Future Challenges and Self Sustaining Research

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In fact, ninety nine percent of their auto customers earn at least one discount progressive. com and see if you can enjoy a little cash back Progressive casualty insurance compompany and affiliates national average twelve month savings of nine hundred and forty six dollars by new customers surveyed who saved with progressive between june twenty twenty four and may twenty twenty five. potential savings will vary Hi, Ia here and you're listening to Science Friday This week, researchers reported an advance in synthetic biology, creating an artificial cell chemicals and biomolecules That at a basic level can grow, eat, duplicate its own genetic code, and reproduce itself properties of living things It's aimed at making biological factories for all the chemicals we need in our modern world But it also opens up the basic question of what does it mean for something to be alive Joining me now is Dr. Kate Adamala a synthetic biology researcher at the University of Minnesota in Minneapolis. Welcome to Science Friday. Thanks for having me. Nice to have you. Okay. Give us an idea of what your lab actually created in this work. Tell me what the objects are. The objects look like cells. And they have a lot of functions, a lot of behaviors that you would normally associate with natural cells. Ecept What we made is fully defined So we know exactly where every molecule, every chemical, every piece of DNA in that thingin goes. and that's the biggest difference between what we made and what real cells are because in real cells we don't know. the full ingredient list. So we basically made an engineerable cell something that looks like a cell quacks like a cell, but is fully understood. teendable and fully engineerable Does it have all the ingredients of what we would consider a cell to have D depends on what you consider a cell needs to have DNA prote translation a membrane and membrane proteins These things are universally shared and our sel does have it, all of it. Our cell also replicates its DNA, which is a function of most of other cells on Earth And it also eats and breeds, makes babies And these are also kind of a hallmarks of most of the cells. So it O this very kind of a fundamental level, it does have most of the building blocks of a living cell, but it's much simpler Is yourself alive I don't know. I I don't think so But it's also really hard to tell because there is no good definition of life. We don't have a universal definition of life that would fit everything we instinctively consider living and exclude things we consider non liivving. and I personally don't think Spadzell is alive because to me life needs to be a little more robust It does grow, it does replicate, but it's the system you can imagine. it's I mean, I love it. it's great, but it's a beginning. So that's why I personally don't think yet qualifies As living, but I also don't have like a scientific reason for it. It's more of a gut feeling So if I looked at it under the microscope, would I recognize it as a cell? I mean, ass a lay person You would recognize it as a cell. It has a membrane, it looks like a blob like you would expect simple cells to look like. Is this a philosophical project or a practical one. What is the practical goal here The practical goal is to make biology better there are some philosophical implications, but that's not what motivated our work biggest problem biology and bioengineering right now, which actually translates into the biggest problem in economy and to some civilization too is that we cannot make biology do everything we want it to do. and what we want it to do is to make molecules, move atoms Right now most of the molecules that run our civilization come from dead biology, they come from petrochemicals Get away from d We need to teach renewable biology how to make all those molecules or we can just give up on civilization, but I don't think that's an attractive idea. So if we want to keep doing everything we're doing use plastics fly places, use fuels, have medicine. We need to find a better way of making molecules And there's a lot of molecules that are very difficult to make with natural biology because Natural cells are not stupid. They're not going to make a toxic molecule just because you ask them nicely.ir metabolism is going to either reject that pathway or the cell is just going to die. So the idea is instead of trying to understand why natural biology c those problems and engineer them out of a natural cell. Let's engineer a cell from scratch And because we engineer that cell from scratch, we have a full control over what it does, over its metabolism. Eventually we're going to build it up to the point when it can move all the atoms that we need to move for our economy. Why do you call it a spud cell?'s a spud is a potato, is it not? A spud is a potato and I'm Polish, so I'm made of potatoes, but that The name um of I can tell you that the pretty story about the name invokes Spotnik, which was the first satellite start at the space age. We're hoping that The first replicating synthetic cell is going to really give a boost to progress in bioengineering. But it really came to be because we needed a name and people in my lab and our collaborators started calling it by my last name And I don't like that. I don't own this technology. I think this is an open source. I want everyone to use it. And so I said call it whatever, call it a potato. And people started calling it a pudzle and the name kind of stuck and I like it. L it. I love it. It's great now You've talked about engineering a cell from scratch. What is wrong with cells we already have? like we have E coli or yeast that are chemical factories like this? What is the shortcoming of those producers too good at what they're doing. Imagine an Eoli is a dreamliner It's a very modern, highly efficient, highly advanced plane And if you wanted to fly from point A to point B or reroute it to another destination, that's great at it But if you want to make a hover craft You're not going to make a hovercraft out of a dreamliner if you want to make something that that very engineered advanced design is not meant to do, you can either try to do a lot of creative and possibly not very good re engineering of an existing chassis, or you can go back to the basics and say, okay, how do we fly and how do we build this hovercraft from the ground up? And that's that analogy holds for biology. ECOi sits on four billion years of evolution. All of that DNA accumulated over time that gave rise to this amazing biofactory that's EOi, but it's highly specialized and not very flexible If we want a flexible biomanufacturing that can be programmed do a lot of things that natural biology is not meant to do, then I know it sounds kind of crazy to say it's easier to make a cell from scratch than modify an existing one, but it really is easier to just redesign the whole metabolism from scratch try to a very complex metabolism that we don't fully understand because we don't have a full map of e coli metabolism of where every molecule goes When you say it's easier, is it just as simple as putting a lot of chemicals in a beaker Well, we use tubes, not because we're not richen up make those molecules at a bigger scale. But no, it's not none of this is easy. It's easier in relative terms. We want to make proteins, drugs, small molecules that are made out of building blocks that E coli or any other natural cell just simply doesn't tolerate so instead of trying to figure out how to take apart an existing complex metabolism that's fighting you every step of the way We kind of want to start from scratch, build it from the ground up. Have you actually made something useful yet? or is this just in a testing phase? Nope, We're not in business of making anything useful at this point. testing phase We made proteins are the size of a useful protein, but they're all reporer proteins. this technology is Very early, it really is like the very beginnings of being able to assemble those lifelike systems from fully defined chemical components We have to take a quick break, but don't go away more on this when we get back In the movies, I'm thinking of Frankenstein. There's always a point where the lightning strikes where the scientist flips the switch and it's alive Now I know you're saying this is not really living or if it may not be dead, it may be alive When do you know it just switches from non functional to functional It switches to functional when it starts making proteins. That's my personal boundary U When The conditions are right, the media composition is optimal, it starts eating and then eventually it starts dividing There is not a single light bulb moment, unfortunately, not very spectacular, but To me, it's the most beautiful thing ever Well, you said the spud cell eats. What does your spud cell eat? It eats pretty much everything but the kitchen sink. It cannot biosynthesize its own building blocks. It has to be fed all of its building blocks So all the small molecules, amino acids. like you, with humans, there are those so called essential amino acids that you have to eat and the rest you can make yourself For S sppad cell, every amin acid is essential. They have to eat all of the building blocks of their DNA and RNA and all of the energy components. And they have to eat lipids because they don't biosynthesize their own lipids Mhm. U If it divides, does it evolve I mean know Can one of your synthetic cells interbreed with another Our cells right now can undergo selection, but not Darwinian evolution. And the distinction here is and again, it's It's not a very strict scientific definitions.s just my personal definition. For a Darwinian evolution, you need spontaneous rise of mutations. In our cell, we can select for beneficial mutations, but we have to introduce those mutations The DNA replication system is too good to introduce spontaneous mutations at the right rate. So it can undergo selection and we show that in our paper that you can select the one that grows faster, but those mutations are artificially introduced. And to me that's a key distinction because it's not yet Darwinian evolution because those mutations don't spontaneously rise in the population. I get it. Speaking of reproducing Does it reproduce indefinitely in your land No, it doesn't. That's part of it not being very robust. It accumulates waste products and eventually it just kind of tapers off. It That's part of the work that we're going to build on it with the Biotic Foundation and the community we're building around it is we have to basically teach it how to take the trash out right now All of the non functional proteins and RNAs just accumulate in the spad cell. and that eventually poisons the metabolism. It' this ability to be able to clean up the waste is something that we urgently need to build into that system so then it can keep going So there's no Fear that something might crawl out of your lab and take over the Eth. Now, it's not going to be crawling anytime soon. But you have to take extra care to keep it alive then, so to speak You have to keep take extra care to keep it functioning. Yes. it's you have to feed it. It's pretty fragile to changes in its conditions, in its environment whichich is why I think it's not robust enough to have to earn the right to be called alive Mhm. So what do you need to make it better? lotots of things. We need to teach it how to assemble a full ribosome. ribosome is that enzyme that makes proteins and it's the most ubiquitous enzyme in cells and that's basically what powers the cell. Right now our spot cell needs to be given ribosomes. It doesn't make its own ribosomes We need to teach it, actually, it sounds counterintuitive, but we need to teach it how to make mistakes Right now the genome replication system is very high fidelity. It doesn't introduce enough random mutations for evolution, Darinian evolution to take over and help us So we need to teach it how to do just the right amount of mutations And we need to teach it how to organize itself better. rightight now it's kind of like a messy teenager's room. It doesn't have cytoskeletons. so everything inside is commingled. It's basically a bug of everything Natural cells are very highly organized. That's one feature that I do admire about natural cells is everything has its own place. So we need to teach ourselves how to build that internal structure, that internal scaffolding organization If you're looking to create a certain object or product Why would you like it to mutate I would like both. I want to be able to introduce genes into it, but I'm also not smart enough to think about every probability, every possibility That's why I would like mutations because I can sketch out the pathway that I want. But maybe I'm made a mistake. mayaybe it's suboptimal, mayaybe it's like two mutations away from being actually perfect. And that's why I would like to give myself the ability to introduce some mutations because then it can learn itself. If I give it a pathway, it can run with it for a while for a few generations and hopefully develop a better improved pathway Mm. how hard is this to do to create these artificial cells is that the kind of thing that that other groups can read your paper and easily replicate There are parts of that protocol that are very easy to replicate and many groups already do those experiments part of that process. There is one part of the process that's particularly challenging And we were only able to teach other labs to do it with hands on instruction. And that is creating the compartment, creating the liposome, the vesicle that encapsulates the pud cell. This is it process. I call it tricky rather than difficult becausecause once you getet a hang of it once you have that knowledge in your hands, muscle memory, you can do it every time. To learn that there the learning curve pretty steep And that's one of the problems that we want to solve with the biotic community is to turn that protocol into something that you can truly just pick up by reading, not by this medieval style hands on instruction. So when when do we expect to see a product? I imagine you'll be patenting this if you haven't already, creating a company We filed IP on this podzle and that IP is going to be used by the Biotic, which is the foundation we started We want to keep the spud cell, the chassis or the kernel of that biological operating system in a public domain. So basically everyone can use it to develop nonprofit applications. So academia and nonprofit researchers can use it to improve on it. We hope they will use it to improve on it. But we did patent it because that's part of our strategy to keep this growing. because it's patented, once we get better at applications, we hope that companies will span out of it and then licensing fees from the products that those companies will make will go back to Biotic, the foundation that supports the research in this field. So it's you know, going to be Pun absolutely intended a self sustaining, self replicating cycle of applications bringing in money back into the foundational research development M, we wish you good luck and will you return to us when you