EBRC In Translation
EBRC In Translation
15. Controlling Cells and Fixing Networks w/ Hana El-Samad
In this episode, we interview Dr. Hana El-Samad, a Professor at UCSF, editor-in-chief of GEN biotechnology, and a founding PI at Altos labs, whose research focuses on controlling mammalian cell behavior with genetic circuits. We talk with Dr. El-Samad about her work on controlling mammalian cell behavior, her role at and transition to Altos labs, committing to equity in STEM, the mission of GEN biotechnology, and more!
Notes and links:
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Episode transcripts are the unedited output from Whisper and likely contain errors.
Hello, and welcome back to EBRC and Translation. We are a group of graduate students and postdocs working to bring your conversation with members of the engineering biology community. My name is Fatimae Nam, and I'm a postdoc in Justin Sonnenberg's lab at Stanford University. And I'm Koke Zili, a postdoc in Fu Zhongzhang's lab at Washington University in St. Louis. Today we are excited to have Hana L. Samad, a professor in the Department of Biochemistry and Biophysics at UCSF, and a founding member of Elto's lab. Thank you so much for joining us today. Thank you so much for having me. It's such a pleasure. Well, let's get started with your personal journey. You are trained as a mechanical engineer. During your PhD, you were studying control theory and dynamic systems in machines. So we are curious, what makes you live into biology? That's a really interesting question, and it's really serendipity. People go and rewrite history and find meaning in things, but it is almost always serendipity. The reason is I was exposed serendipitously to the nascent field of systems biology back at that time. And through that, through listening to many talks and having discussions with various people who are kind of the luminaries of that nascent field, it dawned on me one day that, you know, that realization that circuits, for example, stress responses in cells are actually the ultimate control systems whose principles can really be understood through the lens, through the methods, through the concepts that I were learning in control and dynamical systems theories. So that was kind of a eureka moment that these systems are just such fantastic control systems that keep us alive. Also, you know, following that came the realization that cells can be engineered, which was, you know, I mean, of course, people have been engineering cells for a very long time. That's, you know, since the dawn of really molecular biology. But to me, that realization was just so mind blowing that we can, we can put genes in cells, we can build things into cells, and we can kind of swap genes from one cell type to the next. And that's kind of fully acceptable to the cells, you know, and also the realization that these technologies to engineer cells and organism was really accelerating. These technologies were accelerating. So all of this together made the study of biology so much more exciting than really any of the applications of control theory I was considering at the time. Yeah, I guess you now exclusively have been studying biological feedback control networks. And I guess if we go back to kind of the earliest examples of these feedback systems in synthetic biology and those mainly involved like the construction of circuits capable of the oscillations or by stability. And now we see these feedback loops are being used to implement increasingly sophisticated behaviors. This feedback control is really prevalent in other disciplines like in mechanical engineering. It seems like synthetic biology has been a little slow to implement this in the design of biological systems. We're still struggling with constructing large scale systems to behave more predictably. What do you think are the biggest challenges towards achieving these types of problems? I think it boils down to a couple of things, many things. Let me tell you about three of them that I think are very profound. The first is a matter of understanding. There's still a lot about biological organization and logic that we don't understand. For example, we tend to think about biological molecules as strictly modular. And some of them are and some of them aren't. And there are many concepts outside of this modularity that could be brought to bear on the engineering of biological systems. And I think we still have to come to terms with the limits of modularity and our understanding of modularity in biology. The second is context. So we're building these systems in the background of a cell, a cell that has thousands and thousands of genes that are connected in elaborate networks. And we're hacking into not only the networks, the signal processing of the cell, but also into its resources. And I still don't think we have a full understanding of what that means in terms of the energetics and in terms of the organizational capacity of the cell to accommodate these changes. The third is, of course, evolution. And it's not disconnected from my second point, but cells and organisms kind of have their own agenda, which might be very different from our agenda for them. And they care about surviving and about their fitness. And they're going to do anything they can to maintain that fitness. So we're in an arms race with a cell that wants to maintain its integrity and its fitness. And I think we still have not thought in the field about what that means very profoundly and whether we can turn this tug of war more into a cooperative relationship versus a challenging relationship. What do you say? It's more challenging. I know you do a lot of building these systems in mammalian cells or eukaryotes. Do you think it's more challenging than you would see in prokaryotes? It is definitely more challenging. I mean, to start with, some of the complexity is greater. But it's also, I would say, and maybe that would be unacceptable to some, but I would say that our knowledge of mammalian systems is much less developed than that of, let's say, E. coli, at least for engineering purposes or for, you know, Saccharomyces cerevisiae or various yeasts, where we might have more, you know, thorough understanding of their metabolism, of their regulatory networks and so on. So there is the increased complexity and there is also a lower level of understanding that we have of these systems. For sure. Yeah. And touching back on your, like you mentioned, the modularity, which is definitely challenging, like definitely leads to a lot of iterative design processes. What are ways that you kind of overcome these type of barriers? I think there are many approaches to start thinking about that very deeply, and some of them are done by beautiful work, various researchers in the field. For example, I'm very fond of the work about retroactivity that people like Domitila Delvecchio at MIT do, trying to understand what challenges modularity in terms of the chemical logic of cells. So I think theories that dive deep into the limits of modularity and how we can define it a little bit better are very productive to think about and scale up in the future. Another approach that we have taken is actually using de novo designed proteins in collaboration, of course, with David Baker, who is like kind of the visionary who actually produced some of the most exciting designs there. And what we found there is, and maybe that doesn't relate strictly to modularity, but rather to multifunctionality of biological molecules. But what we found there is that when you design a molecule, de novo, and you decide to do one thing and one thing only, and that design is successful, then that actually simplifies a lot the design and the failure modalities. And in retrospect, this is not very surprising. I mean, when you think about endogenous molecules, evolved molecules, a lot of them have multiple functions. They have multiple binding pockets, they have multiple binding partners, they moonlight something else in addition to their day job. And when you try to squeeze them into any one function, they're still doing all the others. So that induces crosstalk, that induces metabolic load, that induces all kinds of things that we haven't designed for. While with these de novo designed proteins, that crosstalk, undesirable crosstalk, I mean, it still happens sometimes, but to a much lesser extent. Absolutely. And I believe like most logic circuits to date have really focused on control at the transcription level, at the DNA or RNA level. And these de novo protein based circuits, I think in terms of rewiring them or creating these modular systems, it's great. I'd love to hear your thoughts on some applications you see with these type of new systems. We can talk about many, many, many applications. For these systems and also for other systems, I think there is space and there is potential to kind of harness the power of biology at all levels, whether it's evolved biological molecules or it is de novo designed. We have to capitalize on all of it. So in terms of applications, this is going to be a little bit of a simplistic classification, but let me give it a shot in terms of how conceptually I think about it. Actually, before I do that, let me just tell you that it is my deep, deep belief that actually biotechnology, cell engineering, biological engineering, synthetic biology is really the best hope we have for solving our health and environmental challenges. And these are daunting, especially our environmental challenges are daunting. I really believe that very deeply. This said, in terms of application, I think these molecular technologies have really two broad brands. The first I like to think about is bio manufacturing. We are talking here, clothes made out of mushrooms, like beautiful stuff out there, most importantly green agriculture. And of course, this is very much underway. There are so many exciting, so much exciting progress, both in academic labs, in companies, it's all capitalizing on progress and our understanding of biology, as well as machine learning. I'm very excited about the potential of machine learning for bio manufacturing. In addition to that, I'm very excited about the potential of biological engineering and synthetic biology coming from non-model organisms, which I think there is a whole space of biotechnology that remains completely obscure to us because we have so far worked and studied only a very minute number of the biodiversity out there. So I'm sure there are bugs and organisms and various things out there that hold so many biotechnological treasures. And you know that the non-model organisms recently got a champion with Arcadia Science. The second set of applications that are, I think they're going to change medicine is live cell therapies. And these are applications that need, because they relate to human health, they relate in putting engineered cells into human bodies. To me, at least to my mind, they need a very superior level of precision and programmability. So there, I think progress will come from platforms such as hopefully the ones we are developing that make these engineered cells reliable, precise, and controllable mini-robots that not only kill cancer, but actually deliver precise therapeutic payloads. They can sense the environment they work in, adjust their operation in real time based on what they sense, on what they see in the environment of a human, of a living organism. And I remain hopeful that a huge bifurcation, a new age of medicine will really come when we understand enough and we engineer enough so that we transform blunt tools of cell engineering to surgical instruments that can modulate vital variables, that can modulate inflammation in a programmable way. They can rebuild destroyed tissues, heal wounds with high precision and exquisite control. Or, as hopefully you will try to do at Altos Labs, learn how to steer cells through rationally designed interventions or control trajectories from disease to healthy states. So the future is bright, as you can see. And I repeat how I started answering this question. I don't think we have many choices except for engineering the world around us and engineering ourselves back to health. That is certainly very exciting. So building upon what you've just said, and you are part of the Cell Design Institute at UCSF that has been developing engineered cells as a new platform for live cell therapies. So could you tell us a little bit about the work that you are involved in at the Institute? Yes, yes. The Cell Design Institute, or CDI in short, is a very exciting enterprise that my colleagues Wenda Lim, Cole Roybal and myself have been working on and building for a while now. Let me mention here that actually the CDI is an integral part of a bigger initiative, which is the Living Therapeutics Initiative at UCSF, but the CDI occupies a really central place in that big Living Therapeutics Initiative, and that is building foundational technologies. You know, I keep going back to that theme for living therapeutics, we really need precision and safety, and we need to build foundational technologies that are based on understanding of biological molecules on rational circuit design to program cells for next generation therapies. So our group has been contributing multiple elements to that broad vision of foundational technologies. Let me mention a couple. For example, we have been building computational frameworks to navigate the design space of different circuits customized to living cell therapeutics. We also have been working really hard on designing strategies to make these therapies more sophisticated and more reliable by designing plug and play circuits that can do signal processing functions of various types and also feedback control to build resilience and robustness into these circuits. Yeah, I think all of these institutes definitely has been built with like incredible foundation with amazing vision as well as leadership from people like you. I guess to top that, I think Altos Labs has been making quite some headlines recently, and you're one of the founding PIs. So could you tell us a little bit more about the institute? And I'm sure our listeners will be curious about some of the projects that you're working on. So let me start by saying that Altos Labs is actually currently three interconnected institutes of science. One of them is in the Bay Area. This is the one I am part of, and two others. One is in San Diego and one is in Cambridge, England. So we have the kind of the motto of one Altos. So it's a one institute, but it has three physical locations. And we are very keen on calling them the institutes of science because we all share one goal, and that is really to understand, to generate knowledge. First and foremost, to understand cell and organism and health and resilience of cells and organism quantitatively. And that's a key word, quantitatively, so that this understanding can enable rational and safe cellular rejuvenation and reprogramming to restore cell health and resilience. I actually have worked for a couple of decades now on trying to understand how biological networks acquire their resilience, their robustness through feedback control, and also how failures of these feedback structures lead to disease. And I fundamentally believe that actually disease is a failure of networks, first and foremost. So in some sense, the work at Altos Labs that we will be doing will be kind of an integration and a culmination of many ideas that we pursued through the years, but now we are going to be integrating them and synthesizing them to think about the whole cell and in some instances actually the whole organism as the homeostatic entity. As I said, what's exciting about this is that it feels like a point of integration and culmination of a lot of work that we and others have done for a very long time on cellular robustness and homeostasis and how that fails and adding the element on how to fix those failures of homeostasis. We will also continue working on technologies, of course, that would allow us to restore this resilience through cell engineering and synthetic biology. Wow, this is certainly very exciting, like in many aspects. I am very excited. If you can't tell, I am very excited. We are too. So in terms of the leadership, how has your role been changed from running an academic lab to now running a lab and also an institute? So let me actually repeat something that we keep saying whenever people ask us about what is Altos and how is it different from our previous lives and so on. Most of us here are from an academic background. As I said before, our goal at Altos is really, really to generate knowledge, first and foremost. What we would like to try to do is to generate this knowledge in a scientific framework that brings together the best of academia and the best of industry. Now people, of course, have very different ideas about what is the best in academia and what is the best in industry. If you call different people, they give you different answers. So let me give you my simple answer to this. For me, the best of academia is absolutely free inquiry, the ability to follow your curiosity, to be a dreamer, to just get obsessed with something and just pursue it to your heart's content. Absolutely. That's the most beautiful thing about academia. I am absolutely addicted to that. Now the best of industry is there are so many good things about industry. I can't imagine a world without biotechnology and so on. But for me, the best of industry is the value that industry places on teamwork, a heightened sense of mission and purpose toward a common set of goals. So the question here is that we're having at Altos is can we actually merge these two things together? Free inquiry with a heightened value for teamwork so that we continue doing discovery science but in bigger teams with a value structure that encourages teamwork, encourages a large number of people coming together to solve problems that they couldn't do otherwise on their own or within their research groups. So that's what we're going to try to build and implement. The best of academia and the best of industry. It's an experiment. I think it's going to be a successful experiment, but it's an experiment nonetheless. And it's an exciting one. So do you think we are going to see more of these type of research institutes in the future? Oh, I really don't know, but I personally hope so. I think there are so many ways to do science. There are just so many ways to contribute to the enhancement of the human condition. So academic research is certainly one of them. Academic research is one of the best things that civilization has produced. No question about that. So is research an industry? So a hybrid model like Altos is really a prime candidate to fill a gap in the middle. And as scientists we know, the more experiments running, the better, right? So the more science that is being done using different complementary approaches with one goal, which is to help humans and their planet, the better. Don't you think? Absolutely. So cycling back to the Altos lab with the framework you just mentioned, what is your vision for the future of cellular engineering and synthetic biology? So I think that the mission of Altos Labs is much broader than synthetic biology and cell engineering. It is really understanding health, it's quantifying what health means, and then trying to measure and classify diseases as a deviation from the state of health. And there might be many states of health. So understanding the spectrum quantitatively and building predictive models that would allow us to study this with the goal of being able to reprogram those states of health when cells and organisms deviate from them. So that's the broader goal. I have no doubt that cell engineering and synthetic biology and many other technologies we're probably not even thinking about now will be instrumental to that. So we'll see how we can implement the engineering goal of Altos, but I want to really emphasize that knowledge and generation of understanding and science is our first and foremost goal. Yes, thanks for sharing this. I don't think many of us are very familiar with the Altos lab and with your introduction. I believe more of us will be very excited for the future. Yes, I mean, I want to remind you that we're just getting started. I am really hopeful that you're going to get to know us through our publications and through our work and through our talks and through our outreach to our local community, to universities and various other institutions. So you're going to be hearing a lot from us. I guess this is something that we talk about in academia where we do all of this fundamental research, but it doesn't end up getting translated or commercialized. Do you see Altos labs doing this basic research, but also pushing it forward towards either commercializing or making it a real life product or helping patients, for example? Absolutely, absolutely. I think there is a desire and a yearning in everybody who's joined so far in marrying that vision of we are going to understand a bigger swath of biology to, you know, we need to do something about this and we need to bring it to people to improve their health and wellbeing and an increasingly prominent conversation amongst us also is when we do so, how do we do it equitably? How do we benefit the largest number of people in the most effective and equitable way? So it is a conversation that is ongoing. I guess the message that I'm trying to send over and over here is that we hope that whatever, you know, translational work we do, it's going to come from a place of deep understanding of the biology. Yeah, thank you for sharing this brilliant perspective. Switching to a completely different topic. As we know, you are the editor-in-chief of Gen Biotechnology. The journal has both a scientific mission and a mission to elevate diverse voices to promote equitable participation in biotechnology instead. What do you envision achieving with this journal? So first and foremost, I actually would like this journal to be the modern voice of biotechnology, both scientifically and socially. So I wanted to cover all aspects of biotechnology, the full ecosystem of it, the science, the sociology, the talent, the challenges, and so on. Another way I think about it is Gen Biotechnology being a meeting place for the community. And of course, I'm hoping the content of the journal would reflect that. From cutting-edge science to forward-looking perspectives to voices telling the field where it's succeeding, where is it held back, both scientifically and sociologically. I would really love to feature diverse science. And what that means is everything that biotechnology covers from agro technology to medicine to health to the fashion industry that is covered by synthetic biology to everything at all where biological molecules are at play. And also diverse voices who speak for different technological needs of the community and the world. I would really love to focus on young voices and perspectives. I think your generation has just so much talent and so much to say. And we need to start listening to you as early as as soon as possible. So I don't know if you've seen our first inaugural issue, but we're off to a really great start. So if you haven't, please take a read. I'm sure you'll find many things that appeal to you. We have another incredible issue lined up for the journal at the end of April. And it's going to be featuring some, as I said, some young voices to bring some issues facing science and current generations, your generations, frankly, our future into focus. So stay tuned. It was a fantastic inaugural issue. Definitely look forward to reading more. And I'm sure listeners would love to submit their articles and any sort of opinions for sure. I'm sure it'll be welcomed. And you mentioned right now, like talking about how you have been active towards promoting diversity. I think that extent is incredible. And I wanted to talk about an editorial piece that you wrote in Science last year, which was just amazing. You talk about the urgent need for smart and socially minded policymaking to attract people who are the best and the brightest. And it is a difficult task. Mostly because the system has really implicitly created barriers to access and inclusion for the underrepresented. I'd love to hear your thoughts on what can be done to make STEM more equitable. Actually, let me start from the individual because I think we should all hold responsibility for this. It starts from the individual and then it goes to the system. And remember, systems are made up of people. At the end of the day, it's people who make decisions. So the first step should always come from within all of us. And it's simple and sometimes very effective if many of us bind ourselves to upholding the principles of equity, inclusion, and justice. So stand up for what is right and equitable in any capacity you can. Whether it's calling people up on their biases, whether it's demanding in your circle of influence that barriers be dismantled in your department, in your graduate program, in your institution. There are many people in academia and industry, in every walk of life who are in positions of power and privilege. And it is rarely the case that these people, you know, tenured professors like me use our privilege, our voice, our resources to change the status quo. And we need to start doing that individually at a much higher rate. So that is necessary, right? And again, let me repeat, institutions, systems, and structures are made of people. But it is actually in no way sufficient. So institutions need to change. And there are many, many articles out there. There are many studies that detail how institutions, for example, universities in academic settings, how things need to change. So I'm not going to repeat that. I'm going to go actually to a higher level. I think we as a society need to have a pledge that this is a priority. And one idea that I think is not far-fetched, if there is the right will in many people to make it happen, is something like a pledge that public institutions, private foundations, private foundations, industry, go into to negotiate and come to a roadmap for a really big movement in equity and inclusion. You probably know about the giving pledge, right, which was started by Bill Gates and others, where people who have large amounts of wealth came together and pledged that they're going to give a very large proportion of that wealth in their lives to human good, right, to better human condition, to help out. I think we need to have the same pledge. You can call it, for example, the pledge for innovation through diversity. Love that. We're big institutions where the government, the private citizens, NGOs come together and say, this is what we need to do. It's a Manhattan project for diversity. And this is what we're going to contribute. This is where we're going to pledge resources, you know, human resources, financial resources, but we're going to make it happen. It would be like a puzzle, a big puzzle, where every entity will pledge what they can contribute and we'll all come together and they fulfill that pledge in this beautiful private-public partnership. What's stopping us from doing that? What's stopping us from doing that as a society? Right. Yeah, definitely those are absolutely essential. And I think things that need to be done to move that needle. Yeah, absolutely. We can either do incremental things or we can change the whole landscape. And as scientists, we love the big breakthroughs, don't we? You want to solve big problems with big, bold action. And I think we need to take the same approach to the issue of diversity, equity, and inclusion. Absolutely. Yeah, I think this era has been transformative, just not for medicine like you mentioned, but also we're seeing much, much bigger commitment to issues of diversity, equity, and inclusion. And you're absolutely in the right direction as to what should be done. It isn't moral imperative. That's first and foremost what should count. It's a moral imperative on all of us to do that, but it's also an economic imperative. We are not performing as well as we should as an economy, as a technological society. We're not performing to the fullest of our potential in science because we're disregarding a big chunk of our talent. So you can think about it as a moral imperative or you can think about it as an economic imperative. Either way, we need big, transformative action. Absolutely. One of the things while we were Cogsie and we were discussing was you're also a very proud immigrant as well as a woman scientist. Do you have any advice for people like that to thrive in STEM in general? Oh, how much time do you have? Let me start with something that was told to me by many people, and I really cannot trace the first person who told me this, but something that travels with me a lot, that it's there in the back of my mind, and it just helped me do a lot of the things I did. So here's how it goes. If they don't give you a seat at the table, bring your own table. Right? Isn't that beautiful? It's beautiful. Yeah, which is to say that sometimes it's better to grab your courage and grab your friends and start something new in your program, in your affinity group, in your seminar series, something new rather than try to slowly fix every demobile structures. So gather your people, you know, women and immigrants, and everybody else, and build a beautiful, shiny, innovative new table if they want to give you a seat at the table. So the other advice I would give, and this is specifically for women and minoritized population in science, and I hope I'm very clear in what I'm going to say in this advice. You are where you are, and you got the chances you got because you're talented, because you deserved it, because you worked really, really hard for it. So you have to believe that, and you have to make sure not to believe anybody who tells you otherwise. Who tells you otherwise, okay? It's not charity, it's not chance, it's hard work and talent. So believe it, and this is really important to me. It took me a long while to come to terms with that. And finally, and I'll stop after that, I think it is very imperative to never forget to lift each other up. I am 100% confident that my success wouldn't have, any success I have, big or small, wouldn't have been possible without really many people who lifted me up. And projecting into the future, any success I have is absolutely meaningless and insignificant if I don't lift others up along the way. And that was beautiful. I mean, even just hearing about all of the things that you do towards advancing equality and creating opportunities for people, that's amazing. And really aiming at marginalized people is something we are working towards, and it's amazing to see people with a bigger say or power like you trying to push for that. It's definitely the right way to do things, so thank you for that. Thank you for saying this, but I'm actually really hopeful. I mean, the world is currently crazy. We have wars, we have pandemics, we have negativity everywhere, but I'm actually, despite all of that, I'm very optimistic. I see your generation, I see my son's generation, I see their belief systems, and I think we're going to be okay. Thank you. Thank you for being such an inspiring role model for all of us. So before we end the podcast, is there anything you would like to promote? Oh, okay, let me promote a few things. First of all, of course, Altos Labs. So I would be amiss not to say to your audience who are hopefully our next workforce. If you really like synthetic biology and cell engineering, computational work, machine learning, all of that fun stuff, the intersection of all of the above, then please get in touch. We have so many exciting opportunities at Altos Labs. The other important thing I would like to mention is, we talked about it quite a bit, but I want to reiterate. Our new journal, Gen Biotechnology, is your voice, so please use it. We are accepting original papers, reviews, opinions. If there's something you want to talk about, you want to write about it, an idea for a new section in the journal, a research project that you would like to get really fair reviews for, please do send it to us. Get in touch. Again, it's your voice, and I hope you do use it. Thanks for plugging for Altos as well as Gen Biotech. I'm sure you'll find a lot of people excited about positions there, as well as submitting to the journal. Thank you, Hannah, for this super, super exciting conversation, and I believe we have some exciting action plans in mind. I'll definitely follow up with you and see how we can really change how things are right now towards a better, even better era for medicine and diversity. Thank you so much, both of you, for inviting me and for conversing with me. It's such an honor and pleasure. Thank you so much. It was our pleasure. This has been another episode of EBRC in Translation, a production of the Engineering Biology Research Consortia's Student and Postdoc Association. For more information about EBRC, visit our website at ebrc.org. If you are a student or a postdoc and want to get involved with the EBRC Student and Postdoc Association, you can find our membership application linked in the episode description. A big thank you to the entire EBRC SBA podcast team, Katherine Brink, Fatima Inam, Andrew Hunt, Kevin Reed, Ross Jones, Kogze Lee, and David Mai. Thanks also to EBRC for their support and to you, our listeners, for tuning in. We look forward to sharing our next episode with you soon.