ur collaboration episode of Synversations, a podcast that explores the depths of synthetic biology from various multidisciplinary standpoints. I'm Devaki and I'll be your host for today. I'm a second year life science student studying nutritional science and global health. 
Synversations, is a 5 episode long podcast created by the University of Toronto Policy and Practices division of its iGEM team. iGEM is a student association dedicated to the practice of synthetic biology and dissemination of its scientific foundations.

In today's episode we will exploring the depths of engineering and its role in synthetic biology. To make this episode extra special, we have Dr. MacMillan, who will be interviewed by Katariina. 

K: Please introduce yourself and give us a brief description of what you do.

DM: My name is David MacMillan, I'm a professor at the University of Toronto. I'm in the chemistry department, primarily, but I'm cross-appointed to physics and cell and systems biology, and biomedical engineering. I run the Synthetic Biology and Cellular Control Lab, which is based at University of Toronto Mississauga, so we are out at the western campus. We do research on cell-based solutions to problems. 

K: could you give us a quick description of what synthetic biology is?

DM: When I try to define it, I try to say that it is an effort to create an engineering discipline that you can apply in and around living cells. By analogy to mechanical engineering or electrical engineering that have their own, sort of, domains, there's a need for systematic approaches to operate on cells and to modify their behaviour in controlled ways. Synthetic biology is the ongoing effort to create that discipline, is the way I think of it.

K: How did you first come into contact with synthetic biology?

DM: So I visited Jim Collins' group (James J Collins), when he was at Boston University. During my PhD, when he was working on neural systems, primarily, and they were just getting into genetic systems. So I was there during my PhD, and I did some stuff on neurons and systems of coupled neurons, and then I went back for a post-doc[toral researcher], also at his group, at the Centre for Biodynamics. So right at that time, they were transitioning from working mainly on neurons, to mainly working on genes. The term didn't exist yet, but I remember a few years later we heard the term and everyone thought "oh, that's a good name", because there was this new thing that people were doing, but they didn't have the label for it. Maybe an interesting trivia tidbit for your listeners is that the first proposal was to call it 'genetic applets?', which is very old-school now. Applets were a term in the early 2000s or so, for like, what we would now call pop-up windows, or little Javascript things that would download on your computer and run. So the idea was, you know, making these little systems that you'd download onto a cell, and they would run there, but synthetic biology, that was a good label. As soon as we heard that, we thought, that captures a lot of information about what the field should be.

K: What aspect of synthetic biology first captured your attention?

DM: I guess it was this idea of forward engineering in a cellular context, so the idea that you could, rather than passively observing what a cell is doing, you could actively poke it and sort of, increasingly sophisticated ways. That's an interesting idea. Also, I guess, maybe it's not what first captured my attention, but since then, the idea that you could use it as a real vehicle for solutions, so things that you can create out of cells can be made very cheaply, so that's one of the things that we're particularly interested in the group, is to make cheap solutions to problems, so we can maybe talk about that later, I don't remember the order of the questions.

K: What do you forsee as being the major avenues where synthetic biology can make an impact, or what real world applications do you see synthetic biology fulfilling?

DM: So I'll start with my favourite one, and then move on from there I guess. I think the developing world probably has most to gain, in kind of a short to medium term, in a lot of ways, because of this idea that microbes are cheap - if you can grow a solution to something, then you can make a lot of that solution for not very much money. It's been one of the dreams of synthetic biology from the beginning, to make biosensors out of bacteria cells or yeast cells or whatever, and there's been various examples of that. Or cells that attack other cells, cells that can detect, like E Coli. that detects ???? and try to excrete antimicrobials. Our entry on this front lately is a yeast-based system that can be used to screen blood, so it expresses antigens from surfaces of yeast, and then uses a nice??? visual? simple output to tell you whether the antibodies corresponding to those antigens are present in a blood sample. The idea is that you can, once you've got the yeast, that's sort of expensive and involves genetic manipulation to make, but once you've got them you can grow vats of these things for not very much money. That class of solutions seems like something we might see more and more of over time, I mean it still has to go from proof of principle to actual deployment, and that's one of the tricks - is to get things from the lab out into the world, but it at least places? the ground work for things can be made very cheaply. Similar sorts of things with detecting toxins in the environment - anything you can sense with a cell, you can sense for very little money, and very little money is what people have to work with in a lot of the world. 

But then on other fronts, I mean, there's been exciting work towards detecting and using classifier systems to detect the onset of cancer, or discriminate between cancerous and non-cancerous cells, from the Be? and Wyss groups for example, that might one day - that's another early dream of synthetic biology that may one day pay off - it's the ability to have something that sits inside your cells and decides if they're going cancerous and then kills them, although as they always joke, you better be right about that, because if you get that wrong, it's going to just dissolve your body and that's no good, so you're going to make sure you get that 100% correct, but in principal, if it can detect the onset of cancer, then it can shut that down before it gets started, so there might be a way to cure cancer from the inside. Or various other things to do with medical interventions by programming bacteria, we're actually working on one of those as well with the team here to try to make a probiotic that can reside in the gut and produce therapeutics, to try and help inflammatory bowel disease. I think there's going to be medical things that - the big success stories so far is, you know, the artemisinin success that they've had, with the re-engineering yeast cells to produce large amounts of this precursor to an anti-malarial drug, so that's already in the field, I'm sure we'll see more of that because industry loves to build on success, for similar reasons I guess, it makes sense really. cells are very good organic chemists in a sense - you can make them do something for you, it's very appealing for industrial applications. 

K: What are some of the challenges that one might face when trying to realize the real world applications of their synthetic biology research?

DM: It's kind of the same for synthetic biology as it is for a lot of science, which is that there's a gap between proof of principal in a dish or in a lab, in solutions, and things out in the real world. If you look back at things that were shown as proof of principal 10 or 15 years ago, a lot of them are still proof of principal, or they haven't really gone anywhere. It's not the kind of the thing we tend to do, as it might be a little embarassing, right, if we actually went back and looked at all these things that were so exciting a while ago - and I think it's partly because as scientists, we don't get any kind of training about like, what does it take to make a product that you can hand somebody? So I've been working with this place called the Impact Centre here that at the University of Toronto, that has, as one of it's main focus is bridging that gap - so they do training for entrepreneurs, several of my students have gone through their training program and the idea is supposed to fill in some of those gaps about, you know, if you want to create a company based on the sign? of the research you've done, how do you do that? What is market? research, how does IP law work, how do you do development of something from an idea into a product? And it turns out, we probably as a group of scientists, underestimate how hard that is, the merits and values of that whole process. We sort of think "oh, well we've done the hard part, right, we've got the thing that does, you can show in a flask that it will detect arsenic, or it will do antigen? detection" and then you know, the rest will just kind of like, ellipses, product. But that ellipses is actually pretty complicated, and so, I think synthetic biology suffers from that same problem as the rest, there's plenty of non-biological sensors and things that also have this problem, right, you can in principal use a laser to detect something, and then, you know, you need to actually turn that into like some sort of laser based product that you can sell somebody. It's certainly not lacking in attention recently, and I feel like there's more attention being paid to it in Canada recently, so that's good news. People want to encourage entrepreneurship, and they want to encourage scientists in particular to try to commercialize their products. I used to think of commercialization as kind of a dirty word - it sounds like you are violating the purity of science or whatever, and it's actually - I mean, commercialization doesn't have to mean you are trying to become filthy rich, it's actually a label for the process of turning things into reality. Making something into an actual deployed product doesn't have to be, I mean it could be done by a non-profit, it doesn't have to be done, you know, with the goal of world domination that can be done to try to help the world. I now think of it as the mechanism by which you bridge that gap and get things out in the world, so I'm hoping that some of these student-founded companies that have come out of the lab will be the mechanism by which things get out there and we get from an in-principal yeast detection kit to an actual one.

K: What are some of the issues with integrating synthetic biology into real world applications?

DM: Yeah, I think it's definitely a challenge, in some ways I see the public's point. There is actually, I always feel like when I have these discussions, I want to make sure that I don't downplay the potential dangers because sometimes people have discussions where they just completely dismiss the idea that there might be any sort of issue. At the same time, they aren't apocalyptic dangers, so, the issue that I always see is that if you are out there creating new species and releasing them into the ecosystem, you can make changes that are far more rapid than whatever happened on an evolutionary time scale. The argument that you're just creating something that you could do by selective breeding, yeah but that's like, breeding would take years or decades or something, so there would be a lot more time for the rest of the ecology to adjust around it. We do have kind of an analog for that, in the form of invasive species. This is essentially what happens when you bring a new species into an ecosystem and drop it there from a ship or an airplane or something, and it does create problems - we've got zebra mussels in the great lakes, things that have no natural predators, and they start becoming a nuisance, but it's not the end of the world, right, it hasn't sort of taken over and destroyed the ecosystem, but it is an actual thing you have to be aware of. One of the challenges I guess is to maybe have, I don't know if that's a useful way to talk to the public, I mean, in some ways it may be helpful to have a more honest discussion, say 'yes we are aware of the dangers and we're looking into them and we're paying attention'. On the other hand, because there are definitely irrational fears people have, like they sort of have this vague sense that genes are going to escape and take over the world and destroy your crops, and that seems unlikely, it seems like that should be a parallel stream in any discussion of real world applications, is that you should actually be looking into what are the potential downsides. There's been some nice work on, sort of, non-conical amino acids to try to fence in engineering? organisms. Church and Isaacs? Labs have done interesting things on those lines, but those are hard to explain to the public.

K: What do you see is one of the major challenges regarding the public's perception of synthetic biology?

DM: I guess one of the challenges would be to have people have think of synthetic biology solutions as not being the same thing as GMO crops, which have a very strong publicity problem. Largely with panic response, people have been over-reacting to a lot of those concerns. I guess we have to get to talk to legislators and people who make the rules about these things, and we try to convince them that there is actually, there are precautions one can take that make it into an acceptable, that you're managing the risk in an acceptable way. One thing that will help, I guess, is when you start having things that are tangible and substantial benefits, then it'll be an easier sell. Ok, so maybe you're less worried about this thing once you know that when you swallow it, it'll cure whatever disease you have, or whatever, if you have a big upside point to it, then maybe it helps get over people's worries.

K: The benefit outweighs the risk.

DM: Yeah, that kind of thing.

K: One of the main focuses of our podcast is discussing how synthetic biology interacts with multiple different disciplines. Can you maybe give us a little bit of an idea as to what kinds of people you've worked with?

DM: Yeah, so I guess I started with that list of all the places I'm cross-appointed right, so that's one example, so I have people from physical and biological chemistry, I've had biological physicists, and physicists who kind of became biological against their will. I haven't had anybody from biomedical engineering yet, but in a sense we're kind of already all doing biomedical engineering, and then cell and systems biology, people coming from various branches of that. They're actually taking over the lab, because it seems that lately, our focus is such that we're getting more interest from the biologists than we are from the physicists and chemists. So yeah, I mean, all of those -  I run a parallel modelling/theory and experimental group, so I always try to get people who are getting theory, I try to make them do some experiments, just because it keeps them humble, keeps them sort of grounded. And that's become, I think, the standard way - when things started, I think it was pretty standard to have theory only, and experiment only groups, and increasingly, we're not an anomaly anymore. There's lots of groups that have both. I try to get it to be both in one person if I can, just because I think it's very helpful to have that sort of exposure to how uncooperative cells actually are compared to your models, and vice versa. I think it's useful to have at least some exposure to the modelling if you are doing experimental work, so yeah. People with sort of very mathematical backgrounds. I've been pretty lucky to get quite a few students who are capable of doing both, which is kind of unusual, but I think it's maybe something about the recruiting effort, that when I talk about these things, the people that I don't scare away are the ones who sort of end up joining the group. Hard to predict, I guess. I was thinking of this recently, and I don't mean this to be a negative thing, but one possibility is that it will cease to exist, in the sense that as a distinct field, rather than, if it's sort of tool-ified, if it becomes just a standard approach that you use in other things, I'm thinking about like molecular biology. If someone says "I do molecular biology", you then say "on what", or "for what". It's not a field that you can just do, it's something that uses a tool towards something else. In a sense, I think that would be good news, if synthetic biology went the same way - it's just that you are studying regulatory pathways in some cell, and synthetic biology is now just one of the things that you'd obviously do, because rather than proturbing one cell at a time with knockouts, you now make little networks and put them in and you can do dynamical? proturbations? and, if it becomes just a tool in the toolbox of the broader effort of biology/biological engineering, that would kind of, we've made it, right? We've sort of finished the process of creating the discipline and now it becomes a thing you do on the way to other things. Like right now, I think we're early enough that we're still developing the tools, but once those are solid, I don't know whether 20 years is going to be enough time to do that, but one day that may be what actually happens, is that it's not actually, it's something you do as part of a bigger effort. That's my speculative answer, and then the answer to what it might be doing depends on what biological engineering more broadly is doing - what kind of problems are being addressed, and, 20 years sounds like a long time, but I suspect we'll still be, we'll see, hopefully we're not still calling it an emerging field by then, but it will still be, I'm sure there's plenty of work, certainly to keep me busy, for the rest of my career. Maybe to keep you guys busy for yours as well. 

K: What inspires you to continue researching within the field of synthetic biology?

DM: So I've touched on this before I guess, that this potential to lead to applications so I'm becoming increasingly application- interested. I've had now 3 grand challenges Canada Grants that are all about things for the developing world, and that's really sort of changed my way of thinking about these things. That's what really inspires me, the idea that we can try to use cells to solve problems out in the real world. And the reason I keep mentioning, that maybe it's not synthetic biology, is that in some cases, it's not - it doesn't like, the stuff with the yeast, there's no networks involved, so sometimes I get asked "is that synthetic biology?". I don't really care, I'm not going to put in a regulatory control network just because I can, right, if it can solve a problem without it, that's kind of the engineering attitude, is that you do as little as possible to solve a problem in front of you. I mean, I'm fascinated by synthetic biology, but I also, I guess in a sense maybe I'm making this transition I talk about earlier in my head already, I see it as one possible route towards solving things. My wife's from the Philippines, so I spend a fair bit of time in southeast Asia, and when I see, it's just appalling that we're this far into the 21st century and so many people are not partaking of the results of our technological progress. Anything I can do to help some people somewhere, this is what keeps me interested.

K: Thank you for joining us on this rainy day.

DM: No, it's great to be here, thanks very much. 


That concludes our third segment of the podcast, Synversations. Don’t forget to check us out on facebook, instagram, twitter, and igem toronto.ca. We'll see you next time with our episode on arts and communications.