We continue season 3 with another phenomenal look at the fascinating people behind world-class science. Paolo talks with Dr. Hans Renata about his journey from Indonesia, to Singapore, to the U.S. and his unique approach of applying traditional organic chemistry, aided by enzymes, to synthesize complex and difficult products.
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For decades chemists have challenged themselves to reproduce in the lab incredibly complex molecules that can usually only be extracted from plants or other highly evolved (micro)organisms. These are often painfully complex efforts from researchers to design and execute multi-step chemical synthesis, where consideration must be given to intramolecular interactions from to multiple functional groups as well as many stability, configuration, and conformational issues. Yet this is how modern synthetic chemistry has evolved its toolbox of useful reactions and how skilled chemists exhibit creativity in addressing some of the most complex scientific problems.
Hans Renata left native Indonesia as a young child to study in Singapore and later emigrated to the US for his academic career, partly spent in the lab of a Nobel Prize recipient. Perseverance and the ability to adapt skills learned at an early age played that played a key role his becoming the chemist he is today: a chemist that make molecules everybody else struggles to imagine. Hans is known for his chemical creativity and his synthetic approaches look like nothing else out there. In this episode we discuss how combining traditional organic chemistry with the use of enzymes is at the foundation of his research and how this could change organic synthesis as we know it.
Dr. Hans Renata 00:06
There's something about looking for the most efficient way to build things, how we can leverage some of these tools to make things that are useful for the society.
Paolo 00:21
Like many chemists, Hans Renata's research revolves around synthesizing molecules. But his use of enzymes in that process is unique. One colleague said, it's a different type of synthesis going on from anything else out there. Today, we get to learn how it's done. Welcome to season three of Bringing Chemistry to Life, in which we speak to members of the Chemical and Engineering News' 2021 Talented 12, about their work and trends in their field. I'm your host, Paolo Braiuca from Thermo Fisher Scientific. We began by asking Dr. Renata about the opportunity he had, when he was 14, the jump started his scientific career.
Dr. Hans Renata 01:03
I was awarded a scholarship to study in Singapore. So I spent four years there. And in the Singapore education system, there's the O level and A level, it's like, it's like the British system. And for my A level, I went to this school called Rappels Junior College, and they really have a very strong chemistry program. So every year, they would send people as part of the Singapore Chemistry Olympiad team. So I think that was also how I got drawn into study chemistry, it was that I guess a little bit of the motivation or just trying to be competitive, to see just to see what how far I can push myself and along the way, I fell in love with a subject.
Paolo 01:50
So as you progress with your chemical studies, you know, you you started as a pure organic chemist, I would say, right. So you've been focusing on some of the most complex synthetic targets that seem to be very exciting for for for organic chemists, you know, the, you know, doing these sort of natural compounds is an incredibly complicated and where you need to design the synthesis for, you know, with, you know, 40,50 steps. And this, these are an incredibly strong exercise, right to develop creative chemistry and looking at it from a certain perspective. How did you like, how did you approach that?
Dr. Hans Renata 02:30
I still love doing multistep chemical synthesis. I, of course, love reading those publications. I think what I really enjoy about the process is the deconstruction process of trying to dissect a very complex molecule into simpler and simpler fragments in I guess we call it retrosynthesis, where you try to work backwards from the target molecule to simpler and simpler building blocks. And you know, and along the way, I think there's a lot of challenges that requires a lot of problem-solving skills. And I think that was always really fun just trying to troubleshoot reaction. Like say, something doesn't work, but you know, that it works somewhat, it gives low yield, and then you try to figure out why it's not working, then just trying to figure out how to optimize the conditions. I think that I think, for me, it's very rewarding.
Paolo 03:26
The way of looking at, how I've always looked at this type of work is obviously I can see I can see the chemistry angle or how exciting it could be. And you know, as the way you're describing the construction of the molecule, and trying to find out a way to get there, but in a way you have nature that does it so beautifully. And it's really, really hard to compete, isn't it?
Dr. Hans Renata 03:47
Yeah, I think that, you know, there's a subset of synthesis, where we try to mimic how nature does the transformation. We can validate the pathway that someone proposed for the biosynthesis of certain molecules. And you will also learn lessons about chemical reactivity that way. For my PhD work, I think I would also say that part of what we were trying to do was inspired by how nature does things. Specifically, we wanted to do this exercise whether we can start with a carbocyclic skeleton that contains no functional groups on it, and try to see if we can put on functional group, in this case, hydroxyl groups or alcohol in an efficient fashion to get to the target that we want. And we did a proof of concept with a with steroids. We had a particular steroid target in mind that's heavily hydroxylated. And we wanted to see if we can achieve this oxidation sequence through chemical means purely chemical means. So I think in that sense, we were trying to emulate nature. It's just that the toolbox that we have is completely different.
Paolo 04:59
And so gradually you evolve, I suppose your your toolbox and when was it that you first encountered the enzymes?
Dr. Hans Renata 05:08
That was, I think our start considering enzymes, maybe towards the end of my PhD, I think at that point, I had some time to reflect on what I had done. And I realized that I was able to make the target that I wanted to make. But that took 20 steps. And I realized that some of the transformations that we were using are rather inefficient. And that's when I started, when I came across some of the work that's been done in the enzyme world. And that's when I start considering working with enzymes.
Paolo 05:45
You're currently focusing on oxidative enzymes, because they give you something that you cannot really do with alternative methods. Is there any other enzyme class that you're interested in you even though you might not use it yet? Or is is there any other high potential area that you see?
Dr. Hans Renata 06:01
Enzymes that can form carbon carbon bonds, we'll definitely be interested in. I think that's probably the the one thing that interests me the most at this point. If you can stitch together different fragments of, carbon containing fragments, at interesting positions, I think that will be awesome.
Paolo 06:24
Yeah, indeed, indeed, of course. Do you find it complicated from the sort of operational perspective, so if I think about how traditional, you know, synthetic organic chemists rely on what chemical methods work, you know, you can have some sort of transition metal catalysis type of methods, which is relatively easy to set up, right, you have relatively low number of ligand metal combinations to screen, the reaction condition scope is more or less well defined from the start, and, you know, you can see immediately if it works, it doesn't work. In biocatalysis, very often, you know, you have big libraries to screen, or you really don't have an engine that works well enough, and you need to kind of design one, right? And maybe we can get that in how you run your research. So, so it needs a set of competencies, which is not necessarily the bread and butter for for the typical synthetic organic chemists.
Dr. Hans Renata 07:25
Yeah, definitely, I think that's probably one of the biggest challenges that I think has kind of impeded other adoption of the method in the field, that a lot of people, all organic chemists feel like, you have to be in the club, or you have to have some sort of training or expertise in the, in the, in the area to be able to carry out the, the transformations routinely. I think, to some extent this is true, because ideally, you would want something that's that you can just buy, and it's it comes in a bottle. And you can simply just scoop some out, dump it into your reaction mixture, and let it run like a traditional organometallic catalysts and so on. And this is not the case right now with enzymes. Allof the enzymes that we use are not commercially available. So that's definitely a barrier entry. There are possible ways to address this, I think that there are companies that have started that are now starting to outsourcing the work, if you will, that in the sense that they have academic labs, commercialize their, their, their enzymes, so that other people can use them, you know, it's it's definitely a step towards the right direction. It's just that it might take time.
Paolo 08:51
How do you, you approach it in, in in your research, because you're you're you're a chemist by training? How do you integrate enzymes in your in your workflows? Do you, do you actually use existing libraries that you get from collaborators? Or do you actually have a biocatalysis part of the lab and you actually do active evolutions and things like that?
Dr. Hans Renata 09:13
Usually we survey the literature to look for potentially useful enzymes that we can use in our work. And once we identify enzyme candidates, we would get their genes synthesized by an external vendor, and then and then we'll do the you know the testing. the enzyme expression, and so, on in house. So, we have the expertise for that. And then from there, then we can start thinking about how we can use the enzymes. For example, by first looking into the type of substrates that they can accept, and then that becomes a starting point into thinking about how we can apply them.
Paolo 10:02
So you are able to find good enough enzymes for your type of application even without extensive engineering of the enzyme properties. Which is kind of interesting, particularly because you run some very complex reactions, right on very complex substrates. So, feels like your starting points are somehow already quite there, which is kind of refreshing to me. Because in my experience, you know, back in the days when you were starting from somewhere, yeah, you could see some activities, particularly, you had to do a lot of work before getting something which was really useful, usable.
Dr. Hans Renata 10:40
I think this is the advantage of being able to do it around this time period. Because I feel like a couple of decades ago that tools are not there, to optimize these enzymes, and also to identify potential enzyme candidates. But now with all the recent explosion in whole genome sequencing, we can now find a wealth of enzyme candidates to test.
Paolo 11:14
We hope you're enjoying this episode of Bringing Chemistry to Life. I take a few seconds to share some exciting news from Thermo Fisher Scientific. Since the end of 2021, you can find more than 80,000 laboratory chemicals on thermofisher.com. Alfa Aesar, Acros Organics, and Maybridge joined the Thermo Scientific family, and you can find them all there. And now back to our conversation.
Paolo 11:40
Do you want to describe some of your reactions, some of your work, something that you're particularly proud or what an example where the enzyme really did something that surprised you? That you maybe didn't even think that was possible? In some way? Did you ever had that moment?
Dr. Hans Renata 11:58
Yeah, I think that one particular work came to mind where we just did not expect some of the, or the enzymes that we were using to work that well on a variety of substrates. So this work was published last year. And it had to do with the application of several enzymes from the potential myosin biosynthesis,that this pathway itself was discovered by my colleague at Scripps, Ben Shen. And we were able to leverage a couple of enzymes from that pathway to perform sets of active occupations on a terpene scaffold. So the subject that we were using initially is steviol, which is the the A glycan of stevia. So we observed that the two enzymes from that pathway work pretty well on steviol. But as we start modifying the structures of the substrate, we realize that they they're actually quite promiscuous, and they work on a range of substrates. And that allows us to design a variety of synthesis to make many different natural products that belong to that family. And in one particular instance, we actually observe that one of the enzymes that we use actually exhibit a different selectivity profile on one of the substrates. And that allows us to design a different type of sequence where we were able to use that hydroxyl group effect a skeletal rearrangement of the scaffold to access completely different family of natural products.
Paolo 13:44
I am curious now in terms of how you organize your thinking flow and how you are you, you know, your plan, your your research work. So obviously, I suppose you have some sort of interest in terms of the synthetic target. You tend to you still focus on mostly natural compounds, don't you?
Dr. Hans Renata 14:04
For sure, although I think we we do want to start expanding to non-natural compounds or things that are not natural products, but we still want to focus in the pharmaceutical area. So compounds that, or certain motifs, that are present in a lot of medicines and so on.
Paolo 14:23
That makes sense, because, because keeping a look at the potential application of your research is really helpful, isn't it? So, going back to my original thinking process, so, you have on one hand you have your your your targets, then you know your your synthetic strategy, because you want to synthesize a given compound. So, you need you need a certain set of tools to get there and you know, you have all the synthesis design aspect of it. On the other hand, you might have the exploration work award the different tools or they say working on your toolbox, right. Which, which I suppose may be done in a different way. Maybe even in a systematic way you're exploring new activities or new enzymes, what they could do for you, or whatever new chemical approaches, new synthetic approaches? Are these types of work, both happening in your team? And do they run in parallel? Or do they ever converge? How do you organize them? I'm just I'm just curious.
Dr. Hans Renata 15:19
Yeah, I think that both directions are being pursued in parallel in my lab. So different lab members have different projects. And there's a small subset, they're pursuing the development of new biocatalytic methods, as well as discovering new enzymes that exhibit different substrates and selectivity profiles that we've never seen before.
Paolo 15:44
Okay, that makes sense. And once something is interesting, from the more fundamental type of work, then you obviously implement it in, in whatever applications, the synthetic workflow, you make it sound obvious and easy, but it's not. When I think about it, yeah, it's certainly not right. And, you know, how has it been for you, you know, starting from, you know, a pure synthetic chemistry, background, getting to grips with, you know, enzyme discoveries, and having to deal with genomes, and all the biotechnology world, these are all disciplines apart in many ways. And biocatalysis is really multidisciplinary, right? So it's, it's remarkable when you can work at the interface between disciplines and join together the strengths of either, I'm impressed when you're saying, It's not a difficult after all, right, if you understand the logic of the experiments, you can do it. So a chemist can do biology, and the language seems to be at the beginning, at least the the major obstacle. I am always interested in understanding the drive, right? Because you're in your work is extremely interesting. And if you if you love chemistry, like I do, you know, there's a universe just behind your papers. And you know, you can see the thinking process and there's a lot of creativity there. You obviously need to have the right training to catch the most of it. And I'm, I'm probably not completely up to it. But isn't it fascinating? What are you interested in is always difficult to catch from from from the work itself is? What is really your interest? So are you driven by the problem, you know, the fundamental understanding, or the challenge of the synthesis? Or are you dreaming about what this could mean, in the future in terms of applications?
Dr. Hans Renata 17:48
My main motivation, when I started my independent career was to develop strategies to make complex molecules by incorporating all these tools from the enzyme world. And I think I'm still interested in pursuing that direction. In the future, at the end of the day, I like to make molecules and there's something about looking for the most efficient way to build things, how we can leverage some of these tools to make things that are useful for the society and also even enable some biological discovery. And I think that, that's nice. That's one thing that's nice about being at Scripps is that we're surrounded by other biologists and chemical biologists were interested in important biological problems. And I think that gives me a lot of exposure to important problems in that area.
Paolo 18:46
It makes sense, right? You know, it's very natural to start from the intellectual challenge. And then as you as you see that you are up to the task and you can you can meet the challenge and you can beat the challenge. You know, what's next? How can you look beyond it? It is a maturation. So it's a it's a growing kind of thing. It's a process. It is beautiful. It's beautiful, the way you describe it. Hans, it's been fascinating. And as we get to the, to the end of our chat, there's always a question that I used to close the interviews, which is an obvious one for people like yourself,. You're still very young, but but at the same time accomplished, right? You're a bright star in the chemical community. You know, you have this innovation in your in your thinking and, you know, you certainly have a bright future ahead of you. But you know, you're you're sort of already well advanced in your path. And so if you had to stop and look back, what will be the piece of advice that you will pass on to someone younger, who is just starting?
Dr. Hans Renata 19:59
I would say don't be afraid to branch out to new fields. I feel like going forward, science is just going to become more and more interdisciplinary. So I think there will be advantage, there will be a distinct advantage of knowing how to approach problems from many different angles. So I think that I would definitely encourage people to expand their horizon and try to learn new areas if they have the time.
Paolo 20:29
That's a great one. So thank you. Thank you very much. It's, it's been great speaking to you. Congratulations for your Talented 12. And, and for all the great work and best of luck for the future.
Dr. Hans Renata 20:42
Thanks a lot, Paolo. This has been great.
Paolo 20:49
That was Dr. Hans Renata, Associate Professor of Chemistry at Scripps Research in Florida, and one of the Chemical and Engineering News' Talented 12. Thanks for joining us for this season three episode of Bringing Chemistry to Life, and keep an ear out for more. If you enjoyed this conversation, you're sure to enjoy Dr. Renata's content recommendations. These are books, videos, podcasts and other things. Look in the episode notes on whatever app you're using for listening for a web URL, where you can access these recommendations and request your free Bringing Chemistry to Life t-shirt. Finally, if you liked this podcast, I would really appreciate if you shared it with friends and colleagues. We are excited to share our passion for science with a bigger audience. This episode was produced by Sarah Briganti, Matt Ferris and Matthew Stock.