3. Metabolic Engineering and Hypothetical Bus Accidents w/ Kris Prather

In this episode, we interview Dr. Kristala Prather, the Arthur D. Little Professor of Chemical Engineering at MIT. We talk to Dr. Prather about her career spanning both industry and academia and segue into her lab’s current efforts and challenges at the intersection of metabolic engineering and synthetic biology. Along the way, we talk about leadership, mentorship, inclusivity, and why mass transport might not be as important as everybody says it is.

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Transcription:
Episode transcripts are the unedited output from Whisper and likely contain errors.

Transcript

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Hello, and welcome to EBRC in Translation, a production of the Engineering Biology Research Consortia's Student and Postdoc Association. We are a group of graduate students and postdocs working to bring you engaging conversations with members of the engineering biology community. EBRC is a non-profit, public-private partnership dedicated to bringing together an inclusive community committed to advancing engineering biology to address national and global needs. I'm your co-host, Fatima Inam, a postdoc in the Sonnenberg Lab at Stanford University. And I'm Adam Silverman. I'm a graduate student at Northwestern University, working the labs of Mike Jewett and Julius Lux. In this episode, our guest is Cristela Prather, the Arthur D. Little Professor of Chemical Engineering at MIT. Dr. Prather is one of the leading scientists working at the interface of synthetic biology and metabolic engineering today. Welcome to our show, Chris. We are excited to have you with us today. Thank you. It's very nice to be talking to both of you this afternoon. Let's get started. And I just want you to do a brief introduction of yourself and your personal journey. So maybe can you touch a little bit on how you got to where you are today and were you always interested in engineering? What really drew you to biotechnology? Sure. So I'll try to give a somewhat condensed version of this story since we only have a certain amount of time to work with. I grew up in Texas. People usually ask the town from what it's near, and I always say it was not really near anything. I grew up in northeast Texas in a town called Longview. It's about 130 miles due east of Dallas and about 60 miles west of Shreveport, Louisiana. If you've ever seen the TV show Friday Night Lights, I watched that and had a lot of flashbacks because that was basically my high school experience. I got interested in engineering, interestingly enough, as the result of the advice given to me by my 11th grade history teacher. I had taken the PSAT, which most kids in the U.S. do about that time. I'd scored well enough that I started to get information about colleges and figured that meant it was time for me to think about where I wanted to go, which meant I had to think about what I wanted to do. So my history teacher asked me what I liked. I told her I liked math, but I didn't want to just study math. The story I always tell about that is there was a movie that came out called A Beautiful Mind that was sort of a brilliantly gifted mathematician who could speak to numbers, but then sometimes the numbers would speak back to him. And that was kind of my impression of what would happen if I got too immersed in something that was just math without anything to balance it out. And then I liked science. And my history teacher said, well, if you like math and you like science, you should be an engineer. All right, great. That sounds good. I don't have anything better to do. And then she asked what type of science I liked. And I was taking chemistry at the time. And I said, you know, I'm really enjoying my chemistry class. And she said, great, you should be a chemical engineer. And if you're going to be a chemical engineer, you should go to MIT. I went, cool. What's MIT? I literally had never heard of MIT. This was this would have been in 1989. And remember, that was before there was a Google or a Chrome or actually any browser, right? Personal computers existed, but they were not ubiquitous. You know, when I was a freshman in college, very few people had laptop computers, for example. So there wasn't as much access to information by any stretch of the imagination as what happens or what's available to high school kids now to try to figure out where they want to go and what they want to do. So that really led to a series of conversations, interactions with people. And nothing I heard changed my mind about studying chemical engineering or about going to MIT in order to do it. So I was an undergraduate at MIT, majoring in chemical engineering between 90 and 94. The question in terms of what got me interested in biotech that actually went back to when I was in high school as well. So my senior year of high school, once I had been admitted to MIT and was deciding between going there or staying in my home state of Texas and going to Rice University, those are my two options, actually met someone who has become a very, very dear family friend who had been, he had grown up in Longview, Texas. He was about, he was several decades older than me, about the age of my grandmother and had been a chemistry professor. He had gone to Rice as an undergraduate majoring in chemistry, had gone to MIT actually as a graduate student, majored in chemistry there, and then had been a professor at the University of South Carolina, but had returned home to East Texas to run the family business. And I got introduced to him through a friend of my mother's and he handed me, I still remember these very clearly, two publications from the American Chemical Society that were little short books. They were maybe about 50 to 75 pages, geared towards a high school audience, maybe a college freshman audience. And the goal was to introduce young people to different aspects of the chemical sciences and different application areas of chemical sciences. And he gave me two of them. One was on biotech and the other was on polymer science. I read both of them, thought they were both cool. I was like, okay, great. I'm going to go to MIT. I'm going to study chemical engineering and I'm either going to do polymer science or I'm going to do biotech. And while I was at MIT, I took classes that were bio classes. I took general bio and biochemistry. I took a polymer science lab as well. And I liked the biology stuff better. And so I decided that I did want to focus on biotech. I graduated MIT in 1994, went to Berkeley for graduate school, and worked with Jay Keesling, who is one of the founders of EBRC and was the PI for SINBURG, which was the NSF funded engineering research center that preceded EBRC. And worked for him and in his lab when he was still relatively young and where the idea of engineering cells as part of chemical engineering was somewhat new. There had been quite a bit of work done by that point on engineering processes for culturing cells, but actually treating the cell as the substrate that you would engineer was something that wasn't quite standard at the time. And Jay was one of the first people who really used that as the foundation of the work that he was doing. So I did my graduate studies there with him between 1994 and 1999. A really important and influential, I would say, thing that I did during that period was to do an internship. I spent four months at DuPont in Wilmington, Delaware at their central research and development facility. And that got me very much interested in working in industry after I finished my doctoral studies rather than doing a traditional postdoc. So when I graduated from Berkeley, I took a few months off. By the way, if there are graduate students who are listening to this, then I absolutely recommend taking a few months off after you finish graduate school. There aren't too many opportunities for you to have a clear break in your professional path where you actually would have an opportunity to just sit back and relax, sleep a little bit later, read some interesting books, maybe travel a little bit, spend time with your family. So I did that for three months and then started working full-time at Merck Research Labs in Raleigh, New Jersey. I was at Merck for four years. And then in 2004, left Merck to start my academic career at MIT as an assistant professor. And I've been here ever since. So that was 16 years ago, August. I said I was going to give you the condensed version of the story, but that was still kind of long. No, wow. That's a super interesting story. So just wanted to touch upon, you did mention that you had this unconventional path. Did you know that you wanted to come back to academia after your four-year stint or what was going on in your mind then? Yeah, I did. So one interesting story is that when I came back to MIT as a faculty member, I was actually moving into my office and I had boxes that had been carried from my little apartment when I was in grad school to my new apartment in New Jersey, to the house that my husband and I bought, to the house that was here in Massachusetts, to my office at MIT. And I was looking through things and I found this folder that had drafts of the statement of purpose from when I applied for graduate school back in the fall of 1993. Incidentally, not an online application, right? So these were actually, you know, physical hard paper copies of materials that I would have had to send in the mail. And what I had written at the time was that I wanted to get a PhD, that I was interested in academia, but that I wanted to work in industry first. Now, incidentally, I don't remember thinking that four years later or five years later when I was towards the end of my graduate studies, but I mentioned the fact that I did a short internship at DuPont when I was in graduate school. And I did that the summer after my fourth year in graduate school. That came about because I had a fellowship from DuPont and the fellowship required me to go and give a presentation. So I had to give my first full length talk, which was very, it was a little stressful, right? I had done the conference presentations that were 15 or 20 minutes, but this was the real deal. A whole hour set aside, 45 minutes of me talking Q&A afterwards. And I did that in the spring of 1998. So this was towards the second half of my fourth year in graduate school. I put a lot of time into it, put a lot of thought into it, gave this talk, and I thought I nailed it. I was like, hey, people are laughing at my jokes. They're asking me questions. I'm answering the questions and they're nodding and smiling, which means I'm not giving stupid answers to the questions. And this is really good. And then after I gave my talk, I had a one-on-one conversation with one of the scientists there who said to me, your motivation for your research is all wrong. So this is a guy named Charlie Nakamura, who later became my supervisor when I was an intern there. And that's just Charlie, right? Charlie's just going to tell you what he thinks. And he said, don't get me wrong. I think what you're doing is interesting. I think it's important and I think the field is going to learn a lot from it, but you're motivating it by what you think is important in industry. And we just don't care about any of that stuff. And I don't remember the details anymore, but as all good students do, I had three points that were my three motivating factors for why these low copy plasmas were going to be so awesome. And he just like sliced and diced and dismissed them all. And, you know, one was sort of like, yeah, that used to be a problem, but we figured out how to solve it a while ago and we just don't publish as much. And so academics are out of the loop. One was, sure, that's a problem, but you have to solve these other five problems first. So nobody actually cares about that as a problem because these other things are bigger deals. I think the third one, he was like, okay, yeah, I'll give it to you. That's a problem, but it's not like a game changing problem where, you know, fixing it is actually going to resolve anything. So I was suitably humbled, as you might imagine from that experience and thought, okay, you know, even though I had stage presence, apparently I didn't know what the heck I was talking about. And what it did for me was to crystallize the fact that there is not always, but can often be this divide between what happens in academia and what happens in industry. And in the academic world, it can be a little bit too easy to only read each other's papers and criticize, not in a negative way, but constructively critique each other's work without ever having that lens of knowledge and experience from someone who has to bring a product to market. So as academics, largely speaking, our products are our students and post-docs. You guys are the ones who will do great things. We get to amplify our work in essence because if we've trained you well, if we've given you a productive environment to flourish, then you will take those skills and pay it forward. And so academics love after decades to have these academic trees that show how they've been able to help to populate to a certain extent the academic world. But that can also be very insular. And you can miss out on opportunities to actually understand what the barriers are to translation. And I happen to be fortunate that where I am at MIT, we do have a lot of interactions with industry. And I have a lot of opportunity to do the reality checks, as I like to call them, to make sure that we're looking at the right things. But that hasn't always been the case. And I think it's much more common now than it was 25 years ago or so when I was going to graduate school, right? When I was in graduate school or figure out what was going on. So that experience actually got me thinking about spending time in industry after my PhD, because I really wanted to have a better sense of what are the real barriers to adopting new technologies in that environment where there are deadlines and there are milestones that have to be met. And it's not that deadlines don't slip, but if earnings reports don't turn out to be the way they're supposed to be, there are very real consequences to what happens in the company. The time that I spent at Merck was the first time in the history of the research labs that they had to have layoffs. And it was a real shakeup in terms of what that meant for the culture of the place, right? So there are very, very real consequences in the sense of what happens if the organization as a full entity isn't able to meet its expectations or the expectations that the market has for it, as it were, for a publicly traded company. So I decided that I wanted to spend time in industry, not as a postdoc, but actually as a regular employee so that I'd have an opportunity to really see and listen and learn and work in this environment to have that better inform what I would ultimately end up doing as an academic. So I did something which I always recommend, but I think people find surprising, which is that I was completely honest. When I interviewed for industrial positions, I told the companies that I interviewed with that my intention was to work for two to three years, and then I was interested in going back to academia and I'd be looking for faculty positions at that time. And I ended up with offers from DuPont, where I had done the internship for a full-time position, and from Merck, which is where I ended up going. And both of them, again, I had been very upfront with them about it. And so when it came time that I decided that I did want to make this change and look towards an academic career, I got a letter of recommendation from my department head at Merck, right? And he was like, Oh, you know, you told us you were going to do it. So we can't really be surprised. And it allowed me to have, to me was a very productive relationship, but also to really ask the questions and get the kind of information that I personally wanted and felt like I needed in order to be best prepared for what will come next. So I don't know if people are surprised about it now, but for years, people were shocked. We're like, wait a minute, you told them you weren't going to be there for that long? I'm like, yeah. And I still remember my department head at Merck was like, well, you know, we'll try to talk you out of it if we like you. I'm like, sure. Throw money at me. Let's see how that goes. But ultimately I decided that an academic career is what I really wanted. And so I was there for two and a half years and then did submitted faculty applications, did the interviews, ended up staying a year later to help with the transition, but ended up being then at Merck for four years before I started my faculty position at MIT. Thank you. That was really interesting. Touching on a lot of the questions that, I don't know, self-conscious graduate students like ourselves ask whether or not what we're doing is worthwhile. I want to know, you said that you worked there for four years, hoping to get some guidance on how it had shaped your next steps. Can you talk a little bit about what specifically you learned from working at Merck? Yeah. So there are certain things that are very specific skills that I learned that were invaluable. And then there are things I learned in terms of cultural and philosophical differences that have actually helped shape a lot of how I approach the work that I do in my group. So tangible beneficial things. I learned how to supervise people. Fun fact, when you become a professor, you're responsible for a lot of people and nobody teaches you how to take care of them. Right? So you're just sort of expected to figure it out. I have, for my own group, I have an expectation that all of my grad students and post-docs will supervise an undergrad student at some point. And I tell them, quite frankly, the reason that I make them do that is because they're at MIT and I'm expecting they're going to be somebody's boss one day and they should at least start to practice what that's like. But most academics don't really have any sort of formal management training. So I had formal management training. I learned about the different kinds of people and where they are on this axis versus that axis. I don't remember all the details, right? But essentially got formal training and how to think about managing a group. I learned how to troubleshoot experiments I didn't do. That's hard, but it's a skill, right? And so when I had to manage people who were working in the lab, it took me a while to figure out what are the right questions to ask to actually help them to troubleshoot when I wasn't doing it myself. It turned out there were simple things like mixing, right? Did you mix it? Which we think is automatic when we've been doing it for a while. But if somebody is coming in new and hasn't ever done it before, there are little things like that that get lost. So for me, those are the two biggest things that I learned in terms of tangible skills. And I should say there's an advantage to learning them when the stakes are lower, right? So if you learn them in industry, as I did, I had a pretty good salary. I wasn't on a tenure clock. I didn't have to stress out trying to raise a bunch of money by writing grant proposals, right? So I got to learn that part of the academic job in a much less stressful environment. But the skills were definitely transferable skills. Culturally, there are very, very big differences between industry and academia, right? So just in terms of the way research is done is very different. For example, the first project I was ever assigned to at Merck had seven PhDs on it. And each of those PhDs had at least one, what we would call junior staff or associate staff member working for them. So about 20 people on a project that, you know, roughly speaking, if you translated that into an academic lab might be two people. Okay. So that take home message there is that industry, by the way, I should pause and say, you have to remember industry's goal is to minimize failure. And when you do fail to fail as quickly as possible. So when you have a large company like Merck, you end up with a lot of specialization, right? The person who's doing the analytical chemistry, that's all they do is analytical chemistry. People in my lab, new product, you got to figure out that HPLC assay on your own. I'll give you some papers to read and some people to talk to, but you sort of have to take care of the upstream and the downstream altogether. Whereas we had people whose sole goal was, you've got a new product or a new compound we're looking at. They're going to develop the analytics that people were doing the bio catalysis upstream. Don't have to worry about that. Somebody else is taking care of it. So there was a very clear appreciation on the fact that teamwork is a much bigger part of it than it is in most academic, not all, but most academic labs. And this specialization is a very important aspect of it. The other thing is something I just mentioned that I'll come back to, which is there is this issue of how you deal with failure, right? So the mantra when I was at Merck was fail fast, fail fast, fail fast, right? So if you were going to fail, the goal was to have that failure be uncovered as quickly as possible. So you're not continuing to invest resources, both financial resources and human resources in something that wasn't going to go anywhere. Adam is in graduate school. Fatima, you've been in graduate school. There's a lot of failure associated with graduate school, but I think that's the way it should be, right? If I think back to my own graduate experience, I learn as much, if not more, from the things that didn't work than the things that did. Now, this is harder to do now because the technology has evolved. But when I was in graduate school, everybody ran a gel backwards once. Once. You never did it more than once because the time you walk back into the lab and you looked at your gel box and there were no blue bands and you're trying to figure out what the heck happened to the blue bands. And then you look and realize the leads have been reversed and all your DNA ran backwards and it's just floating around in that solution and it's lost and you have nothing that you could do about it. That's not a good day. And that's not a day that you want to relive. So you don't make that mistake again, right? At the same time, if I think about both my own research, but certainly the research that's happened with graduate students in my lab, some of the most interesting papers we've written and the interesting projects that we've pursued were accidents. And not accidents is maybe the wrong word. They were unexpected. They were the result of some observation and it was an observation that we weren't really expecting. And it was an observation that didn't actually help us to advance what was our primary path, if you will, but they were interesting. And so the student was allowed to go off on this tangent and in some cases it's opened up entirely new areas of research. That's a very inefficient way to do research in industry, right? It's a wonderful way to do research in academia because you can pivot at any time to anything that you want to. That's the beauty of academic freedom. But if you're in a company, you have a product that has to be delivered. It needs to be delivered by a certain period of time. It has to meet certain economic metrics and you don't really have time to get interested in what's just interesting observations, what could actually be, quote unquote, cool science, but it's not actually going to make a difference when it comes down to the actual project. And to me, that's a huge difference, a big cultural difference between them that I try to remember. So I try very hard to make sure that my students have as much freedom as they need to be able to explore. And I don't want them just off randomly sitting around, you know, staring off at the sun going, what do I think is the meaning of DNA, right? Like do some work. I'm not saying that, right? But I think there's an advantage to having the ability to have those unexpected observations, to take those left turns when maybe you thought you were going to go right, to fall into a hole, figure out how not to dig it deeper on your way out, right? And you can't really do that in industry. The last thing I'll say, usually when I have senior graduations or post-docs who are trying to figure out their career choices and they ask me about life as an industrial scientist versus life as a scientist in academia, I present for them the hit by a bus scenario, which sounds kind of extreme, but stick with me here and you'll see it, right? And the question is, what happens if I get hit by a bus walking across the street? So if I look at my job at Merck and 16 years later, I would like to think if I had stayed at Merck, I would have advanced past where I was 16 years ago. But even if I'm a vice president at Merck, you can see I'm giving myself a lot of props, right? I'm a vice president at Merck 16 years later. If I get hit by a bus, the structure of that institution is such that fundamentally very little should change. So if I go back 16 years ago, when I had only been there for four years, I was managing a small group of people. I had research projects that both I was engaged in with my own hands and that I was supervising. I had to write so many reports, right? There were monthly reports. There were short weekly reports for some projects. There were monthly reports. There were very extensive quarterly reports and the quarterly reports had to be cross-referenced to notebook numbers and specific pages in the notebooks. And there was so much redundancy built into the program that if I got hit by a bus, my friends wouldn't miss me. I'm not saying like, you know, I had real friends that were there. People would come to my funeral. I think they would be sad, right? But the company would keep going and fundamentally very little would change. Even from the individuals, they would experience a personal loss, but nothing would really change in the way that their jobs were done. Now I want you to pause for a second and imagine what happens to you if your advisor gets hit by a bus, okay? So let's just kind of go through the list of all the things that we have to do, right? Am I teaching a class if I get hit by a bus now? Am I co-teaching the class? Because if I'm solo teaching the class, what happened to the grades? Were the papers on the bus, right? Are the exam papers that the students just did? You know, what happens to where am I in the syllabus? Does someone have access to notes to be able to take care of that? When I used to tell the scenario, I would say, you know, I've got talks and travel scheduled for the next year, but I'm not going anywhere in this pandemic. But, you know, I've got meetings and things that are scheduled. So somebody's got to go through and cancel all this stuff on my calendars. I've got a group that I advise. And if I have graduate students who are realistically speaking, fourth or fifth year, they're fine. They'll be able to keep doing what they're doing. The university, oh, by the way, those grants that are supporting the students are given to the university, but they are given under the expectation that they'll be managed by the PI. Some institutions ask for that money back if the PI gets hit by a bus, right? Some of them will allow it to stay and be managed by someone else to keep supporting the students. But essentially, if you're four or five years in, you're good. First or second year graduate student, you got to have a new advisor. You got to get a new research project. Third year is kind of the buffer zone, right? Depending on how far along you are in terms of whether or not you'd have to start over. I have institute committees that I'm running, right? There are all these different things that really are significantly impacted if I'm hit by a bus, right? So when I go through that, what I bring it back to is that to me, the biggest difference career wise is the focus on group versus individual. And academic careers really, really do have a very individualistic operational system, for lack of a better word. And then I usually end this whole exercise by going, and that's why so many of the academics you know are megalomaniacs, right? Like, how can they help it? Everything that we do is built around the fact that we're doing it and very few people can do what we do. And if we can't do it, then what are the chances that I can still get done? So very, very, very different work environments, very different objectives. And to me, what I came away with that was most important above all is we need both of them. We need a really robust, rigorous academic training environment where students have a lot of intellectual freedom, where they can fail and learn from those failures. But we also have to be able as scientists and engineers to develop technologies, to bring them to market, to be able to have new products, new processes that are going to make the world a better place. Thanks so much, Chris. Yeah, that was very enlightening, like having both market driven research as well as, you know, the push towards doing fundamental basic research. They're all very important. Adam and I were just actually talking, we both did internships and, you know, learned about how industrially relevant research questions are important, how these technologies get adopted. And especially, I feel like this industry experience is particularly relevant to engineering disciplines. Absolutely. And I'm glad you said that because I have, I've given a consistent message to my students that I think as engineers, we have a special responsibility to just know as much as we can and understand what it means to operate in that environment. I should also say I was intellectually satisfied, right? So my, I didn't leave Merck because I felt like I wasn't being, that my intellectual needs weren't being met. I worked on projects that I thought were both important in terms of what their end goals were, but they were also intellectually very challenging and very interesting. I left because, and actually it was my husband's fault. I tell him, I tell him that when we made the move, that if it was disastrous, he'd get the blame, but since it worked out, he gets all the credit. So I still give him the credit for it. I had been at Merck for a little bit over two years and he came to me and said, when you took this job, you said you were only going to do it for a couple of years and you're interested in going to academia. It's okay if you've changed your mind, but I don't want you to stay just because it's comfortable. And so that challenged me to think about what it was that I enjoyed most about my job. And for me, it was not, so for some people, they got really excited about being in meetings with really high level people, right? So if you got into a meeting with the head of Merck research labs of MRL, that was like really exciting and that wasn't exciting to me. I liked working with the junior researchers, my associate staff, as we call them, the people who reported to me and training them to be independent scientists. And I derived joy from their accomplishments. And what I realized is that staying in industry, success would mean moving further and further away from that, right? Whereas in an academic career, the kernel of it, the part that never changes, as long as you have an active lab is that aspect, which is about recruiting and mentoring and developing students. Now, the sad part is that like, right, like Adam, right when you're at the height of your productivity is when you're going to tell Julius and Mike that you're ready to go, that kind of sucks for us. It's great for you, right? Kind of sucks for us, but then we learn how to be happy about it and move on, right? And then, and you start all over again. So there's this, this consistency there, this constant part of what we do, which is about the mentoring and their interactions. And that's what I really wanted to hang on to. And that's the reason why, why I left Merck, you know, all things being equal. If I had said, yeah, I don't really like the supervising students part, no question. I would have stayed at Merck because I had a very, very good experience there. I was happy professionally, personally, like, you know, I didn't mind living in Jersey. Jersey was a cool place, but for me, it really was this part that was about mentoring young scientists that really appealed to me and got me excited about work. And I wanted to be able to do that as long as possible. Fantastic. So I wanted to dive a little deeper into some of your research. So a lot of your research focuses on microbial production of chemicals, including some of the feedstock chemicals like glucaric acid. You actually even started your company that produces glucaric acid, and then you have other flavonoids, a lot of drug precursors. What made you focus on some of these type of molecules? Yeah. So one of the downsides I should say about the way I did my career path, leading to an academic career, is that what's more typical, I would say, is that you go to grad school, you learn what you learn there. You choose a postdoc environment that allows you to complement what you learned in graduate school, so that when you come out of it, you're able to put together a research program that merges the best of both of those worlds. But for most people, what you're able to do as well is to seed projects from your postdoctoral period that can, or take projects rather from your postdoctoral period, that can be used to seed what you're going to start your independent lab with. Can't do that if you worked at a company. They give you a cake and say, have a great life, but you're not taking any materials. You're not really taking any projects because you signed a form on the first day that says all that stuff belongs to them, and then they're going to want to hang on to it. So they do. So I needed to come up. And by the way, I had been out of grad school for four years, so I couldn't do what I was doing in graduate school, both because, well, that kind of, sorry, Adam, that kind of belongs to your grad advisor, right? Same for you, right? You have to figure out how you're going to differentiate. And so what I did in graduate school was narrowly enough to find that it was really hard to differentiate from there. And then what I did at Merck, and I worked in a lot of different areas, but there wasn't anything I could really bring to sort of seed things. And so ironically enough, I don't even remember what I pitched as a set of research projects when I did my interviews, but I ended up deciding they were all bad ideas and went in a different direction. And what I realized was that when I was in graduate school, I had learned metabolic engineering and really I learned biological synthesis. And traditionally, if you think about biological synthesis, it's pathways, right? So you mentioned flavonoids, for example, isoprenoids. These are classes of chemical compounds where you've got, or biochemical compounds where you have a conserved part of the pathway that leads to some common precursor and it branches out to a lot of different things. So we typically think about biological synthesis in that way. We think about what are the pathways that give us diverse chemicals. I had been at Merck, which is filled with a lot of chemists, and I had worked on biocatalysis projects there where the goal was to be able to use biological conversion. Now, I won't even call it synthesis, biological conversion to do single step chemical reactions to give some intermediate that would then be further converted into drug substance, right? So typically what would happen for those kinds of projects is that you would have process chemists or you would have process research chemists who would say, okay, we know that our target is this molecule A and we've got, or actually let's make it X. We're going to start with A. We've got a lot of conversions to get from A to X. We've got this one step in the middle here where there's a stereospecific reduction of a ketone to an alcohol and we know that enzymes do stereospecific reductions with a lot higher specificity than chemical catalysts do. So can you guys come up with an enzyme or a microbial cell that'll do this conversion? So I worked on a few different projects that were like that and what it caused me to think about is the fact that whereas in biology we think about pathways, in chemistry they think about products. So if you go to a typical organic chemist and say, you know, draw whatever structure you want on the board and say, how do you make this? They don't start thinking about what biological pathway might get them to something close to it. They go, okay, that's got, you know, these functional groups and they start this retrosynthetic process to disconnect that into building blocks they know are going to be commercially available and then they can build it. They can't always do it with high efficiency, right? You know, 0.1% yields are not unusual for total synthesis, but there's an approach to thinking about chemical synthesis that's really different, that is product focused versus a pathway focused approach that is utilized more often in biological synthesis. So what I decided I wanted to focus my lab on when I started was merging those two concepts. So thinking about biological synthesis but in a product focused manner. So the question then became if you had some target molecule you wanted to produce and there wasn't a pre-specified pathway to get there, could you identify pathways that were close enough or could you find series of natural biochemical conversions to get you from point A to point X all biologically, right? So the glucaric acid was an example of that where that was a compound had been identified by the DOE as a top value added chemical from biomass. It's actually a natural product, but the natural pathway is really, really convoluted, but we identified a series of enzymatic steps to get from glucose to the final compound in three steps, right? Which is about a quarter of the number of steps that will be required if you tried to reconstitute the entire natural pathway. We also made a whole series of other compounds that were based on structural similarity towards natural products. And so in that case, what we relied on is the promiscuity of enzymes to be able to accept substrates that were close to the structure of the natural substrate, but not identical, right? And the idea being if you can get an enzyme to take a new substrate, it's going to make a new product, right? That's not that revolutionary, but I make it sound like it's revolutionary when I'm talking about it, right? So our goal was to figure out how many of these different novel steps you could string together and think about total biosynthesis and the way that organic chemists think about total synthesis of chemical compounds. So that was the overall vision for my lab when I set it up back in 2004. And we published a number of papers where we were making a wide variety of different compounds. And what we basically figured out is if we were smart about how we chose the targets, right? So for example, we don't pick stuff that's got silicones in it, right? Because that's just not that common. You get silicates in biology, but it's just not that common. We don't pick compounds that have a bunch of heteroatoms, right? So it's largely carbon, oxygen, hydrogen. Occasionally you toss it in nitrogen. But if we're discriminating about the kinds of targets we pick, there's only one thing, and I won't tell you what it is because I still want us to figure it out, where we try to make a pathway to something and couldn't figure out how to make it. However, in almost every case, we can only make very small amounts of it, right? So then we're chemical engineers. If you're not making enough product, it's really only two things that could be at issue here. Either you don't have sufficient catalytic activity, right? So your reaction rate is not fast enough, or your concentration of your reagent is not high enough, right? Chemical catalyst, that's what we learned in reaction engineering. You can fix one of those two things. So over the past really five to eight-ish years, so the second half so far of my academic career, we've been focused more on those problems, which are what are interesting ways where we can try to increase the availability of substrates, and then how do we actually get access to better enzymes to be able to do the conversions that we want to do. Along the way, of course, we've had all sorts of side projects on very, very interesting things, some of which are about bioremediation and novel process concepts for that. We've done some work in multi-phase fermentations, thinking about how to mitigate toxicity for products that are being produced. I co-advised a student who just graduated in the spring, who was looking at microbiomes and competing interactions between healthy human-associated microbes and the pathogenic gut microbes. So there's been a lot of variations on that theme, but overwhelmingly, we're still very much interested in biological production of chemical compounds, and in really trying to figure out what are basic tools and approaches and methodologies that we can help develop to accelerate both the process of designing these kinds of pathways and then our ability to get back to that translational stuff that I first went to Merck about. So how do we actually get past just proof of concept quantities of the compounds that we're making towards amounts that are actually going to be commercially relevant? That's a really fascinating answer, and maybe taking it a little bit of a step even broader, this is the state of metabolic engineering that you're describing right now, and I'm curious if you put on your fortune-telling hat, what do you think is the vision for this field in the next 20 years? Are there particular molecules or pathways or even substrate chassis that you or someone else could be particularly interested in that would really be game-changing if synthetic biologists and metabolic engineers could find a way to unlock? Yeah, so I'll start by saying I'm a terrible fortune-teller. I always tell people if I could predict the future, this is not a lie. I would buy a lottery ticket, because then I would know what the numbers were and what I would have fundamentally are choices. I'm not saying money can buy you happiness, but money buys you choices. So setting aside for now the fact that I am a terrible fortune-teller, I am very excited about the field of metabolic engineering, but at the same time, I'm terrified about the overall state of the world. And so I'm going to answer this by not just saying what gets me excited, but where I think we actually need to be doing the work. And full disclosure, a lot of this is not work I am doing myself. It's just stuff that I think is important, right? So I think climate change is a big deal. I think I said this in a meeting I was in that long ago, that I think obviously the most acute crisis that we're dealing with is a global pandemic, but I think the most significant existential crisis we're dealing with is can we actually figure out some way to reverse the decades and decades, more than a century now, of harm that we humans have caused to the planet, which is now showing up with very, very real consequences, right? I don't know how closely you guys follow this, but I just got a pit in my stomach every time we went one letter further in the Greek alphabet with naming of tropical storms. And we're not done yet. The hurricane season doesn't officially end until the end of November. I did read something that said, yes, there have been hurricanes in December and January before. That's not something to look forward to. So there's something that has to be done. And I think biology is a technology or biology as technology is maybe the best way to describe it. I'm not saying it's the only shot we've got, but we have to make sure we have a lot of bioarals in the quiver to do something about this. And it's going to be necessary on a number of different levels. So with that as a big framework, if I just now dial it back down a little bit, I do think we have to figure out how to replace more of the stuff that we use with sustainable, renewably sourced alternatives. And I'm using alternatives on purpose because we do still have a very significant economic there. There's both an economic issue here and then there is an end of life issue here. Let me give an example. I used to be a big fan of let's figure out how to make bio-basodypic acid. I am no longer a fan of bio-basodypic acid if the dipic acid containing polymers are going to strangle all the fish in the ocean. I think we have got to move past just thinking about the inputs to being much more concerned about the full life cycle analysis. And so that's why I think it's going to have to be more alternatives because I think we're going to have to get to a point where we can reliably design end of life and life cycle into the materials that we're using. And I think biology is perfectly primed to do this because of the fact that there are so many natural biological materials that have structure and function, but are actually renewable and can be recycled in the natural biological environment. So I think that's one area if I'm looking ahead and saying, where do I think we need to go as far as metabolic engineering is concerned? I think we have to be, quite frankly, I think we have to be willing to say, no, just having it bio-derived is not good enough. Just because you didn't use oil to do it, right? If you're building something that still is going to have these downstream effects that are just as harmful, I'm not saying it's nothing that's been an incremental improvement because we aren't using fossil fuels, but it's not getting us nowhere near enough. And then the second thing that I'll mention, just so this doesn't take two hours, is what you asked a little about, Adam, in terms of what are the chassis and things that we should be doing? So I think we have to figure out, and I should say, I think we're already doing this, but there needs to be a broader, more concerted effort to have much more biological diversity in how we're going to handle this. We have got to figure out what to do with CO2. Photosynthesis and cyanobacteria is not good enough. Plants are great. They grow pretty slowly, right? So the amount of CO2 that they actually could, oh, and by the way, and then they degrade and it all goes back, right? That blew my mind recently. I'm like, okay, we're all talking about let's plant trees. And then people are like, no, you know, those leaves fall off. And when they fall off and decompose, all that CO2 goes right back into the atmosphere, right? Just having a lot more trees isn't the answer. We have to figure out other ways to actually sequester CO2 into a form that actually can be useful. So ideally it would be towards making some of this stuff that I said we need to be able to displace fossil-derived fuels with. And I don't think that's going to be done easily using E. coli and Saccharomyces yeast and Pseudomonas florescens, right? Like the common industrial microbes aren't quite going to cut it. Maybe we'll be able to get them up to that point, but at the same time, we've got to be trying to figure out how do we access more biological diversity, more microbial diversity to be able to get towards the input side of it in terms of being able to suck up CO2 to be able to make other stuff. And then I said I was going to just do a second one, but a third one is on the remediation side. So I also think that we have the opportunity to really leverage biology to deal with environmental damage and environmental reclamation. Those are the three that I would say. We have to figure out how to get better at sourcing materials, but doing it from a full LCA type perspective. I think we've got to figure out how to leverage biology more for CO2 sequestration. And then I think we've got to be able to leverage biology to deal with what is the existing environmental disaster that we have. And which, by the way, bioremediation has been very effective over the past several decades. So I'm not saying these for the first time, but I think if we had a more sustained effort within the community, and obviously a sustained effort also has to come with some robust and sustained funding for this and a commitment to really making change happen, I think we may be able to do some interesting things given the way the technology has advanced to be used for synthetic biology and metabolic engineering. That's a super interesting point. I hadn't thought of like when you're looking at the bioeconomy, you typically think of the starting materials never go full circle. So thanks for bringing that up. So also looking forward to the future. I know you said you're a terrible fortune teller, but this all seemed great, but looking at it in a different light. So you have been long an advocate for diversity in biotechnology. So I wanted to ask how has being a woman in science and also a woman of color in science changed over the years? And do you think we're moving in the right direction? So yes, I think we're moving in the right direction. I mean, I, as you might imagine, have thought about this a lot over the past eight months, for sure. We've all had a lot to think about in this past year, but a lot of things have not changed, but a lot of things have changed. So I do think there is, well, let me take a step back. So for myself, one of the things that I, I don't share this, I tell it to people who ask, it doesn't always come up, but I mentioned the fact that I was actually happy in my job at Merck, right? And so being happy in my job at Merck meant that I was only going to leave and go to an academic institution to be a professor if I thought it was going to offer me at least as much opportunity as I felt like I had at Merck. So between that and the fact that having a full-time job meant I didn't have a lot of time, I did not apply to a lot of places and I did not interview at a lot of places. I applied to two, I interviewed at two, I got one offer. And part of my thinking with that was I had a few different criteria, right? I did want an R1 institution, that was important, but I decided I did not want to apply at any department that did not have a woman on their faculty already, preferably a tenured woman. I did not want to apply to any department that did not have a person of color on their faculty. And then the other was I didn't want to apply any place. Now, this is going to seem odd for me to say this now. I didn't want to apply any place where they didn't have someone in biotech who was also tenured. It seems obvious now that everybody has bio, but this was almost 20 years ago when I was doing my applications. And at that time, bio still hadn't really taken off to the extent that it has. Things were starting to change, but there were still some turf wars and some debates about what the proper role was of biology and chemical engineering. And to be honest with you, I had trailblazing parents who both grew up in segregated schools and then went to integrated schools later. My mom was in the first integrated class of her high school, actually, and I ended up being the first black valedictorian of the class for that same high school. And that was in 1990. And in 1990, there were people who were upset that a black person had been quote unquote allowed to be valedictorian of the high school. My dad went to segregated schools and was in the first group of black students to graduate from his college. And, you know, so I say all that to say I knew from many, many stories, and I had aunts and uncles who had lots of stories to tell. My grandparents had lots of stories to tell. Being a trailblazer is a hard choice. If you make that choice, you are, whether purposefully, knowingly or not, you are choosing to be the person that forces people to confront their biases. Right. And, you know, that's a hard place to be. And I didn't, I just didn't want to do that if I didn't have to do that. Right. So I wanted to go to some place where people had already dealt with whatever their implicit, unknown, unconscious biases were about women. And they had already had to deal with whatever their unconscious biases were about people of color. So to be honest, the reason I only applied to two universities is because by the time I had applied that filter, there were only two universities who were advertising positions that met the criteria. Period. Right. Which is amazing to think about. But that's it. There were only two who had biofaculty, a woman, and a person of color. And this was in 2003 when I sent out, I would have sent my applications, they were due later then, so due in February. So in February of 2003, there were two. So things have changed. If I were doing that search now, there would be a lot more places that I would consider. Even if I take the bio out of it, there'd be a lot more places I would think about in terms of the presence of women on the faculty and in terms of the presence of people of color on the faculty as well. So for certain, it's unfair to say that nothing has changed in the past 20 years and in the 20 years before that. But there is still a long way to go. I, as an undergraduate at MIT, and I was thinking about this back in the spring when a lot of these conversations were being held again, there were a couple of very prominent anti-black racist events that happened on campus. I actually went back and saw articles in the school newspaper where I was a protest leader. So I was kind of radical back in those days. And part of the reason why I was looking back at it is because if I, even at the time I've been at MIT, if I look every four to five years or so, there's someone who chooses to write an article in the school newspaper about how the push for diversity is lowering standards. And there are all these black and brown people on campus who are taking away opportunities from people who deserve to be here and they don't deserve to be here. And that's just hard, right? It is exhausting and it is tiring. At the AICHE meeting last week, there were some Zoom bombing incidents that were racist-tinged. It's 2020 and that's still happening. So this is a very long answer that is starting off more to just sort of give you more of a perspective of where I'm coming from here. I will say I have felt personally very blessed and very fortunate to have always had very strong mentors and supporters who were white men, my advisor, my grad advisor was fantastic. I'm still in close contact with Jay and we have a wonderful relationship. I mentioned the family friend, his name is Bob Cargill from my hometown who gave me these books on biotech and on polymer science. And he and I have stayed in close contact and he's like a father to me. And so many other people have been big supporters and champions. Actually when I was an undergrad, Danny Wong, who passed away just a few months ago at MIT, was a supporter and Charlie Cooney, who is an emeritus professor now. I remember he was teaching my kinetics class. He was a bio faculty member my junior year. And I went to him because I wanted to think about graduate schools. And again, this is pre-Google. So I went to ask someone if I'm interested in doing biotech research for graduate school, where should I go? He had a wonderful conversation with me and then he said, you're doing really well in my class. I'm happy to write you a letter of recommendation. And if you want to do a UROP, which is what we call undergraduate research, next year, your senior year, I'm happy to have you in my lab. And that was, UROP was done by maybe 15% of students at that point as opposed now it's like over 90% of people. And having someone offer that to me and reach out and extend themselves in that way was really transformational and very much affirming of what my goals were and of what I hoped was talent that I had shown and that had been observed and respected. So my own experience has been very positive at the same time it's isolated. Two years ago at the metabolic engineering meeting, which was in Munich, Germany, I took my family with me and my kids were telling me that all these people were coming up to them and telling them that they knew their mother. And one of my daughters was like, how do they know that we're your kids? Like, because we're the only black people here, honey. And I told them my family was coming with me. So by the process of elimination, it had to be you, right? So, you know, so it's it, my eye is drawn to another to another black person in the room. It's very rare that there's another black woman in the room. But, you know, I noticed that. And so I can't say that I haven't noticed being the only person in the room, but I have personally had enough support and enough wonderful friendships with colleagues across a spectrum of racial and ethnic and gender backgrounds that I have felt very personally supported. At the same time, I must say I have more than a few friends and colleagues who have not had that same level of support. So for reasons I frankly don't fully understand, I hear consistently that chemical engineering as a community and biochemical engineering as a community tends to be a more supportive, welcoming, inclusive kind of community. And I'm grateful for that. And so I'm always hesitant when I say that I've always had very positive experiences. I don't want anybody to misinterpret that as saying, well, other people are just complaining and there isn't anything real that's happening. Right. Those the stories that you hear from other people are real. They're hurtful and they're harmful and they are stressful and degrading in a way that's very hard to articulate. And so I think we've got to do better. The last thing I will say specifically towards being a woman, it has been incredibly difficult to really move the needle on increasing women in the academy. And I had a very interesting exchange with a student about two or three weeks ago, because MIT has a program called Path to Professorship for graduate students and postdocs who are at MIT across all disciplines. It's not limited to chemical engineering at all to really introduce them to women faculty from all over MIT, but also many other universities, either locally, or we have a lot of our alums who will come back and talk if they're at other places. And the person who runs the program or the office where it's run, I'm very good friends with the head of that office. And she reached out to me and said, you know, we just don't have very many people from chemical engineering. Do you know what's going on? And so I reached out to our graduate women in chemical engineering program and said, Hey, I'm just sort of following up. Maybe is it our women not interested in the program? And she wrote back and said, well, I think we can look into it. But if I look at my year and the year above me, which is the year I know well, you know, we have a good number of women in the program from our years and we appreciate that we have women faculty around, but we've kind of watched what you do and we don't really want that life. And so I'm not sure what to do about that. Right? Like, you know, my life is what it is. Yes, I work a lot all the time, but I have not quite figured out how do we actually make academia more welcoming of women. And frankly, I think part of it needs to be that there has to be a cultural shift where women are not viewed as the primary caregivers and house managers, if you will. And so having men be more involved in those activities, right. And having a more equal distribution, I think will then make it such that everybody realizes that we have to have effective ways to be able to balance the work part of it and the home part of it in order to make sure that the most talented people are able to access the workforce. So I'll stop there. It was a long, multifaceted answer, but, but hopefully it gave you a couple of things to think about and a couple of things for other people who might listen to this to think about and appreciate. Yeah, it really, really did. Thank you so much. All right. So we'll, we'll wrap up soon. I just wanted to end on two maybe lighter notes. The first one, maybe a fun question. What do you think is the most unusual research project that you or your group has worked on? It's been different. Unusual. That's a good question. I don't know that we've done anything too unusual. So I will answer the question. What's the research project that took me furthest away from what I had been doing? How about that? So some years ago, I don't remember exactly how long ago it was. I was on the thesis committee of a student. His advisor was Danny Wong, and Danny actually had a stroke and then asked me afterwards to be the co-advisor for the student. And the project was a bio desulphurization project. What the heck do I know about bio desulphurization? The idea was that you would use these, I don't even remember the genus of the microbes anymore, but there are these microbes that were known to be able to break down organic, sulfur containing organic compounds, organosulfur compounds. But what had been observed over years and years and years was that the conversion rates were really low. And what made this a very unusual project was that Danny was just a very unusual guy. And so Danny early on was like, I got the answer. It's all about mass transfer. The mass transfer is all messed up. Now, mind you, I'm a chemical engineer, so I know what mass transfer is, but I have been working in biology functionally as a molecular biologist for like seven years at that point. And I'm like, really, what the heck do I know about mass transfer? And it turned into a really fascinating project because it only took about six months to prove to Danny that he was wrong. Like Danny, it's not mass transfer. What else you got? Right. So we sort of, we sort of were going around and around and then finally I'm like, well, what, what do I know? I'm like, I know biology, I know biological pathways, I know enzyme chemistry. And we had this theory then that it had nothing to do with mass transfer. And by the way, it was oxygen mass transfer because it's an aerobic degradation process. Fun fact, air and oil, not a good mixture, right? So we had to be very careful to like keep things from between the LAL and UAL so nothing would go boom. I didn't really like that part of it very much. But what ended up happening, the student who was on this project was the most resourceful student that I have ever worked with. There were four enzymes involved in the pathway and he decided he wanted to take on the challenge of purifying all these enzymes and then testing them individually with the different pathway intermediates to figure out whether or not inhibition was actually the issue here. He had never done any molecular biology before, but he got really excited about it and had to learn on that. And then it turns out none of the intermediates were like commercially available. So like the final product that everything got converted to, you could buy the model substrate, obviously that we added, you could buy. So he went on this quest to find a provider of these. He found some company in China that said, send us $250 and we will do initial synthesis. If you confirm it, we'll scale it up. He sent them $250 and then the website went dark and he could never find them again. And then I still don't know how this happened, but then he met some random chemist in the chemistry building next door and was like, I got these compounds and she's like, all right, I'm looking for something to do. And so somebody we had never met before synthesized, did like total synthesis of all these compound intermediates. So then he had purified enzymes, he had compounds, and he ended up with one beautiful paper that showed that mass transfer was not the problem. And then he ended up with another beautiful paper where he showed that pretty much everything inhibited everything else, right? So like the take-home message is this is the worst pathway nature has ever created. It was unusual because it brought to a screeching halt any other work in the space. I'm like, stay away from it. If you've got four intermediates and all of them inhibit everything upstream and downstream, good luck engineering around that. But it ended up being the most meandering path to where it turned out to be a really beautiful, fundamental result where we're like, hey, all you people who are worried about designing reactors, not going to work because your bug's going to die. That paper was published like 10 years ago. I still get people asking me to like review papers on bio-desulfurization and I'm like, I didn't know anything about it then. I know moderately more about it now, but no, I'm not going to review papers on bio-desulfurization. So there you go. There's a story for an unusual project from my lab, but for a totally different set of reasons because it was not my project to begin with. That's amazing. That meets the criteria for unusual, crazy project. I'm glad you shared it with us. So we are running out of time. We had a ton of questions that we would have loved to ask you, but just to end, we wanted to ask if you had anything to pitch or plug. No, I don't have anything to pitch or plug. Not in a scientific sense. I'm going to pitch or plug kindness. I'm going to pitch and plug patience. I'm going to plug respect for your fellow human being. I think one of the many things that I've had time to reflect on in eight plus months of pandemic living is how much we depend on each other. We depend on each other for human contact. One of the most interesting moments I had was we'd all been at home for months and then we started our on-site testing program. And so we had to come in, those of us who had access to campus had to come in and be tested. And I saw a friend and colleague I hadn't seen for years and he was like, you're the first human besides my wife and kids I've seen in three months, right? So there have been lots of these little moments, whereas people who were very shut in started to be reintroduced to society that I think have led me and certainly lots of other people. I hope to reflect on how important it is that we have each other, but it only works if we actually treat each other with kindness and respect that we want people to treat us with. So I'm going to pitch and plug random acts of kindness, random acts of patience, and really a group effort for us to all be kinder, nicer, better, especially as we think about how we're going to live in a post-pandemic world. That was a wonderful answer. Thank you so much. And thank you again, Chris, for coming on the podcast today. This was a great conversation. This has been another episode of EBRC in Translation, a production of the Engineering Biology Research Consortium's Student and Postdoc Association. For more information about the EBRC, you can visit our website at ebrc.org. If you're interested in becoming a member of the EBRC Student and Postdoc Association, you should, and you can find our membership application on our website. And a big thank you to the entire EBRC SPA podcast team. That's Catherine Brank, Fatima Anam, Andrew Hunt, Adam Silverman, and Kevin Reid. This episode was edited by Kevin Reid. Thanks also to EBRC for their support and you to our listeners for tuning in. We look forward to sharing our next episode with you soon.