Synthetic Biology and Natural Products - Dr. Philipp Zerbe

Hi everybody and welcome to this week's Talking Biotech Podcast by Calabra. Today is going to be a discussion of the intersection of natural products and synthetic biology. Two ideas that seem like they belong in separate bins but can actually put together very well. And today we're fortunate to have a co-host so welcome Julia Ball. Hi Julia. Hi how are you doing? Doing great. Thank you very much for joining me here. Julia was a student in plant molecular biology last fall and did a wonderful job so she wanted to expand her horizons a touch and well tell me why don't you tell us about it. So what's your interest in science communication and outreach? Well yeah thank you Dr. Fulta. I am really interested right now in communicating science to audiences that don't necessarily relate to science or feel like they know anything about it so that's what I want to do with my career in the future with science communication is find a way to connect the general public with science and make sure they feel really excited about it especially plant science. It doesn't make you crazy all the cool things that we can do yet so many of them are forbidden because of a public misunderstanding of science. Definitely yeah there are a lot of hot topics in plant science I think I'll add back to the needed transformation is one that I do in my lab with medicinal plants. That is you know something like genetic transformation or genetic modification. Those are words that public might sometimes be a little bit afraid of when talking about food or medicine. Yeah the the funny part for me is that we have all these awesome ways to do really good things for the environment good things for people. You're talking about medicinal plants so ways in which we may be able to elevate the presence of bioactive compounds that can benefit people or maybe standardized formulations. All these things are so positive yet the negative perception is still with us and do you really think that we can educate ourselves out of this? It's hard to educate ourselves out of an issue like this because so many people have previous biases and years related to biotechnology so first you have to connect with the public on a personal level and gain people's trust and then you can start talking and reversing the damage that has been done in the media. Wow you're been well trained. I wonder who taught me that. Well this is really great I'm really glad that you're able to join me today. We mentioned that you were a student in my class at the University of Florida you're in your senior year. Yes my senior semester. The last semester and so what are you doing next? I'm working in a lab in the University of Florida of Agricultural Sciences Department. We study the biosynthetic pathways in all different types of crops and other plants that are important to human health. So one plant that I'm studying right now is a species in the genus scutuaria called scutuaria barbata. It's also known as skull cap and this plant has a variety of different properties that are really beneficial for human health and a lot of those properties come from these bioactive compounds that are made through different specialized metabolic pathways. So I'm really focused on improving those pathways through genetic engineering techniques and then in the future I am planning to pursue a PhD in plant biology and the school that I'm going to is still unknown but I am in the midst of applications right now. Well this is kind of timely then. So if somebody is listening and they go here somebody we must have in our program they could technically actively recruit you. That's true they could for anybody listening in. Have it seems like Julie is a good fit and she probably is. I can speak to her academic excellence and she's hanging out in the laboratory that probably doesn't doesn't tolerate a lot of slackers. I didn't know Dr. Dr. Kim is a pretty serious scientist and I think she probably is an excellent mentor for somebody if you're really interested in learning in that environment. So how do you like the laboratory work compared to the classroom? Definitely the lab work is what makes me so passionate about plant science. I love learning about things in the classroom but you can only learn so much about a laboratory technique without cutting your hands on it yourself. So I really enjoy it. I love one more tissue culture. That's one of my favorite things. Well I've learned how to work with especially working with tissue culture in very specific plant species that maybe haven't had a lot of exposure to the tissue culture around before. So and now we're doing a bunch of different plant species. Not sure how much I can talk about certain ones. No but you don't have to. But that is that is fun. That's my part too. You know I was a solid B student because the laboratory wrecked my A average. I had too much fun in the lab and it was too easy to spend 80 hours a week in the laboratory and spend overnight so I shouldn't have been studying but I had many talks of my advisor is to well it's the classroom that really gives you permission to be in the laboratory and I'm like yeah yeah yeah yeah sure. Uh huh. Laboratories where it's at but in tissue culture I've always had fun when someone hands me a species that's never been cultured before and says figure it out and we do. The mistake everybody makes is they go in the literature and they say okay well how did someone else do it? Because somebody else just went in and said how did somebody else do it? So sitting down and pretending like you know nothing about the species and breaking the pattern. And that that was always a joy of mine back back when I had a whole lot more energy to do those things and stare at a thousand plates every day. Okay so let's cut to our guest. Our guest today is Dr. Phil Obserby. He's a professor at the University of California Davis in beautiful Davis California. Welcome to the podcast thank you much Kevin and Julie. Yeah very much appreciate you having me. Yeah I appreciate having you aboard too. I always like going through your papers because you cover such a diversity of stuff and you kind of you know just like many many different areas that range over such a large scale but I'd really like to focus around today around synthetic biology and the production of natural products and so just to kind of start off I could you please explain what synthetic biology is and why this is an attractive means to generate products that are otherwise present natural. Yeah so starting off with the most difficult question what synthetic biology it's such a broad field and it continues to expand. If I were to define it I would say it's really a field of of signs and research where we're using our knowledge of biological systems to design and engineer biological parts processes and entire organisms toward natural products that are helpful to various industry sectors. To the second part of the question why do it? I think if they're really looking at plant natural products as say the target product in this context it gives a new alternative approach to extraction from just the natural producers to chemical synthesis where we can essentially harness the ingenuity of plants and making all this chemical diversity and redesigning towards natural products that we can make without having to tap into exploiting the natural resources so the hope would be finding ways to do it sustainably and I think that for me is where the hope and synthetic biology in the context of natural product lies. Well speaking on the ingenuity of plants and chemical diversity within those plants I wanted to touch on the fact that your research focuses on the incredible diversity of turpinoids in plants and they're potential to enhance bio products. Can you provide some insight into what turpinoids are and why they're so valuable for applications in medicine industry and even other fields? Yes, heavy too. Turpenids actually happen to be one of the you know if I like to go out on limb and say it's the most diverse class of metabolites in nature they're important and they're fascinating to me as a study system because they're actually abundant all kingdoms of life or organisms make turpines they're extremely diverse in their chemistry and their functions. In plants particularly they make probably the largest diversity of turpenoids in plants they function as hormones so they're critical for plant growth and development and plants extensively use them to communicate with the environment anything from defenses against diseases and insects to attracting coordinators has contributions of turpines to that so they're incredibly important for plants to survive and to thrive in their ecological niche. For me they're beautiful they said but biological importance interfaces with human users as important as they are in nature turpenoids also are really in our everyday life they are important by products in various sectors cosmetics, fragrances, biofuels, therapeutics you name it and maybe to just give you examples right your toothpaste in the morning that sort of mente fresh taste that's menthol that's a monoturpen with the perfume all the sort of fruity citrusy smells a lot of those are turpines they're putics a lot of our current single drugs are turpine derived and so But this kind of goes on and I think why I work on these why I'm been working on these for so long is this really important interface of this Metablet class that's important in nature But barely understand how important it really is and how it functions and what we could do with it Yeah, the big place we ran into it was in flavors in aromas, right? I guess a lot of the flavors and strawberries come through Important ones like little little come through a sesquiturpees, but let me be the devil's advocate in this and that instead of trying to engineer Plants to to make more why not just grow more plants and impute and improve Purification methods so that we could just capture what's naturally there more efficiently It's actually a really important point because I think one thing I would want to stress is that synthetic biology It's not meant to replace those more traditional approaches. I think there are cases where we have Plants that can be cultivated that make important plant nature products and those actually if you think about it can be really important for farmers to diversify their portfolio Especially in times where yield smiloses are apparent Where they have other economic challenges. I think there's actually great opportunity to tap into that. I think where synthetic biology really can be extremely helpful is to expand our access to natural products that are Produced only in very small quantities in plants that cannot be cultivated at scale In plants that are maybe rare or in danger and where we need to protect that biodiversity And likewise products that we cannot easily access with chemical synthesis And I think where synthetic biology is not there in my view to replace that I think it's there to complement it. I think that's it's amazing advantage that we can utilize I remember a years ago learning about compounds like vinblastine and chrystine So compounds that are critical for different types of the therapeutics for cancers that are present in Tiny tiny little amounts that you that they would grow acres and acres of Periwinkle and harvest them just to get a few milligrams of the final compound And is that really where this kind of synthetic biology approaches may really accelerate the ability to produce those rare compounds? Yes, I think that's exactly where it is what you have to think about Periwinkle as a plant You can grow it But it's extremely hard. It's extremely hard to modify as you mentioned these compounds are there in very small amounts in very complex mixtures So purifying it for drug use from those plants is not only complicated It's expensive and that right those costs will be directly laid over to the patients Taxo will be another example right? It's produced in the bark and the needles of a conifer tree the utree many of those species are actually now endangered Because we have exploited them for making this drop nowadays Texel is produced in needle cell cultures at scale But if you think about if we can use The enzymes and pathways that you trees are using to make Texel and we can engineer that In say a micro that you can use by the established fermentation processes There's a way to sustainably make a drug more cost-effective Right, which is super beneficial if you think about the Increasing need especially of chemotherapy like vimlist rastine vincristine and Texel That goes right into my next question. So how do researchers identify which plant species for strains or the most promising for these biosynthetic pathway discoveries and what our mixed tools can help accelerate accelerate this process It's a really good question because in many cases right so when I look at my own research we go back to the old literature We go back to and talk to people who have knowledge of traditional medicine Who work with these plants and you start there and you start there really deep literature reviews trying to understand where where are their compounds that could have At relevant bioactivities That's one approach the other approach that people use is sort of broad chemical screening Right, that's very common in the drug industry But you can do the same from plants where you simply screen large amounts of chemicals and see what has a desire By activity and then try to follow up on where is it produced so you can go both ways sort of big scale Screening versus deep literature of you to find plans of interest and then start to Really screen those analyze those to see if there is potential I think for that part that how can omics technologies help I think omics technologies have made it possible To even think about this right so the way we go about it in the lab and that holds true for many labs in this field is We obtain these plans where we can we do a full metabolite profiling using the tabulomics We do a full transited profrialing and that allows us to then not only unless Where in the plant are these compounds made or accumulate What extent but also then it allows us to say okay This compound is only about in the root so we look for genes and enzymes in the roots that Will allow us to actually now follow up and try to identify the underlying genes Because that knowledge is critical if you want to do synthetic biology You need to know the genes and so omics is absolutely critical and the advances in it and That become a little increasingly cheaper as incredibly help push this field What about the idea of taking things out of plants so you have plants which have You know, they produce some sort of compound But have some limitations because either substrate availability or whatever How useful is it and what are the limitations of moving it in the microbes either finding a Bacterial or fungal host that can do the same job with the same genes Only produce compounds better in a fermenter than they can in a plant growing in soil Yeah, I mean that's this sort of like hurdle number two hurdle number one is find the genes the enzymes in the pathways hurdle number two is exactly what you say is how do you now make it at scale in another organism It is doable and we have many examples where people have successfully moved entire pathways of multiple enzymes from a plant into for example bacteria like ecoli onto yeast systems our days Tobacco writing equitiana binsamiana is very popular to actually move it from a plant into a plant system That is more easily scalable The advantages are That you can scale it and that's a big issue right if you are targeting a natural product within a plant there You know it is not cultivatable at scale That's the next step the hurdles are you're moving it from its natural environment into a hitologous environment That means all the fine tuned regulatory components that you have in the natural producer suddenly are not there anymore And that actually is one of the major hurdles in pathway engineering is that you often see Yes, all my genes are there But I still don't get any product because the organism is quite capable of not wanting to do this And so the understanding of regulation and overcoming these regulatory hurdles is the biggest hurdle in moving to scale When talking about these hurdles Are there advances in technology now that are working towards overcoming them? Yes, absolutely at multiple for multiple perspectives Right there Approaches where a lot of genome engineering is happening where people Reengineer entire chromosomes to adapt them to productivity of an artificial pathway Omics technology again can be extremely helpful in this where you engineer the pathway and then use multi-omics approaches to understand Where are the regulatory hurdles where do I have inhibition of the pathway? Do I have site products that are undesired and when that knowledge then you can use to reengineer your host organism to bypass those issues So there's a lot of these combined approaches happening everything from engineering the proteins to be more efficient more stable Removing undesired site products, increasing specificity all the way to actually engineering the host organism To be more amenable to this new pathway are happening and they're advancing at that That's a good place to take a break. We're speaking with Dr. Phil Obserby and with our co host Julia ball He's a professor at the University of California Davis. This is the talking biotech podcast by Calabra and we'll be back to you in just a moment And now we're back on Calabra's talking biotech podcast. Phil Obserby He's a professor at the University of California Davis Department of Biology and our co-host Julia ball who is an undergraduate student a senior Who is at the University of Florida and someone who survived my molecular biology class? So that's pretty cool. I were talking about using synthetic biology to generate important natural products That kind of combines two very seemingly disparate areas of having natural products that you're producing synthetically And it seems like you know Seems like two ideas that are two separate spheres in the venn diagram yet do have some very nice overlap So could you give us an example right off the bat of what is a real success story of this? Where is somebody done something that is generated a beautiful example of a natural part? product that has been developed through manipulation of the organisms, gene expression, to create it. Yeah, I think the example I would choose is probably one that many people have chosen, but I think it's very timely because we had a major breakthrough in this last year, and that's the production of textiles. So the chemo-septical Iraq that originally was identified in Utrees. And so just last year, several groups in the U.S. and Europe and in China actually had major breakthroughs in understanding the enzymatic pathway on how this product is made. For some very brief background, textiles identified in the early 60s. So it's been decades of work, and many, many groups across the globe have tried to understand how does this dream make it. It was always predicted to be about 19 enzymes to actually make this very complex compound. And so in these recent breakthroughs that were published last year, several groups have used omics technologies, chemical synthesis of substrates, and integrated that with synthetic biology using this Nikotiana and Semiana platform as a whole system. And they were able to now produce a critical precursor to textile called Bacatin 3, but also actually textile itself for the first time using a minimal pathway of I think 10 to 12 enzymes. And since last year, we're now able to use password engineering synthetic biology to make textile. So far, this has been at analytical scales, but I think in the next few years we'll see major advances in the production of textiles. I think seeing how long it has been from the 60s when we learned about textile to now 60 years later, more than 60 years later, we have identified this shows us the scientific advances in the field. And my hope is that it will open new avenues for making these types of drugs more cost-effectively. Do you have any sense of how that relates to, like let's say scale meaning, you know, for every bit we can do in the laboratory would be a thousand acres of uterus. Or do you have, is there any sense of how the laboratory side is enabled the concentration of this or potentially lowering costs for consumers for therapeutic? Yeah, I don't remember the exact numbers, but remember early on reading that right, a dose of textile for clinical use is something around one tree. And you can roughly extrapolate on how many cancer patients we have and who require this drug. So the production levels for the end-of-nate pathway are at the milligram range, low-gram range. This is not industrial scale yet, but with established fermentation procedures in place, I would foresee that in the next two years, we are probably close to industrial scales. What kind of barriers exist when it comes to bringing novel compounds that have potentially life-saving properties like tax-salt to the market? Yeah, there are many. The scientific ones we touched on a little bit, you have to identify the genes, you have to overcome biological regulatory hurdles in engineering and efficient enough pathway. Among other scientific hurdles to actually make the system productive, purifying the compound is another scientific hurdle, right? You have to find a way to purify the compound cost-effectively and using non-toxic approaches as much as you can. There's that in the bigger hurdle, right? Coming from being able to produce a compound to an actually-reaching market, that somewhat outside my expertise, I do live in my little academic bubble there, but right, like bringing these compounds to market that obviously requires extensive testing, extensive clinical trials, extensive regulatory review through the FDA and other agencies depending on what the natural product is. And that requires a lot of time. With synthetic biology making strides and plant biose. Sorry. With synthetic biology making strides and plant product biocentrises, what kind of plant-based natural products can we expect to see more of in everyday consumer products, like cosmetics or cleaning agents? I think we can see a whole range of different products. If I focus in on the turpenets alone, what we mentioned the fragrance industry, there's a great interest in accessing fragrance ingredients that are rare or unsustainable to extract from natural resources or that require extensive chemical synthesis. So I think there's a great interest. My lab worked for some time on for example this Abianol, which is a precursor to Ambrox, which is a base note for fragrances. For massotic cuts, absolutely. We have explored maybe 1% of the plant kingdom. I think we understand the potential that is out there in plans to find new advanced treatments and drugs. I could see certainly new pharmaceuticals coming through this pipeline being accessible through synthetic biology. You can think about biofuels, a lot of turpenets are biohydrocarbons, they burn. And so there's a lot of work for example at UC Berkeley and the Joint Biology Institute for jet fuels, for example, sustainable production of jet fuels. And it can all reach all the way to for example natural rubbers. There is work going on that is trying to engineer the pathway to natural rubber to avoid exploitation of windling natural resources. So the list of possible products is exciting and as long. All these are really cool new technologies. Do you think that the current intellectual property environment is really equipped to handle the complexities of this? Because this is all new stuff, like we saw a crisper cast. You know, nobody knows who owns it, you know, that kind of thing. Are we seeing the same thing happening in synthetic biology? I think it is extremely complex. And I think it really depends on the type of product that will be patented, will be under IP. I could see that for therapeutics, other type of related natural products that the procedures for IP can be adapted from pharmaceuticals that are made microbially or so chemical synthesis. So I think there is probably enough precedence for that. I think it's much more complicated than we endeavor into engineered organisms, plants, where we are reaching the realm of plant patterns and food and agriculture, where they are different rules and regulations, where we have to see how has this to be regulated. Right, it intersects then with consumer preferences and consumer concerns. So this is I think is extremely complex, where I think we are certainly in danger of falling behind the technology development. I think one aspect when we think about plant eras therapeutics is who owns the IP. I think that is something that very much is an urgent need to understand and figure out. Right. Is it the labs and the companies that develop this synthetic pathway? Is it the peoples of the countries and regions where these plants grow? Is it the people who develop the traditional knowledge of their biorectivities? How do we protect the entities that involve this? I think the Nagoya protocol is sort of a first big step in that direction to protect biodiversity and protect, but germplasm and genetic resources. But doesn't extend to knowledge in that sense. And I think that is something that people are very aware of, but I don't think we have arrived yet at really an established way how to appropriately allocate IP rides to all the different people who have contributed to the discoveries. We've touched on how these products made from bioengineering techniques could be used in the consumer field and in the market. But how do you think consumer perceptions of bioengineered plant-based products change depending on their intended use, such as food versus medicine? I think it's extremely complex. My lab does work in the discovery of pathways towards therapeutics. We also do work in aroma metabolism and fruits. And even in our interactions as scientists with the growers and with the consumers, it is apparent that there is an enormous diversity of opinion. There's so much opinion that so rapidly spreads through social media that the problem is very complex. People are, I think, generally more accepting of chemical synthesis and telepology, microbial engineering when it comes to therapeutics. I think we maybe understandably so have a lower threshold to where our medicines come from. Because we have to take them maybe. When it comes to our food, I think it's a whole different matter. A matter of choice, a matter of uncertainty where I think there's a long way to go to really have the consensus between growers, scientists, consumers of what are the tools, what are the approaches that we find mutually agreeable and how we want to produce our food. I think that very much needs a lot of discussion and a lot of work. Yeah, that's something that we've noticed for a long time. When you're talking about food, you're invading on kind of cultural uncertainty. social norms that people can have food choice or as medicine you're talking about hope for cure. And one of those you kind of intellectualize, you know, one of them's in the system one dot the encounter in the cerebral cortex. The other one is kind of food is hitting the reptile brain, right? First level of basalos hierarchy of needs. So the way in which people perceive genetic changes to either food or medicinal are very much at odds. But how much do you think that we are scientists? And I know you got a lot of folks at UC Davis who do this very well. But how much responsibility is it on scientists to really take a lead in explaining this to the public? I think our role is critical. I think our role is critical to really discredit what we're doing. What is the intention? What is the approach? What are the outcomes? What are the risks in our experience? I think we must bring that to the consumers. And I think importantly so we must bring it to them through the media that they use. Right? That to me is something I would say we are scientists. I don't like to say failed. But maybe have overlooked for too long is that our outlets of communicating this knowledge are publications, professional presentations and so forth. All of which are important. But we have overlooked discussing it with the public where the public is reading it. And I think that's your generation Julia. Maybe that is much better at that. And it's in my view urgently needed that we do this because I think that is rebuilding trust. It is rebuilding understanding and can really I think help consumers to make the best choices for themselves. It's interesting that you touched on my generation of scientists and even my generation of just all of us people in society. I think we share a special opportunity with each other to communicate through social media and other means through the internet that in previous generations there was not an opportunity to communicate so broadly across the world and share so many ideas with each other. And so I think just by the nature of the internet and social media our generation has developed the skill that maybe many others don't have or haven't developed in the past which is to communicate each other's thoughts and opinions sometimes in very interesting ways to each other through that media. Yeah, the big problem is that it's hard to make a tick tock video that says tax all might save your butt if we make it in a micro versus you know you see the else are going to kill you again. You know that whole thing is quiet right that's almost what's required and then don't get me wrong. I'm not trying to say right I'm putting it on your generation shoulder. I'm just thinking if I look at myself and I look at my students that my students are so much more open to it, so much more adaptive to it and that's my my own failure that I'm not more adaptive to those technologies and that but I think in general as a scientific community needs to do this actively and constantly and really engage with this. Yeah, but you know the other part of this is that in your generation of scientists and you know mind generation scientists we never got a gold star for doing it. In fact, we were discouraged from wasting our time talking to those people about this stuff because it doesn't matter the science will rule the day and the publications will and we realize that that doesn't work. Absolutely. I have those words very much ringing in my ears, but it has to change. I think we see this more than ever before how important it is. I'm a student looking at graduate school and eventually a career in these areas. I'm wondering what kind of training would you recommend for an undergraduate or even a high school student that is considering a career in synthetic biology or natural products chemistry? I think there are few things you can do. I think the one that I always recommend first and the most is get exposure. Use opportunities for fellowships, internships, workshops and the opportunities that allow you to get hands on experience in what the work is actually like because to me the reality is it's one thing to be fascinated about something from a course. That's great, but actually experiencing doing the work is another thing and I think as a student you can learn a lot about what you're passionate about and what maybe not so much. Every time you're passionate about an idea but the actual work maybe is not so much your thing. And one thing that drives all of us and up in a Korean science is that passion before that science and I always want my students to find that thing that they're passionate about. I think exposure is the one thing that maybe matters the most as much as you can. One thing that everybody recommends and because it is true is networking. It's talking to people in these fields to different people not just as a graduate student to your professors but to people in industry, people in nonprofits, people in government, wherever they are to really get an understanding what is your perspective on this. I think that's really important and it's another generational shift I would argue that me as a professor it is my task to provide them at least the opportunity right it's it's actually not enough anymore that I have a great student in my lab and say this is your project finish it publish it and you'll be fine it just doesn't really hold true anymore. My job is to understand from you where do you want to be what what are your thoughts and it can be different things and then to work with you on thinking okay outside and complimentary to your actual thesis project. What are the trainings what are the professional development options that are important for you to not just make the decision where you want to be but to actually be competitive for it and that includes communication and outreach it includes teaching it can include all the inertia all these components that are actually more and more expected of you as a PhD student when when you finish that was different for me right for me it was still fine you have you published your good it has changed and I think that's an important component that you as a students to understand you have to write to ask your mentor for those opportunities you have to apply for them but you have to write to them and you should be proactive in talking to your mentors about it. Well thank you very much Phil this was really a really nice discussion I appreciate it very much if people wanted to learn more about your program or maybe follow on social media if you're there where would they look. Yeah my website my website so if people just google my name Phil Obserby at UC Davis you will find it I'm also on LinkedIn so that's another opportunity more or less regularly posting updates from the lab so those are probably good spots and I'm always happy for people to email me reach out if they have questions absolutely. I was very good and it's it's phil one L and then I two Ps correct yes almost like Mississippi and then and then and as Zerby Z RBE so that those are the ways that you would find him online so thank you very much for joining us Julia thank you for joining us I really appreciate I hope you do it again. Yeah thank you so much to you Dr. Fulta and to you Dr. Served for joining me in this conversation it was really awesome. And thank the both of you for having me and giving me the opportunity to share some of my perspective and yeah thank you very much and for all those listening thank you very much for listening to another episode of the talking biotech podcast there are a billion podcasts nowadays there used to only be a handful back when we started at 15 so lots of things people can listen to and so we need your help in helping them find us so many times I find somebody who says I can't believe I just found this podcast and now I have 450 episodes to go through share on your social media if you don't mind and write a review on iTunes Spotify or the place where you consume podcast media it's really important because as we go forward and use new innovations like synthetic biology to generate the therapeutics and other compounds that make the human experience better they will move innovations like that to application better if people understand what they are and that's our responsibility to get them there. So this is the Talking Biotech Podcast by Calabra, and we'll talk to you again next week.