Interviewers: Lydia Morrison, Marketing Communications Writer & Podcast Host, New England Biolabs, Inc.
Interviewees: Rupali Dabas, UCL iGEM Team, University College London; Dr. Stefanie Frank, Department of Biochemical Engineering, Faculty of Engineering Science at UCL; Prof John Ward, Department of Biochemical Engineering, Faculty of Engineering Science at UCL; Dr. Qasim Rafiq, Department of Biochemical Engineering, Faculty of Engineering Science at UCL; Noelle Colant, Ph.D. candidate, University College London
Lydia: Hello and welcome to the Lessons from Lab and Life podcast, brought to you by New England Biolabs. I am your host, Lydia Morrison, and I hope that our podcast offers you some new perspective. A few months ago, I received an email from University College London’s iGEM team asking if we might be interested in working with the team to produce a podcast. So today, I will be turning over the reins to Rupali Dabas as she interviews her professors and peers from UCL about perceptions and misconceptions surrounding the field of synthetic biology.
Lydia: Hi Rupali, thanks so much for joining us today.
Rupali: Hi Lydia, thank you for inviting me.
Lydia: So I was wondering if you could tell me what inspired you to participate in the iGEM competition?
Rupali: Well, so as an undergraduate at UCL, we're really at the hub of interdisciplinary research here. So I've been motivated by the sort of interdisciplinary research that goes around UCL for a long time now and it's really been my passion for a long time, to be a part of that. So I heard about the iGEM competition in the beginning of my second year at UCL, and I decided to apply for it and I got through, so that was great.
Lydia: Congratulations. Can you tell us about your project?
Rupali: Yeah, sure. So I think first I'm going to start by introducing what iGEM is. So iGEM basically stands for International Genetically Engineered Machine, and it's an international synthetic biology competition in which undergraduate teams from around the world work over the summer on a project to address a real world issue. Then we present our research at the Giant Jamboree in Boston, in November.
Rupali: So our tickets are booked for that, obviously. So this year, our team is working to develop encapsulins, which are basically bacterial proteinaceous nanocompartments. You can think of them as like protein cages. So we're using them to develop a modular targeted drug delivery platform, and we're targeting breast cancer this year. We also intend to genetically fuse targeting peptides to the surface of the encapsulins, and load the encapsulins with a cytotoxic protein cargo molecule capable of killing the cancer cells that they bind to.
Rupali: So that's basically our project. Apart from all the lab work that we're doing, the super sciency stuff, we're also encouraged to do some public engagement, to do some outreach, to engage with stakeholders of our technology. So for us, that's basically breast cancer patients. We've also been talking to the general public, trying to find out what their opinion of synthetic biology is and how we can change that. And yeah. So it's been pretty fun.
Lydia: Yeah it sounds great. What made you want to be a part of the NEB podcast?
Rupali: Well, I have been listening to NEB podcast for a long time-
Lydia: Oh, thank you.
Rupali: So, I approached you guys hoping that you would be interested in iGEM as much as I am. And I know that you guys have done synthetic biology podcasts before, so I was hoping that you'd be interested and you were, which was great. And also we borrow a lot of equipment from NEB, so it kind of makes sense for us to approach you guys just because I thought it might be a nice way to get the word out about iGEM and what an amazing thing and an amazing opportunity it is. So yeah.
Lydia: That's great. We love to be able to support participants in the iGEM competition and we're excited to have you.
Rupali: Thank you.
Lydia: Yeah, why do you think podcasts are a good way to communicate science?
Rupali: Well, I actually started listening to podcasts at the beginning of last year, and before that I hadn't really heard of them. And I really got into them just because they're such an easy way to learn about so many new things that are happening. And once you find the one that you really like, I mean, I think it's wonderful because I can just listen to it on the go, and I don't have to read anything.
Rupali: And it's a wonderful way of introducing topics and I think it's a wonderful way of engaging the public in something that's a little obscure. I don't think the general public is very familiar with synthetic biology. And so any podcast that talks about that really interests me because I think it's a wonderful and interdisciplinary subject, and it combines so many different fields. And a podcast is just a really quick and easy way, and a hugely entertaining way of getting a lot of information in a small time. So that's why I've been listening to them and for our public engagement, part of the iGEM competition, I think it was a natural choice to do a podcast to get the word out somehow about our project and about iGEM.
Lydia: Well, I think you're absolutely right and I have to say actually that our synthetic biology podcasts have been amongst the most popular podcasts we've produced. So I think you're definitely onto something. So, now we're going to turn the interview reins over to Rupali as she interviews some of her professors and colleagues at the University College London.
Rupali: So for the benefit of our listeners, would you care to introduce yourselves?
Noelle Colant: Sure. I'll start. I'm Noelle Colant, I'm a, soon to be third year, PhD student in the UCL Biochemical Engineering Department. My research focuses on cell-free protein synthesis for making personalized medicine, more specifically vaccines and gene therapy out of self-assembling particles.
Rupali: Cool. Cool, cool, cool.
Stefanie Frank: My name is Stefanie Frank. I'm a lecturer in synthetic biology at the Department of Biochemical Engineering at UCL. My background is, going a few years back, is actually more biochemistry focused. I've been working on antibiotic pathway engineering, in bacteria. And then my focus shifted onto self-assembling protein complexes in particular can be used for various applications like enzyme scaffolding and more recently applying this kind of self-assembling structures for T-like particle synthesis.
John Ward: I'm John Ward. I'm professor of synthetic biology and bioprocessing here in the Department of Chemical Engineering. My research interests have been in bacterial molecular biology for many years. I've worked on systems like filamentous phage, recently we've developed filamentous phage for making a biological laser. We're also using these as a structural templates to build more complex elements containing enzymes on the surface. And over the last 10 years or so, we've been working with chemistry groups here at UCL to build alkaloids, plant alkaloids and their derivatives using bacterial and plant and fungal enzymes, building cascades of enzymes to build quite complex alkaloids.
Rupali: Fascinating. So very strong biological backgrounds. So, from all your studies over such long years, how would you define synthetic biology? What does it mean to you?
Noelle Colant: John, your a professor of synthetic biology, you want to take that one?
John Ward: I suppose I should have a definition. Well, to me a good definition is the engineering of biology. And that really means that if we now have the data and understanding of many of the components, the biological components that we want to use, we can then use that data in a defined way to build new things. Those new things could be cells that do something quite novel, based on the knowledge of the elements you're then putting together, pathways. But it can also be in vitro materials, like the knowledge of how DNA assembles and then that can be built into higher order structures and with other elements on those like enzymes, and fluorophores for example.
Rupali: I think it's being treated, synthetic biology is being treated as the industrial revolution of this century. So, how much would you agree with this statement, how powerful do you think the science is? Could it truly determine the future, the technological future of this era? In a way?
Stefanie Frank: I think it's maybe not just, as you said earlier, synthetic biology that is very powerful. It's combinational. Yeah. Being able to do a lot of... So, there's been a lot of technical advances and as a result of these, just to name a few, I will name a few in a minute, we are now able to do things that we probably can't quite catch up with in terms of the regulation. And in terms of our understanding what the characteristics are of the systems that we can make.
Stefanie Frank: So just to name a few developments, very powerful obviously is being able to sequence DNA, now being able to not just read DNA but to write DNA quite cheaply, to synthesize DNA. There's many companies that have come up over the last 10 years or so and the DNA synthesis becomes so cheap now and it's probably not very well regulated. Pretty much anyone can order some DNA from a company and produce something and combine biological parts that have never been found in nature before. So it is, I agree, you can call this a revolution. And but I think there's some... Obviously there's some concerns and question marks around, how much do we understand what we can make? And how fast can we keep pace of where is this going? I'm sure we'll talk about that in a minute.
Rupali: Yeah. That's true. So, you mentioned something about regulations. So do you think synthetic biology as a field as it is now, do you think it's well-regulated or do you think that there are kind of like leaks in the system? Like the Chinese scientists that we heard about a while back. So people are kind of worried about this. What do you think about the regulations?
John Ward: All our work is done under a very highly regulated system in UK, Europe, America and other countries for the contained construction of genetically manipulated organisms. So for example, in the UK we're not allowed to do any GM work that then involves a deliberate release to the environment, unless that's gone through very long winded committee stages. And there has been one or two plant trials of some genetically modified crops here in the UK. That's not happened in Europe at all because of stricter regulations.
John Ward: And in the US there are quite a lot of GM crops that are being grown. So that's an example of, it is quite a well regulated technology because most synthetic biology that we are perhaps concerned about, what people are concerned about, involves living organisms that have been genetically manipulated, not really the in vitro building of DNA structures, things like that. So I think that it is well controlled and I don't think there needs to be any new regulation just because there's a newly coined term and that we are very well controlled in this country, but it still allows a lot of very exciting research. But it's all done in a contained laboratory environment or in companies that are then using those systems to make a product and that product could then be a small molecule or protein that's then free of any GM material.
Rupali: Yeah. Okay. That's very true. Are there any misconceptions that you had when you entered the field related to synthetic biology? Like what's the biggest misconception, I think, that you found out recently?
Noelle Colant: Well, I learned recently that I am a synthetic biologist. My biggest misconception was that synthetic biology had to involve doing cloning and editing DNA and just doing restriction digests and things. And I don't do that as part of my work at all. But I work with a system that is biologic in nature and it's very much a non-natural system. So, in that regard, I'm a synthetic biologist even though I don't edit DNA.
Qasim Rafiq: My name is Dr. Qasim Rafiq. I'm an associate professor in the Department of Biochemical Engineering with a specific focus on cell and gene therapy and advanced therapy bio-processing.
Rupali: Okay, great. That sounds very complicated but so I heard from Dr. Stefanie Frank that you've been working with CAR T cells, so what is it that you do right now? How do you work with them? What do you do?
Qasim Rafiq: So I think CAR T cells or gene modified cell therapies in particular have generated significant interest over the last two to three, maybe five years or so. And I think it's really built on some of the pioneering work that's been done over at University of Pennsylvania. So the UPenn team and others globally really kind of driven the biological and clinical applications of CAR T cell therapies and other gene modified cell therapies.
Qasim Rafiq: And what we're effectively getting to a point with these cell types is that we're sharing that by taking immune cells, in this case T-cells and being able to engineer them in vitro and then we inset them or administer them back to the patient. We're seeing some huge clinical implications where we're seeing things such as acute lymphoblastic leukemia, response rates been fantastic and the remission rates for patients who have failed every other treatment course, going into complete remission is remarkable.
Qasim Rafiq: So I think that a huge amount of excitement, huge amount of optimism, but our specific focus here at UCL in the department of biochemical engineering, is that despite all of that clinical and biological potential and promise, we have to find a way to be able to manufacture and develop scalable systems for the production of these cells. Because otherwise we may end up in a situation where we're just treating a handful of patients. Whereas really what we want to be able to do is to be able to treat hundreds or thousands of patients.
Rupali: Right. I have heard that CAR T cell therapy is very expensive, so it's not very easily accessible. Do you think what you're trying to do, making it easy to manufacture at a larger scale, do you think that would make it more accessible to people? Or would it make it exclusively marketed by pharmaceutical companies? So would it make it more expensive as well?
Qasim Rafiq: So I think from our perspective, that's exactly our kind of ultimate ambition, which is to reduce the overall cost of these products and to make it a globally accessible product. And so when you look at the, we've had two recent notable products, one produced by Novartis, KYMRIAH®, and the other produced by Kite Pharma. Their product is YESCARTA®. So both of those products have price tags of well in excess of $300,000, which means that in the US, under the healthcare insurance approach, reimbursement is somewhat of a challenge. And some insurance companies may not be able to provide that for their patients or for their customers.
Qasim Rafiq: And in the UK, somewhat surprisingly, but also because the UK wants to be seen as a pioneer in this field. The NHS or NICE specifically have approved reimbursement for certain applications of both of these products. That's a surprise to some extent because the UK is not normally seen to be an early adopter of novel therapeutics, particularly where they are expensive. However, I think the UK has seen, and NICE is seeing the potential for these therapeutic products to have a major radical impact on outcomes, on patient outcomes, particularly for pediatric patients.
Qasim Rafiq: But also as I mentioned, the UK I think is seen to be in pioneering in the sector, both from a clinical perspective, from a manufacturer perspective, from bio processing perspective. So going back to your original question about will this reduce the cost? We believe it will. So, that's the driving kind of research question that we're trying to address is, by improving scalability, by improving the manufacture. Ultimately we believe that will reduce the cost. And so in addition to doing our manufacturing and bioprocessing research, we have complimentary research here in the department, which focuses on things like cost of goods models.
Qasim Rafiq: And what we're trying to do is ensure that the manufacturing changes we make or suggest or process development improvements we make have an impact on overall cost of goods. So one of the things we've demonstrated recently is that we can take CAR T cells, which are at the moment traditionally manufactured in either T flasks or static platforms which are not really scalable. Or they're manufactured in wave bags and we've shown that actually you can use stirred-tank bioreactors which have proven scalability and are being used to manufacture thousands of products at a whole range of scales.
Qasim Rafiq: I mean stirred-tanks are used in the fermentation and brewing industry for producing thousands of liters of alcohol and different beers and so on. It's used in the pharmaceutical industry for small molecule development. It's used extensively in the biologics industry for the production of things like insulin and other recombinant proteins.
Qasim Rafiq: So they have a huge production and engineering heritage. And so what we want to do is to see whether we can use these systems, these proven systems for the production of cell and gene therapies. And I think we're showing we can. So I think that's a huge step. But what we need to be able to do now is start to look at how we can implement automated platforms and systems to improve the manufacture. And one of the other things we're starting to show is where we originally had a seven day process to reach a certain number of cells. We can now achieve that same cell number within half the time period. So by intensifying the process, by changing some of the control strategies, we can optimize and improve the performance of the process itself, which will reduce time and ultimately reduce cost.
Rupali: And this wouldn't reduce the effectiveness or the accuracy of the treatment, right?
Qasim Rafiq: That's a very good question because one of the things we always have to consider is when we make any changes to the process, although we might get the same cell number, does it in any way impact the quality or clinical efficacy of the cells? And that's one of the things we're always checking for. So the work we've published so far and the work we continuously doing, says actually it doesn't, which is a great thing because it means that we can improve the process whilst retaining some of the key quality attributes of the cells.
Qasim Rafiq: So one of the things we look for is certainly from the safety perspective, to make sure that there's no contamination or there's no potential safety or harmful effects of the cells. But also do the cells still have the same therapeutic efficacy. So in this case with CAR T, do they still retain the ability to kill cancerous cells? And again, some of the work we've done shows that they retain the core functionality that we would expect. So it's very promising, still early days, but we think we're making progress in a significant way, in the right direction, and we're working with a whole range of partners to do that.
Rupali: All right. This is a personalized treatment, right?
Qasim Rafiq: Sure.
Rupali: And I know that the public is very excited about personalized treatment. How easy is it to make a treatment personalized? Because it would take a long time, would it not, to manufacture these CAR T cells specific to each patient? so if you're looking to making this more accessible, how would you solve that problem?
Qasim Rafiq: A very good question. And it's one of the questions that we're currently grappling with. So at the moment, both KYMRIAH and YESCARTA are patient specific or personalized treatments. The technical term being autologous. So where you take the T cells from the patient, you engineer them in the lab so they now express this receptor they wouldn't normally express. And then you then re-administer those same cells back to that patient and that patient alone.
Qasim Rafiq: And that presents a major manufacturing challenge. And that is one of the things that we're trying to address, because we feel that in this sector there's perhaps a need for both. There's a need for patient specific treatments where there is no alternative of generating a universal treatment. However, at the same time there are many researchers and research groups and commissions who are looking at developing an allogeneic or universal treatment option. Whereby using novel scientific breakthroughs such as CRISPR, such as ZFN and TALEN's and you can genetically engineer and edit a universal donor cell so that it no longer expresses or would cause an immune reaction if it went into another patient.
Qasim Rafiq: So with that specific focus, we see has two different modalities. So you've got the patient specific autologous modality. And part of our goal is trying to address some of the manufacturing, logistical issues there. As well as addressing some of the manufacturing challenges associated with allogeneic universal donor. And they have similar but also very different challenges. So with allogeneic, you're looking at one huge batch effectively or, I say huge, one large batch, be that 10 liters, 100 liters, 1,000 liters. In the biologics industry, it can be up to 20,000 liters batches. So you have to deal with scale, but you get the economies of scale. So you can really... By developing these universal therapies, you get the economies of scale. However, the advantage of patients' specific or personalized treatments is that you get sometimes significantly better efficacy.
Qasim Rafiq: But also you might not, in all cases, be able to genetically engineer and knock out the right genes to make it a universal donor. So I think there is a need for both. And as a bioprocessing and manufacturing group within this sector, what we're looking at is for both patient specific and universal donor manufacturing modalities, how do we address the core manufacturing issues associated with each?
Qasim Rafiq: Because you're absolutely right for a patient specific therapy, it's actually very difficult to manufacture cost effectively at the moment. And when you think about any manufacturing industry, if you had to manufacture a personalized iPhone® for every single individual that was specific to a person's hand shape, specific to the person's ear or whatever it might be, it would be very, very difficult for Apple to do that cost effectively. Although there is some level of customization, you can choose the color, choose the gigabyte storage, whatever it might be. It's not truly personalized. It's not a specific phone for a specific hand, for a specific individual.
Qasim Rafiq: So to try and then develop personalized therapies, it certainly is the goal, I think for me because I feel that it's better efficacy, but we have to look at how we can address some of the cost effective issues. So some of the expense issues around personalized manufacturing and see how we can reduce the cost.
Rupali: Okay. That sounds amazing. And I think what you're doing is super exciting. I don't actually have any other questions. Do you have any questions for the iGEM team?
Qasim Rafiq: No, I think you're doing a great job. I think it's fantastic to see a talented multidisciplinary group of scientists, engineers working together. And I think it's an excellent initiative. And I hope that this team and the other teams competing in the iGEM competition of this year and future years and previous years go on to become those leaders of the future that develop these therapies, these solutions to, biological solutions to some of the global challenges we now face.
Rupali: So I think the iGEM team also needs to work on finding the right audiences and tailoring the experience with synthetic biology to them. So yeah, that's what we're working on right now.
John Ward: Good. I wish you all the success.
Rupali: Thank you. Thank you so much for letting me interview you and thank you so much for sharing your thoughts.
Lydia: Hope you enjoyed this guest episode of the NEB podcast. Be sure to tune in next time, when I will be joined by James Bevington, who is a graduate of the Masters in Space Studies program at the International Space University and is currently finishing up his Ph.D. at the University of South Wales, where some of his experiments have been conduct on the International Space Station. So be sure to tune in and hear how science in space is more accessible than ever.
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