journey that ultimately brought me here today

[00:03:15] Daniel Goodwin: Cool. Where was this?

[00:03:17] James Weltz: though. And where I'm from is the suburbs of Philadelphia. So hopefully you can't hear that in my voice too strongly that Philly accent. But go birds.

[00:03:25] Daniel Goodwin: Actually no, I thought you're much too nice to be from the Philly suburbs. Did you ever go to these sites with your dad when you were a kid?

[00:03:31] James Weltz: Yeah, definitely. Basically this term industrial hygiene is essentially. Environmental science before that was even a thing. And it's really focused on how to keep people safe when making all of the chemicals, which is now a bad word, but really all the things that we rely on today in our modern world, the clothes on my back and, the adhesives that built this soundproof booth that I'm in right now, and kind of everything in between.

And really seeing how these things are done at scale is both exciting and exhilarating, really. Providing for this modern economy that we all enjoy and live in, but also seeing the tremendous waste and danger and this outsized negative impact that chemicals have had. On our communities, I mentioned, lead and drinking water, I think everyone's heard of Flint, Michigan, but they don't realize that this is happening and in cities all over the country.

And, lead at the time was a miracle material, the soft multiple metal that allowed us to make plumbing. A reality and get safe drinking water to, to millions of people, but, it's had this negative impact. And I think biology is a really exciting opportunity to make the chemicals industry much more compatible with human and planetary health.

And so it's really exciting to be here today on the climate biotech podcast to discuss how, we can make. These amazing materials that improve the quality of life. For everyone around us, but do it in a way that doesn't destroy our communities and our planet.

[00:05:04] Daniel Goodwin: The way you set that up with lead. I never thought about plastics today or the lead of 70 years ago. But that's a pretty fun thing to play with. And one thing that I've noticed in the biotech work that we've done is that when you are a PhD level postdoc scientist, you're looking at everything academically, it's really easy to look at these chemical manufacturing plants and say, Oh, this sounds so bad here.

But there's this humility that I've developed over time, which is that if you haven't gone to a plant and you haven't seen how hard it is to really do something in production, it's very hard, I think, to really innovate. Which is why we had Jesse Liu on the podcast recently to talk about TEAs and to start helping build this.

And so with that kind of kernel in mind, I'd love to go back to imagining young James walking around an industrial planet with his dad. Did you ever know you'd be a world leader in enzyme immobilization?

[00:05:48] James Weltz: Certainly not at that age. It was definitely not on my radar and not something I knew existed. I think a pivotal point in my career was an undergraduate researcher studying chemical engineering and getting the experience of working with enzymes in the lab. And that's where I saw, this light bulb moment.

Of, these nature's chemical tools, really having that atomic level precision being able to break a bond, not by boiling it in some solvent or adding some harsh acid, but by literally gripping onto the molecule and pulling it apart or forcing it together. And that's that atomic precision.

That's what enzymes really do at the molecular level. And so as an undergraduate researcher, we were playing industrially relevant chemistries. In a way that's much more sustainable and, has this long tail of huge benefits not only on the cost of the process, but on the environmental impacts.

And it was really exciting. I think you quickly see, oh, okay, all these pathways in a cell that we learn in bio are really just a bunch of different enzymes that do these really precise chemistries. And, seeing it in the lab, oh my gosh, at room temperature in water under these mild conditions, it's doing this really tough chemistry, really challenging transformation that can produce a lot of value.

But at the same time, as an undergraduate researcher, coming in on the weekends to do an experiment because I knew my enzyme was going to die by Monday morning or having to store everything in the refrigerator, or, having to do all of these purifications ahead of time to produce this enzyme, this biological chemical tool really was to me, the obvious challenge of going from, okay, enzymes are these amazing things in the laboratory to how do we fill a giant reactor and do stuff At scale.

That really has a huge impact on our economy and on our environment. And I think that was the light bulb moment. That was okay. Enzymes are great, but in most cases, they're far too delicate to scale. How do we. Transform that. And so through that experience, I was really, looking around at different graduate schools and programs and advisors to work with.

And I came across this really interesting interdisciplinary collaboration between enzyme engineers and physicists working on this problem of enzyme stability for biocatalysis and other industrial applications of enzymes and proteins as well. And that was to me a really exciting problem. And they were using some really interesting tools and approaches that other folks haven't been doing in the industry.

So that, that was kind of what led me, I think, as a 22 year old. To pick enzyme immobilization. And I've been working on it ever since. 

[00:08:25] Daniel Goodwin: And I'm trying to imagine what year this 

[00:08:27] James Weltz: 2013. 

Yeah, you're a, decade deep. 

Yeah. It's been a minute.

[00:08:31] Daniel Goodwin: So I love it and I'm really excited. And we just, we've used this phrase a few times and I think we just need to be grounded on what the heck we're talking about which is this word enzyme immobilization, right?

And from the outside looking in, it sounds jargony and unimportant. But you could have worked on anything and you chose this. So I think it's important for people listening and kind of as a quick sidebar, I always like dumping on AlphaFold on these conversations. And not that it's anything wrong with that, but it's really easy to think, oh, everything's solved, we're done, right?

So a lot of biotechnologists I meet say, oh, I designed this protein and hooray. It does this thing. And then you have to say how long is it going to live, et cetera. So I think that's who we're really trying to root here is people who might think proteins first and, Hey, I've got this thing.

And my stoichiometry says blah. They have probably no idea what enzyme immobilization is. So why is enzyme immobilization important? And why did you pick, this is what you want to work on.

[00:09:23] James Weltz: Yeah. And it's certainly not a term that rolls off the tongue. But essentially, enzyme immobilization is taking enzymes, these nature's catalysts and converting them from a form where they work in a cell. And making them look a lot more like catalysts that chemists and chemical engineers use at scale today, converting the soluble what we call a homogeneous catalyst and converting it into an insoluble or heterogeneous catalysis.

It's really about gluing enzymes down to a solid surface and it could be a bead or a sand like material, but really converting these things that are dissolved in a liquid. And making them into a solid that doesn't dissolve into your reaction media. And so if you look at, for example, 100 percent of the 300 largest chemical manufacturing processes by scale today are all done.

In what's known as continuous flow with a heterogeneous catalyst. So more jargon here. But essentially what this is we have a liquid. It's your feedstock. It's your raw ingredient and you flow it over a solid. And that solid is a catalyst, a chemical tool that converts it into your product. And if you have that catalyst be a solid material, you can do this reaction under flow where you flow that reactant over the sand like material, it gets converted and it comes out the back end of your process in a continuous flow as your product as a hose with kind of dollar signs coming out the other end.

And really, this is the best way to do chemistry that humans have discovered in terms of scale and unit economics. And so what we want to do is, instead of using these harsh really inefficient and imprecise catalysts, which are solid materials today is used nature's catalysts. These incredibly precise.

And unfortunately, delicate tools glue them down onto a solid material and make them really reliable and long lasting for use. In these large, scalable processes. And in a nutshell, immobilization is again about converting these catalysts into a form that's much more scalable and applicable to current chemical manufacturing processes.

And then making them really robust and long lasting.

[00:11:29] Daniel Goodwin: And you said the word sand. Is that the right way to think about the way you guys think about this 

[00:11:34] James Weltz: We use a bead it's like little balls kind of, like a, nerds, candy size, but there's a few different form factors that we offer and that are available. Today, but that's exactly the way you should be thinking about it is a is an active, chemically active sand or powder that is insoluble.

[00:11:52] Daniel Goodwin: And so immediately you can imagine why this is beneficial if nothing else for the separation, right? You have the product out and you don't need to do any chemical separation. It's just, your catalyst is on the bead and then your product comes out. My guess is that's one of the first big benefits, right?

Are there others?

[00:12:08] James Weltz: Exactly. And there's such a long tail. And that's why I'm really excited to kind of be on this podcast where we can go a little bit into the weeds here. But, there's a number of different benefits. The first is that your enzyme doesn't mix with your product and flow out the end of the reactor.

And that's really important. We've seen a lot of really good traction with our pharmaceutical customers, for example, that don't want some E. coli derived, some microbe derived enzyme in their final active pharmaceutical ingredient. But, of course, it's also important if you want that product to be shelf stable or if you just don't want other stuff in there, you want a pure product coming out.

But really where the, things get really exciting is enabling that continuous chemistry underflow. And then. The improvements and enzyme stability are really where we see these huge multifold improvements in value for our customers. And so what I mean by that is, 1 example, we had a customer, they're doing a chemical transformation.

And by going up just 10 degrees Celsius, which for a chemical engineer, it's like an error in their process, in terms of temperature. But for biologists, it's everything. It's the difference between being alive and being very dead. They are able to increase the conversion of the product from 30 percent to 40%.

So because that higher temperature, they're actually able to increase the full productivity, the dollar signs coming out of that process per unit time by 33%, just by increasing the temperature of that reaction by a few degrees. And that's really what we enable with the stabilization are these huge, improvements in productivity and then, of course, making the enzyme last longer because, I'm sure everyone on here who's worked with enzymes knows they can be quite expensive.

And so by making the enzymes last longer, you dramatically reduce the cost contribution of your catalyst to that process. And can make things really interesting as well. So there's a number of different benefits that our customers have, but the stabilization, I think is where it gets really interesting.

Another example is, Okay. Enzymes really like water. Biology is the chemistry of aqueous solutions of water based solutions, and as you've had on this podcast before, right? Enzymes and non aqueous systems are really exciting. And that's something that we enable here at Cascade. So one of our customers, they have a process where the substrate is not very water soluble.

And so by adding a co solvent, they're able to dramatically increase in this case, by orders of magnitude, the concentration of the substrate going into that reactor and therefore the concentration of product coming out. Again, these multifold improvements and process economics are really enabled by bringing enzymes, out of these biological environments and into these processes that are really exciting for chemical engineers and chemists.

[00:14:56] Daniel Goodwin: I'm glad you brought up Samuel Thompson's work that we had on the podcast. Cause I, there's something really poetic about taking the tools of life and then making them operate where life couldn't exist. And I see there's so much spiritual alignment with your work and theirs. It gets me really excited.

So I think we're going to go in two places and we can go back and forth however you want. One is specific examples. What kind of enzymes are we talking about? And there's the other side of it, which is what biological approaches. Are you using here? I know you've worked with microscopy.

That gets me super excited. But then there's also so many other lenses to think about immobilization. And so I'd love to touch on that. I think you guys are doing some of the best work, but you're also not the first to be doing this.

This is, there's a, decades old history even a hundred years old, I think, as it goes back to charcoal, 1910s. What are some of the specific enzyme, like enzymatic reactions we can think about? And then if you want, we can kind of drift into some of the ways that you've used to develop this technology.

[00:15:50] James Weltz: Yeah, I think it's great to get grounded in some specific examples, some of which going back decades, as you mentioned I think some of the classic examples of immobilized enzymes having. Really huge scales and industry are things like nitrile hydratase, which is used to make a chemical called acrylamide.

And I know I just threw a bunch of big words, but acrylamide is the ingredient used to make nitrile rubber. So things like your rubber gloves in the lab car tires and sort of everything in between a huge commodity chemical produce it at really large scales today. I'm using an immobilized enzyme by some of the world's largest chemical companies out there.

And, the reality is the reason why they use an immobilized enzyme here is dollars and cents, not because of some environmental benefit or green premium. They are just better catalysts, especially when you can get them into a stable. In a mobilized form, the other classic examples include things like glucose isomerase making a fructose corn syrup.

Something where the product is not very expensive as well and done a commodity scales. In the food industry as well, things like lactase to break down lactose and dairy products used a very large scales already today. In the fine and specialty chemicals industry light paces, which I know we'll talk more about, I think, in the context of this discussion are used to make, all of the coatings and adhesives that you would use to, build a house or an office building, or, paint your bedroom, things like that immobilized light paces are used today to produce a lot of those very delicate, Appreciate it.

molecules at huge scale. Probably the biggest example by scale is penicillin G. A. So lace, which is used to make antibiotics at really large scales. Antibiotics are really complicated molecules. They're big. They have heterocycles. They have, multiple different types of atoms and put together in really precise ways.

And, enzymes are able to effortlessly produce them at really large scale and commoditize these things that if you were a chemist looking at them and didn't know what they were you'd say, oh, that would be so much more expensive than it actually is. So there are a lot of examples where immobilized enzymes have already had.

Really huge impacts. And, going back, I think the history is one that's really interesting, right? 1916 was the first published example of an immobilized enzyme. And this is before people knew what an enzyme was, what it looked like, they didn't know what a fold was. That term did not exist.

And I think one, I had this fun competition. This is so nerdy, but we were in our PhD theses, we were trying to incorporate the oldest. Citation possible into the work cited and, I found an application or a note from a really incredible scientist serving Langmuir who discovered that surfaces can actually denature unfold.

Or inactivate enzymes themselves, and that was a really interesting observation because people didn't know at the molecular scale what a surface really looked like, and they didn't know what a protein looked like, but they knew that surfaces could inactivate or destroy enzymes. And the way he did that.

Was he took a protease used in cheese making and he smeared that out on a polished piece of stainless steel and showed that it no longer curdled milk. That was his activity assay, which is just a fantastic, clever use of experimentation. And that's ultimately the problem that now, 100 years later, we set out to solve, which is why do enzymes, why do proteins and biological molecules lose their function?

At surfaces, what is going on there? And that's where, you mentioned kind of the microscopy is we took, these unique tools that other people were using for hardcore biophysics or other application areas and applied it to this real engineering and industrially relevant problem.

[00:19:41] Daniel Goodwin: Before we go into the microscopy, I want to ask a question and I'm going to frame it as a fallacy from my experience in Silicon Valley which is that when you go into a market, you kind of want there to be some things there, but you don't want there to be too much. And it's kind of like when I go surfing, if it's a perfect wave and there's nobody out there, like where are the sharks, but the fallacy in software is ah, Google could do this.

Oh, why would you go build blah? Google's big and Google can move fast. And that's the fallacy I've seen a lot of people just stop. Startups. Because, oh, maybe in theory, and of course it never happens. Google doesn't do it for a thousand reasons. In this case, there are already players in the water, right?

There's other surfers on the wave. It's really cool to know that enzyme mobilization is already working at this crazy huge scale. So then you guys, an eight person company now, what's your novel angle as you go in and into a space where there's already, some really large applications happening.

[00:20:33] James Weltz: Yeah, it's a great question. And all of those examples that I mentioned of, Really home run successes with immobilized enzymes have one thing in common, and that's they're starting with a superhero enzyme. They're starting with an enzyme that's really extremely stable, really cheap and easy to produce at scale and amenable to immobilization.

Light paces are the classic example, and light paces in biological context were really evolved to work at interfaces. They're designed to bind to oil droplets and break them down, fats and oils. And so they are the perfect example of an enzyme that's really amenable to a mobilization because they've evolved in that biological context.

But most enzymes. Are not that they are meant to be dissolved in the cytoplasm of a cell or maybe excreted into, the outside of the cell environment, but in all of these cases, they're meant to work in this homogeneous or sort of dissolved state, and they hate high surface area materials because the same intermolecular forces that cause that protein to fold up and give it that nice shape that, alpha fold can now predict are the same intermolecular forces that cause it to stick to a surface.

And what we showed is that the stickier the surface, the more denaturing, the more it inactivates that enzyme. But all these folks, the current products out there today, these enzyme immobilization resins that, Mitsubishi Chemical produces and some of these really large chemical companies make today they're all designed to be as sticky as possible so that they sop up and immobilize as much enzyme as possible, but they're killing the vast majority of these enzymes through that process.

And so what we set out to do is, okay, how do we make something that's sticky but doesn't denature the enzyme and it's kind of an interesting turn of events because we borrowed an innovation from a completely unrelated field of science and engineering and that's the biomaterials community, right?

It turns out that the same. Problem that the biomaterials folks are solving are the same problems that industrial chemists are trying to solve. They just didn't know it. And that's when you implant a biomaterial into the human body, your artificial heart valves, your screw in a bone, whatever it may be.

It turns out the absorption and presentation, basically the misfolding of proteins on that surface upon implementation, are what governs the host's immune response to that implanted biomaterial, and ultimately determines if it's rejected or accepted by that host body. And so these biomaterial folks were really sophisticated in their understanding of stickiness, essentially.

And so we borrowed a coding process, these things called polymer brushes that reduce the absorption and the unfolding of proteins by acting like essentially a series of springs that repel the protein from that surface. And so that was our Eureka moment that, oh, we can apply these materials.

To industrial biocatalysis, and instead of only getting. 1 percent of the protein that immobilizes remaining active, we're seeing something closer to 100%. So all of a sudden, and this is really applicable across, every enzyme that we've tried now so far which is now a growing number across all enzyme classes.

That was the very roundabout way of answering your question, but something that I think really shows the benefits of interdisciplinary research in these engineering problems.

[00:24:00] Daniel Goodwin: I love the framing of when you have the, Oh, there's this other field that has the answer, but people are just speaking a slightly different language and they miss this. I love it. It tickles me. So let's talk about an example because I think your light base story is super strong, right?

And I think that I'm going to steal the punchline. We have a hundred fold increase. Is this an example of this polymer brush approach? And yeah, please tell us.

[00:24:23] James Weltz: Yeah, absolutely. Lipase is these are enzymes that are used at scale today. In commercially viable processes. There are commercially available immobilized lipases today that we can buy in the laboratory and compare with. And that's really one of the academic motivators.

I think as a company now, the big motivator is this is a 600 million market and there are multiple 10 million plus opportunities to sell immobilized light paces. So it was a really good case study to start with. And really what we wanted to do was demonstrate not only that we could immobilize the enzyme and retain all of its activity, but then also stabilize it.

In the academic demonstrations, this is really about temperature. So can we turn up the heat on these reactions? A lot of chemists will tell you if you heat up the reaction, it will go faster. And that's exactly what we saw. Typically with enzymes, you turn up the heat, the enzymes cook.

Just like your steak on the grill, they inactivate and you no longer see any activity we could keep ratcheting up the temperature because they were so stable. They kept going faster and faster. That's really where we got that dramatic orders of magnitude improvement. And so since then, a cascade, we've improved the technology.

We've done a lot of product development. We've done more comparisons with these commercially available immobilized light paces. And we've discovered that there's no limit to the demands of industry for light pace stability. And, going back to Samuel's work and organic solvents, that's something we've done a lot of here at Cascade is, can we translate the thermo stability, the temperature stability that we showed in these academic demonstrations.

Stability and these solvents or these environments that are really highly relevant to our customers needs. And that's really what's been very exciting because in those examples, not only are we increasing the rate of the enzyme and increasing the efficiency of enzyme use. But we're really getting those multifold improvements in our customers process economics by dramatically increasing the solubility of their substrate.

And then all of a sudden, you have a 10 X improvement in the process facility, the amount of dollars you can produce per unit time per unit volume of your reactor or making them just last so much longer under these really difficult process conditions. And again, going back to this limit of stability, Really, there are no limits to enzyme stability in these processes.

You talk to chemists and they say yeah, of course, why wouldn't I do this reaction in refluxing toluene at 121 degrees Celsius? And as an enzyme person, you're like, Oh, my gosh, please don't put my poor enzyme under these ridiculous conditions. But when you go to scale those are the types of conditions that you really want your catalyst to be active in.

And that's been the huge unlock that we've had here at Cascade is really converting these winds of a few rare enzymes, these jargony words like penicillin, GAC, or lipases, and extending them across the board to all of the chemistries that life uses, which is just profoundly diverse.

[00:27:18] Daniel Goodwin: So you're setting up basically the answer to the last kind of formal question I have. And the core question I have is that, what is that iPhone moment? Or gosh, now it's the GPT moment, right? What is that landmark moment that totally changes the way?

Oh, this is obviously the future. Oh gosh. Like full screen smartphone. Got it. Wow. I can have realistic conversations with a bot. Got it. I think you're kind of pushing towards that, but in your mind at Cascade Bio and you, James. What do you think the GPT moment is for the sort of enzyme work?

[00:27:49] James Weltz: Yeah, I love this question because it really speaks to what we're trying to unlock here at Cascade and the excitement that hopefully you can tell I have four enzymes in industry. There are so many examples that just are really exciting and any one of them, once it happens, I think are going to be that head turning, that iPhone moment.

One example is the true recycling of plastics. Such a huge problem, nobody likes to see, these things in the ocean huge climate impacts as well. And right now, the options are so limited for recycling. Plastics and ultimately it's burning them or partially burning them are kind of our best options and, really leveraging the power of enzymes to precisely break down these ingredients and then upcycle them, turn them into something of truly higher value, not just make new plastic, but use it as a feedstock.

To create value. And then all of a sudden you've now generated a market for use plastics where it's profitable. And you're seeing these companies come out in line today, raising tens, maybe even, in some cases, hundreds of millions of dollars to unlock the potential of enzymes in plastic recycling.

And I think that's something that in the next few years, we're really going to see some really exciting and unit economics come out of these remediation and recycling and upcycling processes that get us all very excited about enzymes and then another one, going back to my, youth chemical remediation is such a big problem and I've seen the cost of, removing lead and pipes and removing asbestos from building materials and now we have things like forever chemicals, right?

PFAS and these fluorinated hydrocarbons that persist in the environment for basically forever. And we all have them, detectable levels of these chemicals in our bloodstream. We don't know what they're doing, but we know they're not going away. They're accumulating, and it's pretty scary. And what's really cool is that we have enzyme practitioners and synthetic biologists going to the effluent of these plants, making these.

Chemicals going to their waste streams and finding microbes that actually not only break these down but live off of these forever chemicals. And so we're also, seeing a lot of investment in these types of remediation processes where we're going to take new to nature enzymes, scale them up, and use them to break down these environmental catastrophes that are unfolding before our eyes.

And I think to me, that's just so exciting. There's so much opportunity here. And for every 1 of those examples, there's 100 more that I'm really excited about. And I'll kind of leave it there. But as hopefully you can see, there's just so many of these opportunities for a chat moment here.

[00:30:27] Daniel Goodwin: Yeah. To use my language on this, it's to imagine the amplification of some of these things, right? So if you really do have immobilized enzymes, they're not being released. You can just put it as an addition to you can operate like a filter. Now you can totally imagine it being something you staple on to the effluent of a chemical plant.

I love that. I'm gonna, you're right, we have to throttle ourselves or we can speak about that for another two hours. There's some really good questions from the community and so I want to surface a few of them. The first one is like, how do you see The AI boom and enzymes, and I'm going to work this question a little bit, which is that, what is the downstream or how does immobilization fit into this new protein design toolkit,

[00:31:04] James Weltz: That's a fantastic question. And really, our philosophy is that the best biocatalyst is the combination of a really good starting enzyme and then a really good immobilization support that adds all this value that we've discussed. And so we've worked with customers that have I generated and highly optimized and engineered enzymes, and that's really exciting to see the further improvements that we can impart.

Through that process I will say, there are so many parameters to optimize with an enzyme and I apologize for going deep into the technical details, but when you're designing an enzyme for an industrial process, you're not just engineering stability, selectivity and activity. You're also optimizing the production process, right?

What is the microbe that's producing it? How much can you crank out per unit sugar feedstock that you're feeding that microbe to make that enzyme? And how is that being produced? Is it being excreted into the supernatant and a really easy downstream purification, to make it at scale.

And, we take a lot of wisdom from, the, Dishwasher light pace market that have really brought down the cost of enzymes that way, and they're not just optimizing for stability there. So what we can do is really come in and give them that stability boost, give them that scalability that comes with an immobilized enzyme, and there's still so much other work to be done with the optimization.

Plus, on top of that, starting with a stable enzyme is always a really great place to start. And we can further improve that. So that's how we see it. And then the last thing I'll say is that. We are using AI tools ourselves that are, now off the shelf. When I started grad school, protein folding was considered the grand challenge of our generation.

It's now basically solved. I will say when you add a solid liquid interface into the protein folding problem, it gets a lot more complicated and we have a lot of fun ideas about how we're using AI to solve that.

[00:32:54] Daniel Goodwin: I want to just hover on that, because I think there's three possible answers you could have said. Which is the first one is there is no AI solution. We can toss that one. The second one is that you co design it. So you could say our mobilization scaffold is going to look like blah, do the whatever, like the diffusion approach, and then end up matching these spatial constraints.

Or the third one, which is, I think is what you said, which is that you do you, make your best enzyme, and then come to us. And is that kind of the workflow that you see people work with?

[00:33:22] James Weltz: Yeah, it's a little bit of the second two, I think. So we have customers that have. An enzyme and they've already scaled up the production process. That is locked in. They are not changing it. They're not adding a single lysine to that thing. It's over. We're going to make our mobilization work really well with their existing solution.

There are other customers that are really interested in engineering their enzyme on resin. So engineering their enzyme as an immobilized biocatalyst, because they know at scale, that's what the enzyme is going to look like. And so you get what you're screened for. So screen the immobilized biocatalyst.

And so we see ourselves as providing value wherever our customers need. And we've had really good success on both sides of that coin.

[00:34:03] Daniel Goodwin: Cool. Another community question, which is a really good one is what about pathways that have multiple enzymes? 

[00:34:08] James Weltz: Yeah. That's why we named the company cascade biocatalyst, right? We see ourselves as enabling cascades of enzymes. Taking pathways out of the cell and converting them into scalable chemical processes under flow, and we are really excited about multi enzyme cascades. We've done our first cascade with a customer where we really increase the performance quite dramatically going from just.

1 to 2 hours, and the system kind of crashes out and dies and then running it for at least 20 hours continuously and probably much longer. We also are developing our own IP around cofactor regeneration. So again, cofactors are these things that power these reactions.

They give you, electrons or they accept electrons or phosphate or all these things like ATP. And we're really developing ways of not only immobilizing the enzymes in the cascade, but immobilizing the cofactors as well, while maintaining actually improving their activity and making that so that your catalyst is still an immobilized system, even though it relies on small molecule cofactors.

And that's something we're really excited to unlock because then All of the chemistry of biology is now scalable on today's CAPEX, on today's chemical factories and reactors.

[00:35:27] Daniel Goodwin: is related to another question, what about a mobilization allows for increased chemical efficiency? My immediate answer is that the effective concentration. at where the catalysis happens is the important part of it, but I'm not the expert and it feels like that's related to this idea of multi enzyme pathways.

[00:35:44] James Weltz: A great question. There's a number of different ways that we can increase efficiency. One is by going to higher temperatures. People don't think of biological catalysts as being Arrhenius or having an exponential increase in catalytic rate with temperature because the enzymes eventually die, they get cooked.

They are. And so if we enable higher temperatures, we can get these dramatic orders of magnitude improvements in the catalytic efficiency of the system. The other is solvents. A lot of things are not water soluble. Or a lot of chemical processes don't use water as a solvent because water's quite reactive and can do all sorts of other things too.

And so we can really increase the solubility of the substrate. When we do enzyme assays in the lab, we think about millimolar concentrations. Absolutely not at scale. There's no way we would ever run a reaction at millimolar concentrations of substrate or feedstocks. We're talking about multiple molar concentrations.

And so there you get your orders of magnitude improvement in yields as well.

[00:36:41] Daniel Goodwin: try to think practically on this, we have a brush polymer, which is holding things in. You can swap out the protein. Is it the same polymer every time or does that have to be designed per enzyme?

[00:36:52] James Weltz: It's a great question. The short answer is no. We tuned the polymer for each enzyme and application, and that allows us to get really good stability. What's been really interesting here in our product development efforts is we found what we call a big six, which are six formulations that stabilize many different enzymes and get our customers really excited.

So all they have to do is try a kit of six resins. Usually they see a really clear winner of those six that enables a lot from the customer and then we can always go back and tune it really? It's just molar ratios of the different monomers. Some proteins really like a hydrophobic kind of greasy environment.

Some like a salty and hydrophilic environment and sort of everything in between. So we mix those ratios, different ingredients and different ratios, but these are all pretty cheap polymers that are already scaled today and other applications.

[00:37:44] Daniel Goodwin: There's an interesting question about the business side of what you're building. And just the last podcast we had was with the awesome crew from grow everything, which is a marketing and storytelling firm and we love them. It was all about bringing people to you. The question basically is like, how does a tiny little company with some cool IP attract pharmaceutical level players to say, we're going to trust you with our IP and so do you kind of, this is really kind of a startup growth and founder question.

How did you go about finding these pharmaceutical customers?

[00:38:12] James Weltz: Yeah, it's a great question and all the credit goes to Alex. My co founder and CEO who's led the business development efforts here at Cascade, and he's been really successful. But the good news is that all of these enzyme practitioners are looking for these types of solutions, and they all go and hang out at the same conferences and professional development events.

And so we've been really fortunate. We've sold our enzyme immobilization residences, body armor into the pharmaceuticals, the flavors and fragrances, especially chemicals, all of these different markets. But these folks all go and hang out at the same places, and they're looking for the same types of solutions.

And so it's been really great. We've been able to get our technology into the hands of over 20 paying customers in these diverse markets, despite having a business team of one person, Alex. So it's been fantastic.

[00:39:01] Daniel Goodwin: I really love it. There's this phrase in startup land, which is that good companies and good products are bought, not sold. So that gets me really excited. And I think there's kind of a meta question here, which is also from the community, which is the broad question is what are the biggest challenges of the enzyme industry?

And I think that's probably pretty well articulated by these major players that are coming to you. So I'm just going to ask you to in the verbatim openness, which is what is the biggest challenge the enzyme industry faces?

[00:39:29] James Weltz: Yeah, it's one of cost. I think it's as simple as that. It's cost and speed but essentially you're competing with traditional catalysts, traditional petrochemical feedstocks and energy and materially inefficient processes that can scale really well and can reach unit economics that are really impressive.

And so what we need to do as an enzyme community is really show that not just in a few cases, but in all cases, that enzymes are not only the superior catalyst in terms of chemical performance, but that they can reach these costs. That are not only competitive, but much, much more attractive than existing chemical processes.

[00:40:11] Daniel Goodwin: It makes me think of the great work that Align Foundation did. Doing an enzyme olympics. So they pick a protein, everyone has to optimize it, everyone sends their designs and then they validate it. Once you think about that, you think, gosh, wouldn't it be great to do an immobilized enzyme olympics, right?

Make this thing work at 200 C or, work at 120 or who can be the fastest? And this is just referring to the use of the word community, which I think is so important. Community was behind AlphaFold. Community was behind a lot of the biggest advances. And has there been any community development in the immobilized space?

And have you ever thought about how Cascade might be able to work with that?

[00:40:48] James Weltz: I love that. It's not something that I've seen or thought much about, but it's a fantastic question. And I think there's some really interesting opportunities where I see that really being an unlock. It's been unfortunate that I've had to go into the nitty gritty, but a lot of these chemical manufacturing problems are nitty gritty.

And so the problem selection, which I know speaks to the homeworld philosophy so much is really an important one. And, in some cases, there are some very specific problems that if you solve them can have these non specific, huge outsize impacts on chemical manufacturing. So I think if we can think and get Industries buy in on those types of things and get the right questions.

There could be some really cool opportunities to engineer some really impactful immobilized biocatalysts. I think that's a great idea.

[00:41:35] Daniel Goodwin: Cool. I'm going to ask one more question before we go into rapid fire. , and I'm just going to scale it into, thinking 100 year Asimov scale. It starts with the idea that if you can do a two enzyme cascade, maybe one day you can do an N, right?

And when you get to N, then you've got synthetic life stapled to a scaffold. And so it brings up this whole idea of artificial cells being stapled in. And that was an idea that came in from the community. And I'm sure that probably has come through, but inside all of this is cofactors, right?

And coenzymes. And so the question I think is really good. Is it, when you think about coenzymes and cofactors, is it the cost of the cofactor that raises the cost of today's system, do people think about currently producing both the cofactor and the coenzyme in the same expression host, or how do people currently think about that today?

And is there a rethinking of this that takes us to the hundred year scale artificial life stapled to a piece of glass?

[00:42:28] James Weltz: Yeah, it's a great question. And I think going to the pharmaceutical industry is a great way to look at this because they've already done this. In a commercially viable way. The pharmaceutical industry is making really complicated molecules, and in some cases, they've gone to 20 enzymes. Plus, some of those are cofactor dependent enzymes in cascades, and they've made money with this.

And of course, they're making pharmaceuticals, but it's been done. And really, when you look at what pharma has been really motivated to solve, it is this problem that enzymes are catalytic, but cofactors are stoichiometric. So what you need. For every mole of product, if you're doing a cofactor dependent reaction, you need a mole of cofactor, but you don't need a mole of enzyme.

You just need a few enzymes cranking away doing the reaction over and over again. The catalyst doesn't get used up. And so what the pharmaceutical industry has done is put a lot of effort into regenerating cofactors using low cost chemicals or electricity. And so if you can instead break that stoichiometric requirement of cofactors.

Then you can really drive down the cost of these reactions and convert them into something that's suitable for pharma and the specialty of specialty chemicals into something that can be used at commodity scales. And that's something that we're working really hard on here at Cascade and developing IP around is how can we make these cofactors.

Last for a really long time and get millions or tens of or hundreds of millions of turnover events per cofactor in these reactions to drive down that unit cost tremendously. But I absolutely see it as it's a cost. And there's some really clever biological tools. By the way, you mentioned these artificial cells, whole cell immobilized bio catalysts have existed for decades.

This is something that's actually being used in industry today, where you take a cell, you permeabilize it, you fix it with your glutaraldehyde and you run your substrate over it, and you get your product out. And these are basically zombies for lack of a better term. These are dead cells, but there's a little bit of action going on in there, chemically speaking and folks have been able to do that.

But really, by making the enzymes discrete steps and not relying on the whole cell, you get rid of so much other. extra things and you exert so much more control over the system that allows us to really reach, I think, some really exciting scale.

[00:44:50] Daniel Goodwin: Wow. I'm going to have the visual of a Gulliver cell stapled down by a lot of little Lilliputians. James, it breaks my heart to start wrapping this up. I want to say this has been so much fun and I've really learned a ton. And we've left stuff undone. We didn't get to talk about microscopy. We could talk more about the cascades of the future.

But I want to wrap with some rapid fire questions and hopefully we do this again. James what's a single book, paper, art piece, or any idea that blew your mind and shaped your development as a scientist?

[00:45:20] James Weltz: Yeah, Rendezvous with Rama by Arthur C. Clarke I think is a fantastic example. If you haven't read it, It's very short. It's like a few hours of your time. It's totally worth it. It introduced me as a young person to the world of synthetic biology and thinking about how you would engineer biological systems to perform a particular task beyond life.

I'll leave it at that. I don't want to spoil it. It's a fantastic story.

[00:45:45] Daniel Goodwin: That's my next book. Now, best advice line that a mentor gave you.

[00:45:49] James Weltz: It's a great question. Fall in love with a problem, not a solution or a technique to solve it. Yeah. I think hopefully this talk it's highlighted some of the interdisciplinary efforts to solve these problems, but really picking up pieces from broad industry and academic work.

But really fall in love with the problem and then keep an open mind don't fall in love with a particular solution.

[00:46:12] Daniel Goodwin: If you had a magic wand to get more attention or resources into one part of bio, what would it be?

[00:46:18] James Weltz: Yeah, I mean we've mentioned alpha fold I think we have 100 years of enzyme structure that's gone into that and made that possible but what we don't have is enzyme dynamics. Enzymes dance, they move, it's required for catalysis, and it's really a big black box. We have very limited tools to do this.

I know this is an answer that other folks on these talks and podcasts have given before. But, huge shout out to Dorothy Kern and all the other academics that are working really hard to elucidate how enzymes are very dynamic things.

[00:46:48] Daniel Goodwin: And the last question is based on the fact that you're obviously a world leader in this topic. And you've seen a lot of people since you've been working this in 2013, you've seen a lot of people be successful and some people be less successful. So what is one skill or part of their professional development in bio that you would advise people to make sure they're investing in on themselves?

[00:47:11] James Weltz: Yeah, I think it's important to have one area where you become an expert. But I also think it's just as important to spread out and get exposed to a lot of different topics. It takes a lot of different types of expertise to really have a huge impact and to solve some of these challenging problems of today.

So I think if you're really interested in biochemistry, also learn about analytical chemistry and the theory of measurement and quantification. That's super important foundation for understanding how we measure the performance of enzymes, for example, so I would say, broaden your horizons and learn as much as you can about as many things

[00:47:49] Daniel Goodwin: Amazing. Now, James, this has been an absolute pleasure. And the last question is how do people find you? Follow your journey, where would you point us to?

[00:47:56] James Weltz: Yeah . You can reach out to me on LinkedIn or by email. My email is james at cascadebio. com and happy to hear from everyone.

[00:48:04] Daniel Goodwin: Thank you so much, James.

[00:48:06] James Weltz: Thanks, Dan.

[00:48:07] Daniel Goodwin: Thank you so much for tuning into this episode of the climate biotech podcast. We hope this has been educational, inspirational, and fun for you as you navigate your own journey and bring the best of biotech into planetary scale solutions, we'll be back with another one soon.

And in the meantime, stay in touch with homeworld on LinkedIn, Twitter, or blue sky. Links are all in the show notes. Huge thanks to our producer, Dave Clark, and operations lead Paul Himmelstein for making these episodes happen.

Catch you on the next one.