 I think she's been putting all the new stuff in the past. Like, besides the new, but like, this is the same. That's new, that's different. Like, she's been doing different stuff. Yeah, so just help. Okay, let's do this. We will start this show. Everybody ready for a podcast? Yay! Yay, look for the podcast. Starting in three, two, this is Twist. This week in Science, episode number 760, recorded Saturday, February 15, 2020. How to make a protein. I'm Dr. Kiki, and today we will fill your head with thoughts and questions. But first... Yes, clamor, disclaimer, disclaimer. From the beginning of human civilization, nature has been altered. The first organic harm was a shock to the senses. What through these strange grains are in this field? It looks like the grains from the far side of the valley and also the ones from the other side of the mountain. What strange goats are these? They're smaller than normal goats. You're not afraid of people. What strange fruits you have growing on the vines? They're so much bigger than the ones I normally can pluck. And what is this insane claim you are making about owning things? These goats, that grain, those fruits? You haven't even plucked them. How can they be yours? And while humans have altered nature in greater ways since the invention of farming, it is important to remember that altering nature has always been an essential strategy for our survival. For example, the hand-picked story you are about to hear on This Week in Science, coming up next. This is the part where the audience dances. If it's loud enough and you can hear it, then we dance. What's happening? What's happening? What's happening? And a good science to you too, Justin Blair and our listener out there. Welcome to another episode of This Week in Science. We are live, recording live at the annual American Association for the Advancement of Science conference in Seattle, Washington on the Sci-Mic Studio stage, presented by the Study Shows, a widely podcast. And we are so glad to be here. Thank you everyone in the audience for joining us today. Welcome. Do you like science? It's a good start. On this week's show, we have a little bit of discussion about the science here at the conference, and we have an interview. But as we jump in, I would like to remind you that if your friends aren't subscribed to This Week in Science, maybe you should tell them to subscribe. And you can send them to twist.org to find information. Or just tell them to search any podcast directory, YouTube, Facebook, all of the things. So for this week in science, they'll find us. Subscribe. Okay. I would love to interview our guest, introduce our guest, Dr. David Baker, his professor of biochemistry and the director of the Institute for Protein Design at the University of Washington. And he is here at the AAAS meeting, talking about his work in designing proteins from scratch. I would love to know why do we want to do that? Well, proteins are the nature machines that carry out essentially all the important functions in our bodies and in all living organisms. And the proteins that we and everything, all other life forms have in them are the products of millions of years of evolution. And they evolved to solve the problems that came about during that time, like running away from tigers and digesting food and things. But we faced a whole bunch of new problems today. The planet's warming up. We're producing all these toxic compounds. So we know how powerful proteins are from all the examples we have in nature, but those proteins don't solve the current problems. So basically the reason why we're designing brand-new proteins is to solve the problems that humans have created that didn't really arise during evolution. Why didn't they arise during evolution? I mean, when we think about evolution, it's these modifications through time to solve problems and to allow the organism to survive better, more efficiently. So don't you think that the things that we need would be here by now? Why do we need to keep going? One of the big problems we face is huge mounds of plastic in the middle of the ocean. And those were not there 50 years ago. And evolution takes millions or billions of years. Another example is Alzheimer's is a big problem now. It wasn't a problem 200 years ago. These people didn't live long enough. We just died. So there just are a lot of new problems. And I guess that might be that protein that we're looking for could already be out there. But finding is the trick. It could exist somewhere in nature, but we would have to look through every protein everywhere in nature to find something that we want for this specific task versus just... Well, it's useful in that regard to think about some numbers. So the number of possible proteins, proteins are made out of amino acids. There's 20 of these types of amino acids. And typical protein would be a string of 100 or 200 amino acids. Even for 100-residue protein, the number of possibilities is a number... It's 20 to the 100th power, which is like... which is 10 to the 130th power. All proteins... you took all the proteins that existed in nature and have ever existed. It's a tiny, tiny, tiny fraction of that. It's numbered like 10 to the 20th. So it's like the tiniest grain of sand. So there's a good chance the proteins we need don't exist in nature. And that's why we have to make them. And even then, wouldn't it need to be folded in the correct way? Yeah. Actually... That's right. There's a whole other layer I'm talking about. Exactly. Yeah. You mentioned that you were talking about fold it yesterday and we have talked about fold it for years on the show and appreciate the way that this crowd-sourced computer, this crowd-sourced human ability to find patterns has enabled us to start really digging into how proteins fold and discover those first principles of that confirmation change. How it goes from a single strand of amino acids into folding and connecting and then tertiary forms and all these changes. So how do you... How do we really start? How do you start approaching this problem of a new protein when you're like, I've got a sequence of DNA. I've got a sequence of amino acids. What's it going to look like? How do you go between those steps? Well, there's two separate problems we're working on and that folded players have approached. One is here's a new gene from some new organism that does some... lives somewhere on Earth and here's its amino acid sequence and hold it up and tell me what it does and that's called protein folding problem or protein structure prediction problem. What we are now doing more of in both my group and on hold it is the opposite problem. Let's say we have a problem. We want to break down plastic or we want to cure cancer and there isn't a protein that already exists that does that. So let's make a protein which does that which could be an improved cancer drug and so we first think, well what properties would that protein have? Now we make a computer model of that protein and then we design an amino acid sequence which will fold up to that protein structure and then we make a synthetic gene. This is a brand new protein. There's no gene that already exists in nature. So we make a synthetic gene that encodes that brand new protein and then we put that into a bacterium and the bacterium makes the protein and then we get the protein out and see if it cures cancer. What does it do? How do you know how the body or a cell is going to react to these proteins? Well, we design them to interact with the body in a very specific way for example to suppress an autoimmune reaction or to kill tumor cells. So that's the way we designed it to work and we know before we actually would get to trying it out in a person that it actually does that sort of biochemically but there's also the possibility we do other things which would not be good things and for that, that's a risk really with any new type of drug. There'll be clinical trials starting on the first design proteins we made later this year and then we'll learn. Try it out and see what happens. That's amazing. Proteins have applications in absolutely everything. Enzymes alone are used in all sorts of industry and they're in everything that we do. How are you narrowing down where to start? That's a really good question. That's almost the hardest question of all. So to give you to amplify what you said some of the things that proteins do is they're involved in forming these really cool materials like tooth and bone and abalone shell and we're trying to design new proteins that will get inorganic chemicals to grow and crystals to grow out of them but out of semiconductors instead. So imagine you could make brand new materials that the world has never seen before and then of course we have disease trying to cure disease. We have a big effort now on vaccines trying to make a universal flu vaccine. We're working hard on coronavirus now. So there are a lot of different things so one good thing is there are a lot of people excited about this area who come to the UW now to try and design new proteins but figuring out exactly what the best most important thing to work on at any given time is we're always looking for ideas. Is this something that you want to then scale to be able to send this ability to make brand new proteins to other universities or to people's garages or is that something that you would want help with or is there a reason that you'd want to keep it kind of controlled for right now? Well no we really want to get it happening everywhere so hold it is an effort to get the whole the general public involved in designing proteins and in fact we published a paper a couple months ago showing that folded players can make brand new proteins. It was a totally unsolved problem just a few years ago but now we've got it so folded players can make totally new proteins and many people who have been in my research group go on to other universities and start their own groups also designing new proteins. From Blair's question though do you think that the potential of this right now DIY bio is growing and people are doing CRISPR in their garage you know meddling with biology is this the kind of thing that would be that people would be able to do in their homes or is this still the technology is too large for that to happen at this point? I think that the computer part I think people could certainly do in their garage and then they would need what's needed to actually make the proteins is nothing more than you would have in an ordinary laboratory so you need to be able to get genes and you need to put them into bacteria and grow the bacteria so it is something that would be accessible it would be a pretty sophisticated garage right it's a garage with venture capital funded well I don't know if you need venture capital funded someone who is serious about it what is your main focus and I guess your hope like if this really goes to fruition and you see it go where you dream it to go what is that? to make the world a better place better place through synthetic biology well you know there's like I said new medicines, new vaccines you know new materials like I mentioned new types of semiconductors degrading toxic compounds in the environment you mentioned catalysts we're working hard on making new catalysts so there's no shortage of problems that human space today that in principle could be solved by proteins it's wonderful is there something we have to be careful of when we're designing new proteins are there kind of warning signs you need to look out for where this could get out of hand yeah it's a good question well I think the example of coronavirus sort of helps think about that I mean the viruses have evolved over hundreds of millions of years to be super sophisticated at infecting people making them sick and spreading and there's so many complicated functions involved in that I think even a bad actor who understood how to use our methodology would simply not be able to do that and unfortunately there already are well known ways of killing lots of people with for example the 1918 Spanish flu sequence is just devastating and that's known so I don't think there's much I think the risk from new design proteins is tiny compared to that what we have in nature because that's one thing that nature has perfected you know viruses have wanted to spread since the beginning of life yeah but this really gets the work that you're doing in designing these proteins really gets down to the mechanisms and how do we create this new tool to help us move forward into that better future that you're mentioning yeah so where can people find you and find out more information about the work that you're doing well let's see on the internet there's the Institute for Protein Design at the University of Washington and we have a lot of information there about what we're doing there's a head talk I gave a few months ago that described some of the grand challenges we're working on great so we'll link to that on our website so that people can find that thank you so much for your time today really appreciate me chatting with you thank you wonderful thank you oh we got class from the audience thank you thank you for listening everyone so we are closing out the show about five more minutes here to be able to discuss AAAS and the science that we've seen that really has struck a chord with us while we're here and for me yesterday I went to a panel on the circular economy the carbon economy and how we will be working as humans to be able to address the grand challenges that we are up against researchers from around the world look using sociological techniques to from here at UW are using sociological techniques to figure out how to work with people to get them to be more likely to make changes how what kind of language is important in talking about cap and trade or talking about a carbon tax what kind of words will make it more likely for people to find that agreeable versus less agreeable and how what kind of setups do you need to make that work another researcher from Finland was working on the circular economy which is really an extension of cradle to grave thinking where everything from the ecosystem and the resources that are available are taken into account in the economy and moved through to how the end of life of products and how people interact with them and then researchers at Reichen are using new methodologies to create new polymers for biodegradable plastics and it was just just fascinating and I found out that natural rubber cannot be replaced by synthetic rubber because natural rubber is all cis proteins 100% and synthetic rubber is a mix of cis and trans and so it doesn't work so we have to use natural rubber and now there's a fungus that's attacking it so we can't we need our natural rubber so there are ecological things that were efficacy what did you find yesterday well I went to an amazing talk about the future of robotic companions it was very interesting but the thing that I actually take away from it is that there's always going to be some motivation that drives technology and a lot of the time it is not what that technology ends up being used for the majority of the time so with the internet we had a lot of different drivers that bring us to the better world that we have today with greater connectivity so yes there might be robotic companions that are driving the economy and innovation with robotics but there's a great opportunity for us to have caregivers and better use of robotics in our homes every day so that was very interesting I also found out that I might someday be able to have a shirt that is linked via bluetooth to my phone so I can change the color through an app on my phone which sounds awesome the point that you brought from that AI and robotics session that you talked about last night was the fact that this sex industry and sex robots may be leading the drive for these home companions the technology that will one day be taking care of our elderly could have come from the sex industry may it may fascinating having slaved over for mentors to at random hopefully get a protein that can do something that we wanted it to do my favorite subject have you found anything Dr Baker that has piqued your interest let's see there's been a lot of really interesting things I've been mainly involved in sessions where I've been speaking to me actually my talks are rather boring I've heard them before not as interesting very interesting to ask so thank you so much for joining us did you have anything to add here my favorite part at these conferences always is having on other people's conversations get the expo hall outside of sessions that's where a lot of the really interesting conclusions come from and I think that that is something that I will I always value it in times like this because people are coming together and mixing together in ways that we don't often in our day to day when we have all of science under one roof and we get to have conversations across fields that are totally new and different and I think that's absolutely my favorite part of this conference and the little ear dropping thing that happens is like oh yeah good luck with your fungus this is the path to scientific recombination thank you everyone for listening thank you for joining us today Dr Baker I hope that everyone enjoyed the show let us know let us know share it with a friend I would love to give shout outs to people who help with our podcast Vada for your help with the social media getting the word out and for show descriptions before thank you for recording audio for our podcast and Gord McLeod thank you for manning the chat room thank you also to the boroughs welcome fund and our patreon sponsors for their generous support I also want to say thank you to this study shows a widely podcast for supporting the Siamite studio stage if anyone is interested in supporting us on patreon you can find the link at twist.org or go directly to patreon.com slash this week in science on Wednesday live at 8pm Pacific time broadcasting on our youtube and facebook channels and twist.org slash live we are also available as a podcast you can just this week in science anywhere where a podcast is found and we should pop right 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