Transcript

Derek Smith:

Hello and welcome to Baylor Connections, a conversation series with the people shaping our future. Each week we go in depth with Baylor leaders, professors and more discussing important topics in higher education, research and student life. I'm Derek Smith and our guest today is Daniel Romo. Dr. Romo is the Schotts Professor of Chemistry and Co-Director of the CPRIT Synthesis and Drug Lead Discovery Laboratory at Baylor. A nationally recognized leader in the research of natural products and compounds for an advances in basic cell biology and drug lead development. Romo came to Baylor in 2015 after 22 years on the faculty at Texas A&M. Last year his research on a new chemical synthesis strategy that can lead to the potential drug leads and impact people with neurodegenerative diseases such as Alzhei1mers was published in the Journal Nature chemistry. He is with us today on the program and we'll dive into what a lot of that means. Dr Romo, thanks so much for joining us. It's great to have you here on Baylor Connections.

Daniel Romo:

Thanks for having me.

Derek Smith:

Well, let's just begin by helping people better wrap their arms around your research and what we're talking about here. How would you describe more broadly the focus of your work?

Daniel Romo:

I would say my group is very interested in the synthesis of organic molecules and sometimes these are done basically step-by-step making an atom, putting one atom, one nitrogen, one hydrogen, one oxygen together, stepwise onto a core structure. And so this is the way we build up organic molecules. And our focus in terms of the types of molecules we like to make are ones that we feel have importance from the standpoint of using them as tools, probes for example, of the cell to understand something more about cellular function and thereby impacting human medicine.

Derek Smith:

Mm-hmm (affirmative). Well, you mentioned impacting human medicine. What is you envision end products down the line, what should people think of when we talk about that?

Daniel Romo:

The organic molecules that we make, as you mentioned in the intro is we're really interested in coming up with drug leads. We're not in the business of developing drugs. That's the pharmaceutical industry. We're very interested in trying to understand how we can perturb cellular function with small molecules and those small molecules that we design and synthesize then have the potential to give us a inroad into how we might perturb a cellular function that might've gone awry in a particular disease.

Derek Smith:

Mm-hmm (affirmative). Visiting with Dr. Daniel Romo. You mentioned natural products and small molecules, what might some of those be?

Daniel Romo:

Yeah, I guess to better define natural products, these are small molecules, organic molecules that have been isolated from natural sources such as plants, bacteria, even marine sponges. These are molecules that typically in the range of 500 to a 1,000 molecular weight. So they're not really large molecules like proteins, these are much smaller. These actually with proteins, so that's how they go about exerting their function. That is by perturbing the activity, let's say, of an enzyme or a protein.

Derek Smith:

Mm-hmm (affirmative). You mentioned a sea sponge. I think that's something a lot of people can picture easily enough. When you see a sea sponge, what potential do you see?

Daniel Romo:

I would say that that kind of question is really good for an isolation chemist. We're synthetic chemist, so we design and synthesize these molecules. I have to say I owe a lot to isolation chemists who are the ones that actually look at these sponges and go, wow, that sponge has the potential to be producing something. And the reason, at least, maybe this is one of the reasons that goes into this is sponges are sessile organisms, they don't move. They have had to develop ways to defend themselves. And a lot of times these small molecules have been optimized and designed to basically interfere with fish eating them. Sometimes sponges will not be very tasty, let's say to fish because of the fact that they're able to produce these small molecules that are sometimes toxic to these fish.

Derek Smith:

You mentioned to isolation chemist you owe a debt of gratitude to them. What's that process like as they isolate some of these small molecules from a natural product? And when it comes to you, what does that look like?

Daniel Romo:

Often we're finding these molecules in the literature, so isolation chemist, just like us, we actually published in the primary literature and so when we're interested in trying to find compounds that we're interested in synthesizing, we go to the literature and over the years that I've been doing independent research, I've come to know these isolation chemists through conferences and things. It's always neat when they've reported and sometimes at a conference I'll find out about a new hot molecule that has come out that they have isolated and characterized, so they isolate these compounds, which is a laborious process and then they have to characterize it, basically determine its structure and that's really where we get involved. Once they've determined the structure, maybe they've reported some interesting biological activity. That's what really gets us excited is the combination of interesting structure and potent and sometimes specific bio-activity. That's really what we're looking for in a natural product.

Derek Smith:

Mm-hmm (affirmative). We're going to talk about that a little more in depth here in just a few moments, but I want to ask you as we get to know you a little bit better and what motivates a lot of your work and the foundation behind that. You had a great conversation in Christianity Today in 2017 where you talked about the intersection of science and faith and you use the analogy of playground and discovery. Could you take us through that a little bit and explain what it means to you to be a... That alignment between faith and science?

Daniel Romo:

Yeah, I guess for me it's really cool I think to think that God has given us the ability to reason, to use our minds to discover and even in some cases create interesting molecules. I think one of the ways I look at the playground as you said, of the universe really, which is it couldn't be considered a second Book of Revelation from God. I think it's God has placed all this information for us to harvest in natural products. And so that's our area of interest. We're actually interested in harvesting this rich information because these small molecules have evolved over time to basically interact with proteins and enzymes so we can harvest that information. And so yeah, we see this as a playground. It's a playground for my students and I to basically explore the world, God's creation. And in doing so we can ideally find small molecules that again can then be used to perturb cellular function. And again, we're looking for things that will perturb cellular function in let's say, cells that have some type of problem, cancer, neurodegenerative diseases and so forth.

Derek Smith:

Mm-hmm (affirmative). You described that process of going through the literature and looking for information on small molecules in the beginning of the process of synthesizing. But what does that look like as you talk about discovery as you kind of play on the playground if you will.

Daniel Romo:

Right.

Derek Smith:

In our discipline with you and your students, what does that look like from the standpoint of the work you do?

Daniel Romo:

Yeah, and I would make sure I preface this by saying that I'm very indebted to my students because there was a time when I was working in the lab, now it's all my students that are working in the lab and I'm just more of a supervisor and I actually tell them that at some point I like to just become their cheerleader where they've become independent researchers to explore these small molecules. What they do in the lab is actually set up chemical reactions in a flask and they are proposing a new strategy for making a particular molecule, let's say. And I would actually make an analogy to construction engineers at the molecular level. That's what my students are doing. That's what I did at one point back in my PhD and postdoc days, they're trying to develop a plan for how to make a molecule. They go into the lab and run a series of reactions to try to implement that plan. And I would also to go further with that analogy of construction, just like a construction engineer, often we have to go back to the drawing board because our initial plan didn't work. And that's a very common thing in synthesis, the things that we do, or things that we plan out first, don't work. We learn from that, we build on that and then try something different until we ultimately get to a solution for what we're trying to do. And I would say one of the things that is very important synthesis today is developing not only a way to make a molecule. I think we have a multitude of methods to make molecules. The big issue today is how efficient can we make these molecules? Is the synthesis scalable? If you're talking about a drug lead one that you might want to test, let's say in an animal, you have to be able to make quantities of this compound. So not only do you want to have ways to make the molecule, you want to have efficient ways to make the molecule. The first iteration of a synthesis by one of my students is often optimized to finally get to something where you can make grand quantities, let's say, of a particular drug lead. And that's kind of what they're doing on a daily basis. Working in the lab, developing reactions, developing a sequence of reactions to prepare a particular compound of interest.

Derek Smith:

That gives us a good segue to talk about this new synthesis strategy. But before we get to that, I do want to ask you, what does success look like? As you said, sometimes you'll try something and it won't work as you anticipated. When you find something that's intriguing that you want to look at further, what does success look like? And I know there might be many different ways that you could see success.

Daniel Romo:

Right. I would say one of the things that my students of course are interested in doing is developing ways, as I mentioned, to make a particular bond connection. So maybe a new carbon-carbon bond or a new carbon-oxygen or carbon-nitrogen bond. Success on a daily basis may be that a reaction has actually given the desired carbon-carbon bond formation. And then as we start talking about the next idea of a new strategy, I can say a little bit more about maybe a bigger goal of putting these sequences together and then arriving at molecules that have a particular biological effect.

Derek Smith:

Visiting with Dr. Daniel Romo. Last spring we saw you're working on a new chemical synthesis strategy to harvest that info from natural products. Tell us a little bit about that. You mentioned that you want that efficiency and how does this lead to that?

Daniel Romo:

Okay, well let me go a little bit further back and just mentioned that this strategy is something that really was inspired by Professor Paul Winter at Stanford. He's coined this term function oriented synthesis and he's also a synthetic chemist that is very interested in the biological... Chemistry biology interface just like my group is. Building off of what he put forward in terms of really bringing function of a molecule early in a synthetic endeavor, we decided to try to approach total synthesis of natural products, that is de novo synthesis of natural products very much at the forefront of a synthetic effort. We turned this strategy Pharmaca for directed retrosynthesis. Sounds like a lot of words, but basically it's the idea of trying to look at a molecule that has a particular biological effect and coming up with a hypothesis as to what part of that molecule is the most important for biological activity. What is it that's exerting this biological activities, is it the whole molecule or just a small fragment? We come up with a hypothesis for that particular fragment being what we call the Pharmaca for the important part for activity. And we actually synthesize that first and the idea is to sequentially then elaborate that fragment ultimately to the natural product. It's just the way that we approach total synthesis. Total synthesis of course is not anything new. People have been doing this for centuries now, but we've been interested now in trying to approach it from a slightly different way and saying, okay, can we start making derivatives of this natural product at a very early stage in our synthetic efforts? And in doing that, we actually ideally will find simplified versions of the natural product in route to the natural product. We can start testing the biological activity of these fragments, let's say at a much earlier stage than what people typically have thought about. I go back to this efficiency idea. For the longest time synthetic chemists, and I think even to this day, as I mentioned earlier, we're still very interested in efficiency. That sort of has taken a front seat, if you will, to biological activity. We're very interested in making the most efficient route regardless of the biological activity. We're just trying to change things a little bit and say, well, let's try to combine those. We want an efficient route, but let's go and start testing for bio-activity very early in a synthetic effort. And again, the goal is to try to identify simplified versions of this natural product that one, might be easier to synthesize and of course we're finding this at a much earlier stage in a synthesis effort.

Derek Smith:

What does this mean obviously as the Journal of a publication which was received by other colleagues and as you mentioned colleagues at Stanford had been working towards this for a while. What does it mean for their research across the country? When you think about the contribution to the discipline, what does that mean to you?

Daniel Romo:

Well, I would hope that one thing it might do is just as I mentioned, get people to think about the way they're approaching their synthetic efforts. Synthetic chemists, as I said, I've been doing natural product synthesis for some time and so now it's just the idea of again, borrowing from Wenders notions of functionaries and synthesis to design a synthesis a little differently and design it in such a way where you could start answering biological questions at a much earlier stage in a synthesis effort.

Derek Smith:

This is Baylor Connections. We are visiting with Dr. Daniel Romo, Schotts Professor of Chemistry and Co-Director of the CPRIT Synthesis and Drug Lead Discovery Laboratory at Baylor. Well, there's that word CPRIT, that I know you know well, but I think maybe a lot of people aren't as familiar with it. What is CPRIT? What's that mean? And more broadly, what is it?

Daniel Romo:

This is a really a neat thing that Texas taxpayers actually decided to fund at one point. And actually they've recently decided to re-up the funding of this Cancer Prevention Research Institute of Texas. This is a funding mechanism, unique to Texas that allows a number of types of grants to be awarded through CPRIT. One of them that has been pretty exciting for Baylor, I think is the new faculty recruitment grant. And there's two levels. One is a more established investigator. And actually that's what led John Wood, a colleague of mine from the Department of Chemistry and Biochemistry to come to Baylor. And quite recently, actually we just got word last week that a new colleague that's coming in received a new faculty recruitment grant, which is again for now for new investigators and so that'll be very exciting that we have another assistant professor coming into the department and we'll be contributing to our research footprint, let's say in the world of... Actually, in this case organic synthesis as well.

Derek Smith:

What factors, you mentioned one there obviously, but what are some of the factors that attracted you to come to Baylor when you did in 2015?

Daniel Romo:

I have to say that John Wood, as I mentioned before, was someone who had been recruited here about two years prior to me coming and that had a major impact on me wanting to come here. In fact, he contacted me and told me there was a position and I was very interested because I had visited and it seemed like a really neat place. John again was recruited by one of these CPRIT grants from Colorado and I think one of the really neat things about having someone like John here is that we're working in very similar areas and so we really saw the opportunity, I saw the opportunity of building something really, really neat together and he works also in natural product synthesis, we felt like we could build something neat here. And again, this aligns very well with what Baylor is trying to do in terms of reaching R1 Status. I think the faculty in general, the collegiality of the department really impressed me. I would say the facilities that the Baylor Sciences Building, which I'm sure you've been there-

Derek Smith:

Mm-hmm (affirmative).

Daniel Romo:

... so a really neat building. They had a number of pieces of equipment that are crucial to my line of work, in particular in nuclear magnetic resonance. That's how we characterize our organic molecules. And all this had been actually made possible through this CPRIT recruitment grant that John Wood had received and was one of the reasons that he ended up also coming to Baylor.

Derek Smith:

Dr. Romo, you mentioned the collegiality of the faculty, certainly that can mean a friendly, welcoming environment. But when you think about Baylor's R1 aspirations and aluminate there's a lot of interdisciplinary work that's a part of that. What's the collaborative cultural like here at Baylor as you think about professors from other areas within the BSB or other departments on campus?

Daniel Romo:

Yeah, and I you bring up a good point in terms of the just proximity of labs in the BSB. So this is the Baylor Sciences Building right now. It houses a number of departments including the biology department. I'll just focus on that one because it was kind of a neat event that I came to my orientation for new faculty at Baylor and I happened to meet an Assistant Professor now in biology Joe Taube, who was just starting out. We started talking and turns out he was interested in cancer in terms of addressing in particular STEM cells and a particular area of cancer STEM cells. We decided to see what we could do with some of the compounds that we were studying. And it turns out one of those compounds had the desired effect that he was looking for. He ended up getting a CPRIT grant for that, to study. So that's a current CPRIT grant that we have between us. I would say, yeah, the collaborative atmosphere in the BSB, but also I would say across Baylor has been quite neat to see as well. I mean, again, just the proximity. If one of my students is synthesizing a compound, he can just walk across to another hallway and deliver it to professor, Joe Taube. That has been kind of a really neat aspect of the way it's set up here at Baylor.

Derek Smith:

Visiting with Dr. Daniel Romo. And as you think about a Baylor's illuminate aspirations becoming an R1 T1 University, idea of becoming the preeminent Christian Research University. How does that vision speak to you in terms of the work you do, the work you do with students, just that broader impact in higher education?

Daniel Romo:

Yeah. First, I mean, I just want to say that I think it's really neat that a Baylor really has this as a mission to become a preeminent research institution that also happens to be Christian. I think, looking back historically at some of the great giants in science, Pastore, Carver, Kepler, Lord Kelvin, all these guys were Christian and they were giants. I mean everybody knows these names and there's a reason they were giants in science, but they were also Christians. I think it's just kind of neat to think that we're trying to make our small mark in the world of science and we also happen to be Christian. I think the idea of reaching this are when status is an important one from this standpoint of letting the world know that you can be a Christian and you can do great science.

Derek Smith:

Talking to Dr. Daniel Romo and Dr. Romo, looking ahead, what's next for you is you have enjoyed some of these recent findings or successes. What further questions does that lead to? And I know a process that's never done in the work you do.

Daniel Romo:

Right? Yeah. I think if you wanted to talk about a specific project, the one that you brought up earlier that was published last year in terms of neurodegenerative diseases, one thing that we're quite excited about is these molecules actually interact with two proteins that are related. One of the things we're trying to do is tease apart the interaction of these molecules with these two proteins, because one of these proteins leads to neuroprotective effects. And the other one leads to immunosuppressive effects. And immunosuppressants are things that people that have heart transcends for example, have to be on for the rest of their lives so their body doesn't reject the organ. We need to be able to distinguish those two activities because if you're trying to do neuroprotection, you certainly don't want to suppress someone's immune system. And so we have to have molecules that are very selective. We have a group of undergraduates that are working in the CPRIT Lab that you mentioned to actually come up with new molecules to synthesize that might have this selectivity. That's one aspect of our research I'm quite excited about. But I think generally my grad students, my postdocs that are going after these simplified versions of natural products and being able to find simplified versions that have bio-activity, that's related, closely related in some cases to the natural product is quite exciting.

Derek Smith:

Well, we will look forward to that and appreciate your thoughts very much. Exciting times and look forward to what's in store. Dr. Roma, thanks so much for joining us, it's great to have here on the program.

Daniel Romo:

Thank you, Derek.

Derek Smith:

Dr. Daniel Romo, Schotts Professor of Chemistry and Co-Director of the CPRIT Synthesis and Drug Lead Discovery Laboratory at Baylor. Our guest today, here on Baylor connections. I'm Derek Smith, reminder, you can hear this and other programs online, baylor.edu/connections. Thanks for joining us here on Baylor Connections.